{"id":1348,"date":"2026-01-29T22:30:23","date_gmt":"2026-01-29T22:30:23","guid":{"rendered":"https:\/\/science.peta.org\/biomedical-research\/"},"modified":"2026-07-02T18:42:43","modified_gmt":"2026-07-02T18:42:43","slug":"investigacion-biomedica","status":"publish","type":"page","link":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/","title":{"rendered":"Investigaci\u00f3n biom\u00e9dica"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\"><strong>C\u00e1ncer<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Aunque las mejoras en los programas de detecci\u00f3n han permitido un avance significativo en el diagn\u00f3stico temprano del c\u00e1ncer y la reducci\u00f3n de las tasas de mortalidad,<sup data-fn=\"b5d1e717-bfa3-4939-9c1a-04301e350ee5\" class=\"fn\"><a href=\"#b5d1e717-bfa3-4939-9c1a-04301e350ee5\" id=\"b5d1e717-bfa3-4939-9c1a-04301e350ee5-link\">1<\/a><\/sup><sup data-fn=\"3532e163-51af-49b6-b56e-6ad0e9bc691c\" class=\"fn\"><a href=\"#3532e163-51af-49b6-b56e-6ad0e9bc691c\" id=\"3532e163-51af-49b6-b56e-6ad0e9bc691c-link\">2<\/a><\/sup> esta enfermedad sigue siendo una de las principales causas de muerte en el continente americano y en 2022 caus\u00f3 1,4 millones de fallecimientos.<sup data-fn=\"35e17b68-cd0c-4261-a697-47ece3fc8cf3\" class=\"fn\"><a href=\"#35e17b68-cd0c-4261-a697-47ece3fc8cf3\" id=\"35e17b68-cd0c-4261-a697-47ece3fc8cf3-link\">3<\/a><\/sup> La disminuci\u00f3n de la incidencia de c\u00e1ncer en las \u00faltimas dos d\u00e9cadas se ha atribuido, en parte, a cambios espec\u00edficos en el estilo de vida, como la reducci\u00f3n del tabaquismo, el aumento de la actividad f\u00edsica y el mantenimiento de un peso corporal estable.<sup data-fn=\"156dd4d7-6f00-4510-8b02-e0748c64e448\" class=\"fn\"><a href=\"#156dd4d7-6f00-4510-8b02-e0748c64e448\" id=\"156dd4d7-6f00-4510-8b02-e0748c64e448-link\">4<\/a><\/sup><sup data-fn=\"49977b17-baec-430d-830f-599d34cf61f0\" class=\"fn\"><a href=\"#49977b17-baec-430d-830f-599d34cf61f0\" id=\"49977b17-baec-430d-830f-599d34cf61f0-link\">5<\/a><\/sup> Aunque la investigaci\u00f3n biom\u00e9dica ha avanzado en la comprensi\u00f3n de la carcinog\u00e9nesis, los ensayos cl\u00ednicos no han logrado extrapolar los resultados del laboratorio al \u00e1mbito cl\u00ednico de manera eficaz. Incluso tras importantes inversiones en investigaci\u00f3n para el desarrollo de tratamientos contra el c\u00e1ncer, la tasa de \u00e9xito de los medicamentos oncol\u00f3gicos es inferior al 10%.<sup data-fn=\"4d2bcedf-235e-45eb-b2c2-aa074f90968d\" class=\"fn\"><a href=\"#4d2bcedf-235e-45eb-b2c2-aa074f90968d\" id=\"4d2bcedf-235e-45eb-b2c2-aa074f90968d-link\">6<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-1&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-1-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-1\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-1\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-1-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Un metaan\u00e1lisis reciente concluy\u00f3 que los experimentos de c\u00e1ncer en animales tienen efectos m\u00e1s bajos y su probabilidad de replicaci\u00f3n es menor en comparaci\u00f3n con los experimentos de c\u00e1ncer sin animales.<sup data-fn=\"649ff382-081f-46b1-9e2d-ed90a9afca45\" class=\"fn\"><a href=\"#649ff382-081f-46b1-9e2d-ed90a9afca45\" id=\"649ff382-081f-46b1-9e2d-ed90a9afca45-link\">7<\/a><\/sup> Los onc\u00f3logos han se\u00f1alado que \u201clas diferencias gen\u00e9ticas, moleculares, inmunol\u00f3gicas y celulares cruciales entre los humanos y los ratones impiden que los modelos animales sirvan como medios eficaces para buscar una cura contra el c\u00e1ncer\u201d.<sup data-fn=\"a5157d53-deb5-4531-a934-3b02f2288a3d\" class=\"fn\"><a href=\"#a5157d53-deb5-4531-a934-3b02f2288a3d\" id=\"a5157d53-deb5-4531-a934-3b02f2288a3d-link\">8<\/a><\/sup> En este sentido, Richard Klausner, exdirector del Instituto Nacional del C\u00e1ncer de EE. UU., se\u00f1al\u00f3 que \u201c[l]a historia de la investigaci\u00f3n en c\u00e1ncer ha sido una historia de curar el c\u00e1ncer en el rat\u00f3n. Llevamos d\u00e9cadas curando el c\u00e1ncer en ratones, pero no en humanos\u201d.<sup data-fn=\"42a19a54-55f0-4de6-b5ca-dfe280ac45ef\" class=\"fn\"><a href=\"#42a19a54-55f0-4de6-b5ca-dfe280ac45ef\" id=\"42a19a54-55f0-4de6-b5ca-dfe280ac45ef-link\">9<\/a><\/sup> Adem\u00e1s, el enorme dolor y el sufrimiento que experimentan los animales plantean problemas \u00e9ticos y de bienestar.<sup data-fn=\"27ff85ba-0983-4744-a4fc-ef4fccbbf5ed\" class=\"fn\"><a href=\"#27ff85ba-0983-4744-a4fc-ef4fccbbf5ed\" id=\"27ff85ba-0983-4744-a4fc-ef4fccbbf5ed-link\">10<\/a><\/sup><sup data-fn=\"d9823697-d716-43f2-8d32-bffeeb2a7e4f\" class=\"fn\"><a href=\"#d9823697-d716-43f2-8d32-bffeeb2a7e4f\" id=\"d9823697-d716-43f2-8d32-bffeeb2a7e4f-link\">11<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">De acuerdo con el mecanismo usado para desarrollar el tumor, existen varios m\u00e9todos para usar roedores, principalmente ratones, en experimentos de c\u00e1ncer. Estos son el xenoinjerto, la ingenier\u00eda gen\u00e9tica y, con menor frecuencia, la inducci\u00f3n espont\u00e1nea por exposici\u00f3n a agentes carcin\u00f3genos.<sup data-fn=\"e6504616-eeff-4478-8418-807f98d84778\" class=\"fn\"><a href=\"#e6504616-eeff-4478-8418-807f98d84778\" id=\"e6504616-eeff-4478-8418-807f98d84778-link\">12<\/a><\/sup><sup data-fn=\"7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320\" class=\"fn\"><a href=\"#7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320\" id=\"7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320-link\">13<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Para crear animales con xenoinjertos, se trasplantan c\u00e9lulas cancerosas humanas inmortalizadas o derivadas de un paciente, ya sea de forma subcut\u00e1nea o en un \u00f3rgano de roedores inmunodeprimidos, que luego pueden ser sometidos a una serie de experimentos, como el tratamiento con un f\u00e1rmaco candidato o una sustancia de inter\u00e9s. Aunque el xenoinjerto es el m\u00e9todo m\u00e1s com\u00fan para generar tumores en roedores, un an\u00e1lisis de 1110&nbsp;modelos tumorales de xenoinjerto en ratones concluy\u00f3 que estos modelos tienen problemas fundamentales que comprometen su capacidad para predecir los resultados terap\u00e9uticos en humanos.<sup data-fn=\"c72f94bc-8970-434b-a1f0-c875b4a80fd6\" class=\"fn\"><a href=\"#c72f94bc-8970-434b-a1f0-c875b4a80fd6\" id=\"c72f94bc-8970-434b-a1f0-c875b4a80fd6-link\">14<\/a><\/sup> El trasplante de c\u00e9lulas humanas altera el paisaje gen\u00e9tico de los ratones de formas improbables de ocurrir en humanos, y estos cambios alteran las respuestas al tratamiento farmacol\u00f3gico.&nbsp;<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los ratones modificados gen\u00e9ticamente (transg\u00e9nicos) se crean mediante la inserci\u00f3n o eliminaci\u00f3n de genes humanos en el ADN de un rat\u00f3n para inducir la expresi\u00f3n de oncogenes o desactivar los genes supresores de tumores, respectivamente. Dado que estas modificaciones ocurren de forma aleatoria, los investigadores no pueden controlar la expresi\u00f3n g\u00e9nica, por lo que es frecuente que se produzcan alteraciones imprevistas.<sup data-fn=\"60918212-9812-4989-97ec-69df548590b0\" class=\"fn\"><a href=\"#60918212-9812-4989-97ec-69df548590b0\" id=\"60918212-9812-4989-97ec-69df548590b0-link\">15<\/a><\/sup> Los modelos de c\u00e1ncer en ratones transg\u00e9nicos no consiguen imitar la naturaleza espor\u00e1dica del desarrollo tumoral, lo que da lugar a resultados inesperados que no se dar\u00edan en pacientes humanos. Adem\u00e1s, estos modelos exigen mucho tiempo y son costosos, ya que requieren del uso de muchos animales para obtener el genotipo deseado y estable, y los \u201canimales sobrantes\u201d se asesinan.<sup data-fn=\"d3031221-f943-4eed-b6c1-5d8f812f961e\" class=\"fn\"><a href=\"#d3031221-f943-4eed-b6c1-5d8f812f961e\" id=\"d3031221-f943-4eed-b6c1-5d8f812f961e-link\">16<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Un reporte sobre inmunooncolog\u00eda publicado en 2021 por el Centro de Investigaci\u00f3n Conjunta de la Comisi\u00f3n Europea destac\u00f3 m\u00e9todos prometedores basados en la biolog\u00eda humana y sin animales para desarrollar nuevos tratamientos, estudiar la biolog\u00eda del c\u00e1ncer y la inmunomodulaci\u00f3n e identificar biomarcadores moleculares espec\u00edficos, entre otros.<sup data-fn=\"85c1ed46-9d65-4969-861d-9ab0e5e84484\" class=\"fn\"><a href=\"#85c1ed46-9d65-4969-861d-9ab0e5e84484\" id=\"85c1ed46-9d65-4969-861d-9ab0e5e84484-link\">17<\/a><\/sup> Algunos &nbsp;de estos modelos son las plataformas tridimensionales, como los tumores bioimpresos a partir de muestras de pacientes,<sup data-fn=\"9708627f-2772-43aa-8bdd-465c51d8e6af\" class=\"fn\"><a href=\"#9708627f-2772-43aa-8bdd-465c51d8e6af\" id=\"9708627f-2772-43aa-8bdd-465c51d8e6af-link\">18<\/a><\/sup><sup data-fn=\"ea5e7dd5-be13-4fe5-b608-97f12f2049db\" class=\"fn\"><a href=\"#ea5e7dd5-be13-4fe5-b608-97f12f2049db\" id=\"ea5e7dd5-be13-4fe5-b608-97f12f2049db-link\">19<\/a><\/sup><sup data-fn=\"d472cc93-352a-4415-a8d6-41d3acd94809\" class=\"fn\"><a href=\"#d472cc93-352a-4415-a8d6-41d3acd94809\" id=\"d472cc93-352a-4415-a8d6-41d3acd94809-link\">20<\/a><\/sup><sup data-fn=\"fb72839a-f026-462a-952d-8761e9613ae7\" class=\"fn\"><a href=\"#fb72839a-f026-462a-952d-8761e9613ae7\" id=\"fb72839a-f026-462a-952d-8761e9613ae7-link\">21<\/a><\/sup> los \u00f3rganos en chip para la medicina de precisi\u00f3n a partir de diferentes l\u00edneas celulares de c\u00e1ncer<sup data-fn=\"f8b870f3-62c4-4953-87f4-65ac056998ad\" class=\"fn\"><a href=\"#f8b870f3-62c4-4953-87f4-65ac056998ad\" id=\"f8b870f3-62c4-4953-87f4-65ac056998ad-link\">22<\/a><\/sup><sup data-fn=\"73670505-ba59-4f3b-99b9-d4a8bf64ef8f\" class=\"fn\"><a href=\"#73670505-ba59-4f3b-99b9-d4a8bf64ef8f\" id=\"73670505-ba59-4f3b-99b9-d4a8bf64ef8f-link\">23<\/a><\/sup><sup data-fn=\"9a3cd416-6989-4a15-b090-d41239bc6fed\" class=\"fn\"><a href=\"#9a3cd416-6989-4a15-b090-d41239bc6fed\" id=\"9a3cd416-6989-4a15-b090-d41239bc6fed-link\">24<\/a><\/sup><sup data-fn=\"1eb45f77-2665-440c-aab1-9b3f9885ada3\" class=\"fn\"><a href=\"#1eb45f77-2665-440c-aab1-9b3f9885ada3\" id=\"1eb45f77-2665-440c-aab1-9b3f9885ada3-link\">25<\/a><\/sup><sup data-fn=\"c1002ca2-b660-4b53-b87a-804b0fb1ea37\" class=\"fn\"><a href=\"#c1002ca2-b660-4b53-b87a-804b0fb1ea37\" id=\"c1002ca2-b660-4b53-b87a-804b0fb1ea37-link\">26<\/a><\/sup> y los organoides derivados de pacientes.<sup data-fn=\"9f007b5a-8eae-4c12-9820-3c76c6617c69\" class=\"fn\"><a href=\"#9f007b5a-8eae-4c12-9820-3c76c6617c69\" id=\"9f007b5a-8eae-4c12-9820-3c76c6617c69-link\">27<\/a><\/sup><sup data-fn=\"af0cbef2-46ce-4c7c-9597-235e3fe5b056\" class=\"fn\"><a href=\"#af0cbef2-46ce-4c7c-9597-235e3fe5b056\" id=\"af0cbef2-46ce-4c7c-9597-235e3fe5b056-link\">28<\/a><\/sup><sup data-fn=\"a88c7153-224b-4804-9440-0e87416cea3e\" class=\"fn\"><a href=\"#a88c7153-224b-4804-9440-0e87416cea3e\" id=\"a88c7153-224b-4804-9440-0e87416cea3e-link\">29<\/a><\/sup> Adem\u00e1s, existen conjuntos de datos gen\u00f3micos del c\u00e1ncer<sup data-fn=\"4fd24010-f6b8-4123-bf87-cb49796b6ebe\" class=\"fn\"><a href=\"#4fd24010-f6b8-4123-bf87-cb49796b6ebe\" id=\"4fd24010-f6b8-4123-bf87-cb49796b6ebe-link\">30<\/a><\/sup><sup data-fn=\"141fc7e4-6182-4414-abfe-3f2ffb60bbb7\" class=\"fn\"><a href=\"#141fc7e4-6182-4414-abfe-3f2ffb60bbb7\" id=\"141fc7e4-6182-4414-abfe-3f2ffb60bbb7-link\">31<\/a><\/sup><sup data-fn=\"80be0c70-14ca-4a2f-bbc3-897bd0d042b6\" class=\"fn\"><a href=\"#80be0c70-14ca-4a2f-bbc3-897bd0d042b6\" id=\"80be0c70-14ca-4a2f-bbc3-897bd0d042b6-link\">32<\/a><\/sup><sup data-fn=\"c05b6008-28cc-4c3b-8d4c-28963c57275e\" class=\"fn\"><a href=\"#c05b6008-28cc-4c3b-8d4c-28963c57275e\" id=\"c05b6008-28cc-4c3b-8d4c-28963c57275e-link\">33<\/a><\/sup><sup data-fn=\"15ee1a33-89ca-4d05-9f01-02aa6a8c5123\" class=\"fn\"><a href=\"#15ee1a33-89ca-4d05-9f01-02aa6a8c5123\" id=\"15ee1a33-89ca-4d05-9f01-02aa6a8c5123-link\">34<\/a><\/sup> y herramientas de aprendizaje autom\u00e1tico<sup data-fn=\"f90baee9-90cb-4311-b5df-2486ae499638\" class=\"fn\"><a href=\"#f90baee9-90cb-4311-b5df-2486ae499638\" id=\"f90baee9-90cb-4311-b5df-2486ae499638-link\">35<\/a><\/sup><sup data-fn=\"d86bb19e-05b3-4fcf-97d9-21ec5593a362\" class=\"fn\"><a href=\"#d86bb19e-05b3-4fcf-97d9-21ec5593a362\" id=\"d86bb19e-05b3-4fcf-97d9-21ec5593a362-link\">36<\/a><\/sup><sup data-fn=\"39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c\" class=\"fn\"><a href=\"#39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c\" id=\"39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c-link\">37<\/a><\/sup><sup data-fn=\"20f51e18-62a3-49d6-80ca-f5303d7d27e6\" class=\"fn\"><a href=\"#20f51e18-62a3-49d6-80ca-f5303d7d27e6\" id=\"20f51e18-62a3-49d6-80ca-f5303d7d27e6-link\">38<\/a><\/sup> disponibles para mejorar el diagn\u00f3stico y predecir las respuestas a los tratamientos en tiempo real.&nbsp;&nbsp;<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Quienes emplean m\u00e9todos sin animales para la investigaci\u00f3n del c\u00e1ncer se enfrentan a una barrera traslacional menor, ya que estos m\u00e9todos se basan en la biolog\u00eda humana, no en la de los roedores.<sup data-fn=\"8276aa67-b7ba-478f-8708-a88fda55c8a7\" class=\"fn\"><a href=\"#8276aa67-b7ba-478f-8708-a88fda55c8a7\" id=\"8276aa67-b7ba-478f-8708-a88fda55c8a7-link\">39<\/a><\/sup> Con los recursos financieros adecuados, estas nuevas herramientas har\u00e1n avanzar la investigaci\u00f3n del c\u00e1ncer, producir\u00e1n resultados relevantes para los humanos y acelerar\u00e1n la marcha hacia la medicina de precisi\u00f3n.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Enfermedad cardiovascular<\/strong><\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">La enfermedad cardiovascular (ECV) es la primordial causa de muerte en todo el mundo, con aproximadamente 17,9&nbsp;millones de v\u00edctimas al a\u00f1o, y se prev\u00e9 que las tasas de mortalidad sigan aumentando.<sup data-fn=\"f63e9cf1-a54a-494e-a5de-c104dda7e778\" class=\"fn\"><a href=\"#f63e9cf1-a54a-494e-a5de-c104dda7e778\" id=\"f63e9cf1-a54a-494e-a5de-c104dda7e778-link\">40<\/a><\/sup> A pesar de la disponibilidad de tratamientos para la ECV, la tasa de fracaso de nuevas terapias farmacol\u00f3gicas fue cercana al 75% en&nbsp;2022, especialmente debido a las limitaciones de los modelos animales en el descubrimiento y la evaluaci\u00f3n de medicamentos.<sup data-fn=\"e3fbad9e-65f3-4067-804a-b3f3f693c075\" class=\"fn\"><a href=\"#e3fbad9e-65f3-4067-804a-b3f3f693c075\" id=\"e3fbad9e-65f3-4067-804a-b3f3f693c075-link\">41<\/a><\/sup> Un an\u00e1lisis de 121&nbsp;estudios que usaron animales para la investigaci\u00f3n de la ECV en humanos encontr\u00f3 que en el 79% de los casos sus resultados no lograron replicarse en humanos.<sup data-fn=\"05798e28-e21b-4414-9ce7-fb8679906d4d\" class=\"fn\"><a href=\"#05798e28-e21b-4414-9ce7-fb8679906d4d\" id=\"05798e28-e21b-4414-9ce7-fb8679906d4d-link\">42<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-2&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-2-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-2\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-2\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-2-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Para estudiar la ECV en humanos, los experimentadores usan diversas especies animales, como ranas, ratas y vacas. Sin embargo, la etiolog\u00eda y la patolog\u00eda de la ECV en estos animales suelen diferir significativamente de las de los humanos.<sup data-fn=\"84249d2d-5f00-4f4e-9473-bfd3c656c5df\" class=\"fn\"><a href=\"#84249d2d-5f00-4f4e-9473-bfd3c656c5df\" id=\"84249d2d-5f00-4f4e-9473-bfd3c656c5df-link\">43<\/a><\/sup><sup data-fn=\"b07c0d63-d807-429b-b44b-bcc74cbb1da2\" class=\"fn\"><a href=\"#b07c0d63-d807-429b-b44b-bcc74cbb1da2\" id=\"b07c0d63-d807-429b-b44b-bcc74cbb1da2-link\">44<\/a><\/sup> La mayor\u00eda de las especies presenta par\u00e1metros cardiovasculares funcionales y estructurales distintos, como la frecuencia card\u00edaca en reposo, los potenciales de acci\u00f3n, las isoformas proteicas, la contracci\u00f3n y la respuesta fuerza-frecuencia.<sup data-fn=\"14a6ac36-8a42-4782-8319-cdc0b7a2f6d8\" class=\"fn\"><a href=\"#14a6ac36-8a42-4782-8319-cdc0b7a2f6d8\" id=\"14a6ac36-8a42-4782-8319-cdc0b7a2f6d8-link\">45<\/a><\/sup><sup data-fn=\"1c48bfe9-c016-4967-b5dd-d613944fa130\" class=\"fn\"><a href=\"#1c48bfe9-c016-4967-b5dd-d613944fa130\" id=\"1c48bfe9-c016-4967-b5dd-d613944fa130-link\">46<\/a><\/sup><sup data-fn=\"75144ee4-253c-4014-9ae4-4667488fb05f\" class=\"fn\"><a href=\"#75144ee4-253c-4014-9ae4-4667488fb05f\" id=\"75144ee4-253c-4014-9ae4-4667488fb05f-link\">47<\/a><\/sup> Otros animales tambi\u00e9n presentan mecanismos gen\u00e9ticos espec\u00edficos que afectan la susceptibilidad a la ECV y la respuesta a los f\u00e1rmacos destinados al tratamiento en humanos.<sup data-fn=\"e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880\" class=\"fn\"><a href=\"#e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880\" id=\"e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880-link\">48<\/a><\/sup><sup data-fn=\"72fd6b41-02d1-4590-b1c3-a77f531923a2\" class=\"fn\"><a href=\"#72fd6b41-02d1-4590-b1c3-a77f531923a2\" id=\"72fd6b41-02d1-4590-b1c3-a77f531923a2-link\">49<\/a><\/sup><sup data-fn=\"bbaa06a9-31bc-4c16-8050-6e6597eaf437\" class=\"fn\"><a href=\"#bbaa06a9-31bc-4c16-8050-6e6597eaf437\" id=\"bbaa06a9-31bc-4c16-8050-6e6597eaf437-link\">50<\/a><\/sup> Por ejemplo, los roedores son resistentes a la aterosclerosis,<sup data-fn=\"7b91ef3a-c5c0-4e38-9db8-d40d699edac2\" class=\"fn\"><a href=\"#7b91ef3a-c5c0-4e38-9db8-d40d699edac2\" id=\"7b91ef3a-c5c0-4e38-9db8-d40d699edac2-link\">51<\/a><\/sup> un componente clave de la ECV. La enfermedad arterial coronaria, que conduce a la aterosclerosis, rara vez se produce en animales y es dif\u00edcil de inducir, lo que frecuentemente requiere intervenciones quir\u00fargicas o farmac\u00e9uticas que no son relevantes en el contexto humano.<sup data-fn=\"8a669361-e64f-44e4-b564-4e243ed88c76\" class=\"fn\"><a href=\"#8a669361-e64f-44e4-b564-4e243ed88c76\" id=\"8a669361-e64f-44e4-b564-4e243ed88c76-link\">52<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s, los factores de riesgo conductuales y ambientales, como la alimentaci\u00f3n, el sedentarismo, el tabaquismo y la contaminaci\u00f3n del aire<sup data-fn=\"989f960c-b634-4f16-b294-474fa48fd78b\" class=\"fn\"><a href=\"#989f960c-b634-4f16-b294-474fa48fd78b\" id=\"989f960c-b634-4f16-b294-474fa48fd78b-link\">53<\/a><\/sup> son complejos y no se pueden reproducir de forma confiable en animales. Estos factores contribuyen a la limitada relevancia y a la escasa traslaci\u00f3n cl\u00ednica de los experimentos de ECV en animales. Como se\u00f1alaron los autores de un estudio reciente, \u201cla comprensi\u00f3n profunda de la progresi\u00f3n de la enfermedad es limitada. Este estancamiento se debe a la falta de modelos precl\u00ednicos biol\u00f3gicamente relevantes y robustos que permitan comprender de verdad los fundamentos moleculares de las enfermedades card\u00edacas y su fisiopatolog\u00eda\u201d.<sup data-fn=\"37d9bf7d-1dbf-43d4-a6db-e02c246fd526\" class=\"fn\"><a href=\"#37d9bf7d-1dbf-43d4-a6db-e02c246fd526\" id=\"37d9bf7d-1dbf-43d4-a6db-e02c246fd526-link\">54<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los m\u00e9todos <em>in vitro<\/em> e <em>in silico<\/em> basados en la biolog\u00eda humana son m\u00e1s adecuados para la investigaci\u00f3n cardiovascular que los modelos animales. Los investigadores han generado organoides card\u00edacos a partir de c\u00e9lulas madre pluripotentes inducidas humanas (hiPSC), que imitan la composici\u00f3n celular del coraz\u00f3n y se organizan para crear estructuras similares a los ventr\u00edculos. Estos organoides card\u00edacos pueden recapitular el deterioro funcional observado en afecciones como la fibrosis card\u00edaca y la miocardiopat\u00eda hipertr\u00f3fica.<sup data-fn=\"a78ed81d-1af3-4074-b6c2-28881e7a4f50\" class=\"fn\"><a href=\"#a78ed81d-1af3-4074-b6c2-28881e7a4f50\" id=\"a78ed81d-1af3-4074-b6c2-28881e7a4f50-link\">55<\/a><\/sup><sup data-fn=\"d2ac872c-a177-485e-a2e9-86c6e6a44d94\" class=\"fn\"><a href=\"#d2ac872c-a177-485e-a2e9-86c6e6a44d94\" id=\"d2ac872c-a177-485e-a2e9-86c6e6a44d94-link\">56<\/a><\/sup><sup data-fn=\"017577c0-c43a-4056-add0-716f3b2577cd\" class=\"fn\"><a href=\"#017577c0-c43a-4056-add0-716f3b2577cd\" id=\"017577c0-c43a-4056-add0-716f3b2577cd-link\">57<\/a><\/sup> Un equipo de ingenieros en Taiw\u00e1n desarroll\u00f3 un sistema de chip microflu\u00eddico para cuantificar r\u00e1pidamente cuatro biomarcadores de ECV y mejorar la intervenci\u00f3n temprana.<sup data-fn=\"a79f293e-21a0-47ce-9a8e-3dae9ecd32b1\" class=\"fn\"><a href=\"#a79f293e-21a0-47ce-9a8e-3dae9ecd32b1\" id=\"a79f293e-21a0-47ce-9a8e-3dae9ecd32b1-link\">58<\/a><\/sup> Un estudio reciente demostr\u00f3 que la tecnolog\u00eda de coraz\u00f3n en chip puede utilizarse para modelar arritmias card\u00edacas.<sup data-fn=\"9059e30b-faf7-4ca2-bbc6-f01ca65bf884\" class=\"fn\"><a href=\"#9059e30b-faf7-4ca2-bbc6-f01ca65bf884\" id=\"9059e30b-faf7-4ca2-bbc6-f01ca65bf884-link\">59<\/a><\/sup><sup data-fn=\"6e8aa3b6-b816-4f9c-ac4b-b7309b218341\" class=\"fn\"><a href=\"#6e8aa3b6-b816-4f9c-ac4b-b7309b218341\" id=\"6e8aa3b6-b816-4f9c-ac4b-b7309b218341-link\">60<\/a><\/sup> Adem\u00e1s, las t\u00e9cnicas de aprendizaje autom\u00e1tico, en combinaci\u00f3n con los datos de los pacientes, pueden crear modelos para predecir el riesgo de ECV, lo que permite una identificaci\u00f3n m\u00e1s temprana de las enfermedades y resultados terap\u00e9uticos m\u00e1s eficaces.<sup data-fn=\"f5699161-2a50-42f2-b785-204a6d1b7e3b\" class=\"fn\"><a href=\"#f5699161-2a50-42f2-b785-204a6d1b7e3b\" id=\"f5699161-2a50-42f2-b785-204a6d1b7e3b-link\">61<\/a><\/sup><sup data-fn=\"86c9eda2-bf94-428c-a230-dc3d6a869166\" class=\"fn\"><a href=\"#86c9eda2-bf94-428c-a230-dc3d6a869166\" id=\"86c9eda2-bf94-428c-a230-dc3d6a869166-link\">62<\/a><\/sup><sup data-fn=\"6657df79-120c-47f1-8a40-4ffe5128bfb1\" class=\"fn\"><a href=\"#6657df79-120c-47f1-8a40-4ffe5128bfb1\" id=\"6657df79-120c-47f1-8a40-4ffe5128bfb1-link\">63<\/a><\/sup> Cient\u00edficos y m\u00e9dicos han colaborado en el desarrollo de un algoritmo con datos cl\u00ednicos que predice la progresi\u00f3n de la miocardiopat\u00eda hipertr\u00f3fica a 10&nbsp;a\u00f1os.<sup data-fn=\"db08ab77-1578-4ba9-81a6-c439ac2d78cb\" class=\"fn\"><a href=\"#db08ab77-1578-4ba9-81a6-c439ac2d78cb\" id=\"db08ab77-1578-4ba9-81a6-c439ac2d78cb-link\">64<\/a><\/sup> Por \u00faltimo, el modelado y la simulaci\u00f3n <em>in silico<\/em> pueden emplearse para evaluar la informaci\u00f3n sobre los mecanismos de la fisiopatolog\u00eda card\u00edaca.<sup data-fn=\"7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b\" class=\"fn\"><a href=\"#7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b\" id=\"7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b-link\">65<\/a><\/sup> Estos m\u00e9todos son plataformas valiosas para el estudio del coraz\u00f3n humano, la identificaci\u00f3n y selecci\u00f3n de medicamentos para el tratamiento de la ECV y la aplicaci\u00f3n en medicina regenerativa y personalizada.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Si se tiene en cuenta que \u201cno existe un modelo animal ideal para la investigaci\u00f3n card\u00edaca\u201d,<sup data-fn=\"7ca34966-87e6-437e-9220-395c39ad6de5\" class=\"fn\"><a href=\"#7ca34966-87e6-437e-9220-395c39ad6de5\" id=\"7ca34966-87e6-437e-9220-395c39ad6de5-link\">66<\/a><\/sup> la investigaci\u00f3n de la ECV debe evolucionar hacia m\u00e9todos innovadores basados en c\u00e9lulas humanas y datos procedentes de pacientes. Estos nuevos modelos experimentales son m\u00e1s costo-efectivos y recapitulan mejor la fisiolog\u00eda humana.<sup data-fn=\"ee8810ef-3b00-4aa2-8f48-9c90b69523cf\" class=\"fn\"><a href=\"#ee8810ef-3b00-4aa2-8f48-9c90b69523cf\" id=\"ee8810ef-3b00-4aa2-8f48-9c90b69523cf-link\">67<\/a><\/sup> A diferencia de los modelos animales, los m\u00e9todos de investigaci\u00f3n sin animales proporcionan una informaci\u00f3n biol\u00f3gica m\u00e1s precisa de la funci\u00f3n card\u00edaca y mejoran la traslaci\u00f3n de los hallazgos precl\u00ednicos a la atenci\u00f3n efectiva de los pacientes humanos.<sup data-fn=\"992d3102-c04c-4130-a926-f5d84a8fc8b5\" class=\"fn\"><a href=\"#992d3102-c04c-4130-a926-f5d84a8fc8b5\" id=\"992d3102-c04c-4130-a926-f5d84a8fc8b5-link\">68<\/a><\/sup><sup data-fn=\"c38c9aba-b804-4236-a611-1810ebc6ebc0\" class=\"fn\"><a href=\"#c38c9aba-b804-4236-a611-1810ebc6ebc0\" id=\"c38c9aba-b804-4236-a611-1810ebc6ebc0-link\">69<\/a><\/sup><sup data-fn=\"14d49a8b-5a9c-4fa1-bdde-da3bf47c459c\" class=\"fn\"><a href=\"#14d49a8b-5a9c-4fa1-bdde-da3bf47c459c\" id=\"14d49a8b-5a9c-4fa1-bdde-da3bf47c459c-link\">70<\/a><\/sup><\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Terapia celular<\/strong><\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">La terapia celular adoptiva (terapia celular) consiste en trasplantar c\u00e9lulas humanas para reparar o reemplazar tejidos da\u00f1ados. Esta terapia usa c\u00e9lulas madre hematopoy\u00e9ticas, c\u00e9lulas madre mesenquimales y c\u00e9lulas inmunitarias obtenidas de los propios pacientes (aut\u00f3logas) o de donantes (alog\u00e9nicas) para tratar diversas afecciones.<sup data-fn=\"24ad7787-9c22-4326-ad63-c12f686c7a19\" class=\"fn\"><a href=\"#24ad7787-9c22-4326-ad63-c12f686c7a19\" id=\"24ad7787-9c22-4326-ad63-c12f686c7a19-link\">71<\/a><\/sup><sup data-fn=\"2c63ece2-3530-40f5-bda7-915aff52a346\" class=\"fn\"><a href=\"#2c63ece2-3530-40f5-bda7-915aff52a346\" id=\"2c63ece2-3530-40f5-bda7-915aff52a346-link\">72<\/a><\/sup> La terapia celular se ha estudiado para tratar enfermedades relacionadas con la sangre, c\u00e1nceres s\u00f3lidos y diabetes, y para aplicaciones en medicina regenerativa.<sup data-fn=\"6d385ef5-32fc-44a7-84be-471ce649c370\" class=\"fn\"><a href=\"#6d385ef5-32fc-44a7-84be-471ce649c370\" id=\"6d385ef5-32fc-44a7-84be-471ce649c370-link\">73<\/a><\/sup><sup data-fn=\"8002d682-8084-422f-b6a1-6e5d5b4ae89b\" class=\"fn\"><a href=\"#8002d682-8084-422f-b6a1-6e5d5b4ae89b\" id=\"8002d682-8084-422f-b6a1-6e5d5b4ae89b-link\">74<\/a><\/sup><sup data-fn=\"fdf2504d-5830-4398-981a-6e3f9fd554d8\" class=\"fn\"><a href=\"#fdf2504d-5830-4398-981a-6e3f9fd554d8\" id=\"fdf2504d-5830-4398-981a-6e3f9fd554d8-link\">75<\/a><\/sup><sup data-fn=\"f5a6c26c-c887-4758-8be1-55e1b55bbc46\" class=\"fn\"><a href=\"#f5a6c26c-c887-4758-8be1-55e1b55bbc46\" id=\"f5a6c26c-c887-4758-8be1-55e1b55bbc46-link\">76<\/a><\/sup><sup data-fn=\"5de69205-f37b-4989-8692-2b22ad62ce4b\" class=\"fn\"><a href=\"#5de69205-f37b-4989-8692-2b22ad62ce4b\" id=\"5de69205-f37b-4989-8692-2b22ad62ce4b-link\">77<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-3&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-3-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-3\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-3\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-3-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">La investigaci\u00f3n en terapia celular suele realizarse en animales, en su mayor\u00eda ratones modificados gen\u00e9ticamente, y presenta limitaciones significativas. Los experimentos en animales suelen usar animales j\u00f3venes y sanos, que no reflejan la compleja etiolog\u00eda de las enfermedades humanas, a menudo influidas por la edad y las comorbilidades. Los experimentos en animales carecen del an\u00e1lisis y el seguimiento a largo plazo necesarios para evaluar la eficacia en humanos, lo que plantea un reto a la hora de predecir los resultados.<sup data-fn=\"c83ae1eb-5b9d-440e-89dc-9b0948a54047\" class=\"fn\"><a href=\"#c83ae1eb-5b9d-440e-89dc-9b0948a54047\" id=\"c83ae1eb-5b9d-440e-89dc-9b0948a54047-link\">78<\/a><\/sup> Adem\u00e1s, las diferencias inmunol\u00f3gicas y fisiol\u00f3gicas entre especies derivan en una mala traslaci\u00f3n de los resultados.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Aunque se ha aprobado el uso de algunas terapias celulares, estos tratamientos siguen planteando dificultades, especialmente en el caso de los c\u00e1nceres s\u00f3lidos, debido a la heterogeneidad de los tumores y a la escasez de ant\u00edgenos tumorales espec\u00edficos.<sup data-fn=\"70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf\" class=\"fn\"><a href=\"#70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf\" id=\"70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf-link\">79<\/a><\/sup> Las terapias dise\u00f1adas con c\u00e9lulas T de receptores de ant\u00edgenos quim\u00e9ricos (CAR) han mostrado actividad antitumoral en experimentos en ratones, pero no han funcionado en ensayos cl\u00ednicos en humanos para c\u00e1ncer de ovario y c\u00e1ncer metast\u00e1sico de c\u00e9lulas renales.<sup data-fn=\"efaeede9-a56c-4eb9-8c54-391507b8f2ed\" class=\"fn\"><a href=\"#efaeede9-a56c-4eb9-8c54-391507b8f2ed\" id=\"efaeede9-a56c-4eb9-8c54-391507b8f2ed-link\">80<\/a><\/sup><sup data-fn=\"5a7a5765-6c73-4366-92b6-5c46c2f16195\" class=\"fn\"><a href=\"#5a7a5765-6c73-4366-92b6-5c46c2f16195\" id=\"5a7a5765-6c73-4366-92b6-5c46c2f16195-link\">81<\/a><\/sup> Una de las causas de este fracaso es que en los estudios precl\u00ednicos suelen usarse ratones inmunodeficientes con tumores humanos xenoinjertados, mientras que en la pr\u00e1ctica cl\u00ednica estas c\u00e9lulas act\u00faan dentro del sistema inmunitario complejo e intacto del paciente.<sup data-fn=\"bb130843-5efa-436c-914b-0bca564799cd\" class=\"fn\"><a href=\"#bb130843-5efa-436c-914b-0bca564799cd\" id=\"bb130843-5efa-436c-914b-0bca564799cd-link\">82<\/a><\/sup> En la secci\u00f3n sobre c\u00e1ncer encontrar\u00e1s m\u00e1s informaci\u00f3n sobre los problemas de los modelos de xenoinjerto en rat\u00f3n.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Dado que los animales no reproducen con exactitud la biolog\u00eda humana, tampoco pueden predecir de manera confiable los efectos adversos de las terapias celulares, como el s\u00edndrome de liberaci\u00f3n de citocinas y la neurotoxicidad asociada a las c\u00e9lulas efectoras inmunitarias. Adem\u00e1s, la variabilidad en la preparaci\u00f3n y caracterizaci\u00f3n de las c\u00e9lulas durante los experimentos precl\u00ednicos en animales puede dar lugar a resultados inconsistentes e irreproducibles.<sup data-fn=\"c5f12286-b96f-448c-90b7-7a1d9be301ed\" class=\"fn\"><a href=\"#c5f12286-b96f-448c-90b7-7a1d9be301ed\" id=\"c5f12286-b96f-448c-90b7-7a1d9be301ed-link\">83<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los m\u00e9todos precl\u00ednicos sin animales para estudiar y probar terapias celulares incluyen modelos <em>in vitro<\/em>, como los organoides y aquellos que usan hiPSC. Estos modelos reproducen la fisiolog\u00eda humana con mayor exactitud, lo que permite la evaluaci\u00f3n de una gran cantidad de f\u00e1rmacos, la identificaci\u00f3n de mecanismos espec\u00edficos para humanos y el desarrollo de enfoques de medicina personalizada.<sup data-fn=\"06c453ea-95ab-4dac-93ad-196e72f41bf7\" class=\"fn\"><a href=\"#06c453ea-95ab-4dac-93ad-196e72f41bf7\" id=\"06c453ea-95ab-4dac-93ad-196e72f41bf7-link\">84<\/a><\/sup><sup data-fn=\"402d9886-6f97-4a17-a8df-0d763b43373d\" class=\"fn\"><a href=\"#402d9886-6f97-4a17-a8df-0d763b43373d\" id=\"402d9886-6f97-4a17-a8df-0d763b43373d-link\">85<\/a><\/sup> Maulana y colaboradores introdujeron un modelo en chip de c\u00e1ncer de mama derivado de pacientes que permite el monitoreo en tiempo real de la actividad de las c\u00e9lulas T&nbsp;CAR y la prevenci\u00f3n del s\u00edndrome de liberaci\u00f3n de citocinas con un f\u00e1rmaco aprobado por la FDA.<sup data-fn=\"f872aa91-c354-42c6-b6e4-1949b2a33933\" class=\"fn\"><a href=\"#f872aa91-c354-42c6-b6e4-1949b2a33933\" id=\"f872aa91-c354-42c6-b6e4-1949b2a33933-link\">86<\/a><\/sup> En otro estudio, en el que se utilizaron muestras de pacientes y datos cl\u00ednicos, se identific\u00f3 el&nbsp;CD22 como marcador potencial para el desarrollo de la terapia con c\u00e9lulas T&nbsp;CAR en el c\u00e1ncer de mama triple negativo, que, a pesar de los ensayos cl\u00ednicos de terapia celular en curso, carece actualmente de tratamiento.<sup data-fn=\"48bbc6e3-e783-4a97-91ff-9f2125362f3f\" class=\"fn\"><a href=\"#48bbc6e3-e783-4a97-91ff-9f2125362f3f\" id=\"48bbc6e3-e783-4a97-91ff-9f2125362f3f-link\">87<\/a><\/sup><sup data-fn=\"54799e1e-00dd-48c5-98d6-17eca4dcdda9\" class=\"fn\"><a href=\"#54799e1e-00dd-48c5-98d6-17eca4dcdda9\" id=\"54799e1e-00dd-48c5-98d6-17eca4dcdda9-link\">88<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El inter\u00e9s por las terapias celulares adoptivas ha aumentado en la \u00faltima d\u00e9cada y sigue extendi\u00e9ndose a diversos tipos de c\u00e1ncer y otras enfermedades. Los recientes avances en las tecnolog\u00edas de ingenier\u00eda, los modelos humanos <em>in vitro<\/em> y las terapias combinadas est\u00e1n mejorando el desarrollo de la terapia celular, ya que proporcionan plataformas robustas para estudiar los mecanismos de las enfermedades y las intervenciones terap\u00e9uticas, adem\u00e1s de arrojar resultados m\u00e1s aplicables.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Diabetes<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Durante muchos a\u00f1os, los experimentadores han inducido intencionalmente s\u00edntomas de diabetes mellitus (diabetes) en roedores, cerdos, perros y primates.<sup data-fn=\"5452aaab-df18-450c-8107-5b7c9667ad44\" class=\"fn\"><a href=\"#5452aaab-df18-450c-8107-5b7c9667ad44\" id=\"5452aaab-df18-450c-8107-5b7c9667ad44-link\">89<\/a><\/sup> Sin embargo, estos modelos presentan limitaciones considerables, como la diferencia en la progresi\u00f3n de la enfermedad en comparaci\u00f3n con los humanos. Para intentar reproducir la patolog\u00eda de la diabetes en animales, los experimentadores inducen los s\u00edntomas mediante una alimentaci\u00f3n inadecuada y la destrucci\u00f3n qu\u00edmica o viral de las c\u00e9lulas beta pancre\u00e1ticas, pero su empe\u00f1o ha fracasado sistem\u00e1ticamente debido a importantes limitaciones, como la necrosis tisular y las diferencias en la susceptibilidad de cada especie a la diabetes.<sup data-fn=\"fe87a148-e467-4639-97e2-3d5685a06099\" class=\"fn\"><a href=\"#fe87a148-e467-4639-97e2-3d5685a06099\" id=\"fe87a148-e467-4639-97e2-3d5685a06099-link\">90<\/a><\/sup><sup data-fn=\"a68fbfca-e143-4937-bf1f-cd16c9b716fc\" class=\"fn\"><a href=\"#a68fbfca-e143-4937-bf1f-cd16c9b716fc\" id=\"a68fbfca-e143-4937-bf1f-cd16c9b716fc-link\">91<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-4&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-4-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-4\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-4\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-4-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">M\u00e1s all\u00e1 de las limitaciones t\u00e9cnicas, el uso de animales para estudiar la diabetes tambi\u00e9n plantea limitaciones biol\u00f3gicas significativas en relaci\u00f3n con la anatom\u00eda, la fisiolog\u00eda y la vulnerabilidad a la enfermedad.<sup data-fn=\"f22ea257-0ab6-4bd2-ad29-c59d32cdda61\" class=\"fn\"><a href=\"#f22ea257-0ab6-4bd2-ad29-c59d32cdda61\" id=\"f22ea257-0ab6-4bd2-ad29-c59d32cdda61-link\">92<\/a><\/sup><sup data-fn=\"d711ff14-8e6d-4927-9f65-cb0d2b9d86d0\" class=\"fn\"><a href=\"#d711ff14-8e6d-4927-9f65-cb0d2b9d86d0\" id=\"d711ff14-8e6d-4927-9f65-cb0d2b9d86d0-link\">93<\/a><\/sup> Por ejemplo, los ratones dependen principalmente del h\u00edgado para la homeostasis de la glucosa, mientras que en el caso de los humanos, el m\u00fasculo esquel\u00e9tico tambi\u00e9n es crucial en el metabolismo de la glucosa.<sup data-fn=\"e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5\" class=\"fn\"><a href=\"#e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5\" id=\"e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5-link\">94<\/a><\/sup> Adem\u00e1s, algunos modelos de ratones transg\u00e9nicos de diabetes tipo&nbsp;2 se basan en la deficiencia de leptina, que no contribuye de manera esencial a la diabetes en humanos.<sup data-fn=\"3f6d07cb-9410-46e3-9a25-a8c25a6c58a4\" class=\"fn\"><a href=\"#3f6d07cb-9410-46e3-9a25-a8c25a6c58a4\" id=\"3f6d07cb-9410-46e3-9a25-a8c25a6c58a4-link\">95<\/a><\/sup> Debido a la baja tasa de diabetes espont\u00e1nea (solo el 2%), el modelo de rata LEW-iddm para diabetes tipo&nbsp;1 requiere alteraciones compensatorias en la gama de c\u00e9lulas inmunol\u00f3gicas de la rata para desarrollar un perfil diab\u00e9tico, pero sigue sin replicar fielmente la condici\u00f3n humana.<sup data-fn=\"86a9999f-a017-4225-b2c2-8c5d4a064658\" class=\"fn\"><a href=\"#86a9999f-a017-4225-b2c2-8c5d4a064658\" id=\"86a9999f-a017-4225-b2c2-8c5d4a064658-link\">96<\/a><\/sup><sup data-fn=\"60fde9d7-47ed-4c25-b2b3-8e8111108b61\" class=\"fn\"><a href=\"#60fde9d7-47ed-4c25-b2b3-8e8111108b61\" id=\"60fde9d7-47ed-4c25-b2b3-8e8111108b61-link\">97<\/a><\/sup> Del mismo modo, el p\u00e1ncreas humano difiere del de los roedores en su arquitectura tisular y composici\u00f3n celular, as\u00ed como en los mecanismos de regulaci\u00f3n de la insulina.<sup data-fn=\"858c6af8-fa4d-44f6-ae85-3336dfd17bb1\" class=\"fn\"><a href=\"#858c6af8-fa4d-44f6-ae85-3336dfd17bb1\" id=\"858c6af8-fa4d-44f6-ae85-3336dfd17bb1-link\">98<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Muchos f\u00e1rmacos desarrollados para tratar la diabetes tienen efectos secundarios adversos, como edemas, riesgo card\u00edaco y aumento de peso, y algunos f\u00e1rmacos han sido retirados del mercado.<sup data-fn=\"acf07f13-22a1-4619-afe8-fb37b99097c8\" class=\"fn\"><a href=\"#acf07f13-22a1-4619-afe8-fb37b99097c8\" id=\"acf07f13-22a1-4619-afe8-fb37b99097c8-link\">99<\/a><\/sup><sup data-fn=\"209c7d6c-df7b-4e18-92c8-18f002c33c97\" class=\"fn\"><a href=\"#209c7d6c-df7b-4e18-92c8-18f002c33c97\" id=\"209c7d6c-df7b-4e18-92c8-18f002c33c97-link\">100<\/a><\/sup> Hallazgos recientes revelan importantes diferencias entre las personas con diabetes tipo 2 en cuanto a la patolog\u00eda, el entorno, el origen \u00e9tnico y las respuestas al tratamiento,<sup data-fn=\"dae01dad-95d5-483f-8ebf-b28c079f2477\" class=\"fn\"><a href=\"#dae01dad-95d5-483f-8ebf-b28c079f2477\" id=\"dae01dad-95d5-483f-8ebf-b28c079f2477-link\">101<\/a><\/sup><sup data-fn=\"42239f74-e967-4ed1-bd7c-70e1639735f8\" class=\"fn\"><a href=\"#42239f74-e967-4ed1-bd7c-70e1639735f8\" id=\"42239f74-e967-4ed1-bd7c-70e1639735f8-link\">102<\/a><\/sup><sup data-fn=\"685997dc-6304-499a-9e46-2e6382171a0c\" class=\"fn\"><a href=\"#685997dc-6304-499a-9e46-2e6382171a0c\" id=\"685997dc-6304-499a-9e46-2e6382171a0c-link\">103<\/a><\/sup><sup data-fn=\"a31634e4-a5ff-42b3-bf9b-f472ca10c627\" class=\"fn\"><a href=\"#a31634e4-a5ff-42b3-bf9b-f472ca10c627\" id=\"a31634e4-a5ff-42b3-bf9b-f472ca10c627-link\">104<\/a><\/sup> lo que evidencia por qu\u00e9 la heterogeneidad de esta enfermedad no puede reproducirse en animales. En consecuencia, los experimentos en animales no han dado lugar a resultados transferibles a los humano.<sup data-fn=\"d44f1095-ad37-48c6-967e-912592204bda\" class=\"fn\"><a href=\"#d44f1095-ad37-48c6-967e-912592204bda\" id=\"d44f1095-ad37-48c6-967e-912592204bda-link\">105<\/a><\/sup><sup data-fn=\"921b9db1-bf0e-4e98-aecb-3de96684dba3\" class=\"fn\"><a href=\"#921b9db1-bf0e-4e98-aecb-3de96684dba3\" id=\"921b9db1-bf0e-4e98-aecb-3de96684dba3-link\">106<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Dado que siguen identific\u00e1ndose diferencias entre especies, existe una clara necesidad de avanzar en la investigaci\u00f3n sobre la diabetes mediante el uso de m\u00e9todos basados en la biolog\u00eda humana que permitan cerrar la brecha entre los experimentos precl\u00ednicos y los ensayos cl\u00ednicos, y descubrir nuevas formas de prevenir la progresi\u00f3n de la enfermedad.<sup data-fn=\"0c743c36-f712-4726-a55a-ddc534ef96e1\" class=\"fn\"><a href=\"#0c743c36-f712-4726-a55a-ddc534ef96e1\" id=\"0c743c36-f712-4726-a55a-ddc534ef96e1-link\">107<\/a><\/sup><sup data-fn=\"c04e205f-e2b8-4bc6-9f38-21a1597456b0\" class=\"fn\"><a href=\"#c04e205f-e2b8-4bc6-9f38-21a1597456b0\" id=\"c04e205f-e2b8-4bc6-9f38-21a1597456b0-link\">108<\/a><\/sup><sup data-fn=\"5302ab5c-8233-42c1-af54-5381f693f4ab\" class=\"fn\"><a href=\"#5302ab5c-8233-42c1-af54-5381f693f4ab\" id=\"5302ab5c-8233-42c1-af54-5381f693f4ab-link\">109<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Se han desarrollado numerosos modelos de \u00f3rgano en chip para estudiar la resistencia a la insulina y la funci\u00f3n glomerular de la nefropat\u00eda diab\u00e9tica, descubrir mecanismos biol\u00f3gicos y explorar oportunidades de tratamiento eficaces. Por ejemplo,un glom\u00e9rulo en chip con c\u00e9lulas humanas permite a los investigadores evaluar el da\u00f1o renal inducido por niveles altos de glucosa.<sup data-fn=\"44692265-c894-4db3-b4aa-3b0aee4d9e56\" class=\"fn\"><a href=\"#44692265-c894-4db3-b4aa-3b0aee4d9e56\" id=\"44692265-c894-4db3-b4aa-3b0aee4d9e56-link\">110<\/a><\/sup> En otro estudio, el glom\u00e9rulo en chip imit\u00f3 la respuesta renal humana <em>in vivo<\/em> a lesiones en pacientes expuestos a suero y agentes t\u00f3xicos, lo que proporcion\u00f3 una herramienta valiosa para investigar el da\u00f1o renal.<sup data-fn=\"f0043d28-9f95-48de-9e1c-adc9f5c2e405\" class=\"fn\"><a href=\"#f0043d28-9f95-48de-9e1c-adc9f5c2e405\" id=\"f0043d28-9f95-48de-9e1c-adc9f5c2e405-link\">111<\/a><\/sup> En otro modelo&nbsp;3D, se utilizaron islotes de p\u00e1ncreas cadav\u00e9ricos para hacer mediciones continuas de insulina, lo que constituye un modelo escalable para estudiar la diabetes y evaluar medicamentos.<sup data-fn=\"c2cb5737-725a-4f48-a58d-1b41b153f68e\" class=\"fn\"><a href=\"#c2cb5737-725a-4f48-a58d-1b41b153f68e\" id=\"c2cb5737-725a-4f48-a58d-1b41b153f68e-link\">112<\/a><\/sup> El modelado <em>in silico<\/em> con datos de personas con diabetes tambi\u00e9n muestra resultados prometedores.<sup data-fn=\"30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e\" class=\"fn\"><a href=\"#30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e\" id=\"30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e-link\">113<\/a><\/sup><sup data-fn=\"3be906f0-c3e3-4cc2-a495-175ffe626fd8\" class=\"fn\"><a href=\"#3be906f0-c3e3-4cc2-a495-175ffe626fd8\" id=\"3be906f0-c3e3-4cc2-a495-175ffe626fd8-link\">114<\/a><\/sup><sup data-fn=\"39d47f23-c7e6-402c-9d28-918904685942\" class=\"fn\"><a href=\"#39d47f23-c7e6-402c-9d28-918904685942\" id=\"39d47f23-c7e6-402c-9d28-918904685942-link\">115<\/a><\/sup> Por ejemplo, en un estudio cl\u00ednico con personas sanas se prob\u00f3 un modelo dise\u00f1ado para cuantificar la insulina plasm\u00e1tica end\u00f3gena e inhalada despu\u00e9s de una comida, que puede ayudar a estimar la biodisponibilidad y la farmacocin\u00e9tica de la insulina inhalada en humanos.<sup data-fn=\"cd041d9e-460a-427c-a29d-a1857d5be948\" class=\"fn\"><a href=\"#cd041d9e-460a-427c-a29d-a1857d5be948\" id=\"cd041d9e-460a-427c-a29d-a1857d5be948-link\">116<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Se est\u00e1n explorando muchos otros modelos humanos en&nbsp;3D, como las c\u00e9lulas madre<sup data-fn=\"0771f530-192a-499d-b750-ffb500715fbd\" class=\"fn\"><a href=\"#0771f530-192a-499d-b750-ffb500715fbd\" id=\"0771f530-192a-499d-b750-ffb500715fbd-link\">117<\/a><\/sup><sup data-fn=\"c64b7c17-a34d-40fb-866d-61d5f747cd76\" class=\"fn\"><a href=\"#c64b7c17-a34d-40fb-866d-61d5f747cd76\" id=\"c64b7c17-a34d-40fb-866d-61d5f747cd76-link\">118<\/a><\/sup> y los islotes pancre\u00e1ticos<sup data-fn=\"6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a\" class=\"fn\"><a href=\"#6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a\" id=\"6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a-link\">119<\/a><\/sup><sup data-fn=\"aa7808d1-ccd1-4cf3-9b63-e04658b8bbde\" class=\"fn\"><a href=\"#aa7808d1-ccd1-4cf3-9b63-e04658b8bbde\" id=\"aa7808d1-ccd1-4cf3-9b63-e04658b8bbde-link\">120<\/a><\/sup> para el desarrollo de medicamentos y futuros trasplantes de \u00f3rganos en personas con diabetes.<sup data-fn=\"41bcd3ad-1d97-4d89-ad10-21e0e4c93145\" class=\"fn\"><a href=\"#41bcd3ad-1d97-4d89-ad10-21e0e4c93145\" id=\"41bcd3ad-1d97-4d89-ad10-21e0e4c93145-link\">121<\/a><\/sup><sup data-fn=\"f63c9ded-49b5-4b46-869f-a65bba1c8876\" class=\"fn\"><a href=\"#f63c9ded-49b5-4b46-869f-a65bba1c8876\" id=\"f63c9ded-49b5-4b46-869f-a65bba1c8876-link\">122<\/a><\/sup><sup data-fn=\"5504406f-3b1e-44b7-9184-fa1f6b68e63c\" class=\"fn\"><a href=\"#5504406f-3b1e-44b7-9184-fa1f6b68e63c\" id=\"5504406f-3b1e-44b7-9184-fa1f6b68e63c-link\">123<\/a><\/sup> Estos enfoques innovadores, basados en c\u00e9lulas de pacientes, tienen el potencial de acelerar la investigaci\u00f3n sobre la diabetes humana, ya que permiten investigar los mecanismos biol\u00f3gicos subyacentes a las complicaciones inducidas por esta enfermedad que no pueden reproducirse en experimentos en animales.<sup data-fn=\"7f0642c5-e462-4edd-aea0-04bea6a930f0\" class=\"fn\"><a href=\"#7f0642c5-e462-4edd-aea0-04bea6a930f0\" id=\"7f0642c5-e462-4edd-aea0-04bea6a930f0-link\">124<\/a><\/sup><sup data-fn=\"ed855932-6197-4ca0-95fd-5db032564172\" class=\"fn\"><a href=\"#ed855932-6197-4ca0-95fd-5db032564172\" id=\"ed855932-6197-4ca0-95fd-5db032564172-link\">125<\/a><\/sup><\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Inflamaci\u00f3n e inmunolog\u00eda<\/strong><\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">El uso de animales en la investigaci\u00f3n para estudiar la inflamaci\u00f3n y la inmunolog\u00eda humanas abarca gran parte de la investigaci\u00f3n b\u00e1sica y relacionada con las enfermedades. Analizaremos brevemente tres \u00e1reas principales: el uso de animales para la investigaci\u00f3n del VIH\/sida, el uso de ratones para la investigaci\u00f3n inmunol\u00f3gica humana y el uso de animales para estudiar la septicemia humana.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>VIH\/sida<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">La incapacidad de extrapolar los experimentos en animales a aplicaciones humanas eficaces de las vacunas contra el virus de la inmunodeficiencia humana (VIH) se reconoci\u00f3 hace mas de 30 a\u00f1os, cuando, en&nbsp;1995, los NIH instituyeron una moratoria sobre la reproducci\u00f3n de chimpanc\u00e9s, la especie m\u00e1s usada en ese momento en la investigaci\u00f3n sobre el VIH y el s\u00edndrome de inmunodeficiencia adquirida (sida), y se reconoci\u00f3 que los estudios en esta especie no hab\u00edan logrado producir datos cl\u00ednicamente \u00fatiles. Posteriormente, los experimentadores comenzaron a usar otras especies de primates no humanos, sobre todo macacos.&nbsp;<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-5&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-5-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-5\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-5\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-5-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Dado que los humanos son los \u00fanicos primates que pueden contraer el VIH y desarrollar sida, en su lugar, los experimentadores infectan a los monos con el virus de la inmunodeficiencia de los simios (VIS), un virus exclusivo de los primates africanos. La homolog\u00eda gen\u00e9tica entre el VIH y el VIS es solo del 55%, y el VIS es menos diverso gen\u00e9ticamente que el VIH.<sup data-fn=\"5bbf758b-f16c-41a4-bfec-460eaa861d89\" class=\"fn\"><a href=\"#5bbf758b-f16c-41a4-bfec-460eaa861d89\" id=\"5bbf758b-f16c-41a4-bfec-460eaa861d89-link\">126<\/a><\/sup><sup data-fn=\"691a380a-a5dc-4ecd-8e3a-26aea1b9a26c\" class=\"fn\"><a href=\"#691a380a-a5dc-4ecd-8e3a-26aea1b9a26c\" id=\"691a380a-a5dc-4ecd-8e3a-26aea1b9a26c-link\">127<\/a><\/sup> Debido a las diferencias en las prote\u00ednas de superficie y otros marcadores moleculares, los anticuerpos que neutralizan el VIS no tienen efecto sobre el VIH y viceversa.<sup data-fn=\"fd011132-72e5-4599-a105-4b865c846131\" class=\"fn\"><a href=\"#fd011132-72e5-4599-a105-4b865c846131\" id=\"fd011132-72e5-4599-a105-4b865c846131-link\">128<\/a><\/sup> Es importante destacar que la dosis de VIS administrada a un primate no humano en un experimento suele ser muy superior a la cantidad t\u00edpica de VIH-1 a la que se expone un humano durante la transmisi\u00f3n sexual.<sup data-fn=\"947ee380-bf77-458a-b11a-1b73f8bb08d5\" class=\"fn\"><a href=\"#947ee380-bf77-458a-b11a-1b73f8bb08d5\" id=\"947ee380-bf77-458a-b11a-1b73f8bb08d5-link\">129<\/a><\/sup> A veces, los experimentadores utilizan una mezcla dise\u00f1ada de VIS\/VIH. De acuerdo con Mark Girard, investigador en esta \u00e1rea, \u201c[h]ay que darse cuenta de que todav\u00eda no sabemos c\u00f3mo se compara el modelo del VIS o el VISH con la infecci\u00f3n de VIH en humanos. Extrapolar los resultados de protecci\u00f3n de la vacuna en estudios en primates no humanos a la eficacia en seres humanos puede ser enga\u00f1oso\u201d.<sup data-fn=\"e0d2d497-a11e-42e8-9028-cfb2005abeaf\" class=\"fn\"><a href=\"#e0d2d497-a11e-42e8-9028-cfb2005abeaf\" id=\"e0d2d497-a11e-42e8-9028-cfb2005abeaf-link\">130<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Incluso aquellos que usan primates no humanos como modelos del VIH han admitido que estos animales \u201cno permiten realizar pruebas directas de vacunas contra el VIH\u201d y que \u201cdebido a la complejidad y las limitaciones de los modelos de primates no humanos, sigue siendo dif\u00edcil extrapolar datos de estos modelos para desarrollar vacunas contra el VIH\u201d.<sup data-fn=\"fd9ccee5-d94b-4975-99ba-ce0dcfabe145\" class=\"fn\"><a href=\"#fd9ccee5-d94b-4975-99ba-ce0dcfabe145\" id=\"fd9ccee5-d94b-4975-99ba-ce0dcfabe145-link\">131<\/a><\/sup> Los experimentadores han desarrollado decenas de vacunas potenciales en monos, pero todas han fracasado en los ensayos en humanos.<sup data-fn=\"31c78c72-a1e4-4e0b-932c-21417c7a9342\" class=\"fn\"><a href=\"#31c78c72-a1e4-4e0b-932c-21417c7a9342\" id=\"31c78c72-a1e4-4e0b-932c-21417c7a9342-link\">132<\/a><\/sup> Al menos dos ensayos cl\u00ednicos han resultado en un aumento de la probabilidad de infecci\u00f3n por VIH en humanos.<sup data-fn=\"bd0ef70e-9918-40b3-8774-34b0c6524cc7\" class=\"fn\"><a href=\"#bd0ef70e-9918-40b3-8774-34b0c6524cc7\" id=\"bd0ef70e-9918-40b3-8774-34b0c6524cc7-link\">133<\/a><\/sup><sup data-fn=\"ff5ca556-0244-440a-baf3-b8228abd4389\" class=\"fn\"><a href=\"#ff5ca556-0244-440a-baf3-b8228abd4389\" id=\"ff5ca556-0244-440a-baf3-b8228abd4389-link\">134<\/a><\/sup> Tras uno de los ensayos fallidos de vacunas, Anthony Fauci, exdirector del Instituto Nacional de Alergias y Enfermedades Infecciosas de EE.&nbsp;UU., reconoci\u00f3 que los resultados positivos originales de un estudio en macacos \u201cpodr\u00edan ser una casualidad\u201d.<sup data-fn=\"6c940557-c7ae-4372-ae6a-4062a7bd3747\" class=\"fn\"><a href=\"#6c940557-c7ae-4372-ae6a-4062a7bd3747\" id=\"6c940557-c7ae-4372-ae6a-4062a7bd3747-link\">135<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">De acuerdo con cient\u00edficos que trabajan en esta \u00e1rea, \u201c[l]os modelos animales existentes que predicen las traslaciones cl\u00ednicas son simplistas, extremadamente reduccionistas y, por lo tanto, no son adecuados\u201d y esto se ve reflejado en el fracaso de los ensayos cl\u00ednicos, que adem\u00e1s de \u201ccentrar la atenci\u00f3n en la selecci\u00f3n temprana de objetivos\/generaci\u00f3n de candidatos potenciales&#8230; cuestiona la idoneidad de los modelos animales actuales en t\u00e9rminos de su congruencia con los hallazgos en hu\u00e9spedes humanos y su extrapolaci\u00f3n\u201d<sup data-fn=\"7e5d28ab-b432-4efe-85ba-a9de952787f3\" class=\"fn\"><a href=\"#7e5d28ab-b432-4efe-85ba-a9de952787f3\" id=\"7e5d28ab-b432-4efe-85ba-a9de952787f3-link\">136<\/a><\/sup> a dichos hu\u00e9spedes.&nbsp;<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Debido a los numerosos fracasos en la investigaci\u00f3n sobre el VIH\/sida en primates no humanos, los experimentadores han migrado al uso de ratones, una especie a\u00fan m\u00e1s distante gen\u00e9ticamente de los humanos. El modelo de rat\u00f3n \u201chumanizado\u201d para la investigaci\u00f3n del VIH\/sida es un rat\u00f3n repoblado parcialmente con c\u00e9lulas inmunitarias humanas que permiten infectar al animal con el VIH-1. Sin embargo, los ratones humanizados infectados tienen una longevidad limitada y conservan partes de su sistema inmunitario, lo que \u201ccomplica las interpretaciones de la respuesta inmunitaria\u201d.<sup data-fn=\"ccf58197-a4c7-42e7-9c73-5076bd8a7326\" class=\"fn\"><a href=\"#ccf58197-a4c7-42e7-9c73-5076bd8a7326\" id=\"ccf58197-a4c7-42e7-9c73-5076bd8a7326-link\">137<\/a><\/sup> No es sorprendente que el uso de ratones humanizados tampoco haya generado resultados \u00fatiles para el tratamiento cl\u00ednico del VIH\/sida.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Al considerar las diferencias entre un entorno de laboratorio y la sociedad humana, est\u00e1 claro que los experimentos en animales nunca captar\u00e1n la complejidad de esta enfermedad. Las ratas y los ratones usados en los experimentos se mantienen en condiciones en las que los pat\u00f3genos primarios son los que se encuentran en sus heces, y los cofactores que pueden estar presentes en los pacientes humanos, como otras infecciones microbianas, est\u00e1n ausentes. Esta falta de cofactores altera de manera significativa la adquisici\u00f3n y la progresi\u00f3n del virus.<sup data-fn=\"212aba32-9855-4565-9282-e0f815170d8b\" class=\"fn\"><a href=\"#212aba32-9855-4565-9282-e0f815170d8b\" id=\"212aba32-9855-4565-9282-e0f815170d8b-link\">138<\/a><\/sup> Por otra parte, se ha descubierto que los primates no humanos usados en la investigaci\u00f3n del VIH albergan infecciones como la coccidioidomicosis, que constituyen variables de confusi\u00f3n y comprometen los resultados de los estudios sobre el VIH.<sup data-fn=\"8b7df6e5-f6b4-4699-aab7-fc4b152fd96e\" class=\"fn\"><a href=\"#8b7df6e5-f6b4-4699-aab7-fc4b152fd96e\" id=\"8b7df6e5-f6b4-4699-aab7-fc4b152fd96e-link\">139<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los cient\u00edficos admiten que, despu\u00e9s de realizar costosos y poco fiables experimentos en animales, a\u00fan hacen falta datos en humanos para determinar si un medicamento es apto para el \u00e1mbito cl\u00ednico. Los miembros del Programa Militar de Investigaci\u00f3n sobre el VIH de EE.&nbsp;UU. se\u00f1alaron que, \u201cal parecer, los ensayos cl\u00ednicos en humanos siguen siendo la \u00fanica forma fiable de determinar si una vacuna candidata contra el VIH tendr\u00e1 actividad o eficacia en humanos\u201d,<sup data-fn=\"ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b\" class=\"fn\"><a href=\"#ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b\" id=\"ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b-link\">140<\/a><\/sup> algo que ya en 2007 el editor asociado de <em>The BMJ <\/em>se\u00f1alaba: \u201c[c]uando se trata de probar vacunas contra el VIH, solo servir\u00e1 hacerlo en humanos\u201d.<sup data-fn=\"e950dc7d-ba59-4fe2-88c9-7b4c37297cfb\" class=\"fn\"><a href=\"#e950dc7d-ba59-4fe2-88c9-7b4c37297cfb\" id=\"e950dc7d-ba59-4fe2-88c9-7b4c37297cfb-link\">141<\/a><\/sup> Los investigadores reconocen que se necesitan modelos humanos <em>in vitro <\/em>capaces de replicar esta enfermedad humana y desarrollar tratamientos.<sup data-fn=\"de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52\" class=\"fn\"><a href=\"#de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52\" id=\"de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52-link\">142<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Entre las investigaciones recientes sin animales sobre el VIH se incluyen simulaciones interactivas de din\u00e1mica molecular para predecir c\u00f3mo se unir\u00e1n las mol\u00e9culas de f\u00e1rmacos a las prote\u00ednas del VIH,<sup data-fn=\"fea94a25-6186-4382-b9dc-6b93c88abc08\" class=\"fn\"><a href=\"#fea94a25-6186-4382-b9dc-6b93c88abc08\" id=\"fea94a25-6186-4382-b9dc-6b93c88abc08-link\">143<\/a><\/sup><sup data-fn=\"a532aecc-0fa7-4532-bca6-5398c1f8b21e\" class=\"fn\"><a href=\"#a532aecc-0fa7-4532-bca6-5398c1f8b21e\" id=\"a532aecc-0fa7-4532-bca6-5398c1f8b21e-link\">144<\/a><\/sup><sup data-fn=\"a30c0a94-ff81-4a61-a8de-26889bb06ad2\" class=\"fn\"><a href=\"#a30c0a94-ff81-4a61-a8de-26889bb06ad2\" id=\"a30c0a94-ff81-4a61-a8de-26889bb06ad2-link\">145<\/a><\/sup><sup data-fn=\"4bff9792-36f1-4f95-b5d2-5272f4353e62\" class=\"fn\"><a href=\"#4bff9792-36f1-4f95-b5d2-5272f4353e62\" id=\"4bff9792-36f1-4f95-b5d2-5272f4353e62-link\">146<\/a><\/sup> t\u00e9cnicas novedosas de diagn\u00f3stico por im\u00e1genes que revelan aspectos previamente desconocidos de la estructura del VIH y abren la posibilidad a nuevas terapias,<sup data-fn=\"3cf51db2-8e6a-4609-83db-3b54784af073\" class=\"fn\"><a href=\"#3cf51db2-8e6a-4609-83db-3b54784af073\" id=\"3cf51db2-8e6a-4609-83db-3b54784af073-link\">147<\/a><\/sup> y an\u00e1lisis bioinform\u00e1ticos de muestras de individuos con viremia y c\u00e9lulas infectadas<em>in vitro<\/em> de donantes sanos para generar un atlas de fenotipos celulares susceptibles al VIH.<sup data-fn=\"8d9b0e43-f194-42aa-85cb-88836a341fcf\" class=\"fn\"><a href=\"#8d9b0e43-f194-42aa-85cb-88836a341fcf\" id=\"8d9b0e43-f194-42aa-85cb-88836a341fcf-link\">148<\/a><\/sup> Adem\u00e1s, los an\u00e1lisis multi\u00f3micos unicelulares de muestras de donantes sanos y aquellos infectados con VIH han revelado diferencias en las poblaciones de c\u00e9lulas&nbsp;T, la expresi\u00f3n de prote\u00ednas y la expresi\u00f3n de glicanos que podr\u00edan ser determinantes en el desarrollo de nuevas estrategias terap\u00e9uticas dirigidas al sistema inmunitario.<sup data-fn=\"8624236b-267a-4a8e-80e5-273f333c9ad3\" class=\"fn\"><a href=\"#8624236b-267a-4a8e-80e5-273f333c9ad3\" id=\"8624236b-267a-4a8e-80e5-273f333c9ad3-link\">149<\/a><\/sup><sup data-fn=\"9e2d8fee-c83a-4b26-ab43-4a9675673e2b\" class=\"fn\"><a href=\"#9e2d8fee-c83a-4b26-ab43-4a9675673e2b\" id=\"9e2d8fee-c83a-4b26-ab43-4a9675673e2b-link\">150<\/a><\/sup><sup data-fn=\"95da9a6a-fe0c-4619-a12f-e5e223b7cca4\" class=\"fn\"><a href=\"#95da9a6a-fe0c-4619-a12f-e5e223b7cca4\" id=\"95da9a6a-fe0c-4619-a12f-e5e223b7cca4-link\">151<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Cient\u00edficos de todo el mundo han estado estudiando las c\u00e9lulas inmunitarias de individuos llamados \u201ccontroladores del VIH\u201d, que pueden infectarse con el VIH, pero pueden controlar la propagaci\u00f3n del virus sin requerir intervenci\u00f3n terap\u00e9utica.<sup data-fn=\"17bab855-46cc-4186-85db-e09a2ac641ef\" class=\"fn\"><a href=\"#17bab855-46cc-4186-85db-e09a2ac641ef\" id=\"17bab855-46cc-4186-85db-e09a2ac641ef-link\">152<\/a><\/sup><sup data-fn=\"162ead82-a6d8-45d6-ab0a-d8492e7eb17b\" class=\"fn\"><a href=\"#162ead82-a6d8-45d6-ab0a-d8492e7eb17b\" id=\"162ead82-a6d8-45d6-ab0a-d8492e7eb17b-link\">153<\/a><\/sup><sup data-fn=\"b3fa3635-ec79-4fe9-83d1-aec0141aeb80\" class=\"fn\"><a href=\"#b3fa3635-ec79-4fe9-83d1-aec0141aeb80\" id=\"b3fa3635-ec79-4fe9-83d1-aec0141aeb80-link\">154<\/a><\/sup><sup data-fn=\"4584cf68-2da0-4527-af9a-d61666458ccf\" class=\"fn\"><a href=\"#4584cf68-2da0-4527-af9a-d61666458ccf\" id=\"4584cf68-2da0-4527-af9a-d61666458ccf-link\">155<\/a><\/sup><sup data-fn=\"13a969ed-7287-4251-8d6a-f8c4fac36b15\" class=\"fn\"><a href=\"#13a969ed-7287-4251-8d6a-f8c4fac36b15\" id=\"13a969ed-7287-4251-8d6a-f8c4fac36b15-link\">156<\/a><\/sup> La esperanza es que las c\u00e9lulas inmunitarias de los controladores del VIH puedan transferirse a personas infectadas con VIH para ayudarlas a combatir el virus. Esta prometedora investigaci\u00f3n es espec\u00edfica para los humanos y requiere m\u00e9todos basados en la biolog\u00eda humana.<sup data-fn=\"ba0d86e2-86bd-43d0-8fa8-23f00d79134e\" class=\"fn\"><a href=\"#ba0d86e2-86bd-43d0-8fa8-23f00d79134e\" id=\"ba0d86e2-86bd-43d0-8fa8-23f00d79134e-link\">157<\/a><\/sup><\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Inmunolog\u00eda murina<\/strong><\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">Desde la aparici\u00f3n de las cepas endog\u00e1micas de rat\u00f3n en los a\u00f1os&nbsp;40 y el desarrollo de los transg\u00e9nicos en los&nbsp;80, se han usado ratones en cantidades alarmantes para la investigaci\u00f3n en inmunolog\u00eda. M\u00e1s all\u00e1 de las preocupaciones \u00e9ticas que suscitan dichas cantidades, la mayor\u00eda de los hallazgos generados en estos experimentos no se traslada a los humanos y no es replicable.<sup data-fn=\"e68a59c6-dff5-4701-8d42-94d0ca8d05bd\" class=\"fn\"><a href=\"#e68a59c6-dff5-4701-8d42-94d0ca8d05bd\" id=\"e68a59c6-dff5-4701-8d42-94d0ca8d05bd-link\">158<\/a><\/sup><sup data-fn=\"64baf987-b033-4d02-8057-d48a8eb446d0\" class=\"fn\"><a href=\"#64baf987-b033-4d02-8057-d48a8eb446d0\" id=\"64baf987-b033-4d02-8057-d48a8eb446d0-link\">159<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-6&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-6-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-6\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-6\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-6-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Las diferencias fisiol\u00f3gicas y celulares clave entre los tejidos humanos y los de los ratones revelan la inadecuaci\u00f3n de estos \u00faltimos como sustitutos experimentales humanos y deber\u00edan descalificar su uso en experimentos.<sup data-fn=\"acdc8a1f-7ba2-48e5-8092-6c7e288ab443\" class=\"fn\"><a href=\"#acdc8a1f-7ba2-48e5-8092-6c7e288ab443\" id=\"acdc8a1f-7ba2-48e5-8092-6c7e288ab443-link\">160<\/a><\/sup><sup data-fn=\"29d5a1f1-893f-4c4c-80bd-9aba0e053b89\" class=\"fn\"><a href=\"#29d5a1f1-893f-4c4c-80bd-9aba0e053b89\" id=\"29d5a1f1-893f-4c4c-80bd-9aba0e053b89-link\">161<\/a><\/sup> Por ejemplo, los ratones tienen c\u00e9lulas&nbsp;T epid\u00e9rmicas dendr\u00edticas \u00fanicas con funciones sensoriales inexistentes en humanos.<sup data-fn=\"9c3301e1-207e-4f94-8881-7bd7acfc9c4e\" class=\"fn\"><a href=\"#9c3301e1-207e-4f94-8881-7bd7acfc9c4e\" id=\"9c3301e1-207e-4f94-8881-7bd7acfc9c4e-link\">162<\/a><\/sup> Adem\u00e1s, la composici\u00f3n de las c\u00e9lulas inmunitarias en la sangre humana (55-70% de neutr\u00f3filos y 20-40% de linfocitos)<sup data-fn=\"8d031a6b-6b2b-4a42-afa6-7a58fdf651b0\" class=\"fn\"><a href=\"#8d031a6b-6b2b-4a42-afa6-7a58fdf651b0\" id=\"8d031a6b-6b2b-4a42-afa6-7a58fdf651b0-link\">163<\/a><\/sup> es diferente a la de los ratones usados en experimentos (20-30% de neutr\u00f3filos y 70-80% de linfocitos),<sup data-fn=\"afe94fd7-d6f8-4eca-961c-c223e14a0f92\" class=\"fn\"><a href=\"#afe94fd7-d6f8-4eca-961c-c223e14a0f92\" id=\"afe94fd7-d6f8-4eca-961c-c223e14a0f92-link\">164<\/a><\/sup> lo que afecta los mecanismos de defensa inmunitaria espec\u00edficos de cada especie.<sup data-fn=\"41356df1-cf70-4255-8db9-775bc9d5e936\" class=\"fn\"><a href=\"#41356df1-cf70-4255-8db9-775bc9d5e936\" id=\"41356df1-cf70-4255-8db9-775bc9d5e936-link\">165<\/a><\/sup><sup data-fn=\"f8f0a535-012a-4e7e-a266-1e483e7e1a05\" class=\"fn\"><a href=\"#f8f0a535-012a-4e7e-a266-1e483e7e1a05\" id=\"f8f0a535-012a-4e7e-a266-1e483e7e1a05-link\">166<\/a><\/sup> Estas diferencias tienen sentido dado que los humanos tenemos una esperanza de vida mayor<sup>8<\/sup> y \u201cno vivimos con la cabeza a media pulgada del suelo\u201d.<sup data-fn=\"7a6e3743-f714-4639-852f-c4c3a825e969\" class=\"fn\"><a href=\"#7a6e3743-f714-4639-852f-c4c3a825e969\" id=\"7a6e3743-f714-4639-852f-c4c3a825e969-link\">167<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los ratones tienen una composici\u00f3n gen\u00e9tica \u00fanica que contribuye a sus diferencias fenot\u00edpicas con los humanos, como la falta de expresi\u00f3n del ant\u00edgeno leucocitario humano de clase&nbsp;II en los linfocitos&nbsp;T y la distinta activaci\u00f3n de estas c\u00e9lulas durante la respuesta inmunitaria.<sup data-fn=\"9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e\" class=\"fn\"><a href=\"#9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e\" id=\"9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e-link\">168<\/a><\/sup> Estas especificidades inmunitarias, junto con las modificaciones epigen\u00e9ticas exclusivas de los ratones, dificultan la traslaci\u00f3n de datos y hacen que las comparaciones entre ratones y humanos sean poco realistas y arriesgadas.<sup data-fn=\"37da492c-af45-490c-9b6a-8543467fa9d1\" class=\"fn\"><a href=\"#37da492c-af45-490c-9b6a-8543467fa9d1\" id=\"37da492c-af45-490c-9b6a-8543467fa9d1-link\">169<\/a><\/sup><sup data-fn=\"72afd8b1-3651-4048-ae5d-46e24ea94224\" class=\"fn\"><a href=\"#72afd8b1-3651-4048-ae5d-46e24ea94224\" id=\"72afd8b1-3651-4048-ae5d-46e24ea94224-link\">170<\/a><\/sup> Por ejemplo, una deficiencia de mol\u00e9culas&nbsp;CD28 causa una disfunci\u00f3n inmunitaria grave en ratones, mientras que los humanos con esta deficiencia permanecen sanos.<sup data-fn=\"3f10983f-1bc6-4461-a24b-9fc31d40be7f\" class=\"fn\"><a href=\"#3f10983f-1bc6-4461-a24b-9fc31d40be7f\" id=\"3f10983f-1bc6-4461-a24b-9fc31d40be7f-link\">171<\/a><\/sup> Debido, en parte, a las diferencias en la expresi\u00f3n de&nbsp;CD28 entre especies, los ensayos cl\u00ednicos con fialuridina causaron insuficiencia de \u00f3rganos en humanos que tomaron solo 1\/500<sup>avo<\/sup> de la dosis que se hab\u00eda considerado segura en las pruebas precl\u00ednicas en animales.<sup data-fn=\"5ce45f89-9bd1-4c46-8635-d55770c8ff27\" class=\"fn\"><a href=\"#5ce45f89-9bd1-4c46-8635-d55770c8ff27\" id=\"5ce45f89-9bd1-4c46-8635-d55770c8ff27-link\">172<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El sistema inmunitario de los ratones tambi\u00e9n se ve alterado por las condiciones desoladas y controladas de confinamiento en los laboratorios, a las cuales se adapta su microbioma intestinal,<sup data-fn=\"62fbf8f3-2558-491e-8747-4d16ac1714a5\" class=\"fn\"><a href=\"#62fbf8f3-2558-491e-8747-4d16ac1714a5\" id=\"62fbf8f3-2558-491e-8747-4d16ac1714a5-link\">173<\/a><\/sup> que es distinto al de los ratones silvestres y a\u00fan m\u00e1s divergente del de los humanos.<sup data-fn=\"d1644946-e86d-4e6c-8efa-1e1482d09199\" class=\"fn\"><a href=\"#d1644946-e86d-4e6c-8efa-1e1482d09199\" id=\"d1644946-e86d-4e6c-8efa-1e1482d09199-link\">174<\/a><\/sup> Un estudio que analiz\u00f3 m\u00e1s de 1900&nbsp;genomas de rat\u00f3n encontr\u00f3 que los humanos y los ratones solo tienen en com\u00fan el 2% de las especies de bacterias intestinales.<sup data-fn=\"51ddb5d0-b90f-4a76-9321-f4ea28d14631\" class=\"fn\"><a href=\"#51ddb5d0-b90f-4a76-9321-f4ea28d14631\" id=\"51ddb5d0-b90f-4a76-9321-f4ea28d14631-link\">175<\/a><\/sup> El proceso de reproducci\u00f3n utilizado para generar cepas espec\u00edficas de ratones con variaciones gen\u00e9ticas tambi\u00e9n hace que sean m\u00e1s susceptibles a los pat\u00f3genos humanos que los humanos mismos, lo que a\u00f1ade otro punto de discrepancia.<sup data-fn=\"1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1\" class=\"fn\"><a href=\"#1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1\" id=\"1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1-link\">176<\/a><\/sup><sup data-fn=\"8d3ff126-87fa-4f93-9e8d-f9610aed9d9d\" class=\"fn\"><a href=\"#8d3ff126-87fa-4f93-9e8d-f9610aed9d9d\" id=\"8d3ff126-87fa-4f93-9e8d-f9610aed9d9d-link\">177<\/a><\/sup> Los ratones confinados en laboratorios no representan la variabilidad gen\u00e9tica que se encuentra entre los humanos o entre los individuos de su propia especie en condiciones silvestres.<sup data-fn=\"53fabe99-4180-4bd8-8807-a1bf300156ff\" class=\"fn\"><a href=\"#53fabe99-4180-4bd8-8807-a1bf300156ff\" id=\"53fabe99-4180-4bd8-8807-a1bf300156ff-link\">178<\/a><\/sup><sup data-fn=\"348f49f5-b9c6-4923-ab8d-5f5b7841f538\" class=\"fn\"><a href=\"#348f49f5-b9c6-4923-ab8d-5f5b7841f538\" id=\"348f49f5-b9c6-4923-ab8d-5f5b7841f538-link\">179<\/a><\/sup> A pesar de estas numerosas y evidentes desventajas, los ratones siguen siendo usados para la investigaci\u00f3n en inmunolog\u00eda.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los m\u00e9todos basados en la biolog\u00eda humana para la investigaci\u00f3n en esta \u00e1rea est\u00e1n avanzando a un ritmo lento, pero con resultados prometedores. Las grandes bases de datos y la biolog\u00eda computacional (prote\u00f3mica, metabol\u00f3mica y datos cl\u00ednicos), integradas con novedosos modelos tridimensionales, pueden superar la brecha existente en la ciencia traslacional y aprovechar los enfoques personalizados.<sup data-fn=\"51876190-2d5e-4c7d-acbe-3769bf0fe093\" class=\"fn\"><a href=\"#51876190-2d5e-4c7d-acbe-3769bf0fe093\" id=\"51876190-2d5e-4c7d-acbe-3769bf0fe093-link\">180<\/a><\/sup><sup data-fn=\"a89d3e28-3bfb-4c44-a100-f2a2e1677392\" class=\"fn\"><a href=\"#a89d3e28-3bfb-4c44-a100-f2a2e1677392\" id=\"a89d3e28-3bfb-4c44-a100-f2a2e1677392-link\">181<\/a><\/sup><sup data-fn=\"b98a3765-1a86-4ed5-b8fe-7e37032bdf87\" class=\"fn\"><a href=\"#b98a3765-1a86-4ed5-b8fe-7e37032bdf87\" id=\"b98a3765-1a86-4ed5-b8fe-7e37032bdf87-link\">182<\/a><\/sup><sup data-fn=\"15d069ae-4d90-4281-9805-7f389cfff709\" class=\"fn\"><a href=\"#15d069ae-4d90-4281-9805-7f389cfff709\" id=\"15d069ae-4d90-4281-9805-7f389cfff709-link\">183<\/a><\/sup> Se est\u00e1n usando muestras humanas, por ejemplo, de m\u00e9dula \u00f3sea,<sup data-fn=\"5694b598-9785-41ba-a37f-8db92f3ff39f\" class=\"fn\"><a href=\"#5694b598-9785-41ba-a37f-8db92f3ff39f\" id=\"5694b598-9785-41ba-a37f-8db92f3ff39f-link\">184<\/a><\/sup> ganglios linf\u00e1ticos,<sup data-fn=\"e0d7d79e-4b97-455e-8e44-0d3de37c47bc\" class=\"fn\"><a href=\"#e0d7d79e-4b97-455e-8e44-0d3de37c47bc\" id=\"e0d7d79e-4b97-455e-8e44-0d3de37c47bc-link\">185<\/a><\/sup> am\u00edgdalas,<sup data-fn=\"c3d97ba9-469d-4167-b365-67ca8fb1c792\" class=\"fn\"><a href=\"#c3d97ba9-469d-4167-b365-67ca8fb1c792\" id=\"c3d97ba9-469d-4167-b365-67ca8fb1c792-link\">186<\/a><\/sup> e h\u00edgado,<sup data-fn=\"e2dc6cd4-424e-497e-b88b-a250becceaac\" class=\"fn\"><a href=\"#e2dc6cd4-424e-497e-b88b-a250becceaac\" id=\"e2dc6cd4-424e-497e-b88b-a250becceaac-link\">187<\/a><\/sup> para generar organoides derivados de pacientes que permitan explorar los mecanismos del sistema inmunitario y evaluar hip\u00f3tesis en diferentes contextos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">De acuerdo con un an\u00e1lisis de los modelos inmunocompetentes de enfermedades cut\u00e1neas humanas, el fracaso de los experimentos en animales para traducirse en tratamientos eficaces para enfermedades como la fibrosis, la psoriasis, el c\u00e1ncer, la alergia de contacto y las enfermedades autoinmunes se debe, en parte, a la naturaleza inmunitaria de estas afecciones. Los autores de este an\u00e1lisis afirman que los cocultivos, los sistemas de organotipos tridimensionales y la tecnolog\u00eda de \u00f3rganos en chip \u201cpermitir\u00e1n crear modelos humanos complejos y bien controlados que proporcionar\u00e1n datos minuciosos y confiables y constituir\u00e1n una soluci\u00f3n adecuada para el proceso de desarrollo de medicamentos\u201d.<sup data-fn=\"2a37d948-a323-4dc5-b596-86514b8f1a23\" class=\"fn\"><a href=\"#2a37d948-a323-4dc5-b596-86514b8f1a23\" id=\"2a37d948-a323-4dc5-b596-86514b8f1a23-link\">188<\/a><\/sup><\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h3 class=\"wp-block-heading\"><strong>Septicemia&nbsp;<\/strong>&nbsp;<\/h3>\n\n\n\n<p class=\"wp-block-paragraph\">La septicemia es una enfermedad potencialmente mortal causada por la respuesta del organismo a una infecci\u00f3n. Los datos de incidencia mundial m\u00e1s recientes muestran que la septicemia afect\u00f3 aproximadamente a 48,9&nbsp;millones de personas en todo el mundo y provoc\u00f3 la muerte de 11&nbsp;millones de ellas en&nbsp;2017.<sup data-fn=\"c5328c41-0091-4932-acf1-c8f07f2de141\" class=\"fn\"><a href=\"#c5328c41-0091-4932-acf1-c8f07f2de141\" id=\"c5328c41-0091-4932-acf1-c8f07f2de141-link\">189<\/a><\/sup> Es una de las principales causas de muerte en los hospitales estadounidenses y es una de las afecciones m\u00e1s costosas de tratar.<sup data-fn=\"ae392600-303c-49f5-8594-71f8a226f3fb\" class=\"fn\"><a href=\"#ae392600-303c-49f5-8594-71f8a226f3fb\" id=\"ae392600-303c-49f5-8594-71f8a226f3fb-link\">190<\/a><\/sup><sup data-fn=\"84c2ad96-b605-47c4-a395-b818d8ca66a8\" class=\"fn\"><a href=\"#84c2ad96-b605-47c4-a395-b818d8ca66a8\" id=\"84c2ad96-b605-47c4-a395-b818d8ca66a8-link\">191<\/a><\/sup> En Am\u00e9rica Latina, la septicemia es una de las principales causas prevenibles de muerte.<sup data-fn=\"5e2a6c80-3559-4ff8-8bbf-fe90dc470af5\" class=\"fn\"><a href=\"#5e2a6c80-3559-4ff8-8bbf-fe90dc470af5\" id=\"5e2a6c80-3559-4ff8-8bbf-fe90dc470af5-link\">192<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-7&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-7-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-7\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-7\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-7-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Los ratones son los animales m\u00e1s usados en la investigaci\u00f3n de la septicemia, no porque sean buenos modelos de esta enfermedad en los humanos, sino porque abundan, son baratos, peque\u00f1os y d\u00f3ciles.<sup data-fn=\"4ab6ecbd-f4d7-4917-857e-81da0f368917\" class=\"fn\"><a href=\"#4ab6ecbd-f4d7-4917-857e-81da0f368917\" id=\"4ab6ecbd-f4d7-4917-857e-81da0f368917-link\">193<\/a><\/sup> La dificultad para extrapolar de forma confiable los resultados de los ratones a los humanos es considerada una de las principales causas del fracaso de pr\u00e1cticamente todos los ensayos de tratamientos contra la septicemia en humanos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En&nbsp;2013, la revista <em>Proceedings of the National Academy of Sciences of the United States of America <\/em>public\u00f3 un importante estudio que tom\u00f3 10&nbsp;a\u00f1os en desarrollarse y cont\u00f3 con la colaboraci\u00f3n de 39&nbsp;investigadores de varias instituciones, incluidas la Universidad de Stanford y la Escuela de Medicina de Harvard. El estudio compar\u00f3 los datos de cientos de pacientes humanos con los resultados de experimentos en animales y demostr\u00f3 que las respuestas gen\u00e9ticas de humanos y ratones a enfermedades inflamatorias graves como la septicemia, las quemaduras y los traumatismos son diferentes.<sup data-fn=\"71a2860c-9e9c-47eb-a34a-ea38fdbed8d9\" class=\"fn\"><a href=\"#71a2860c-9e9c-47eb-a34a-ea38fdbed8d9\" id=\"71a2860c-9e9c-47eb-a34a-ea38fdbed8d9-link\">194<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En un art\u00edculo sobre estos resultados, Francis Collins, exdirector de los NIH, lament\u00f3 el tiempo y los recursos dedicados al desarrollo de 150&nbsp;f\u00e1rmacos que trataron con \u00e9xito la septicemia en ratones, pero fracasaron en los ensayos cl\u00ednicos en humanos, y calific\u00f3 este desastre como \u201cuna p\u00e9rdida desgarradora de d\u00e9cadas de investigaci\u00f3n y miles de millones de d\u00f3lares\u201d.<sup data-fn=\"fa11862a-51c6-4904-9fee-bf1e3a30dd10\" class=\"fn\"><a href=\"#fa11862a-51c6-4904-9fee-bf1e3a30dd10\" id=\"fa11862a-51c6-4904-9fee-bf1e3a30dd10-link\">195<\/a><\/sup> El art\u00edculo se\u00f1ala que, en los humanos, muchos de los mismos genes participan en el proceso de recuperaci\u00f3n ante la septicemia, las quemaduras y los traumatismos, pero que era \u201ccasi al azar\u201d qu\u00e9 genes murinos podr\u00edan coincidir con estos perfiles. Collins lo explica as\u00ed:<\/p>\n\n\n\n<blockquote class=\"wp-block-quote simple is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Sin embargo, parece que los ratones usan diferentes conjuntos de genes para enfrentar los traumatismos, las quemaduras y las toxinas bacterianas. Cuando los autores compararon la actividad de los genes humanos relacionados con la septicemia, los traumatismos y las quemaduras con la de los genes equivalentes en ratones, se observ\u00f3 muy poca coincidencia. No es de extra\u00f1ar que los medicamentos dise\u00f1ados para los ratones fracasaran en humanos: en efecto, \u00a1trataban enfermedades diferentes!<sup data-fn=\"5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb\" class=\"fn\"><a href=\"#5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb\" id=\"5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb-link\">196<\/a><\/sup><\/p>\n<\/blockquote>\n\n\n\n<p class=\"wp-block-paragraph\">Incluso antes de este emblem\u00e1tico estudio, las cr\u00edticas a los modelos murinos se hab\u00edan documentado en m\u00e1s de 20 art\u00edculos cient\u00edficos. Los ratones usados en los experimentos de septicemia son j\u00f3venes, endog\u00e1micos, de la misma edad y peso y viven en entornos sin g\u00e9rmenes. Por el contrario, son principalmente los lactantes y ancianos, que viven en una variedad de entornos no esterilizados e impredecibles, quienes padecen septicemia.<sup data-fn=\"672a37b7-a8d4-4e08-b77c-255ce0951cce\" class=\"fn\"><a href=\"#672a37b7-a8d4-4e08-b77c-255ce0951cce\" id=\"672a37b7-a8d4-4e08-b77c-255ce0951cce-link\">197<\/a><\/sup><sup data-fn=\"144dc1e0-30e2-42ff-ba10-3d82d0598aa4\" class=\"fn\"><a href=\"#144dc1e0-30e2-42ff-ba10-3d82d0598aa4\" id=\"144dc1e0-30e2-42ff-ba10-3d82d0598aa4-link\">198<\/a><\/sup> Cuando los experimentadores inducen la enfermedad en ratones, la aparici\u00f3n de los s\u00edntomas se produce en cuesti\u00f3n de horas o d\u00edas, mientras que en los seres humanos los s\u00edntomas aparecen en cuesti\u00f3n de d\u00edas o semanas. A los ratones no suele proporcion\u00e1rseles el tratamiento de apoyo que reciben los pacientes humanos, como fluidos, vasopresores y respiradores.<sup data-fn=\"7a2f7943-7793-41b5-81c3-6720fe4b887e\" class=\"fn\"><a href=\"#7a2f7943-7793-41b5-81c3-6720fe4b887e\" id=\"7a2f7943-7793-41b5-81c3-6720fe4b887e-link\">199<\/a><\/sup> A diferencia de los humanos, a los ratones rara vez se les administran analg\u00e9sicos,<sup data-fn=\"fc538274-1545-45d8-8ed6-b2c2475b7c93\" class=\"fn\"><a href=\"#fc538274-1545-45d8-8ed6-b2c2475b7c93\" id=\"fc538274-1545-45d8-8ed6-b2c2475b7c93-link\">200<\/a><\/sup> otra diferencia que socava datos de valor ya cuestionable, pues el dolor afecta otros procesos fisiol\u00f3gicos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El m\u00e9todo de referencia usado por los experimentadores para inducir la septicemia en ratones es abrir el abdomen del animal, perforar sus intestinos con una aguja y cerrar la incisi\u00f3n, lo que se conoce como ligadura cecal y punci\u00f3n. Sin embargo, las respuestas de los ratones a este procedimiento var\u00edan en funci\u00f3n de la edad, el sexo, la cepa, el tama\u00f1o de la incisi\u00f3n y la aguja, as\u00ed como del lugar donde se realiza el experimento, lo que hace que los resultados sean incomparables entre laboratorios.<sup data-fn=\"ce8396bc-62be-40fe-8690-93373242d41f\" class=\"fn\"><a href=\"#ce8396bc-62be-40fe-8690-93373242d41f\" id=\"ce8396bc-62be-40fe-8690-93373242d41f-link\">201<\/a><\/sup> Adem\u00e1s, el procedimiento causa un absceso, cuyos efectos pueden enmascarar la septicemia o ser enmascarados por los efectos de esta enfermedad.<sup data-fn=\"c343fa9a-015b-49ac-813f-a808eb1ce42a\" class=\"fn\"><a href=\"#c343fa9a-015b-49ac-813f-a808eb1ce42a\" id=\"c343fa9a-015b-49ac-813f-a808eb1ce42a-link\">202<\/a><\/sup> Esto significa que una intervenci\u00f3n que parece tratar la septicemia puede ser beneficiosa solo por sus efectos sobre el absceso.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Tambi\u00e9n se han usado ratas, perros, gatos, cerdos, ovejas, conejos, caballos y primates no humanos, incluidos babuinos y macacos, en los experimentos de septicemia. Ninguna de estas especies logra replicar todas las caracter\u00edsticas fisiol\u00f3gicas de la enfermedad en humanos. Las respuestas de la presi\u00f3n arterial pulmonar en cerdos y ovejas difieren de las de los humanos, por lo que este aspecto de la septicemia no puede compararse entre estas especies.<sup data-fn=\"fd240d66-c2c2-4fb0-a50b-802b9bea1af6\" class=\"fn\"><a href=\"#fd240d66-c2c2-4fb0-a50b-802b9bea1af6\" id=\"fd240d66-c2c2-4fb0-a50b-802b9bea1af6-link\">203<\/a><\/sup> Adem\u00e1s, los babuinos y los ratones son menos sensibles a una bacteria usada habitualmente para inducir la septicemia en entornos experimentales.<sup data-fn=\"2aff7613-3913-4cef-9984-f332596cae38\" class=\"fn\"><a href=\"#2aff7613-3913-4cef-9984-f332596cae38\" id=\"2aff7613-3913-4cef-9984-f332596cae38-link\">204<\/a><\/sup> Un estudio reciente encontr\u00f3 que los macacos Rhesus y los babuinos difieren notablemente de los humanos en su respuesta inmunitaria innata a los pat\u00f3genos.<sup data-fn=\"84ac3132-fe9e-46d3-b53c-e564dd62fe49\" class=\"fn\"><a href=\"#84ac3132-fe9e-46d3-b53c-e564dd62fe49\" id=\"84ac3132-fe9e-46d3-b53c-e564dd62fe49-link\">205<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Un informe publicado en 2019 por el grupo de trabajo sobre septicemia del Consejo Consultivo Nacional de Ciencias M\u00e9dicas Generales de EE. UU. (NAGMSC) se\u00f1ala que \u201c[a] pesar de d\u00e9cadas de estudio intensivo de los mecanismos subyacentes de esta afecci\u00f3n, no ha surgido un f\u00e1rmaco nuevo ni una tecnolog\u00eda de diagn\u00f3stico significativamente nueva. Docenas de ensayos prospectivos de agentes o estrategias dirigidos a la base inflamatoria de la septicemia han fracasado\u201d.<sup>16<\/sup> El informe recomend\u00f3 que el Instituto Nacional de Ciencias M\u00e9dicas Generales de EE. UU. (NIGMS), que forma parte de los NIH, \u201creequilibrara\u201d su portafolio de financiaci\u00f3n para la investigaci\u00f3n en septicemia para \u201cincluir un enfoque m\u00e1s cl\u00ednico\u201d.<sup data-fn=\"cba825d9-a6b9-4d8d-ae79-4aa3a4572f23\" class=\"fn\"><a href=\"#cba825d9-a6b9-4d8d-ae79-4aa3a4572f23\" id=\"cba825d9-a6b9-4d8d-ae79-4aa3a4572f23-link\">206<\/a><\/sup> Tras el informe, el NIGMS indic\u00f3 su intenci\u00f3n de apoyar investigaciones sobre sepsis que \u201cusen enfoques nuevos y emergentes, como la inform\u00e1tica cl\u00ednica, los an\u00e1lisis computarizados, el modelado predictivo en pacientes y nuevas aplicaciones de t\u00e9cnicas bioanal\u00edticas de alta resoluci\u00f3n y gran capacidad a materiales obtenidos de pacientes s\u00e9pticos\u201d, y se\u00f1al\u00f3 que el apoyo a \u201cestudios que usen modelos de roedores para la septicemia\u201d es una \u201cprioridad baja\u201d.<sup data-fn=\"306e53ee-17f2-4d95-8e3e-5edd158d9d9c\" class=\"fn\"><a href=\"#306e53ee-17f2-4d95-8e3e-5edd158d9d9c\" id=\"306e53ee-17f2-4d95-8e3e-5edd158d9d9c-link\">207<\/a><\/sup> En la Conferencia Anual de la Sociedad de Shock de&nbsp;2024, el NIGMS anunci\u00f3 que \u201cno estaba dispuesto\u201d a financiar proyectos en los que se propusiera el uso de modelos murinos de la septicemia humana y recomend\u00f3 que, en adelante, se empleen m\u00e9todos de investigaci\u00f3n sin animales.<sup data-fn=\"2ee291f7-7a8a-477d-b14a-24143e4ea365\" class=\"fn\"><a href=\"#2ee291f7-7a8a-477d-b14a-24143e4ea365\" id=\"2ee291f7-7a8a-477d-b14a-24143e4ea365-link\">208<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En&nbsp;2015, un grupo de trabajo de expertos formado por veterinarios, zoot\u00e9cnicos y cient\u00edficos public\u00f3 un informe sobre la aplicaci\u00f3n de las 3R (reemplazo, reducci\u00f3n y refinamiento del uso de animales) en la investigaci\u00f3n sobre septicemia.<sup data-fn=\"0a687cc1-d57c-4d56-9940-a307ce2b6be5\" class=\"fn\"><a href=\"#0a687cc1-d57c-4d56-9940-a307ce2b6be5\" id=\"0a687cc1-d57c-4d56-9940-a307ce2b6be5-link\">209<\/a><\/sup> El grupo identific\u00f3 varios m\u00e9todos que podr\u00edan usarse en lugar de los experimentos en animales, como los modelos de cultivo celular <em>in vitro <\/em>para estudiar los mecanismos de la septicemia, la biolog\u00eda de sistemas y computacional para exponer los procesos inflamatorios que ocurren en esta enfermedad, los modelos de cultivo celular tridimensionales para explorar la progresi\u00f3n de la enfermedad humana y los mecanismos infecciosos, los modelos humanos sint\u00e9ticos para recrear tipos de c\u00e9lulas y tejidos relacionados con la septicemia, y la informaci\u00f3n gen\u00f3mica humana para comprender c\u00f3mo esta condici\u00f3n afecta a los individuos de manera diferente y qu\u00e9 grupos pueden tener mayor riesgo. De acuerdo con los autores del reporte, la informaci\u00f3n gen\u00f3mica \u201ccomplementar\u00e1 o incluso sustituir\u00e1 la necesidad de modelos murinos en el descubrimiento de enfermedades y el desarrollo de medicamentos\u201d.<sup data-fn=\"4e40a7d9-f652-4dc0-ad61-7351938898d9\" class=\"fn\"><a href=\"#4e40a7d9-f652-4dc0-ad61-7351938898d9\" id=\"4e40a7d9-f652-4dc0-ad61-7351938898d9-link\">210<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los siguientes son ejemplos de avances recientes en la investigaci\u00f3n en septicemia relevante para los humanos:&nbsp;<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Cient\u00edficos japoneses usaron organoides hep\u00e1ticos derivados de hiPSC para modelar los eventos patol\u00f3gicos de la disfunci\u00f3n hep\u00e1tica asociada a la septicemia y la recuperaci\u00f3n tras la infecci\u00f3n.<sup data-fn=\"74c35407-82d3-429a-9170-646e670bc3ba\" class=\"fn\"><a href=\"#74c35407-82d3-429a-9170-646e670bc3ba\" id=\"74c35407-82d3-429a-9170-646e670bc3ba-link\">211<\/a><\/sup><\/li>\n\n\n\n<li>Un equipo de ingenieros, m\u00e9dicos e investigadores de la Universidad de Temple identific\u00f3 una asociaci\u00f3n entre los tipos de neutr\u00f3filos y la gravedad de la septicemia en un modelo de pulm\u00f3n humano en chip, que puede utilizarse para determinar la intervenci\u00f3n terap\u00e9utica adecuada en funci\u00f3n de la gravedad de la enfermedad.<sup data-fn=\"0502e20c-9f16-4f09-baa2-c922aa359819\" class=\"fn\"><a href=\"#0502e20c-9f16-4f09-baa2-c922aa359819\" id=\"0502e20c-9f16-4f09-baa2-c922aa359819-link\">212<\/a><\/sup><\/li>\n\n\n\n<li>Investigadores y m\u00e9dicos en China crearon un dispositivo microflu\u00eddico de seis unidades que analiza exhaustivamente la actividad de los gl\u00f3bulos blancos de pacientes con septicemia para determinar la progresi\u00f3n y la gravedad de la enfermedad.<sup data-fn=\"a09f042c-a14e-4a37-af85-c44bd8698691\" class=\"fn\"><a href=\"#a09f042c-a14e-4a37-af85-c44bd8698691\" id=\"a09f042c-a14e-4a37-af85-c44bd8698691-link\">213<\/a><\/sup><\/li>\n\n\n\n<li>Cient\u00edficos y m\u00e9dicos del Hospital General de Massachusetts dise\u00f1aron un dispositivo microflu\u00eddico para detectar con precisi\u00f3n, a trav\u00e9s de una gota de sangre, un biomarcador de la fisiopatolog\u00eda de la septicemia y mejorar el seguimiento de la enfermedad.<sup data-fn=\"6be35304-9b3f-460e-8555-01e234414b60\" class=\"fn\"><a href=\"#6be35304-9b3f-460e-8555-01e234414b60\" id=\"6be35304-9b3f-460e-8555-01e234414b60-link\">214<\/a><\/sup><\/li>\n\n\n\n<li>Dado que la detecci\u00f3n precoz de la septicemia es probablemente el factor m\u00e1s importante para reducir la mortalidad por esta afecci\u00f3n,<sup data-fn=\"b2091492-ceda-4d8e-a415-5fd9bf06d708\" class=\"fn\"><a href=\"#b2091492-ceda-4d8e-a415-5fd9bf06d708\" id=\"b2091492-ceda-4d8e-a415-5fd9bf06d708-link\">215<\/a><\/sup> investigadores de todo el mundo est\u00e1n explorando varias herramientas de inteligencia artificial y aprendizaje autom\u00e1tico para apoyar la predicci\u00f3n y el diagn\u00f3stico tempranos de esta enfermedad.<sup data-fn=\"13bd5a62-32f4-4841-bcda-510cc4c7b9e2\" class=\"fn\"><a href=\"#13bd5a62-32f4-4841-bcda-510cc4c7b9e2\" id=\"13bd5a62-32f4-4841-bcda-510cc4c7b9e2-link\">216<\/a><\/sup><sup data-fn=\"6e0849ea-9eed-40fa-acb8-f9c6aa853a74\" class=\"fn\"><a href=\"#6e0849ea-9eed-40fa-acb8-f9c6aa853a74\" id=\"6e0849ea-9eed-40fa-acb8-f9c6aa853a74-link\">217<\/a><\/sup><sup data-fn=\"675d4f40-91d5-4534-88b2-1c69d5ebe7c6\" class=\"fn\"><a href=\"#675d4f40-91d5-4534-88b2-1c69d5ebe7c6\" id=\"675d4f40-91d5-4534-88b2-1c69d5ebe7c6-link\">218<\/a><\/sup><sup data-fn=\"e2ae2e42-2c61-421f-b49e-4863b4dda374\" class=\"fn\"><a href=\"#e2ae2e42-2c61-421f-b49e-4863b4dda374\" id=\"e2ae2e42-2c61-421f-b49e-4863b4dda374-link\">219<\/a><\/sup><sup data-fn=\"f601e191-3068-4a7d-a051-45baad3853f3\" class=\"fn\"><a href=\"#f601e191-3068-4a7d-a051-45baad3853f3\" id=\"f601e191-3068-4a7d-a051-45baad3853f3-link\">220<\/a><\/sup><sup data-fn=\"3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef\" class=\"fn\"><a href=\"#3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef\" id=\"3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef-link\">221<\/a><\/sup><sup data-fn=\"3ebe7abf-ede3-473e-89d1-4b489da97faa\" class=\"fn\"><a href=\"#3ebe7abf-ede3-473e-89d1-4b489da97faa\" id=\"3ebe7abf-ede3-473e-89d1-4b489da97faa-link\">222<\/a><\/sup><sup data-fn=\"97719922-c79b-4289-8c50-2ba0350fd80f\" class=\"fn\"><a href=\"#97719922-c79b-4289-8c50-2ba0350fd80f\" id=\"97719922-c79b-4289-8c50-2ba0350fd80f-link\">223<\/a><\/sup><sup data-fn=\"3e860dc8-2651-4f71-bce7-062a90e5f08c\" class=\"fn\"><a href=\"#3e860dc8-2651-4f71-bce7-062a90e5f08c\" id=\"3e860dc8-2651-4f71-bce7-062a90e5f08c-link\">224<\/a><\/sup><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Trastornos gastrointestinales<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Solo en EE. UU., los trastornos gastrointestinales (GI) resultaron en 14,5 millones de visitas a&nbsp; salas de emergencia en 2021 y causaron un gasto de casi 112 mil millones de d\u00f3lares en servicios m\u00e9dicos.<sup data-fn=\"59a178f8-8781-4a3e-b606-99413f1d07e4\" class=\"fn\"><a href=\"#59a178f8-8781-4a3e-b606-99413f1d07e4\" id=\"59a178f8-8781-4a3e-b606-99413f1d07e4-link\">225<\/a><\/sup> La carga de estas enfermedades es asombrosa, ya que contribuyen significativamente a la morbilidad, la mortalidad y los costos de atenci\u00f3n m\u00e9dica, y se espera que la prevalencia aumente.<sup data-fn=\"ad910464-1694-4ecd-966c-bf099cde1281\" class=\"fn\"><a href=\"#ad910464-1694-4ecd-966c-bf099cde1281\" id=\"ad910464-1694-4ecd-966c-bf099cde1281-link\">226<\/a><\/sup> Debido a esto, se han dedicado enormes esfuerzos al desarrollo de medicamentos para los trastornos GI, pero el \u00e9xito ha sido escaso para muchas afecciones.<sup data-fn=\"e075402e-a5aa-407f-8089-f2b5fa1c1117\" class=\"fn\"><a href=\"#e075402e-a5aa-407f-8089-f2b5fa1c1117\" id=\"e075402e-a5aa-407f-8089-f2b5fa1c1117-link\">227<\/a><\/sup> Existen tratamientos para las enfermedades GI, pero estos a menudo tienen importantes desventajas, en parte porque mucho de lo que se conoce sobre los mecanismos de estas enfermedades se ha derivado de modelos animales.<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-8&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-8-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-8\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-8\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-8-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Las diferencias cruciales de los animales no humanos los hacen modelos inadecuados para estudiar las enfermedades GI humanas. Las dos especies m\u00e1s usadas en estos experimentos son las ratas y los cerdos.<sup data-fn=\"9c724b9f-77e8-409a-b187-45541bbf2e9f\" class=\"fn\"><a href=\"#9c724b9f-77e8-409a-b187-45541bbf2e9f\" id=\"9c724b9f-77e8-409a-b187-45541bbf2e9f-link\">228<\/a><\/sup> Ambas tienen tractos gastrointestinales anat\u00f3micamente distintos al de los humanos. Por ejemplo, el yeyuno constituye el 90% del intestino delgado de la rata, pero solo el 38% del intestino delgado humano.<sup data-fn=\"62db0c02-6bf4-4d4b-926f-9dc9352759c7\" class=\"fn\"><a href=\"#62db0c02-6bf4-4d4b-926f-9dc9352759c7\" id=\"62db0c02-6bf4-4d4b-926f-9dc9352759c7-link\">229<\/a><\/sup> Las ratas carecen de colon sigmoide, ves\u00edcula biliar y conductos c\u00edsticos, mientras que el colon de los cerdos es m\u00e1s grande que el de los humanos.<sup data-fn=\"1151c5a8-61f7-48b9-a909-7a55c593ad07\" class=\"fn\"><a href=\"#1151c5a8-61f7-48b9-a909-7a55c593ad07\" id=\"1151c5a8-61f7-48b9-a909-7a55c593ad07-link\">230<\/a><\/sup><sup data-fn=\"377f6f1c-6e54-423d-89e1-e284c6a54e5b\" class=\"fn\"><a href=\"#377f6f1c-6e54-423d-89e1-e284c6a54e5b\" id=\"377f6f1c-6e54-423d-89e1-e284c6a54e5b-link\">231<\/a><\/sup><sup data-fn=\"a81ace1f-686c-4d29-b812-d6189aa29796\" class=\"fn\"><a href=\"#a81ace1f-686c-4d29-b812-d6189aa29796\" id=\"a81ace1f-686c-4d29-b812-d6189aa29796-link\">232<\/a><\/sup> Adem\u00e1s de las diferencias anat\u00f3micas, existen disparidades conductuales: las ratas suelen consumir porciones peque\u00f1as con frecuencia, mientras que los humanos comen porciones m\u00e1s abundantes con menos frecuencia.<sup data-fn=\"8f9ff7f5-d1ce-4590-bdff-06d8d8302610\" class=\"fn\"><a href=\"#8f9ff7f5-d1ce-4590-bdff-06d8d8302610\" id=\"8f9ff7f5-d1ce-4590-bdff-06d8d8302610-link\">233<\/a><\/sup> Los cerdos, por su parte, consumen m\u00e1s comida en relaci\u00f3n con su peso corporal que los humanos.<sup data-fn=\"171f7ced-d186-43aa-b299-fe4c470f9f55\" class=\"fn\"><a href=\"#171f7ced-d186-43aa-b299-fe4c470f9f55\" id=\"171f7ced-d186-43aa-b299-fe4c470f9f55-link\">234<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las condiciones de laboratorio pueden influir a\u00fan m\u00e1s en el estudio de las enfermedades GI. Un estudio publicado en 2024 encontr\u00f3 que la temperatura a la que se confinan los ratones en los laboratorios puede afectar significativamente su motilidad intestinal y microbiota.<sup data-fn=\"0314f180-05d5-4f7d-8122-53497f394f6f\" class=\"fn\"><a href=\"#0314f180-05d5-4f7d-8122-53497f394f6f\" id=\"0314f180-05d5-4f7d-8122-53497f394f6f-link\">235<\/a><\/sup> La procedencia de los animales tambi\u00e9n puede causar variaciones en los microbiomas intestinales debido a distintos factores ambientales.<sup data-fn=\"08d2402a-efc6-4987-9d14-ced355060954\" class=\"fn\"><a href=\"#08d2402a-efc6-4987-9d14-ced355060954\" id=\"08d2402a-efc6-4987-9d14-ced355060954-link\">236<\/a><\/sup> Las diferencias en los microbiomas propios de cada especie tambi\u00e9n influyen: los cerdos tienen poco <em>Bifidobacterium<\/em>, una especie importante en el intestino humano.<sup data-fn=\"5bdedddb-9ab0-4ed4-b7ab-e75196205472\" class=\"fn\"><a href=\"#5bdedddb-9ab0-4ed4-b7ab-e75196205472\" id=\"5bdedddb-9ab0-4ed4-b7ab-e75196205472-link\">237<\/a><\/sup> Dado el papel de la microbiota intestinal en la respuesta inmunitaria, estas diferencias pueden afectar significativamente los resultados de los experimentos.<sup data-fn=\"96f15b44-e375-4442-b63a-c86c95a3584a\" class=\"fn\"><a href=\"#96f15b44-e375-4442-b63a-c86c95a3584a\" id=\"96f15b44-e375-4442-b63a-c86c95a3584a-link\">238<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los modelos animales de afecciones GI humanas son criticados por su escaso valor predictivo sobre los resultados de la enfermedad y la eficacia cl\u00ednica en humanos, especialmente en el caso de afecciones como el s\u00edndrome del intestino irritable (SII) y las enfermedades del intestino irritable (EII), cuya patog\u00e9nesis sigue sin comprenderse del todo.<sup data-fn=\"c1564d1c-e472-4030-8d4e-416f469d4f96\" class=\"fn\"><a href=\"#c1564d1c-e472-4030-8d4e-416f469d4f96\" id=\"c1564d1c-e472-4030-8d4e-416f469d4f96-link\">239<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El SII es un trastorno cr\u00f3nico que afecta el tracto gastrointestinal inferior. La prevalencia de esta enfermedad en Am\u00e9rica Latina es del 15,4% y sus s\u00edntomas incluyen dolor y distensi\u00f3n abdominal, evacuaci\u00f3n incompleta y estre\u00f1imiento, entre otros.<sup data-fn=\"087348ee-2cae-4458-8053-02a0561223a4\" class=\"fn\"><a href=\"#087348ee-2cae-4458-8053-02a0561223a4\" id=\"087348ee-2cae-4458-8053-02a0561223a4-link\">240<\/a><\/sup> Aunque la causa exacta del SII sigue sin estar clara, se cree que implica una combinaci\u00f3n de factores f\u00edsicos y psicol\u00f3gicos, especialmente estr\u00e9s y ansiedad,<sup data-fn=\"8564b728-bf71-4475-aae9-cb890d58ca7b\" class=\"fn\"><a href=\"#8564b728-bf71-4475-aae9-cb890d58ca7b\" id=\"8564b728-bf71-4475-aae9-cb890d58ca7b-link\">241<\/a><\/sup> que no pueden reproducirse fielmente en modelos no humanos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El desarrollo de modelos animales del SII suele implicar el sometimiento de los animales a estr\u00e9s durante su desarrollo temprano.<sup data-fn=\"548eb557-1e85-4626-9aa2-43c24e47c8b2\" class=\"fn\"><a href=\"#548eb557-1e85-4626-9aa2-43c24e47c8b2\" id=\"548eb557-1e85-4626-9aa2-43c24e47c8b2-link\">242<\/a><\/sup> Estos modelos tienen limitaciones significativas, como la incapacidad de replicar el estre\u00f1imiento o las respuestas intestinales mixtas de los pacientes humanos. Adem\u00e1s, las personas con SII suelen presentar trastornos superpuestos, como s\u00edndrome de dolor vesical, dolor p\u00e9lvico cr\u00f3nico, ansiedad y depresi\u00f3n, ninguno de los cuales se modela en experimentos en animales. Los cambios de comportamiento, como la ansiedad o la depresi\u00f3n, son dif\u00edciles, si no imposibles, de medir en animales. En la mayor\u00eda de los experimentos se usan animales machos, a pesar de que el SII se diagnostica m\u00e1s com\u00fanmente en las mujeres. Adem\u00e1s, el dolor abdominal, principal s\u00edntoma del SII, no puede evaluarse con precisi\u00f3n en animales, ya que no existe un fenotipo espec\u00edfico del dolor visceral que padecen los humanos. Estas deficiencias hacen que los experimentos del SII en animales sean inadecuados para comprender la fisiopatolog\u00eda de esta condici\u00f3n y desarrollar tratamientos eficaces.<sup data-fn=\"6a5e556e-aad5-44ad-aa57-aa0ab2c9333c\" class=\"fn\"><a href=\"#6a5e556e-aad5-44ad-aa57-aa0ab2c9333c\" id=\"6a5e556e-aad5-44ad-aa57-aa0ab2c9333c-link\">243<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las EII, que incluyen la colitis ulcerosa y la enfermedad de Crohn, son afecciones inflamatorias cr\u00f3nicas que suelen afectar a los intestinos grueso y delgado. En Am\u00e9rica Latina, la incidencia y la prevalencia de las EII han venido aumentando de manera constante.<sup data-fn=\"71426e73-b382-415c-ba77-755bcd43b89b\" class=\"fn\"><a href=\"#71426e73-b382-415c-ba77-755bcd43b89b\" id=\"71426e73-b382-415c-ba77-755bcd43b89b-link\">244<\/a><\/sup> En EE. UU., las EII afectan a entre dos y tres millones de personas,<sup data-fn=\"1d13560e-c572-410e-98bc-b2356753fdbc\" class=\"fn\"><a href=\"#1d13560e-c572-410e-98bc-b2356753fdbc\" id=\"1d13560e-c572-410e-98bc-b2356753fdbc-link\">245<\/a><\/sup> que sufren hemorragias rectales, diarrea grave, dolor abdominal, fiebre y p\u00e9rdida de peso. Se cree que las causas de las EII son una combinaci\u00f3n de factores gen\u00e9ticos, inmunitarios, microbianos y ambientales, aunque los mecanismos precisos no se conocen del todo.<sup data-fn=\"49282ffc-ff3e-4b12-aff9-7579f364abd0\" class=\"fn\"><a href=\"#49282ffc-ff3e-4b12-aff9-7579f364abd0\" id=\"49282ffc-ff3e-4b12-aff9-7579f364abd0-link\">246<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En la investigaci\u00f3n de las EII, se induce la colitis mediante la administraci\u00f3n de sustancias irritantes o se usan ratones modificados gen\u00e9ticamente. Sin embargo, la reproducibilidad sigue siendo un problema importante. Diversas cepas de ratones muestran distintas susceptibilidades a la colitis inducida con sustancias qu\u00edmicas, y las diferencias en el microbioma entre cepas o proveedores tambi\u00e9n pueden influir en el desarrollo de la enfermedad en ratones modificados gen\u00e9ticamente. Dado que tanto los factores gen\u00e9ticos como los ambientales contribuyen a las EII, un modelo animal que carezca de estas caracter\u00edsticas humanas espec\u00edficas no puede reproducir eficazmente estas enfermedades. Por ejemplo, los ratones modificados gen\u00e9ticamente suelen crearse mediante la mutaci\u00f3n de un \u00fanico gen, pero las EII humanas son polig\u00e9nicas.<sup data-fn=\"310d60a1-e143-4d41-aaed-33bc1773bbdd\" class=\"fn\"><a href=\"#310d60a1-e143-4d41-aaed-33bc1773bbdd\" id=\"310d60a1-e143-4d41-aaed-33bc1773bbdd-link\">247<\/a><\/sup> Adem\u00e1s, la colitis inducida qu\u00edmicamente en ratones suele causar lesiones agudas en unos pocos d\u00edas, mientras que las EII humanas se desarrollan durante a\u00f1os.<sup data-fn=\"8da8a509-f25e-4cff-917e-1217f360f79e\" class=\"fn\"><a href=\"#8da8a509-f25e-4cff-917e-1217f360f79e\" id=\"8da8a509-f25e-4cff-917e-1217f360f79e-link\">248<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Un ejemplo clave de las limitaciones de los modelos animales es la inhibici\u00f3n de la IL-17, que trata eficazmente la colitis en ratones, pero ha fracasado en pacientes con enfermedad de Crohn, incluso empeorando la afecci\u00f3n en algunas ocasiones.<sup data-fn=\"8a1cd113-0fb9-492f-8888-ebe6a1ed55ab\" class=\"fn\"><a href=\"#8a1cd113-0fb9-492f-8888-ebe6a1ed55ab\" id=\"8a1cd113-0fb9-492f-8888-ebe6a1ed55ab-link\">249<\/a><\/sup><sup data-fn=\"063369f1-af67-4c51-86c5-e2251d086e58\" class=\"fn\"><a href=\"#063369f1-af67-4c51-86c5-e2251d086e58\" id=\"063369f1-af67-4c51-86c5-e2251d086e58-link\">250<\/a><\/sup> Un an\u00e1lisis publicado en 2019 concluy\u00f3 que \u201caunque existen muchos modelos <em>in vivo<\/em> de EII, ninguno predice adecuadamente la respuesta a los tratamientos\u201d.<sup data-fn=\"f7e4a5f8-bf6f-4985-81c1-db6ec619038f\" class=\"fn\"><a href=\"#f7e4a5f8-bf6f-4985-81c1-db6ec619038f\" id=\"f7e4a5f8-bf6f-4985-81c1-db6ec619038f-link\">251<\/a><\/sup> El fracaso de la inhibici\u00f3n de la IL-17 en los ensayos cl\u00ednicos ilustra c\u00f3mo un tratamiento que funciona en modelos animales puede fallar en humanos. Por el contrario, algunos tratamientos prometedores para las EII en pacientes humanos han fracasado en modelos de rat\u00f3n.<sup data-fn=\"9a1694a8-8c0d-4ac4-ad13-35237b1b96cc\" class=\"fn\"><a href=\"#9a1694a8-8c0d-4ac4-ad13-35237b1b96cc\" id=\"9a1694a8-8c0d-4ac4-ad13-35237b1b96cc-link\">252<\/a><\/sup><sup data-fn=\"4c5278ca-4c4b-42a6-a4b9-48cd2a3261be\" class=\"fn\"><a href=\"#4c5278ca-4c4b-42a6-a4b9-48cd2a3261be\" id=\"4c5278ca-4c4b-42a6-a4b9-48cd2a3261be-link\">253<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Dadas estas limitaciones, est\u00e1 claro que ning\u00fan modelo animal puede reproducir con exactitud los trastornos GI humanos. Estas afecciones est\u00e1n atravesadas por una compleja interacci\u00f3n de factores ambientales, gen\u00e9ticos y microbianos que no pueden captarse por completo en modelos animales inducidos artificialmente. Por lo tanto, es crucial dar prioridad a los m\u00e9todos de investigaci\u00f3n relevantes para los humanos, como los organoides, los dispositivos microflu\u00eddicos y los \u00f3rganos en chip. Los siguientes son algunos de los avances recientes en esta \u00e1rea:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Ingenieros biol\u00f3gicos del Instituto de Tecnolog\u00eda de Massachusetts (MIT) desarrollaron un modelo humano multiorg\u00e1nico de colitis ulcerosa para estudiar su impacto en el eje intestino-h\u00edgado-sistema inmunol\u00f3gico.<sup data-fn=\"d01b8e18-0a80-449e-88af-3dc1cee8820f\" class=\"fn\"><a href=\"#d01b8e18-0a80-449e-88af-3dc1cee8820f\" id=\"d01b8e18-0a80-449e-88af-3dc1cee8820f-link\">254<\/a><\/sup><\/li>\n\n\n\n<li>En el Reino Unido, un equipo de cient\u00edficos us\u00f3 un enfoque multi\u00f3mico para identificar una nueva v\u00eda biol\u00f3gica relacionada con las EII y hall\u00f3 que el gen ETS2 est\u00e1 vinculado a un mayor riesgo de EII.<sup data-fn=\"436d4997-bdca-45d4-8405-d2e4e9f5136b\" class=\"fn\"><a href=\"#436d4997-bdca-45d4-8405-d2e4e9f5136b\" id=\"436d4997-bdca-45d4-8405-d2e4e9f5136b-link\">255<\/a><\/sup><\/li>\n\n\n\n<li>Un grupo de investigadores y m\u00e9dicos de Misuri y Carolina del Norte cre\u00f3 un intestino neonatal en chip para estudiar la enterocolitis necrosante, una enfermedad gastrointestinal mortal que afecta a los beb\u00e9s prematuros. El grupo demostr\u00f3 con \u00e9xito que este modelo puede recapitular la patolog\u00eda de la enfermedad, y planea usarlo para probar posibles tratamientos.<sup data-fn=\"6731e81f-03c9-4b2f-b172-b33a839fd671\" class=\"fn\"><a href=\"#6731e81f-03c9-4b2f-b172-b33a839fd671\" id=\"6731e81f-03c9-4b2f-b172-b33a839fd671-link\">256<\/a><\/sup><\/li>\n\n\n\n<li>En Boston, m\u00e9dicos y cient\u00edficos obtuvieron biopsias y muestras de sangre y heces de pacientes de varios hospitales para crear un perfil molecular longitudinal de sus microbiomas. A trav\u00e9s de un enfoque multi\u00f3mico, identificaron factores microbianos, bioqu\u00edmicos y del hu\u00e9sped involucrados en la desregulaci\u00f3n inducida por la EII.<sup data-fn=\"77162fdb-fe27-449c-b7dc-844e721c53da\" class=\"fn\"><a href=\"#77162fdb-fe27-449c-b7dc-844e721c53da\" id=\"77162fdb-fe27-449c-b7dc-844e721c53da-link\">257<\/a><\/sup><\/li>\n\n\n\n<li>Investigadores y m\u00e9dicos en Houston usaron organoides intestinales derivados de pacientes para explorar la relaci\u00f3n entre la disfunci\u00f3n de los tel\u00f3meros y las EII, lo que sugiere que abordar la disfunci\u00f3n telom\u00e9rica podr\u00eda ser una estrategia terap\u00e9utica.<sup data-fn=\"04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3\" class=\"fn\"><a href=\"#04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3\" id=\"04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3-link\">258<\/a><\/sup><\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Las diferencias anat\u00f3micas y fisiol\u00f3gicas entre los sistemas gastrointestinales de los humanos y los no humanos, sumadas a la inducci\u00f3n artificial de enfermedades GI en animales, dificultan la obtenci\u00f3n de resultados confiables en los estudios. Asimismo, muchos de estos m\u00e9todos de inducci\u00f3n implican procedimientos invasivos y dolorosos que causan angustia en los animales antes de ser asesinados.<sup data-fn=\"78b363a5-f936-4123-a1d9-213d1a962421\" class=\"fn\"><a href=\"#78b363a5-f936-4123-a1d9-213d1a962421\" id=\"78b363a5-f936-4123-a1d9-213d1a962421-link\">259<\/a><\/sup><sup data-fn=\"7aaf2d99-918c-415f-a2dc-d25e9e1af49c\" class=\"fn\"><a href=\"#7aaf2d99-918c-415f-a2dc-d25e9e1af49c\" id=\"7aaf2d99-918c-415f-a2dc-d25e9e1af49c-link\">260<\/a><\/sup><sup data-fn=\"3f691159-1b47-45d1-87e1-97dde4fd0db7\" class=\"fn\"><a href=\"#3f691159-1b47-45d1-87e1-97dde4fd0db7\" id=\"3f691159-1b47-45d1-87e1-97dde4fd0db7-link\">261<\/a><\/sup><sup data-fn=\"165bfb66-d7ee-4bb7-8fe0-fbf660f9f961\" class=\"fn\"><a href=\"#165bfb66-d7ee-4bb7-8fe0-fbf660f9f961\" id=\"165bfb66-d7ee-4bb7-8fe0-fbf660f9f961-link\">262<\/a><\/sup><sup data-fn=\"eb4dddb0-2df2-4376-8359-4cf6fdf8e502\" class=\"fn\"><a href=\"#eb4dddb0-2df2-4376-8359-4cf6fdf8e502\" id=\"eb4dddb0-2df2-4376-8359-4cf6fdf8e502-link\">263<\/a><\/sup> Dado que los modelos animales de enfermedades GI no reflejan de forma confiable la patolog\u00eda humana y contribuyen al sufrimiento animal, resulta imprescindible hacer la transici\u00f3n hacia los diversos m\u00e9todos sin animales que usan tejidos humanos o pacientes voluntarios.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Regeneraci\u00f3n nerviosa<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Se han desarrollado muchos medicamentos neuroprotectores que tienen \u00e9xito en el tratamiento de las lesiones de m\u00e9dula espinal (LME) en modelos animales, pero los ensayos cl\u00ednicos han sido decepcionantes. La neur\u00f3loga Aysha Akhtar identifica tres razones principales de este fracaso: \u201cdiferencias en el tipo de lesi\u00f3n entre la LME inducida en laboratorio y la LME cl\u00ednica, dificultades para interpretar el resultado funcional en animales y diferencias entre especies y cepas en la fisiopatolog\u00eda de la LME\u201d. <sup data-fn=\"efc86773-d02d-4337-a80f-6d06cde91197\" class=\"fn\"><a href=\"#efc86773-d02d-4337-a80f-6d06cde91197\" id=\"efc86773-d02d-4337-a80f-6d06cde91197-link\">264<\/a><\/sup> De acuerdo con una revisi\u00f3n sistem\u00e1tica del uso de modelos animales para estudiar la regeneraci\u00f3n nerviosa en estructuras de ingenier\u00eda tisular, la mayor\u00eda de los \u201cbiomateriales usados en modelos animales no han recibido autorizaci\u00f3n para probarse en ensayos cl\u00ednicos a pesar del beneficio casi uniforme descrito en los trabajos experimentales\u201d.<sup data-fn=\"be726af9-0da0-47f9-a010-d1ac77843d1a\" class=\"fn\"><a href=\"#be726af9-0da0-47f9-a010-d1ac77843d1a\" id=\"be726af9-0da0-47f9-a010-d1ac77843d1a-link\">265<\/a><\/sup> Los autores de la revisi\u00f3n lamentaron la baja calidad de los experimentos en animales descritos, ya que omitieron informaci\u00f3n fundamental y necesaria, lo que dificult\u00f3 la comparaci\u00f3n de los datos.&nbsp;&nbsp;<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-9&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-9-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-9\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-9\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-9-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">La metilprednisolona, un tratamiento de uso habitual para la LME aguda, ha generado resultados inconsistentes en modelos animales. Una revisi\u00f3n sistem\u00e1tica que examin\u00f3 62 estudios de este medicamento en una amplia variedad de especies, desde roedores hasta monos, encontr\u00f3 que el 34% de los estudios report\u00f3 resultados beneficiosos, el 58% no encontr\u00f3 ning\u00fan efecto y el 8% tuvo resultados mixtos.<sup data-fn=\"1605ad63-928f-4b4a-8a0c-c569f1083844\" class=\"fn\"><a href=\"#1605ad63-928f-4b4a-8a0c-c569f1083844\" id=\"1605ad63-928f-4b4a-8a0c-c569f1083844-link\">266<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las ratas son especialmente inadecuadas para la investigaci\u00f3n de la reparaci\u00f3n o regeneraci\u00f3n nerviosa, y su uso implica tres grandes problemas:\u00a0(1) en la actualidad, la mayor\u00eda de los datos sobre regeneraci\u00f3n nerviosa se produce en ratas, lo que puede sesgar los resultados del tratamiento y llevar a una evaluaci\u00f3n inadecuada de los riesgos y beneficios; (2) la rata es un modelo particularmente deficiente para la reparaci\u00f3n de defectos de brecha cr\u00edticos en humanos debido tanto a su peque\u00f1o tama\u00f1o como a su perfil neurobiol\u00f3gico regenerativo espec\u00edfico de la especie; y (3) la translaci\u00f3n de la rata al ser humano ha demostrado no ser confiable para la regeneraci\u00f3n nerviosa, al igual que para muchas otras aplicaciones.<sup data-fn=\"da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de\" class=\"fn\"><a href=\"#da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de\" id=\"da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de-link\">267<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las inconsistencias entre los modelos animales y el contexto cl\u00ednico son significativas<sup data-fn=\"c132c9d7-6067-45ab-be00-8fde1d671af4\" class=\"fn\"><a href=\"#c132c9d7-6067-45ab-be00-8fde1d671af4\" id=\"c132c9d7-6067-45ab-be00-8fde1d671af4-link\">268<\/a><\/sup> e incluyen lo siguiente:\u00a0\u00a0(1) animales sanos frente a pacientes enfermos; (2) brechas cortas frente a largas (la necesidad cl\u00ednica de reparaciones de <em>grandes <\/em>brechas, mientras que el 90% de los estudios <em>in vivo <\/em>se realizan en ratas y conejos donde las longitudes de las brechas suelen ser \u22643\u00a0cm); (3) modelos animales que casi siempre emplean autoinjertos <em>sensitivo-motores mixtos <\/em>para reparar defectos mixtos, frente a reparaciones cl\u00ednicas que casi siempre implican autoinjertos <em>sensitivos <\/em>(normalmente nervio sural) para reparar defectos mixtos; (4) zonas anat\u00f3micas protegidas en modelos animales, frente a reparaciones que, a menudo, deben atravesar articulaciones en humanos; y (5) cepas animales y edades altamente homog\u00e9neas y endog\u00e1micas, frente a poblaciones de pacientes y edades diversas: es bien sabido que los modelos animales no imitan la condici\u00f3n humana en cuanto a la <em>uniformidad <\/em>de los sujetos animales usados.<sup data-fn=\"7ad6b49c-da20-4530-9577-47928b199909\" class=\"fn\"><a href=\"#7ad6b49c-da20-4530-9577-47928b199909\" id=\"7ad6b49c-da20-4530-9577-47928b199909-link\">269<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Para inducir una lesi\u00f3n medular en modelos animales, los experimentadores aplican fuerza f\u00edsica directamente sobre la m\u00e9dula espinal. Existen muchos m\u00e9todos diferentes, como la contusi\u00f3n, que consiste en desplazar la m\u00e9dula espinal dej\u00e1ndole caer un peso, o la separaci\u00f3n por tracci\u00f3n, en la que se aplica fuerza para estirar la m\u00e9dula espinal. Independientemente del m\u00e9todo usado, lograr consistencia y reproducibilidad es un reto debido a la imposibilidad de reproducir la misma lesi\u00f3n medular cada vez que se realiza el procedimiento. Por ejemplo, en las lesiones inducidas por contusi\u00f3n, la variabilidad puede surgir del rebote de la varilla despu\u00e9s de golpear la m\u00e9dula espinal, lo que puede causar m\u00faltiples impactos.<sup data-fn=\"5237fd46-854a-41a8-b5aa-44ad772b1fae\" class=\"fn\"><a href=\"#5237fd46-854a-41a8-b5aa-44ad772b1fae\" id=\"5237fd46-854a-41a8-b5aa-44ad772b1fae-link\">270<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s de los problemas de consistencia, muchos de estos modelos no reflejan con exactitud los mecanismos de la LME en humanos. Un modelo de compresi\u00f3n creado con f\u00f3rceps no reproduce el impacto agudo que se observa en la mayor\u00eda de las lesiones medulares humanas, y los dispositivos usados para el modelo de separaci\u00f3n por tracci\u00f3n suelen inducir lesiones muy lentamente para emular las lesiones humanas. La LME inducida qu\u00edmicamente se emplea para estudiar las lesiones secundarias asociadas a la LME y suele implicar la inyecci\u00f3n o aplicaci\u00f3n de un producto qu\u00edmico t\u00f3xico en la zona de inter\u00e9s. Sin embargo, uno de los desaf\u00edos de este m\u00e9todo es lograr la administraci\u00f3n precisa de la sustancia qu\u00edmica en la regi\u00f3n correcta de la columna vertebral.<sup data-fn=\"d22b862d-a56b-41d0-8cd7-ffe63a301648\" class=\"fn\"><a href=\"#d22b862d-a56b-41d0-8cd7-ffe63a301648\" id=\"d22b862d-a56b-41d0-8cd7-ffe63a301648-link\">271<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los ingenieros biom\u00e9dicos han observado que los experimentadores \u201cson incapaces de imitar realmente las lesiones neurales humanas en modelos animales debido a las grandes diferencias anat\u00f3micas, funcionales, moleculares, inmunol\u00f3gicas y patol\u00f3gicas entre los humanos y los animales estudiados con frecuencia\u201d.<sup data-fn=\"544d66a2-622b-40c6-95e3-e53bc3b44279\" class=\"fn\"><a href=\"#544d66a2-622b-40c6-95e3-e53bc3b44279\" id=\"544d66a2-622b-40c6-95e3-e53bc3b44279-link\">272<\/a><\/sup> Los m\u00e9todos relevantes para los humanos pueden superar estas limitaciones y deber\u00edan ser el foco de la investigaci\u00f3n.&nbsp;&nbsp;<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Diversos grupos han examinado m\u00e9todos relevantes para los humanos para estudiar las lesiones y la regeneraci\u00f3n nerviosas, como organoides humanos, dispositivos microflu\u00eddicos, moldes para andamiajes de tejidos humanos dise\u00f1ados, bioimpresi\u00f3n y otros usos <em>in vitro <\/em>de c\u00e9lulas humanas. Los modelos <em>ex vivo<\/em>, como los que usan estructuras de dise\u00f1o tridimensional, biorreactores, neuroesferas y organoides, permiten realizar estudios m\u00e1s controlados sobre par\u00e1metros espec\u00edficos que los experimentos en animales.<sup data-fn=\"328d07cb-d0e7-45f7-9a24-7aea35715d34\" class=\"fn\"><a href=\"#328d07cb-d0e7-45f7-9a24-7aea35715d34\" id=\"328d07cb-d0e7-45f7-9a24-7aea35715d34-link\">273<\/a><\/sup> La bioimpresi\u00f3n puede usar biotintas que contienen c\u00e9lulas y materiales humanos para construir modelos de tejidos heterog\u00e9neos en un solo paso y con gran consistencia,<sup data-fn=\"a5dc6b9d-7af7-4290-94e3-de4a81215f6a\" class=\"fn\"><a href=\"#a5dc6b9d-7af7-4290-94e3-de4a81215f6a\" id=\"a5dc6b9d-7af7-4290-94e3-de4a81215f6a-link\">274<\/a><\/sup> un aspecto de la investigaci\u00f3n sobre la regeneraci\u00f3n nerviosa que ha estado especialmente ausente en los modelos animales.<sup data-fn=\"e9c5f67b-bcbc-4ac5-8e83-776367874baa\" class=\"fn\"><a href=\"#e9c5f67b-bcbc-4ac5-8e83-776367874baa\" id=\"e9c5f67b-bcbc-4ac5-8e83-776367874baa-link\">275<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Ingenieros e investigadores del Centro M\u00e9dico de la Universidad de Pittsburgh y de la Universidad Carnegie Mellon han imitado traumatismos craneoencef\u00e1licos (TCE) leves y moderados en organoides cerebrales humanos. Su estudio permiti\u00f3 identificar importantes repercusiones gen\u00e9ticas del TCE en el cerebro que pueden usarse para diagnosticar la enfermedad y crear tratamientos personalizados.<sup data-fn=\"c85d3c45-a0be-481e-9789-1ee224b265a5\" class=\"fn\"><a href=\"#c85d3c45-a0be-481e-9789-1ee224b265a5\" id=\"c85d3c45-a0be-481e-9789-1ee224b265a5-link\">276<\/a><\/sup> Tambi\u00e9n se han creado organoides de m\u00e9dula espinal humana que muestran actividad neuronal funcional y son prometedores para investigar terapias para la LME.<sup data-fn=\"afa9e3ab-8b66-436e-8bf5-4d25a1903ebd\" class=\"fn\"><a href=\"#afa9e3ab-8b66-436e-8bf5-4d25a1903ebd\" id=\"afa9e3ab-8b66-436e-8bf5-4d25a1903ebd-link\">277<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los dispositivos microflu\u00eddicos son \u201cadaptables para modelar una amplia gama de lesiones\u201d y proporcionan ventajas sobre los experimentos tradicionales <em>in vivo <\/em>e <em>in vitro<\/em>, ya que \u201cpermiten a los investigadores (1) examinar el efecto de la lesi\u00f3n en componentes neuronales espec\u00edficos, (2) aislar mediante fluidos las regiones neuronales para examinar efectos espec\u00edficos en componentes subcelulares y (3) crear de forma reproducible una variedad de lesiones para modelar el TCE y la LME\u201d.<sup data-fn=\"e827147a-3b4f-4c97-a902-a70ce9541ba5\" class=\"fn\"><a href=\"#e827147a-3b4f-4c97-a902-a70ce9541ba5\" id=\"e827147a-3b4f-4c97-a902-a70ce9541ba5-link\">278<\/a><\/sup> Por ejemplo, las plataformas de cerebro en chip ofrecen una v\u00eda prometedora para la medicina personalizada, ya que las propias c\u00e9lulas de un paciente pueden usarse para crear un dispositivo a medida que permita investigar opciones de tratamiento.<sup data-fn=\"e0c3e4c2-7d04-4e9d-ab3c-a18053304776\" class=\"fn\"><a href=\"#e0c3e4c2-7d04-4e9d-ab3c-a18053304776\" id=\"e0c3e4c2-7d04-4e9d-ab3c-a18053304776-link\">279<\/a><\/sup> Los axones en chip pueden servir para modelar lesiones axonales difusas, lo que permite hacer seguimiento a los cambios intracelulares inmediatamente despu\u00e9s de la lesi\u00f3n y ofrece una plataforma para evaluar tratamientos.<sup data-fn=\"794dc1ae-894a-40c7-a53e-8172f45c8508\" class=\"fn\"><a href=\"#794dc1ae-894a-40c7-a53e-8172f45c8508\" id=\"794dc1ae-894a-40c7-a53e-8172f45c8508-link\">280<\/a><\/sup> Estos sistemas tienen ventajas en precisi\u00f3n, escalabilidad y costo-efectividad en comparaci\u00f3n con los cultivos celulares tradicionales o los experimentos en animales y est\u00e1n disponibles en el mercado para la investigaci\u00f3n en medicina regenerativa neuronal.<sup data-fn=\"c162ec0f-5ec1-460b-b69d-601bebdda678\" class=\"fn\"><a href=\"#c162ec0f-5ec1-460b-b69d-601bebdda678\" id=\"c162ec0f-5ec1-460b-b69d-601bebdda678-link\">281<\/a><\/sup><\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Enfermedades neurodegenerativas<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Existe suficiente bibliograf\u00eda que documenta los fracasos de diversos modelos animales de enfermedades neurodegenerativas, como la enfermedad de Alzheimer (EA), la enfermedad de Parkinson (EP), la enfermedad de Huntington (EH) y la esclerosis lateral amiotr\u00f3fica (ELA). Aunque se podr\u00eda escribir un extenso ap\u00e9ndice para cada enfermedad, muchas de las mismas limitaciones de los modelos animales obstaculizan la traslaci\u00f3n entre estas afecciones, y se discutir\u00e1n brevemente en conjunto.<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-10&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-10-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-10\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-10\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-10-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Todas estas enfermedades son espec\u00edficas de los humanos y no ocurren de forma natural en otros animales. No se ha desarrollado ning\u00fan modelo animal que sintetice todos los aspectos de una enfermedad neurodegenerativa en particular.<sup data-fn=\"873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2\" class=\"fn\"><a href=\"#873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2\" id=\"873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2-link\">282<\/a><\/sup> En cuanto a la investigaci\u00f3n de la EA, la tasa de fracaso cl\u00ednico de los nuevos f\u00e1rmacos se estim\u00f3 por \u00faltima vez en un 99,6%<sup data-fn=\"8d0db68d-494d-426c-bafb-4462c61c8fa9\" class=\"fn\"><a href=\"#8d0db68d-494d-426c-bafb-4462c61c8fa9\" id=\"8d0db68d-494d-426c-bafb-4462c61c8fa9-link\">283<\/a><\/sup><sup data-fn=\"01aa3885-6f22-4e4d-9242-74e389eef972\" class=\"fn\"><a href=\"#01aa3885-6f22-4e4d-9242-74e389eef972\" id=\"01aa3885-6f22-4e4d-9242-74e389eef972-link\">284<\/a><\/sup> y los recientes medicamentos monoclonales aprobados para la EA son problem\u00e1ticos debido a sus efectos adversos y cuestionable eficacia.<sup data-fn=\"ef4cc749-ce97-44df-809f-e4d92142b681\" class=\"fn\"><a href=\"#ef4cc749-ce97-44df-809f-e4d92142b681\" id=\"ef4cc749-ce97-44df-809f-e4d92142b681-link\">285<\/a><\/sup><sup data-fn=\"fa6531b8-bdce-4349-8b91-a601f9ddc566\" class=\"fn\"><a href=\"#fa6531b8-bdce-4349-8b91-a601f9ddc566\" id=\"fa6531b8-bdce-4349-8b91-a601f9ddc566-link\">286<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Un an\u00e1lisis bioinform\u00e1tico que compar\u00f3 las firmas transcripcionales de la EA, la EP, la EH y la ELA humanas con modelos de rat\u00f3n de estas enfermedades concluy\u00f3 lo siguiente:&nbsp;<\/p>\n\n\n\n<blockquote class=\"wp-block-quote simple is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">[L]a mayor\u00eda de los modelos de rat\u00f3n disponibles para enfermedades neurodegenerativas no logra recapitular las alteraciones transcripcionales m\u00e1s destacadas de la neurodegeneraci\u00f3n humana e incluso los mejores modelos disponibles muestran diferencias significativas y reproducibles en comparaci\u00f3n con la neurodegeneraci\u00f3n humana. Aunque fueron varias las razones del mal desempe\u00f1o transcripcional de los modelos de rat\u00f3n, el com\u00fan denominador fue el fracaso de [estos] modelos\u2026 a la hora de mostrar la variedad y gravedad de los diversos defectos observados en la neurodegeneraci\u00f3n humana.<sup data-fn=\"e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa\" class=\"fn\"><a href=\"#e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa\" id=\"e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa-link\">287<\/a><\/sup><\/p>\n<\/blockquote>\n\n\n\n<p class=\"wp-block-paragraph\">Estas discrepancias moleculares ponen de manifiesto los m\u00e9todos artificiales usados para crear los modelos animales. A menudo, se causan lesiones f\u00edsicas o qu\u00edmicas y se administran toxinas de forma sist\u00e9mica. Estos m\u00e9todos constituyen factores estresantes agudos, no procesos degenerativos a largo plazo y, por lo tanto, desencadenan respuestas en los animales que no se observan en los pacientes humanos. La naturaleza aguda e inmediata de ciertos modelos de enfermedad, como los modelos animales 6-OHDA y MPTP de la EP y el modelo animal 3-NP de la EH, no logran captar la naturaleza progresiva de los trastornos que pretenden imitar. Adem\u00e1s, los experimentadores suelen usar animales j\u00f3venes para \u201cmodelar\u201d enfermedades asociadas al envejecimiento,<sup data-fn=\"50be7246-a3b2-4332-a69d-c850094ed9cf\" class=\"fn\"><a href=\"#50be7246-a3b2-4332-a69d-c850094ed9cf\" id=\"50be7246-a3b2-4332-a69d-c850094ed9cf-link\">288<\/a><\/sup> lo que minimiza a\u00fan m\u00e1s su relevancia. Por ejemplo, \u201c[l]os modelos de rat\u00f3n de EA utilizados com\u00fanmente, como el 5xFAD, muestran dep\u00f3sitos de amiloide a partir de los 2 a 4 meses de edad\u2026 Esta acumulaci\u00f3n precoz puede traducirse en dep\u00f3sitos de A\u03b2 en humanos de 4 a 8 a\u00f1os, un escenario que no se encuentra ni siquiera en los casos m\u00e1s agresivos\u201d<sup data-fn=\"4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d\" class=\"fn\"><a href=\"#4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d\" id=\"4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d-link\">289<\/a><\/sup> de EA.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los modelos de ratones modificados gen\u00e9ticamente presentan fenotipos patol\u00f3gicos y conductuales inconsistentes, en parte debido a variaciones en los transgenes usados, inconsistencias en la inserci\u00f3n y la expresi\u00f3n de los transgenes y diferencias en los antecedentes &nbsp;gen\u00e9ticos de los ratones.<sup data-fn=\"75e7b8bd-fd91-4959-98f0-03ac53c32781\" class=\"fn\"><a href=\"#75e7b8bd-fd91-4959-98f0-03ac53c32781\" id=\"75e7b8bd-fd91-4959-98f0-03ac53c32781-link\">290<\/a><\/sup> Hasta 2024, se hab\u00edan desarrollado 210 modelos transg\u00e9nicos de roedores para estudiar la EA.<sup data-fn=\"18c0e15a-3d08-4195-a498-6d3c582b1afb\" class=\"fn\"><a href=\"#18c0e15a-3d08-4195-a498-6d3c582b1afb\" id=\"18c0e15a-3d08-4195-a498-6d3c582b1afb-link\">291<\/a><\/sup> Un an\u00e1lisis sobre la relevancia y la validez traslacional de los modelos de rat\u00f3n describi\u00f3 las siguientes deficiencias:<\/p>\n\n\n\n<blockquote class=\"wp-block-quote simple is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Algunos modelos transg\u00e9nicos pueden presentar un fenotipo de enfermedad muy agresivo en comparaci\u00f3n con la forma humana de la enfermedad\u2026 mientras que otros no demuestran aspectos de p\u00e9rdida y disfunci\u00f3n neuronales\u2026 Resulta preocupante, adem\u00e1s, el hecho de que los modelos murinos no suelen mostrar una p\u00e9rdida neuronal significativa, incluso en presencia de dep\u00f3sitos de amiloides, y generan p\u00e9ptidos amiloides diferentes a los que se encuentran en el cerebro humano\u2026 En algunos casos, las fallas encontradas en los modelos animales transg\u00e9nicos reflejan el hecho de que se basan en hip\u00f3tesis y constructos usados para responderlas que son intr\u00ednsecamente err\u00f3neos; en otros casos, reflejan la falta de cuidado de los investigadores para garantizar las mejores pr\u00e1cticas en la reproducci\u00f3n y el uso de estos modelos. A pesar de sus limitaciones, estos modelos defectuosos han sido ampliamente adoptados y su relevancia se ha sobreestimado ante la ausencia de alternativas viables. Su validez solo se menciona superficialmente, mientras se consolidan como pr\u00e1ctica habitual y se perpet\u00faan, lo que ha conducido al \u00e1rea [de investigaci\u00f3n] a un callej\u00f3n sin salida.<sup data-fn=\"81b4d110-03b6-450e-a0c0-d55e188a391f\" class=\"fn\"><a href=\"#81b4d110-03b6-450e-a0c0-d55e188a391f\" id=\"81b4d110-03b6-450e-a0c0-d55e188a391f-link\">292<\/a><\/sup><\/p>\n<\/blockquote>\n\n\n\n<p class=\"wp-block-paragraph\">Las diferencias gen\u00e9ticas fundamentales dificultan a\u00fan m\u00e1s la traslaci\u00f3n. Por ejemplo, \u201clos modelos <em>knock-in<\/em> requieren la presencia de m\u00faltiples mutaciones de prote\u00edna precursora amiloide (APP) que no se encuentran en humanos\u201d, la prote\u00edna T (o tau) murina difiere estructuralmente de la prote\u00edna T humana y \u201clas sustituciones de amino\u00e1cidos clave hacen que la A\u03b2 murina sea menos propensa a la agregaci\u00f3n en comparaci\u00f3n con su hom\u00f3loga humana\u201d.<sup data-fn=\"ae257fdb-8274-4389-aa88-91390084c54f\" class=\"fn\"><a href=\"#ae257fdb-8274-4389-aa88-91390084c54f\" id=\"ae257fdb-8274-4389-aa88-91390084c54f-link\">293<\/a><\/sup> Estas diferencias hacen que los modelos animales de enfermedades neurodegenerativas sean enga\u00f1osos y generen una p\u00e9rdida de tiempo valioso: en el caso de un objetivo gen\u00e9tico para la investigaci\u00f3n de la EA previamente identificado como sobreexpresado &nbsp;en modelos de rat\u00f3n, como era de esperar, no se encontr\u00f3 sobreexpresado en humanos en un reciente estudio <em>post mortem<\/em>.<sup data-fn=\"1e763afc-bab0-4d38-93d0-3137846469dc\" class=\"fn\"><a href=\"#1e763afc-bab0-4d38-93d0-3137846469dc\" id=\"1e763afc-bab0-4d38-93d0-3137846469dc-link\">294<\/a><\/sup> \u202fPara la EP, los estudios en primates no humanos no \u201cconstituyen una modalidad cient\u00edfica v\u00e1lida para comprender completamente la EP ni para desarrollar&nbsp; futuras estrategias terap\u00e9uticas de neuromodulaci\u00f3n\u201d.<sup data-fn=\"1eb3a4e0-8cb3-4530-af51-be7f6183eaac\" class=\"fn\"><a href=\"#1eb3a4e0-8cb3-4530-af51-be7f6183eaac\" id=\"1eb3a4e0-8cb3-4530-af51-be7f6183eaac-link\">295<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Como en gran parte de la investigaci\u00f3n biom\u00e9dica, los animales sufren enormemente cuando se usan para imitar enfermedades neurodegenerativas. En un an\u00e1lisis de las investigaciones publicadas sobre modelos animales de la EH, 51 estudios hac\u00edan referencia a experimentos \u201cen los que se esperaba que los animales desarrollaran d\u00e9ficits motores tan graves que tendr\u00edan dificultades para comer y beber con normalidad\u201d.<sup data-fn=\"0b986690-ffac-45d4-82d3-660badf2ce23\" class=\"fn\"><a href=\"#0b986690-ffac-45d4-82d3-660badf2ce23\" id=\"0b986690-ffac-45d4-82d3-660badf2ce23-link\">296<\/a><\/sup> Sin embargo, solo en tres de estos estudios se adapt\u00f3 el \u00e1rea de confinamiento de los animales para facilitar la ingesta de comida y agua. El an\u00e1lisis concluy\u00f3 que los experimentadores no est\u00e1n cumpliendo los principios de las 3R y ponen en peligro no solo el bienestar de los animales, sino la relevancia de sus estudios para la EH.<sup data-fn=\"ff9ccac2-2850-434a-b2c7-139a8eeb0f98\" class=\"fn\"><a href=\"#ff9ccac2-2850-434a-b2c7-139a8eeb0f98\" id=\"ff9ccac2-2850-434a-b2c7-139a8eeb0f98-link\">297<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Dadas las fallas de los experimentos en animales, la comunidad cient\u00edfica y las instancias decisorias han venido reconociendo la necesidad de contar con estrategias de investigaci\u00f3n relevantes para los humanos. Tras una revisi\u00f3n de la investigaci\u00f3n sobre la EA, un panel interdisciplinario recomend\u00f3 reasignar la financiaci\u00f3n previamente destinada a estudios en animales a t\u00e9cnicas m\u00e1s prometedoras, como los modelos de hiPSC derivadas de pacientes, la tecnolog\u00eda \u201c\u00f3mica\u201d (gen\u00f3mica, prote\u00f3mica, etc.), los modelos <em>in silico, <\/em>la neuroimagen y los estudios epidemiol\u00f3gicos.<sup data-fn=\"cec7dce4-7bcf-4c87-87bc-501ca3f2f565\" class=\"fn\"><a href=\"#cec7dce4-7bcf-4c87-87bc-501ca3f2f565\" id=\"cec7dce4-7bcf-4c87-87bc-501ca3f2f565-link\">298<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Estos son algunos ejemplos de investigaci\u00f3n de vanguardia y relevante para los humanos sobre enfermedades neurodegenerativas:&nbsp;<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Un equipo del Hospital Brigham and Women diferenci\u00f3 hiPSC en neuronas que desarrollan r\u00e1pidamente inclusiones proteicas que imitan las que se encuentran en los cerebros de individuos que murieron con inclusionopat\u00edas. Con este m\u00e9todo, se crearon m\u00e1s de 60 modelos celulares humanos que otros laboratorios pueden usar para estudiar enfermedades neurodegenerativas humanas.<sup data-fn=\"61053cdb-d3e1-49e0-93d3-338c3f79c215\" class=\"fn\"><a href=\"#61053cdb-d3e1-49e0-93d3-338c3f79c215\" id=\"61053cdb-d3e1-49e0-93d3-338c3f79c215-link\">299<\/a><\/sup><\/li>\n\n\n\n<li>En la Universidad de Washington en St. Louis usaron c\u00e9lulas de pacientes con EA para desarrollar un modelo celular humano tridimensional relevante para la EA de inicio tard\u00edo (que representa el 95% de los casos). Este modelo permite estudiar la neurodegeneraci\u00f3n asociada a la edad.<sup data-fn=\"32013bed-278a-45ce-abec-6bd25e3aaa24\" class=\"fn\"><a href=\"#32013bed-278a-45ce-abec-6bd25e3aaa24\" id=\"32013bed-278a-45ce-abec-6bd25e3aaa24-link\">300<\/a><\/sup> Otro equipo de la misma instituci\u00f3n realiz\u00f3 un estudio prote\u00f3mico del l\u00edquido cefalorraqu\u00eddeo de pacientes con EA para identificar biomarcadores que puedan detectarse d\u00e9cadas antes de que aparezcan los s\u00edntomas.<sup data-fn=\"6b631497-7d4a-4306-99cd-6999f25b3b6e\" class=\"fn\"><a href=\"#6b631497-7d4a-4306-99cd-6999f25b3b6e\" id=\"6b631497-7d4a-4306-99cd-6999f25b3b6e-link\">301<\/a><\/sup><\/li>\n\n\n\n<li>Investigadores del Instituto de Ciencia y Tecnolog\u00eda de Barcelona desarrollaron un \u00f3rgano en chip para evaluar la permeabilidad cerebral de los nanoterap\u00e9uticos y facilitar la investigaci\u00f3n y la terapia personalizadas de la EA.<sup data-fn=\"fbdab90e-1fa8-4ee4-9e3b-04368b8eb397\" class=\"fn\"><a href=\"#fbdab90e-1fa8-4ee4-9e3b-04368b8eb397\" id=\"fbdab90e-1fa8-4ee4-9e3b-04368b8eb397-link\">302<\/a><\/sup><\/li>\n\n\n\n<li>En el Vienna BioCenter crearon un modelo <em>in vitro <\/em>del sistema dopamin\u00e9rgico humano con ensambloides de mesenc\u00e9falo ventral-estriato-corteza para mejorar el estudio de los tratamientos celulares de la EP.<sup data-fn=\"f43fdfcb-49bf-4b80-86e5-3f049aa8ce59\" class=\"fn\"><a href=\"#f43fdfcb-49bf-4b80-86e5-3f049aa8ce59\" id=\"f43fdfcb-49bf-4b80-86e5-3f049aa8ce59-link\">303<\/a><\/sup><\/li>\n\n\n\n<li>Un equipo de la Universidad de Luxemburgo us\u00f3 organoides y ensambloides humanos \u2013incluidos los desarrollados con c\u00e9lulas de pacientes\u2013 para comprender las primeras fases de la EP y los factores que influyen en la susceptibilidad.<sup data-fn=\"507b2c90-f1ed-4995-b00c-ea58a2759f7f\" class=\"fn\"><a href=\"#507b2c90-f1ed-4995-b00c-ea58a2759f7f\" id=\"507b2c90-f1ed-4995-b00c-ea58a2759f7f-link\">304<\/a><\/sup><sup data-fn=\"55b207c4-27c2-4ef5-b1d0-36758b72c1c1\" class=\"fn\"><a href=\"#55b207c4-27c2-4ef5-b1d0-36758b72c1c1\" id=\"55b207c4-27c2-4ef5-b1d0-36758b72c1c1-link\">305<\/a><\/sup><\/li>\n\n\n\n<li>Emulate, Inc., con sede en Boston, dise\u00f1\u00f3 un cerebro humano en chip que representa \u00e1reas afectadas por la EP, reproduce caracter\u00edsticas de la enfermedad y puede usarse para identificar y probar nuevos objetivos de tratamiento.<sup data-fn=\"18463416-0bda-47d8-aae6-d0f9c5bf3a87\" class=\"fn\"><a href=\"#18463416-0bda-47d8-aae6-d0f9c5bf3a87\" id=\"18463416-0bda-47d8-aae6-d0f9c5bf3a87-link\">306<\/a><\/sup><\/li>\n\n\n\n<li>En Alemania, un equipo us\u00f3 organoides cerebrales humanos para identificar un gen afectado en la EH que puede da\u00f1ar el cerebro antes de que aparezcan los s\u00edntomas y que podr\u00eda servir como foco para el desarrollo de medicamentos. Restaurar la funci\u00f3n de este gen revirti\u00f3 el fenotipo de la EH.<sup data-fn=\"4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7\" class=\"fn\"><a href=\"#4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7\" id=\"4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7-link\">307<\/a><\/sup><\/li>\n\n\n\n<li>En la Universidad de Florida Central usaron c\u00e9lulas de pacientes con ELA para desarrollar una uni\u00f3n neuromuscular espec\u00edfica de la enfermedad en chip y evaluaron los efectos de un compuesto en medidas funcionales cl\u00ednicamente relevantes de la ELA.<sup data-fn=\"ee570513-5ef3-4945-9b8f-ed59f2e72a54\" class=\"fn\"><a href=\"#ee570513-5ef3-4945-9b8f-ed59f2e72a54\" id=\"ee570513-5ef3-4945-9b8f-ed59f2e72a54-link\">308<\/a><\/sup><\/li>\n\n\n\n<li>En otro estudio espec\u00edfico sobre pacientes, un equipo de la Universidad de Utrecht us\u00f3 organoides cerebrales humanos para comprender mejor los cambios sin\u00e1pticos en pacientes con ELA antes de la aparici\u00f3n de los s\u00edntomas.<sup data-fn=\"fcf754ae-f526-4abd-b088-8533715b34b6\" class=\"fn\"><a href=\"#fcf754ae-f526-4abd-b088-8533715b34b6\" id=\"fcf754ae-f526-4abd-b088-8533715b34b6-link\">309<\/a><\/sup><\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Durante d\u00e9cadas, los experimentadores han atormentado a monos, ratones, perros y otros animales en un esfuerzo por modelar estas enfermedades devastadoras. Sin embargo, dado que otros animales no desarrollan estas enfermedades neurodegenerativas humanas de forma natural, los experimentadores han manipulado los genomas para forzar s\u00edntomas moderados. Los resultados, tras d\u00e9cadas de pruebas, incluyen m\u00e1s de 100 medicamentos fallidos, un n\u00famero incalculable de muertes de animales y el sufrimiento continuo de los humanos que viven con estas afecciones. Es preciso usar m\u00e9todos relevantes para los humanos para ofrecerles alternativas efectivas a estos pacientes.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Trastornos neuropsiqui\u00e1tricos y neurodivergencia&nbsp;<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Al igual que muchos otros modelos animales de enfermedades humanas, aquellos usados en un intento de estudiar los trastornos neuropsiqui\u00e1tricos humanos y la neurodivergencia carecen de &nbsp;validez de constructo porque los mecanismos fundamentales que crean los s\u00edntomas observados en animales son diferentes de los que causan el trastorno en humanos. Tambi\u00e9n carecen de validez aparente porque los animales no pueden \u201crecapitular caracter\u00edsticas anat\u00f3micas, bioqu\u00edmicas, neuropatol\u00f3gicas o conductuales importantes de una enfermedad humana\u201d. <sup data-fn=\"53b3febe-7a31-444c-900d-e1b1de9a4329\" class=\"fn\"><a href=\"#53b3febe-7a31-444c-900d-e1b1de9a4329\" id=\"53b3febe-7a31-444c-900d-e1b1de9a4329-link\">310<\/a><\/sup> Por \u00faltimo, carecen de validez predictiva porque los resultados de los experimentos en animales no se traducen de forma confiable en resultados similares en humanos.<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-11&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-11-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-11\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-11\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-11-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Ning\u00fan modelo animal es capaz de reproducir todos los aspectos de un trastorno neuropsiqui\u00e1trico concreto. Adem\u00e1s, los rasgos del comportamiento humano propios de estos trastornos no pueden producirse con precisi\u00f3n ni evaluarse adecuadamente en animales.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Por ejemplo, los trastornos depresivos humanos se caracterizan, en parte, por sentimientos de tristeza y desesperanza o desesperaci\u00f3n. En un esfuerzo por medir la \u201cdesesperaci\u00f3n\u201d en roedores, la prueba de comportamiento m\u00e1s usada es la de nado forzado, en la que se arroja una rata o un rat\u00f3n en un recipiente con agua sin posibilidad de escapar ni de descansar fuera del agua. Los experimentadores interpretan err\u00f3neamente la cantidad de tiempo que el animal pasa nadando o luchando por escapar como una medida de la falta de desesperaci\u00f3n del animal. Esta noci\u00f3n err\u00f3nea se origin\u00f3 a partir de la observaci\u00f3n de que el tiempo de nado y lucha pod\u00eda prolongarse si se administraba alg\u00fan tipo de antidepresivo humano al animal. Sin embargo, esta suposici\u00f3n ignora los numerosos falsos positivos y falsos negativos que produce la prueba. Como se ha debatido ampliamente en la bibliograf\u00eda cient\u00edfica, el comportamiento de un animal en la prueba de nado forzado puede representar una adaptaci\u00f3n evolutiva a la situaci\u00f3n estresante y no debe usarse para determinar su estado de \u00e1nimo.<sup data-fn=\"15bcc946-dbc4-4285-b449-0a1e3ed20de1\" class=\"fn\"><a href=\"#15bcc946-dbc4-4285-b449-0a1e3ed20de1\" id=\"15bcc946-dbc4-4285-b449-0a1e3ed20de1-link\">311<\/a><\/sup> La cepa del animal y muchas variaciones experimentales, como la profundidad del agua, las dimensiones del recipiente y la temperatura,<sup>3-6<\/sup> pueden influir en los resultados.<sup data-fn=\"ec47efa9-5e69-4f9b-ad87-966051395383\" class=\"fn\"><a href=\"#ec47efa9-5e69-4f9b-ad87-966051395383\" id=\"ec47efa9-5e69-4f9b-ad87-966051395383-link\">312<\/a><\/sup><sup data-fn=\"48383639-ef56-4724-b89f-5402cee096f4\" class=\"fn\"><a href=\"#48383639-ef56-4724-b89f-5402cee096f4\" id=\"48383639-ef56-4724-b89f-5402cee096f4-link\">313<\/a><\/sup><sup data-fn=\"f300d69f-1114-4fe9-b89b-10e73b590a95\" class=\"fn\"><a href=\"#f300d69f-1114-4fe9-b89b-10e73b590a95\" id=\"f300d69f-1114-4fe9-b89b-10e73b590a95-link\">314<\/a><\/sup><sup data-fn=\"3af7fa0f-c28a-4f4d-b696-8b7806493522\" class=\"fn\"><a href=\"#3af7fa0f-c28a-4f4d-b696-8b7806493522\" id=\"3af7fa0f-c28a-4f4d-b696-8b7806493522-link\">315<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Una neurocient\u00edfica de PETA y sus colaboradores han publicado art\u00edculos que llaman la atenci\u00f3n sobre la falta de validez de la prueba de nado forzado para la evaluaci\u00f3n de f\u00e1rmacos antidepresivos. Su estudio revel\u00f3 que el uso de esta prueba por parte de las 15 empresas farmac\u00e9uticas m\u00e1s grandes del mundo no produjo ning\u00fan f\u00e1rmaco actualmente aprobado para el tratamiento de la depresi\u00f3n en humanos.<sup data-fn=\"a1c96c7c-308b-44c2-9d9c-a94f356c01cd\" class=\"fn\"><a href=\"#a1c96c7c-308b-44c2-9d9c-a94f356c01cd\" id=\"a1c96c7c-308b-44c2-9d9c-a94f356c01cd-link\">316<\/a><\/sup> Su trabajo tambi\u00e9n se\u00f1ala los pasos que los entes reguladores podr\u00edan adoptar para eliminar el uso de la prueba de nado forzado (y la prueba similar de suspensi\u00f3n por la cola) en la industria farmac\u00e9utica.<sup data-fn=\"8baafa78-0984-4108-afe4-8ff9cd7de325\" class=\"fn\"><a href=\"#8baafa78-0984-4108-afe4-8ff9cd7de325\" id=\"8baafa78-0984-4108-afe4-8ff9cd7de325-link\">317<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Otras pruebas de comportamiento animal, como la de preferencia por la sacarosa para detectar la anhedonia,<sup data-fn=\"105f4c65-2212-4260-a890-1bc13b938a42\" class=\"fn\"><a href=\"#105f4c65-2212-4260-a890-1bc13b938a42\" id=\"105f4c65-2212-4260-a890-1bc13b938a42-link\">318<\/a><\/sup><sup data-fn=\"dfd3ec4d-2db6-46f5-a353-1843757c62c2\" class=\"fn\"><a href=\"#dfd3ec4d-2db6-46f5-a353-1843757c62c2\" id=\"dfd3ec4d-2db6-46f5-a353-1843757c62c2-link\">319<\/a><\/sup><sup data-fn=\"7f85a86e-aab3-4876-ad19-d4f43354a2c5\" class=\"fn\"><a href=\"#7f85a86e-aab3-4876-ad19-d4f43354a2c5\" id=\"7f85a86e-aab3-4876-ad19-d4f43354a2c5-link\">320<\/a><\/sup> la de campo abierto y los laberintos elevados para detectar la ansiedad,<sup data-fn=\"9d722a92-a161-4ccf-a8bf-8ec463094268\" class=\"fn\"><a href=\"#9d722a92-a161-4ccf-a8bf-8ec463094268\" id=\"9d722a92-a161-4ccf-a8bf-8ec463094268-link\">321<\/a><\/sup><sup data-fn=\"bd273750-7c2d-41a3-b1b2-799ae3f50da5\" class=\"fn\"><a href=\"#bd273750-7c2d-41a3-b1b2-799ae3f50da5\" id=\"bd273750-7c2d-41a3-b1b2-799ae3f50da5-link\">322<\/a><\/sup> el enterramiento de canicas para detectar la compulsi\u00f3n<sup data-fn=\"7114cae6-10c1-4c92-b0e9-6c525c15b1b6\" class=\"fn\"><a href=\"#7114cae6-10c1-4c92-b0e9-6c525c15b1b6\" id=\"7114cae6-10c1-4c92-b0e9-6c525c15b1b6-link\">323<\/a><\/sup> y el estr\u00e9s cr\u00f3nico impredecible para inducir psicopatolog\u00edas<sup data-fn=\"cbbb1555-7416-4d5e-8cf5-545ca8e5ace7\" class=\"fn\"><a href=\"#cbbb1555-7416-4d5e-8cf5-545ca8e5ace7\" id=\"cbbb1555-7416-4d5e-8cf5-545ca8e5ace7-link\">324<\/a><\/sup> presentan fallas similares. Dichas falencias han llevado a concluir que \u201calgunos de estos ensayos deben suspenderse y dejarse en el pasado mientras buscamos estrategias mejores e innovadoras para medir resultados\u201d.<sup data-fn=\"73c43d59-914d-45af-9856-e8e3fb27b829\" class=\"fn\"><a href=\"#73c43d59-914d-45af-9856-e8e3fb27b829\" id=\"73c43d59-914d-45af-9856-e8e3fb27b829-link\">325<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Una serie de an\u00e1lisis de citas bibliogr\u00e1ficas sirvi\u00f3 para demostrar que los investigadores que estudian el trastorno depresivo mayor en humanos rara vez citan resultados de experimentos en ratas o monos, dos de las especies m\u00e1s usadas en este campo. En su lugar, se basan con mayor frecuencia en los resultados de investigaciones con c\u00e9lulas humanas y datos biol\u00f3gicos humano.<sup data-fn=\"2cbc6467-404a-40a5-a811-4cafa6e7323c\" class=\"fn\"><a href=\"#2cbc6467-404a-40a5-a811-4cafa6e7323c\" id=\"2cbc6467-404a-40a5-a811-4cafa6e7323c-link\">326<\/a><\/sup><sup data-fn=\"19c00b04-2260-4382-b5c4-0ec626ca2cf0\" class=\"fn\"><a href=\"#19c00b04-2260-4382-b5c4-0ec626ca2cf0\" id=\"19c00b04-2260-4382-b5c4-0ec626ca2cf0-link\">327<\/a><\/sup><sup data-fn=\"a3d63714-be52-43f5-b22f-067ac761d110\" class=\"fn\"><a href=\"#a3d63714-be52-43f5-b22f-067ac761d110\" id=\"a3d63714-be52-43f5-b22f-067ac761d110-link\">328<\/a><\/sup> Los experimentos en animales tampoco han contribuido al conocimiento cl\u00ednico en la investigaci\u00f3n de la depresi\u00f3n bipolar,<sup data-fn=\"f7b711be-9c6e-473b-8f65-f1ffaa1a52df\" class=\"fn\"><a href=\"#f7b711be-9c6e-473b-8f65-f1ffaa1a52df\" id=\"f7b711be-9c6e-473b-8f65-f1ffaa1a52df-link\">329<\/a><\/sup> y se han se\u00f1alado como la principal causa del fracaso de los medicamentos en los ensayos cl\u00ednicos neuroconductuales.<sup data-fn=\"10cd95b2-cd00-4032-9a50-00a8e4ac720b\" class=\"fn\"><a href=\"#10cd95b2-cd00-4032-9a50-00a8e4ac720b\" id=\"10cd95b2-cd00-4032-9a50-00a8e4ac720b-link\">330<\/a><\/sup> A pesar de esto, miles de investigadores han seguido usando pruebas deficientes como la de nado forzado para sacar conclusiones err\u00f3neas sobre el estado de \u00e1nimo de un animal<sup data-fn=\"461ca1ab-6fb9-4155-b15b-a75736395edc\" class=\"fn\"><a href=\"#461ca1ab-6fb9-4155-b15b-a75736395edc\" id=\"461ca1ab-6fb9-4155-b15b-a75736395edc-link\">331<\/a><\/sup> o los efectos potenciales de los compuestos en los trastornos depresivos humanos.<sup data-fn=\"ffb83547-3d7b-46ac-8ff0-4c6a15a9993c\" class=\"fn\"><a href=\"#ffb83547-3d7b-46ac-8ff0-4c6a15a9993c\" id=\"ffb83547-3d7b-46ac-8ff0-4c6a15a9993c-link\">332<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las enormes diferencias fisiol\u00f3gicas entre los humanos y otros animales contribuyen a la baja tasa de traslaci\u00f3n. Por ejemplo, el gen que codifica la tirosina hidroxilasa, la enzima involucrada en la formaci\u00f3n de dopamina, se regula de forma diferente en los humanos que en los ratones.<sup data-fn=\"66d85322-bc6a-4931-9993-e0e3fb65598c\" class=\"fn\"><a href=\"#66d85322-bc6a-4931-9993-e0e3fb65598c\" id=\"66d85322-bc6a-4931-9993-e0e3fb65598c-link\">333<\/a><\/sup> La mala regulaci\u00f3n de la tirosina hidroxilasa se ha visto implicada en varias enfermedades psiqui\u00e1tricas, como el trastorno bipolar y la esquizofrenia. En un estudio publicado en <em>Nature<\/em> en2019, 64&nbsp;investigadores analizaron los cerebros de ratones y humanos y encontraron diferencias sustanciales entre especies en los tipos de c\u00e9lulas cerebrales y las formas en que producen prote\u00ednas imprescindibles para la funci\u00f3n neuropsiqui\u00e1trica. Los autores se\u00f1alaron numerosos \u201cfracasos en el uso del rat\u00f3n para estudios precl\u00ednicos\u201d debido a \u201ctantas diferencias [entre especies] en la organizaci\u00f3n celular de la expresi\u00f3n g\u00e9nica\u201d.<sup data-fn=\"e2e0f43d-54d5-44a7-823e-2828119473d8\" class=\"fn\"><a href=\"#e2e0f43d-54d5-44a7-823e-2828119473d8\" id=\"e2e0f43d-54d5-44a7-823e-2828119473d8-link\">334<\/a><\/sup> Los roedores y los humanos tambi\u00e9n difieren en otras \u00e1reas cr\u00edticas para la investigaci\u00f3n neuropsiqui\u00e1trica, como la diversidad, la organizaci\u00f3n y el volumen de los tipos de c\u00e9lulas neuronales, los circuitos neuronales relevantes, el volumen de neurotransmisores disponibles en tipos celulares espec\u00edficos y la disponibilidad y cin\u00e9tica de los receptores de neurotransmisores.<sup data-fn=\"ad0c603b-47da-4e3b-8c00-382ab2cc7884\" class=\"fn\"><a href=\"#ad0c603b-47da-4e3b-8c00-382ab2cc7884\" id=\"ad0c603b-47da-4e3b-8c00-382ab2cc7884-link\">335<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">M\u00e1s all\u00e1 de la falta de aplicabilidad, los modelos neuropsiqui\u00e1tricos animales causan un inmenso sufrimiento. Para inducir la \u201cdepresi\u00f3n\u201d, los experimentadores someten a los animales a un dolor incontrolable mediante descargas el\u00e9ctricas o estresores cr\u00f3nicos, como inmovilizarlos durante largos per\u00edodos, negarles la comida o el agua, inclinar las jaulas, forzarlos a vivir en lechos mojados, sacudirlos o alterar sus ritmos circadianos. A menudo, se obliga a los animales a vivir completamente aislados de otros miembros de su especie, acosados y agredidos f\u00edsicamente por otros animales, privados de cuidados parentales y sometidos a manipulaciones gen\u00e9ticas o quir\u00fargicas para inducirles un estado mental alterado o similar a la depresi\u00f3n. En este campo en particular, \u201ces probable que los animales sean sometidos a procedimientos experimentales que no aportan el beneficio epist\u00e9mico por el que los sacrificamos\u201d.<sup data-fn=\"56c06caf-27d2-45d6-bd6f-96d9c7e23157\" class=\"fn\"><a href=\"#56c06caf-27d2-45d6-bd6f-96d9c7e23157\" id=\"56c06caf-27d2-45d6-bd6f-96d9c7e23157-link\">336<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los recursos financieros deben reorientarse hacia m\u00e9todos experimentales relevantes, basados en la biolog\u00eda humana, incluidos los siguientes:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Organoides cerebrales humanos: cultivos avanzados de c\u00e9lulas cerebrales humanas <em>in vitro<\/em> y 3D que reproducen la organizaci\u00f3n celular y las se\u00f1ales del tejido cerebral humano. Se han usado para estudiar los trastornos del estado de \u00e1nimo, las psicosis y la neurodivergencia.<sup data-fn=\"cf80c8c8-283b-4b42-b9c1-83914b277c9e\" class=\"fn\"><a href=\"#cf80c8c8-283b-4b42-b9c1-83914b277c9e\" id=\"cf80c8c8-283b-4b42-b9c1-83914b277c9e-link\">337<\/a><\/sup><sup data-fn=\"cfaa5c04-0e1d-49c9-ab46-3478a46d5055\" class=\"fn\"><a href=\"#cfaa5c04-0e1d-49c9-ab46-3478a46d5055\" id=\"cfaa5c04-0e1d-49c9-ab46-3478a46d5055-link\">338<\/a><\/sup><sup data-fn=\"40f25b41-71f5-487c-8a09-557d3a7239bf\" class=\"fn\"><a href=\"#40f25b41-71f5-487c-8a09-557d3a7239bf\" id=\"40f25b41-71f5-487c-8a09-557d3a7239bf-link\">339<\/a><\/sup><sup data-fn=\"62aaba4c-f8dd-4c16-a08d-a9291860872b\" class=\"fn\"><a href=\"#62aaba4c-f8dd-4c16-a08d-a9291860872b\" id=\"62aaba4c-f8dd-4c16-a08d-a9291860872b-link\">340<\/a><\/sup> Los organoides pueden combinarse para formar ensambloides autoorganizados que imitan interacciones complejas entre distintas partes del cerebro,<sup data-fn=\"04c6d376-007b-4984-a980-ea0c394298ef\" class=\"fn\"><a href=\"#04c6d376-007b-4984-a980-ea0c394298ef\" id=\"04c6d376-007b-4984-a980-ea0c394298ef-link\">341<\/a><\/sup><sup data-fn=\"49701689-071a-469a-8f89-96348f80a41a\" class=\"fn\"><a href=\"#49701689-071a-469a-8f89-96348f80a41a\" id=\"49701689-071a-469a-8f89-96348f80a41a-link\">342<\/a><\/sup> como el circuito c\u00f3rtico-estriatal-tal\u00e1mico-cortical y los ensambloides t\u00e1lamo-corticales desarrollados recientemente por un equipo de la Universidad de Stanford para estudiar afecciones de neurodesarrollo humano como el autismo, el s\u00edndrome de Tourette y la esquizofrenia.<sup data-fn=\"eff889ea-73f1-4833-b314-b41ce2e4872b\" class=\"fn\"><a href=\"#eff889ea-73f1-4833-b314-b41ce2e4872b\" id=\"eff889ea-73f1-4833-b314-b41ce2e4872b-link\">343<\/a><\/sup><sup data-fn=\"645fe329-137e-4c03-93a9-57491fdef324\" class=\"fn\"><a href=\"#645fe329-137e-4c03-93a9-57491fdef324\" id=\"645fe329-137e-4c03-93a9-57491fdef324-link\">344<\/a><\/sup> Investigadores de la Universidad de California en San Diego y de la Universidad de Massachusetts en Amherst est\u00e1n desarrollando organoides cerebrales para enfermedades espec\u00edficas y aplicaciones terap\u00e9uticas a partir de c\u00e9lulas de pacientes con mutaciones gen\u00e9ticas vinculadas a trastornos neuropsiqui\u00e1tricos.<sup data-fn=\"9f130a40-a0ec-4328-81ed-3b0324dffba4\" class=\"fn\"><a href=\"#9f130a40-a0ec-4328-81ed-3b0324dffba4\" id=\"9f130a40-a0ec-4328-81ed-3b0324dffba4-link\">345<\/a><\/sup><sup data-fn=\"72ee992e-0472-41b7-ae34-82d3a862dc9a\" class=\"fn\"><a href=\"#72ee992e-0472-41b7-ae34-82d3a862dc9a\" id=\"72ee992e-0472-41b7-ae34-82d3a862dc9a-link\">346<\/a><\/sup><sup data-fn=\"3910c00c-f1db-422f-a179-6bfd160a9cee\" class=\"fn\"><a href=\"#3910c00c-f1db-422f-a179-6bfd160a9cee\" id=\"3910c00c-f1db-422f-a179-6bfd160a9cee-link\">347<\/a><\/sup><\/li>\n\n\n\n<li>Investigaci\u00f3n \u00f3mica: se est\u00e1 aplicando para comprender mejor los fundamentos de las afecciones neuropsiqui\u00e1tricas humanas. El Consorcio PsychENCODE, una coalici\u00f3n de equipos multidisciplinarios, usa m\u00e9todos de vanguardia para crear grandes bases de datos a partir de muestras de cerebro humano <em>post mortem<\/em>.<sup data-fn=\"75310f32-3c8b-493a-8f8f-e724cbd50d97\" class=\"fn\"><a href=\"#75310f32-3c8b-493a-8f8f-e724cbd50d97\" id=\"75310f32-3c8b-493a-8f8f-e724cbd50d97-link\">348<\/a><\/sup> Algunos equipos analizan los datos existentes para caracterizar las variantes gen\u00e9ticas relacionadas con estos trastornos.<sup data-fn=\"b5a77dda-c499-4768-9dd3-9444735b707a\" class=\"fn\"><a href=\"#b5a77dda-c499-4768-9dd3-9444735b707a\" id=\"b5a77dda-c499-4768-9dd3-9444735b707a-link\">349<\/a><\/sup><\/li>\n\n\n\n<li>Im\u00e1genes cerebrales: t\u00e9cnicas como la magnetoencefalograf\u00eda, la electroencefalograf\u00eda de alta densidad, la espectroscop\u00eda de resonancia magn\u00e9tica, la morfometr\u00eda basada en transporte y la resonancia magn\u00e9tica funcional, a menudo combinadas con el aprendizaje autom\u00e1tico y la gen\u00f3mica, se est\u00e1n usando para estudiar las afecciones psiqui\u00e1tricas humanas y la neurodivergencia directamente en personas que viven con estas condiciones.<sup data-fn=\"e95708ec-9c5c-499a-af7d-d97da684ee59\" class=\"fn\"><a href=\"#e95708ec-9c5c-499a-af7d-d97da684ee59\" id=\"e95708ec-9c5c-499a-af7d-d97da684ee59-link\">350<\/a><\/sup><sup data-fn=\"52842d9d-5897-4519-8652-6238040bd79c\" class=\"fn\"><a href=\"#52842d9d-5897-4519-8652-6238040bd79c\" id=\"52842d9d-5897-4519-8652-6238040bd79c-link\">351<\/a><\/sup><sup data-fn=\"a62f2103-16d6-4119-bf8c-6ef909497ce4\" class=\"fn\"><a href=\"#a62f2103-16d6-4119-bf8c-6ef909497ce4\" id=\"a62f2103-16d6-4119-bf8c-6ef909497ce4-link\">352<\/a><\/sup><sup data-fn=\"fb25b73c-00f8-4933-8aa3-fea428d33690\" class=\"fn\"><a href=\"#fb25b73c-00f8-4933-8aa3-fea428d33690\" id=\"fb25b73c-00f8-4933-8aa3-fea428d33690-link\">353<\/a><\/sup><sup data-fn=\"3d0b3e37-06b7-409d-bbb1-1edad662cca2\" class=\"fn\"><a href=\"#3d0b3e37-06b7-409d-bbb1-1edad662cca2\" id=\"3d0b3e37-06b7-409d-bbb1-1edad662cca2-link\">354<\/a><\/sup><\/li>\n\n\n\n<li>Estudios longitudinales: el seguimiento de los individuos durante per\u00edodos prolongados permite obtener informaci\u00f3n sobre los efectos de los est\u00edmulos ambientales, los antecedentes m\u00e9dicos y los acontecimientos vitales en la incidencia y la progresi\u00f3n de las afecciones del neurodesarrollo.<sup data-fn=\"f755388f-8bb7-4686-8c1a-010a06c3b97a\" class=\"fn\"><a href=\"#f755388f-8bb7-4686-8c1a-010a06c3b97a\" id=\"f755388f-8bb7-4686-8c1a-010a06c3b97a-link\">355<\/a><\/sup><sup data-fn=\"9b6f7cbc-b839-4867-b28c-37af2caa2714\" class=\"fn\"><a href=\"#9b6f7cbc-b839-4867-b28c-37af2caa2714\" id=\"9b6f7cbc-b839-4867-b28c-37af2caa2714-link\">356<\/a><\/sup><\/li>\n\n\n\n<li>Ensayos cl\u00ednicos<em> <em>in silico<\/em><\/em>: se han usado modelos virtuales de pacientes para evaluar el potencial de medicamentos para afecciones como el trastorno por d\u00e9ficit de atenci\u00f3n con hiperactividad y la esquizofrenia.<sup data-fn=\"44c88bc5-46b1-41b6-8636-2d25573e24e1\" class=\"fn\"><a href=\"#44c88bc5-46b1-41b6-8636-2d25573e24e1\" id=\"44c88bc5-46b1-41b6-8636-2d25573e24e1-link\">357<\/a><\/sup><sup data-fn=\"635c7069-655c-4a7a-b847-a653310086b0\" class=\"fn\"><a href=\"#635c7069-655c-4a7a-b847-a653310086b0\" id=\"635c7069-655c-4a7a-b847-a653310086b0-link\">358<\/a><\/sup><\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Dada la angustia que se causa a los animales y la inaplicabilidad de los resultados a los humanos, deber\u00eda eliminarse el uso de animales en experimentos de neuropsiquiatr\u00eda y neurodivergencia humanas. Los recursos financieros deben orientarse hacia la investigaci\u00f3n basada en la biolog\u00eda humana, como los ejemplos citados anteriormente.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Preparaci\u00f3n ante una pandemia<\/strong>&nbsp;&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Decir que la pandemia del COVID-19 cambi\u00f3 la vida tal como la conoc\u00edamos es quedarse corto. Sin embargo, algo que se puede rescatar es su potencial para conducir a una era completamente nueva de investigaci\u00f3n biom\u00e9dica y desarrollo de vacunas. Para acelerar el desarrollo de la vacuna contra el COVID-19, tanto la FDA como los NIH autorizaron ensayos cl\u00ednicos de vacunas en humanos sin exigir exhaustivas pruebas en animales previamente. En su lugar, las pruebas en humanos y animales se realizaron de forma paralela,<sup data-fn=\"631ed052-332a-4871-a503-304085e05104\" class=\"fn\"><a href=\"#631ed052-332a-4871-a503-304085e05104\" id=\"631ed052-332a-4871-a503-304085e05104-link\">359<\/a><\/sup> un cambio que PETA inst\u00f3 a la FDA a extender a todos los f\u00e1rmacos nuevos en desarrollo (comunicaci\u00f3n por correo electr\u00f3nico, 5 de mayo de 2020, <a href=\"https:\/\/app-science-peta-prod-eastus2.azurewebsites.net\/wp-content\/uploads\/2026\/03\/FDA_Commissioner_COVID-19_letter-20200505.pdf\" target=\"_blank\" rel=\"noreferrer noopener\">science.peta.org\/wp-content\/uploads\/sites\/6\/2026\/03\/FDA_Commissioner_COVID-19_letter-20200505.pdf<\/a> ).<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-12&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-12-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-12\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-12\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-12-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Aunque la urgencia fue un factor evidente en esta decisi\u00f3n, es esencial se\u00f1alar que muchas especies no responden a la infecci\u00f3n por SARS-CoV-2 de la misma manera que los humanos. Cuando <em>The New York Times<\/em> pregunt\u00f3 sobre los resultados aparentemente prometedores en macacos Rhesus, Malcolm Martin, vir\u00f3logo de los NIH, \u201cadvirti\u00f3 que los monos son diferentes de los humanos en aspectos importantes\u201d.<sup data-fn=\"bb996f9c-ea71-434b-afd1-4dfad51260c3\" class=\"fn\"><a href=\"#bb996f9c-ea71-434b-afd1-4dfad51260c3\" id=\"bb996f9c-ea71-434b-afd1-4dfad51260c3-link\">360<\/a><\/sup> El entrevistador se\u00f1al\u00f3 que \u201clos monos no vacunados en [el experimento] no desarrollaron ninguno de los s\u00edntomas graves que algunas personas presentan tras la infecci\u00f3n por coronavirus; seg\u00fan Martin, solo \u201cparece que estuvieran resfriados\u201d.<sup data-fn=\"144630d0-7843-4f94-8ad5-fefb0694d349\" class=\"fn\"><a href=\"#144630d0-7843-4f94-8ad5-fefb0694d349\" id=\"144630d0-7843-4f94-8ad5-fefb0694d349-link\">361<\/a><\/sup> Incluso los ratones modificados gen\u00e9ticamente, a quienes se hace susceptibles a la enfermedad, solo muestran s\u00edntomas leves. Los ratones \u201chumanizados\u201d (dise\u00f1ados para expresar factores inmunol\u00f3gicos humanos) no resuelven este problema, ya que \u201cmuchos factores humanos reaccionan de forma cruzada con c\u00e9lulas murinas, lo que puede causar cambios fenot\u00edpicos inesperados\u201d.<sup data-fn=\"9d652e52-1ad6-4e0b-8357-2cf52c9512c7\" class=\"fn\"><a href=\"#9d652e52-1ad6-4e0b-8357-2cf52c9512c7\" id=\"9d652e52-1ad6-4e0b-8357-2cf52c9512c7-link\">362<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Con la pandemia de COVID-19 y los brotes de otras enfermedades infecciosas como la H5N1, se ha hecho m\u00e1s claro que la investigaci\u00f3n sobre estas enfermedades y la preparaci\u00f3n para afrontar pandemias potenciales deben priorizarse. Los m\u00e9todos relevantes para los humanos pueden liderar este proceso.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Muchos equipos cient\u00edficos est\u00e1n usando m\u00e9todos innovadores sin animales para estudiar los pat\u00f3genos existentes y los que tienen potencial pand\u00e9mico. Estos m\u00e9todos incluyen organoides pulmonares e intestinales humanos, modelos de tejidos respiratorios humanos reconstruidos tridimensionalmente, muestras de tejidos orales humanos de voluntarios sanos, simulaci\u00f3n computacional avanzada y supercomputadores, an\u00e1lisis gen\u00e9ticos humanos, ensayos cl\u00ednicos de provocaci\u00f3n en humanos, anticuerpos derivados de humanos y \u00f3rganos en chips humanos que modelan los pulmones, la boca, los ojos, la nariz y los intestinos humanos. Se espera que los modelos humanos <em>in vitro<\/em> complejos, como los organoides y los \u00f3rganos en chip, sean especialmente valiosos para la investigaci\u00f3n de enfermedades infecciosas y el desarrollo de vacunas y medicamentos antivirales.<sup data-fn=\"373448ee-683a-4b04-9597-572c1b5a7de2\" class=\"fn\"><a href=\"#373448ee-683a-4b04-9597-572c1b5a7de2\" id=\"373448ee-683a-4b04-9597-572c1b5a7de2-link\">363<\/a><\/sup><sup data-fn=\"e6dea537-908f-4b0c-9480-14f5795949b1\" class=\"fn\"><a href=\"#e6dea537-908f-4b0c-9480-14f5795949b1\" id=\"e6dea537-908f-4b0c-9480-14f5795949b1-link\">364<\/a><\/sup><sup data-fn=\"8ff615ed-1d18-4610-a1c2-42ad26a70a9f\" class=\"fn\"><a href=\"#8ff615ed-1d18-4610-a1c2-42ad26a70a9f\" id=\"8ff615ed-1d18-4610-a1c2-42ad26a70a9f-link\">365<\/a><\/sup><sup data-fn=\"64e35358-f1e7-4f80-af2e-272dfc96e0e4\" class=\"fn\"><a href=\"#64e35358-f1e7-4f80-af2e-272dfc96e0e4\" id=\"64e35358-f1e7-4f80-af2e-272dfc96e0e4-link\">366<\/a><\/sup><sup data-fn=\"9beaf43b-f224-4306-80f6-cd7c8bf4e721\" class=\"fn\"><a href=\"#9beaf43b-f224-4306-80f6-cd7c8bf4e721\" id=\"9beaf43b-f224-4306-80f6-cd7c8bf4e721-link\">367<\/a><\/sup><sup data-fn=\"ed152674-6dd3-453c-adfb-bd758ba65b96\" class=\"fn\"><a href=\"#ed152674-6dd3-453c-adfb-bd758ba65b96\" id=\"ed152674-6dd3-453c-adfb-bd758ba65b96-link\">368<\/a><\/sup> Estos son algunos ejemplos recientes:&nbsp;<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Se est\u00e1n usando organoides de pulm\u00f3n y cerebro humanos para estudiar los mecanismos de infecci\u00f3n por SARS-CoV-2, evaluar tratamientos potenciales e investigar los efectos del virus en el cerebro de individuos sanos y aquellos con comorbilidades.<sup data-fn=\"ff49183b-ccbc-41df-a8bf-d41dfe7273b6\" class=\"fn\"><a href=\"#ff49183b-ccbc-41df-a8bf-d41dfe7273b6\" id=\"ff49183b-ccbc-41df-a8bf-d41dfe7273b6-link\">369<\/a><\/sup><sup data-fn=\"2df06206-65b6-4a16-b541-341b1b1c7b36\" class=\"fn\"><a href=\"#2df06206-65b6-4a16-b541-341b1b1c7b36\" id=\"2df06206-65b6-4a16-b541-341b1b1c7b36-link\">370<\/a><\/sup><sup data-fn=\"6c9ebdf4-5dba-40a3-b243-7d7fd4339558\" class=\"fn\"><a href=\"#6c9ebdf4-5dba-40a3-b243-7d7fd4339558\" id=\"6c9ebdf4-5dba-40a3-b243-7d7fd4339558-link\">371<\/a><\/sup><sup data-fn=\"755591bc-12f5-47c4-9707-611b12bbd782\" class=\"fn\"><a href=\"#755591bc-12f5-47c4-9707-611b12bbd782\" id=\"755591bc-12f5-47c4-9707-611b12bbd782-link\">372<\/a><\/sup><sup data-fn=\"c39857f0-1282-4745-9fe0-6d880890f7f5\" class=\"fn\"><a href=\"#c39857f0-1282-4745-9fe0-6d880890f7f5\" id=\"c39857f0-1282-4745-9fe0-6d880890f7f5-link\">373<\/a><\/sup><\/li>\n\n\n\n<li>Un equipo japon\u00e9s cre\u00f3 h\u00edgados en chip espec\u00edficos de pacientes para explorar la disfunci\u00f3n hep\u00e1tica inducida por el SARS-CoV-2 y evaluar f\u00e1rmacos para tratarla.<sup data-fn=\"10ff12ed-0301-4ed7-b0b0-ece1deaf5a60\" class=\"fn\"><a href=\"#10ff12ed-0301-4ed7-b0b0-ece1deaf5a60\" id=\"10ff12ed-0301-4ed7-b0b0-ece1deaf5a60-link\">374<\/a><\/sup><\/li>\n\n\n\n<li>A trav\u00e9s de c\u00e9lulas aisladas de tejido pulmonar humano, un equipo dise\u00f1\u00f3 organoides pulmonares humanos para estudiar la replicaci\u00f3n del virus H5N1, la supervivencia de las c\u00e9lulas hu\u00e9sped y las respuestas inmunitarias pulmonares a diferentes cepas virales.<sup data-fn=\"3fea169c-56bc-47ad-8a48-9565778ab980\" class=\"fn\"><a href=\"#3fea169c-56bc-47ad-8a48-9565778ab980\" id=\"3fea169c-56bc-47ad-8a48-9565778ab980-link\">375<\/a><\/sup><\/li>\n\n\n\n<li>De acuerdo con un an\u00e1lisis reciente, \u201clos sistemas microfisiol\u00f3gicos y los organoides ya se utilizan en la I+D farmac\u00e9utica porque est\u00e1n prefigurados para superar la brecha traslacional entre los sistemas modelo y los estudios cl\u00ednicos\u201d.<sup data-fn=\"d224f830-fdf4-4e89-93ec-d969dd1aae7d\" class=\"fn\"><a href=\"#d224f830-fdf4-4e89-93ec-d969dd1aae7d\" id=\"d224f830-fdf4-4e89-93ec-d969dd1aae7d-link\">376<\/a><\/sup> El an\u00e1lisis concluy\u00f3 que &nbsp;los sistemas complejos derivados de humanos, como los organoides y los sistemas microfisiol\u00f3gicos, ser\u00e1n esenciales para la investigaci\u00f3n sobre la infecci\u00f3n por filovirus y bornavirus en humanos, para los que \u201clos modelos animales no pueden captar las correspondientes patog\u00e9nesis y enfermedad en su totalidad\u201d.<sup data-fn=\"fa3da7c4-1f25-4fca-9f2f-ef2e38f63491\" class=\"fn\"><a href=\"#fa3da7c4-1f25-4fca-9f2f-ef2e38f63491\" id=\"fa3da7c4-1f25-4fca-9f2f-ef2e38f63491-link\">377<\/a><\/sup><\/li>\n\n\n\n<li>El virus respiratorio sincitial se est\u00e1 estudiando con muestras <em>ex vivo<\/em> de pacientes para determinar por qu\u00e9 algunos tienen una reacci\u00f3n m\u00e1s grave a la infecci\u00f3n<sup data-fn=\"c7492489-64fb-4dc4-a070-e35a44606b5d\" class=\"fn\"><a href=\"#c7492489-64fb-4dc4-a070-e35a44606b5d\" id=\"c7492489-64fb-4dc4-a070-e35a44606b5d-link\">378<\/a><\/sup> y con organoides de v\u00edas respiratorias humanas para desarrollar y probar tratamientos con anticuerpos.<sup data-fn=\"c1d71a5d-5536-406e-b897-30f225b653cb\" class=\"fn\"><a href=\"#c1d71a5d-5536-406e-b897-30f225b653cb\" id=\"c1d71a5d-5536-406e-b897-30f225b653cb-link\">379<\/a><\/sup><\/li>\n\n\n\n<li>Se ha estudiado a personas con s\u00edndromes posinfecciosos como el COVID prolongado y el s\u00edndrome de encefalomielitis mi\u00e1lgica\/fatiga cr\u00f3nica mediante im\u00e1genes cerebrales, an\u00e1lisis de biopsias de piel, sangre y l\u00edquido cefalorraqu\u00eddeo, seguimiento de la alimentaci\u00f3n, el sue\u00f1o y los par\u00e1metros card\u00edacos, entre otros, para determinar el fenotipo de estas afecciones, comprender c\u00f3mo se producen y explorar posibles tratamientos.<sup data-fn=\"4551c279-9048-4cb0-84c2-f08a1b31b2d8\" class=\"fn\"><a href=\"#4551c279-9048-4cb0-84c2-f08a1b31b2d8\" id=\"4551c279-9048-4cb0-84c2-f08a1b31b2d8-link\">380<\/a><\/sup><\/li>\n\n\n\n<li>Se han utilizado herramientas <em>in silico<\/em> en estudios para identificar nuevos usos de medicamentos existentes para el tratamiento del COVID-19.<sup data-fn=\"96a33d3b-142e-4b89-a4d4-914cd3024804\" class=\"fn\"><a href=\"#96a33d3b-142e-4b89-a4d4-914cd3024804\" id=\"96a33d3b-142e-4b89-a4d4-914cd3024804-link\">381<\/a><\/sup><\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s de adoptar m\u00e9todos sin animales para evaluar y desarrollar tratamientos, es a\u00fan m\u00e1s apremiante tomar medidas para prevenir la propagaci\u00f3n de pat\u00f3genos emergentes. Poner fin a la importaci\u00f3n de especies silvestres hacia los laboratorios para su experimentaci\u00f3n es un paso clave. Los macacos de cola larga y los macacos Rhesus son los primates no humanos m\u00e1s usados en experimentaci\u00f3n, la especie de primate m\u00e1s comercializada y la que alberga el mayor volumen de posibles enfermedades zoon\u00f3ticas.<sup data-fn=\"bd4db79e-2652-4294-aa48-4c8e226cc8f4\" class=\"fn\"><a href=\"#bd4db79e-2652-4294-aa48-4c8e226cc8f4\" id=\"bd4db79e-2652-4294-aa48-4c8e226cc8f4-link\">382<\/a><\/sup><sup data-fn=\"f57a02e5-7129-49a1-8601-4be949222377\" class=\"fn\"><a href=\"#f57a02e5-7129-49a1-8601-4be949222377\" id=\"f57a02e5-7129-49a1-8601-4be949222377-link\">383<\/a><\/sup> Aunque los proveedores y compradores de primates dicen apoyar los esfuerzos para reducir el uso en la investigaci\u00f3n de macacos capturados en la naturaleza, se ha revelado que los proveedores internacionales han etiquetado falsamente a estos animales como reproducidos en cautiverio y los han vendido a laboratorios.<sup data-fn=\"e403585c-97ae-48cb-84ad-f55190da4c36\" class=\"fn\"><a href=\"#e403585c-97ae-48cb-84ad-f55190da4c36\" id=\"e403585c-97ae-48cb-84ad-f55190da4c36-link\">384<\/a><\/sup> Esta pr\u00e1ctica implica un riesgo de propagaci\u00f3n de enfermedades y compromete los resultados de los experimentos realizados en dichos animales, cuyos antecedentes de salud se desconocen.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Son comunes la captura y la importaci\u00f3n de macacos provenientes de regiones donde es end\u00e9mica la melioidosis, una enfermedad potencialmente mortal causada por <em>Burkholderia pseudomallei<\/em>. Aunque los Centros para el Control y la Prevenci\u00f3n de Enfermedades de EE. UU. (CDC) exigen que los monos importados de estas regiones se sometan a una cuarentena obligatoria, la<em> B. pseudomallei <\/em>puede permanecer latente durante largos per\u00edodos y se han confinado animales en laboratorios cuando a\u00fan estaban infectados.<sup data-fn=\"3bfc99c5-89e1-4a25-986a-a53a30bdae5f\" class=\"fn\"><a href=\"#3bfc99c5-89e1-4a25-986a-a53a30bdae5f\" id=\"3bfc99c5-89e1-4a25-986a-a53a30bdae5f-link\">385<\/a><\/sup> Tambi\u00e9n se han importado macacos que albergaban micobacterias causantes de tuberculosis.<sup data-fn=\"a6777a7b-9c4f-47f0-bafb-4f077ce56f56\" class=\"fn\"><a href=\"#a6777a7b-9c4f-47f0-bafb-4f077ce56f56\" id=\"a6777a7b-9c4f-47f0-bafb-4f077ce56f56-link\">386<\/a><\/sup><sup data-fn=\"ff8ab1a3-ff0f-41d5-b214-db885d564bfe\" class=\"fn\"><a href=\"#ff8ab1a3-ff0f-41d5-b214-db885d564bfe\" id=\"ff8ab1a3-ff0f-41d5-b214-db885d564bfe-link\">387<\/a><\/sup> Seg\u00fan los CDC, \u201cen Estados Unidos, no existe un sistema centralizado para notificar TB en NHPs que no est\u00e9n en cuarentena seg\u00fan lo exigido por los CDC (un m\u00ednimo de 31 d\u00edas tras la importaci\u00f3n). Por lo tanto, se desconoce qu\u00e9 tan frecuente es la TB en los NHP en Estados Unidos\u201d.<sup data-fn=\"f993a22d-b249-40ac-8f79-5fa6805de934\" class=\"fn\"><a href=\"#f993a22d-b249-40ac-8f79-5fa6805de934\" id=\"f993a22d-b249-40ac-8f79-5fa6805de934-link\">388<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Acabar con el comercio mundial de monos para experimentaci\u00f3n eliminar\u00eda un importante factor de riesgo en la propagaci\u00f3n de enfermedades zoon\u00f3ticas, reducir\u00eda la difusi\u00f3n de datos no confiables derivados de animales de origen desconocido y estimular\u00eda el avance hacia m\u00e9todos de investigaci\u00f3n relevantes para los humanos. Se trata de un paso crucial para proteger la salud p\u00fablica y prevenir la pr\u00f3xima pandemia.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\">Accidente cerebrovascular<\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">El accidente cerebrovascular (ACV), una enfermedad grave que afecta a los vasos sangu\u00edneos del cerebro, es una de las principales causas de muerte y discapacidad en el continente americano.<sup data-fn=\"0a2f23b5-c867-495b-a162-e9c14045b93e\" class=\"fn\"><a href=\"#0a2f23b5-c867-495b-a162-e9c14045b93e\" id=\"0a2f23b5-c867-495b-a162-e9c14045b93e-link\">389<\/a><\/sup> El ACV se produce cuando se interrumpe el flujo sangu\u00edneo al cerebro, ya sea por un co\u00e1gulo (ictus isqu\u00e9mico) o por la rotura de un vaso sangu\u00edneo (ictus hemorr\u00e1gico), lo que causa da\u00f1os y la muerte de c\u00e9lulas cerebrales por falta de ox\u00edgeno. Tras un accidente cerebrovascular isqu\u00e9mico, la recanalizaci\u00f3n (restablecimiento del flujo sangu\u00edneo al cerebro) es el \u00fanico tratamiento inmediato disponible en la fase aguda.<sup data-fn=\"2d0f7a5d-a3d3-4e54-b29c-ca5388087736\" class=\"fn\"><a href=\"#2d0f7a5d-a3d3-4e54-b29c-ca5388087736\" id=\"2d0f7a5d-a3d3-4e54-b29c-ca5388087736-link\">390<\/a><\/sup> Cuando es posible, la terapia endovascular es el tratamiento est\u00e1ndar para el ictus isqu\u00e9mico, pero solo es eficaz en aproximadamente el 25% de los casos.<sup data-fn=\"eaeb746d-c222-44f6-b0d4-f4e74075388b\" class=\"fn\"><a href=\"#eaeb746d-c222-44f6-b0d4-f4e74075388b\" id=\"eaeb746d-c222-44f6-b0d4-f4e74075388b-link\">391<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-13&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-13-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-13\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-13\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-13-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">A pesar de que m\u00e1s de mil medicamentos neuroprotectores han resultado prometedores en modelos animales, ninguno se ha traducido en tratamientos eficaces para el ACV en humanos.<sup data-fn=\"eb60afbf-5adb-4991-b61e-9cc44e9cb661\" class=\"fn\"><a href=\"#eb60afbf-5adb-4991-b61e-9cc44e9cb661\" id=\"eb60afbf-5adb-4991-b61e-9cc44e9cb661-link\">392<\/a><\/sup> Nuestra comprensi\u00f3n de los procesos biol\u00f3gicos que promueven la recuperaci\u00f3n de los humanos frente a un ACV sigue siendo limitada,<sup data-fn=\"5f1a8344-e9fc-4d16-a763-acc54b7f036b\" class=\"fn\"><a href=\"#5f1a8344-e9fc-4d16-a763-acc54b7f036b\" id=\"5f1a8344-e9fc-4d16-a763-acc54b7f036b-link\">393<\/a><\/sup> y el desarrollo de modelos precisos del sistema nervioso central es un reto debido a la complejidad del cerebro humano. Los modelos animales actuales, que usan principalmente ratas, carecen de caracter\u00edsticas humanas esenciales, difieren de los humanos en la recuperaci\u00f3n del ACV y plantean problemas \u00e9ticos.<sup data-fn=\"edfdae4a-5ee1-41a1-9330-74975e1d31a5\" class=\"fn\"><a href=\"#edfdae4a-5ee1-41a1-9330-74975e1d31a5\" id=\"edfdae4a-5ee1-41a1-9330-74975e1d31a5-link\">394<\/a><\/sup><sup data-fn=\"5da4d2a4-b809-4100-bad0-5b91ab5214ee\" class=\"fn\"><a href=\"#5da4d2a4-b809-4100-bad0-5b91ab5214ee\" id=\"5da4d2a4-b809-4100-bad0-5b91ab5214ee-link\">395<\/a><\/sup> Por ejemplo, el ictus isqu\u00e9mico suele presentarse en adultos mayores con comorbilidades, mientras que los experimentos se llevan a cabo predominantemente en animales j\u00f3venes y sanos que, a menudo, muestran una recuperaci\u00f3n espont\u00e1nea.<sup data-fn=\"34edb820-89da-48a7-bf8c-5e0031661029\" class=\"fn\"><a href=\"#34edb820-89da-48a7-bf8c-5e0031661029\" id=\"34edb820-89da-48a7-bf8c-5e0031661029-link\">396<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las diferencias significativas en la composici\u00f3n del cerebro \u2013como que la sustancia blanca constituya el 60% del cerebro humano, pero solo el 10% del cerebro de rat\u00f3n\u2013<sup data-fn=\"f8092f5e-63fa-44c9-98e1-04e8c02f0acd\" class=\"fn\"><a href=\"#f8092f5e-63fa-44c9-98e1-04e8c02f0acd\" id=\"f8092f5e-63fa-44c9-98e1-04e8c02f0acd-link\">397<\/a><\/sup> y las variaciones en la fisiolog\u00eda de la barrera hematoencef\u00e1lica<sup data-fn=\"e1bacd73-eaf2-4aee-8b27-2218c3de4262\" class=\"fn\"><a href=\"#e1bacd73-eaf2-4aee-8b27-2218c3de4262\" id=\"e1bacd73-eaf2-4aee-8b27-2218c3de4262-link\">398<\/a><\/sup><sup data-fn=\"da0d54b4-afcf-441d-a62b-38be76628208\" class=\"fn\"><a href=\"#da0d54b4-afcf-441d-a62b-38be76628208\" id=\"da0d54b4-afcf-441d-a62b-38be76628208-link\">399<\/a><\/sup> desempe\u00f1an funciones cruciales en la patolog\u00eda del ACV. Adem\u00e1s, las diferencias en la composici\u00f3n de los co\u00e1gulos, la funci\u00f3n neuronal y los procesos inflamatorios entre especies contribuyen a\u00fan m\u00e1s a la escasa traslaci\u00f3n de los modelos animales en la investigaci\u00f3n del ACV.<sup data-fn=\"76b8b5a8-c7c3-4d91-a334-be8b8ebf756d\" class=\"fn\"><a href=\"#76b8b5a8-c7c3-4d91-a334-be8b8ebf756d\" id=\"76b8b5a8-c7c3-4d91-a334-be8b8ebf756d-link\">400<\/a><\/sup><sup data-fn=\"0eadcbaf-9db9-4784-b39e-268bd7e45112\" class=\"fn\"><a href=\"#0eadcbaf-9db9-4784-b39e-268bd7e45112\" id=\"0eadcbaf-9db9-4784-b39e-268bd7e45112-link\">401<\/a><\/sup><sup data-fn=\"4f3be857-ebad-40e2-a0fa-68d6c55c170b\" class=\"fn\"><a href=\"#4f3be857-ebad-40e2-a0fa-68d6c55c170b\" id=\"4f3be857-ebad-40e2-a0fa-68d6c55c170b-link\">402<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Un an\u00e1lisis de 16&nbsp;evaluaciones sistem\u00e1ticas (que inclu\u00edan 525&nbsp;estudios diferentes) sobre intervenciones para el ACV humano probadas en modelos animales revel\u00f3 que la eficacia de estos experimentos en animales hab\u00eda sido exagerada en aproximadamente un tercio de los estudios debido al sesgo de publicaci\u00f3n (la propensi\u00f3n de los investigadores y las revistas cient\u00edficas a publicar resultados que muestran conclusiones positivas y a omitir estudios con datos negativos o nulos). Los autores de este an\u00e1lisis, publicado en 2010, se\u00f1alaron que \u201clos participantes en ensayos cl\u00ednicos pueden correr riesgos innecesarios si se ha exagerado la eficacia en animales\u201d.<sup data-fn=\"cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d\" class=\"fn\"><a href=\"#cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d\" id=\"cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d-link\">403<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El modelado <em>in silico<\/em> puede sustituir la experimentaci\u00f3n animal en la investigaci\u00f3n del ACV. Proyectos como IN-Silico trials for treatment of acute Ischemic STroke(INSIST) usan pacientes virtuales para simular tratamientos para el ACV y replican caracter\u00edsticas cl\u00ednicas, como las propiedades de los co\u00e1gulos, las formas, estructuras y configuraciones espaciales de los vasos y los antecedentes m\u00e9dicos de los pacientes.<sup data-fn=\"47246d3c-73ca-421f-894a-c2d8eea14a42\" class=\"fn\"><a href=\"#47246d3c-73ca-421f-894a-c2d8eea14a42\" id=\"47246d3c-73ca-421f-894a-c2d8eea14a42-link\">404<\/a><\/sup> Estos modelos, que permiten realizar pruebas virtuales de medicamentos y estudiar de manera detallada la trombosis y la perfusi\u00f3n cerebral en humanos, \u201ctienen el potencial de conducir a un dise\u00f1o m\u00e1s eficaz de los ensayos cl\u00ednicos en humanos, reducir las pruebas en animales, disminuir los costos de desarrollo y acortar el tiempo de comercializaci\u00f3n de nuevos productos m\u00e9dicos\u201d.<sup data-fn=\"dc7f62f1-8e40-4f0d-80e9-2458d3bcb870\" class=\"fn\"><a href=\"#dc7f62f1-8e40-4f0d-80e9-2458d3bcb870\" id=\"dc7f62f1-8e40-4f0d-80e9-2458d3bcb870-link\">405<\/a><\/sup> Un innovador ensayo <em>in silico<\/em> publicado en&nbsp;2021 permiti\u00f3 predecir las respuestas al tratamiento del aneurisma mediante 164&nbsp;pacientes virtuales con 82&nbsp;anatom\u00edas \u00fanicas.<sup data-fn=\"67b971cc-070b-4611-9bdf-c25b9af6a212\" class=\"fn\"><a href=\"#67b971cc-070b-4611-9bdf-c25b9af6a212\" id=\"67b971cc-070b-4611-9bdf-c25b9af6a212-link\">406<\/a><\/sup> Este modelo super\u00f3 a los experimentos en animales e identific\u00f3 nuevos factores de riesgo de fracaso del tratamiento en d\u00edas en lugar de d\u00e9cadas. El modelado virtual tambi\u00e9n puede ayudar a tomar decisiones cl\u00ednicas adaptadas al paciente en casos de ACV y otras afecciones neurol\u00f3gicas. Sin embargo, para hacer avanzar este campo, se necesita urgentemente que se regulen los ensayos <em>in silico<\/em>.<sup data-fn=\"987c44a0-91a1-4d26-b38c-1c064c57b25d\" class=\"fn\"><a href=\"#987c44a0-91a1-4d26-b38c-1c064c57b25d\" id=\"987c44a0-91a1-4d26-b38c-1c064c57b25d-link\">407<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Tambi\u00e9n se est\u00e1n explorando nuevas tecnolog\u00edas y m\u00e9todos para fortalecer el proceso de &nbsp;recuperaci\u00f3n mediante el uso de c\u00e9lulas madre para sustituir el tejido cerebral da\u00f1ado.<sup data-fn=\"a8eea9c0-848b-4cc4-a46f-e4edb52bfb80\" class=\"fn\"><a href=\"#a8eea9c0-848b-4cc4-a46f-e4edb52bfb80\" id=\"a8eea9c0-848b-4cc4-a46f-e4edb52bfb80-link\">408<\/a><\/sup> Recientemente, el tratamiento con c\u00e9lulas madre que usa m\u00e9dula \u00f3sea de pacientes o sangre de cord\u00f3n umbilical alog\u00e9nica ha mostrado mejores resultados neurol\u00f3gicos en ensayos cl\u00ednicos.<sup data-fn=\"40b042b5-436a-48b6-8849-12d4892046b9\" class=\"fn\"><a href=\"#40b042b5-436a-48b6-8849-12d4892046b9\" id=\"40b042b5-436a-48b6-8849-12d4892046b9-link\">409<\/a><\/sup><sup data-fn=\"9588dbd0-4cab-4b03-ae82-7d53c390f868\" class=\"fn\"><a href=\"#9588dbd0-4cab-4b03-ae82-7d53c390f868\" id=\"9588dbd0-4cab-4b03-ae82-7d53c390f868-link\">410<\/a><\/sup><sup data-fn=\"be6adede-e5bd-40c6-ba43-8b7ce3c7b774\" class=\"fn\"><a href=\"#be6adede-e5bd-40c6-ba43-8b7ce3c7b774\" id=\"be6adede-e5bd-40c6-ba43-8b7ce3c7b774-link\">411<\/a><\/sup><sup data-fn=\"7778f291-1832-432e-af97-ef5fd26513a2\" class=\"fn\"><a href=\"#7778f291-1832-432e-af97-ef5fd26513a2\" id=\"7778f291-1832-432e-af97-ef5fd26513a2-link\">412<\/a><\/sup> En la investigaci\u00f3n precl\u00ednica, el aislamiento de c\u00e9lulas madre humanas y de hiPSC ha avanzado el desarrollo de modelos humanos escalables en neurobiolog\u00eda.<sup data-fn=\"01d5c1f8-bd1a-4a87-99ef-5443d725d910\" class=\"fn\"><a href=\"#01d5c1f8-bd1a-4a87-99ef-5443d725d910\" id=\"01d5c1f8-bd1a-4a87-99ef-5443d725d910-link\">413<\/a><\/sup><sup data-fn=\"22a9b601-88ca-4b7f-96f9-5eb244a7f379\" class=\"fn\"><a href=\"#22a9b601-88ca-4b7f-96f9-5eb244a7f379\" id=\"22a9b601-88ca-4b7f-96f9-5eb244a7f379-link\">414<\/a><\/sup> Los sistemas innovadores en 3D, como los \u00f3rganos en chip y los organoides cerebrales,<sup data-fn=\"73ad396d-6e18-4f1d-ad65-3022472d9492\" class=\"fn\"><a href=\"#73ad396d-6e18-4f1d-ad65-3022472d9492\" id=\"73ad396d-6e18-4f1d-ad65-3022472d9492-link\">415<\/a><\/sup><sup data-fn=\"d3c0265e-e376-4e92-a35f-c440a168ac95\" class=\"fn\"><a href=\"#d3c0265e-e376-4e92-a35f-c440a168ac95\" id=\"d3c0265e-e376-4e92-a35f-c440a168ac95-link\">416<\/a><\/sup> pueden imitar las complejas interacciones celulares y la fisiolog\u00eda <em>in vivo<\/em> mejor que los modelos animales, mientras que la impresi\u00f3n en 3D<sup data-fn=\"435807fc-b9b6-404c-92d9-34cbbe802784\" class=\"fn\"><a href=\"#435807fc-b9b6-404c-92d9-34cbbe802784\" id=\"435807fc-b9b6-404c-92d9-34cbbe802784-link\">417<\/a><\/sup> permite la creaci\u00f3n de modelos detallados del sistema nervioso para pruebas precl\u00ednicas de medicamentos y aplicaciones cl\u00ednicas.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Es necesario comprender las interacciones celulares que influyen en la permeabilidad de la barrera hematoencef\u00e1lica, el edema cerebral y las respuestas neurovasculares en condiciones patol\u00f3gicas para modelar con precisi\u00f3n las respuestas isqu\u00e9micas.Dado que estas interacciones afectan en \u00faltima instancia los resultados del ACV, es esencial crear modelos realistas. La combinaci\u00f3n de hiPSC con tecnolog\u00edas avanzadas de cultivo celular ha permitido replicar caracter\u00edsticas espec\u00edficas del sistema nervioso humano. Por ejemplo, se desarroll\u00f3 un modelo vascularizado mediante el cocultivo de esferoides vasculares y cerebrales generados por hiPSCs.<sup data-fn=\"b8d85711-7480-4aaa-9a8f-6031e19eac86\" class=\"fn\"><a href=\"#b8d85711-7480-4aaa-9a8f-6031e19eac86\" id=\"b8d85711-7480-4aaa-9a8f-6031e19eac86-link\">418<\/a><\/sup> En otro estudio sobre organoides cerebrales se observaron cambios morfol\u00f3gicos y sin\u00e1pticos en c\u00e9lulas de microgl\u00eda tras la exposici\u00f3n a un virus.<sup data-fn=\"fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee\" class=\"fn\"><a href=\"#fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee\" id=\"fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee-link\">419<\/a><\/sup> Adem\u00e1s, los modelos microflu\u00eddicos permiten el uso de c\u00e9lulas de pacientes y el monitoreo en tiempo real de la din\u00e1mica del cerebro humano, como la permeabilidad de la barrera hematoencef\u00e1lica y las fuerzas hemodin\u00e1micas, que no son factibles en experimentos en otras especies. Los cortes cerebrales <em>ex vivo<\/em> son otro m\u00e9todo valioso para estudiar el tejido cerebral humano, ya que preservan las propiedades <em>in vivo<\/em>, la organizaci\u00f3n espacial y las complejas redes de diversos tipos de c\u00e9lulas.<sup data-fn=\"f15c3464-da52-4c68-84cb-66b0383cec7f\" class=\"fn\"><a href=\"#f15c3464-da52-4c68-84cb-66b0383cec7f\" id=\"f15c3464-da52-4c68-84cb-66b0383cec7f-link\">420<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En los \u00faltimos a\u00f1os, los sistemas <em>in vitro<\/em> para estudiar el ACV y el sistema nervioso humano han avanzado considerablemente y se han convertido en herramientas atractivas para estudiar la funci\u00f3n del cerebro humano y mejorar las estrategias de tratamiento del ACV.<sup data-fn=\"731a0be8-829f-4336-8472-6c2684b488f0\" class=\"fn\"><a href=\"#731a0be8-829f-4336-8472-6c2684b488f0\" id=\"731a0be8-829f-4336-8472-6c2684b488f0-link\">421<\/a><\/sup> Ahora que estas herramientas est\u00e1n disponibles, la comunidad cient\u00edfica debe adoptarlas y las agencias financiadoras deben apoyar este proceso.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Trastorno por uso de sustancias<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Las caracter\u00edsticas fundamentales de los animales no humanos los hacen inadecuados para el estudio de trastornos por uso de sustancias (TUS). En primer lugar, el uso y la dependencia de las drogas en humanos son experiencias enormemente complejas que han sido imposibles de imitar en animales en un entorno de laboratorio.<sup data-fn=\"478686f0-319a-44fe-bd19-0829119c4017\" class=\"fn\"><a href=\"#478686f0-319a-44fe-bd19-0829119c4017\" id=\"478686f0-319a-44fe-bd19-0829119c4017-link\">422<\/a><\/sup> Se ha argumentado que los intentos de modelar trastornos humanos como la adicci\u00f3n en animales no humanos, especialmente roedores, son \u201cdemasiado ambiciosos\u201d y que la \u201c\u2018validez\u2019 de dichos modelos suele limitarse a similitudes superficiales, denominadas \u2018validez aparente\u2019, que reflejan fen\u00f3menos y procesos biol\u00f3gicos subyacentes bastante diferentes de la situaci\u00f3n cl\u00ednica\u201d.<sup data-fn=\"4ffd49eb-cd83-4da1-99d2-77724138687b\" class=\"fn\"><a href=\"#4ffd49eb-cd83-4da1-99d2-77724138687b\" id=\"4ffd49eb-cd83-4da1-99d2-77724138687b-link\">423<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-14&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-14-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-14\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-14\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-14-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<blockquote class=\"wp-block-quote simple is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">[L]os modelos animales no pueden captar muchos aspectos clave de los trastornos cerebrales humanos que pueden ser causados por un TUS y suelen implicar la interacci\u00f3n de factores gen\u00e9ticos, de desarrollo y ambientales\u2026 Adem\u00e1s, el estudio del cerebro en animales vivos implica t\u00e9cnicas invasivas que pueden afectar la salud y el comportamiento de los sujetos, confundiendo potencialmente los resultados\u2026 En consecuencia, es dif\u00edcil extrapolar los resultados de la investigaci\u00f3n a partir de modelos animales a tratamientos cl\u00ednicos eficaces para los TUS debido a las diferencias\u2026 en los sistemas neurol\u00f3gicos entre los humanos y los modelos animales.<sup data-fn=\"a874773c-626e-4576-bb3c-925a46ff2b18\" class=\"fn\"><a href=\"#a874773c-626e-4576-bb3c-925a46ff2b18\" id=\"a874773c-626e-4576-bb3c-925a46ff2b18-link\">424<\/a><\/sup><\/p>\n<\/blockquote>\n\n\n\n<p class=\"wp-block-paragraph\">Varios criterios diagn\u00f3sticos del TUS son imposibles de modelar en animales, ya que requieren que el individuo autoinforme. Entre estos se incluyen \u201c(i) el deseo subjetivo, (ii) tomar la sustancia en cantidades mayores o durante m\u00e1s tiempo de lo previsto y (iii) querer abandonar o reducir el uso de sustancias, pero no poder hacerlo\u201d.<sup data-fn=\"b9a896ec-9700-4f0b-bb7e-638cc9246093\" class=\"fn\"><a href=\"#b9a896ec-9700-4f0b-bb7e-638cc9246093\" id=\"b9a896ec-9700-4f0b-bb7e-638cc9246093-link\">425<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En segundo lugar, las acciones farmacocin\u00e9ticas de las drogas difieren entre especies. Por ejemplo, \u201cel metabolismo de la MDMA y sus principales metabolitos es m\u00e1s lento en humanos que en ratas o monos, lo que podr\u00eda permitir que los mecanismos neuroprotectores end\u00f3genos funcionen de forma particular a cada especie\u201d.<sup data-fn=\"b6b0acbe-0757-4016-b380-d819e2b85bfb\" class=\"fn\"><a href=\"#b6b0acbe-0757-4016-b380-d819e2b85bfb\" id=\"b6b0acbe-0757-4016-b380-d819e2b85bfb-link\">426<\/a><\/sup> Las diferencias farmacocin\u00e9ticas entre los humanos y los animales \u201cmodelo\u201d probablemente explican por qu\u00e9 la neurotoxicidad observada en roedores tras la administraci\u00f3n de MDMA no se ha observado en el \u00e1mbito cl\u00ednico.<sup data-fn=\"a694aa88-dc92-4fec-b9a8-66d976b91025\" class=\"fn\"><a href=\"#a694aa88-dc92-4fec-b9a8-66d976b91025\" id=\"a694aa88-dc92-4fec-b9a8-66d976b91025-link\">427<\/a><\/sup> Dado que la MDMA se est\u00e1 estudiando no solo por su uso ilegal como droga recreativa, sino por su posible uso terap\u00e9utico, es imprescindible conocer con exactitud su seguridad en humanos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En tercer lugar, las graves fallas en el dise\u00f1o de los experimentos de uso de sustancias en animales sesgan la interpretaci\u00f3n de sus resultados. A diferencia de los humanos, cuya experiencia con el TUS est\u00e1 determinada principalmente por la decisi\u00f3n individual de consumir una sustancia adictiva \u2013a menudo, frente a otras alternativas gratificantes\u2013, los animales confinados en laboratorios no suelen tener esta opci\u00f3n. Cuando la tienen, la mayor\u00eda elige una recompensa alternativa, como az\u00facar, en lugar de la droga.<sup data-fn=\"b496e41f-7fcc-495e-af35-a45e56e7832d\" class=\"fn\"><a href=\"#b496e41f-7fcc-495e-af35-a45e56e7832d\" id=\"b496e41f-7fcc-495e-af35-a45e56e7832d-link\">428<\/a><\/sup> Esto es v\u00e1lido tanto para primates como para ratones y ratas. Incluso entre los animales con un historial de consumo excesivo de drogas, solo alrededor del 10% sigue autoadministr\u00e1ndose la droga cuando se le presenta otra opci\u00f3n gratificante.<sup data-fn=\"348c6826-d221-4ec6-9129-4c289fd386b9\" class=\"fn\"><a href=\"#348c6826-d221-4ec6-9129-4c289fd386b9\" id=\"348c6826-d221-4ec6-9129-4c289fd386b9-link\">429<\/a><\/sup> Un an\u00e1lisis sobre la \u201ccrisis de validaci\u00f3n\u201d de los modelos animales de drogadicci\u00f3n concluy\u00f3 que no ofrecerles a los animales la posibilidad de elegir en estos experimentos plantea \u201cserias dudas\u201d sobre \u201cla interpretaci\u00f3n del uso de drogas en animales de experimentaci\u00f3n\u201d.<sup data-fn=\"15626447-9ea8-43ed-8451-a26a46b599c5\" class=\"fn\"><a href=\"#15626447-9ea8-43ed-8451-a26a46b599c5\" id=\"15626447-9ea8-43ed-8451-a26a46b599c5-link\">430<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El animal no humano ha sido calificado como el \u201ccolaborador m\u00e1s reacio\u201d al estudiar el trastorno por consumo de alcohol, y se ha observado que tiene una \u201csobriedad con determinaci\u00f3n\u201d contra la que el experimentador debe luchar para superar \u201csu fracaso constante a la hora de reproducir el consumo voluntario de etanol hasta el punto de la dependencia f\u00edsica\u201d.<sup data-fn=\"ada753d0-5ec6-43ee-a4cc-09214894de11\" class=\"fn\"><a href=\"#ada753d0-5ec6-43ee-a4cc-09214894de11\" id=\"ada753d0-5ec6-43ee-a4cc-09214894de11-link\">431<\/a><\/sup> Investigadores del Instituto Nacional de Salud Mental de EE. UU. se\u00f1alan que \u201ces dif\u00edcil argumentar que [la autoadministraci\u00f3n de drogas por parte de roedores] modela realmente la compulsi\u00f3n, cuando la alternativa a la autoadministraci\u00f3n es la soledad en una jaula del tama\u00f1o de una caja de zapatos\u201d.<sup data-fn=\"3e6ce804-260d-40c5-b2a8-07978bef88f8\" class=\"fn\"><a href=\"#3e6ce804-260d-40c5-b2a8-07978bef88f8\" id=\"3e6ce804-260d-40c5-b2a8-07978bef88f8-link\">432<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">A pesar de la gravedad del fen\u00f3meno de drogodependencia y sobredosis y de la prevalencia de la investigaci\u00f3n sobre el TUS realizada en animales, las opciones de tratamiento disponibles para las personas adictas a los opi\u00e1ceos, la nicotina y el alcohol son limitadas, y no existen tratamientos aprobados para los consumidores de marihuana o estimulantes, ni para aquellos que usan m\u00faltiples sustancias.<sup data-fn=\"e9519310-ad76-4394-89e6-6f8b3fe3cb62\" class=\"fn\"><a href=\"#e9519310-ad76-4394-89e6-6f8b3fe3cb62\" id=\"e9519310-ad76-4394-89e6-6f8b3fe3cb62-link\">433<\/a><\/sup> El Instituto Nacional sobre el Abuso de Drogas de EE. UU. ha se\u00f1alado que las empresas farmac\u00e9uticas muestran poco inter\u00e9s en invertir en tratamientos para el TUS debido al estigma y la complejidad de la enfermedad.<sup data-fn=\"92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886\" class=\"fn\"><a href=\"#92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886\" id=\"92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886-link\">434<\/a><\/sup><sup data-fn=\"b16b4a49-22b5-47f0-bdad-df89d194f80a\" class=\"fn\"><a href=\"#b16b4a49-22b5-47f0-bdad-df89d194f80a\" id=\"b16b4a49-22b5-47f0-bdad-df89d194f80a-link\">435<\/a><\/sup> Aunque los datos de los estudios en animales fueron considerados prometedores para ciertas clases de drogas y para prevenir reca\u00eddas, la mayor\u00eda de estos ha fracasado en los ensayos en humanos o no han sido bien tolerados por los participantes.<sup data-fn=\"c057a541-01c5-4388-a74b-5f415c0d56a0\" class=\"fn\"><a href=\"#c057a541-01c5-4388-a74b-5f415c0d56a0\" id=\"c057a541-01c5-4388-a74b-5f415c0d56a0-link\">436<\/a><\/sup><sup data-fn=\"049c4d00-2dc8-4a1d-97bc-90abb269f266\" class=\"fn\"><a href=\"#049c4d00-2dc8-4a1d-97bc-90abb269f266\" id=\"049c4d00-2dc8-4a1d-97bc-90abb269f266-link\">437<\/a><\/sup> Algunos investigadores sostienen que \u201cestos fracasos demuestran la incapacidad de los modelos animales para captar la compleja naturaleza de la adicci\u00f3n y su tratamiento\u201d, y que \u201clos hallazgos de los modelos animales de adicci\u00f3n han generado una percepci\u00f3n enga\u00f1osa de la naturaleza de la conducta adictiva en humanos\u201d.<sup data-fn=\"b636d063-90cb-4b41-9c7d-e6cc3773b0a9\" class=\"fn\"><a href=\"#b636d063-90cb-4b41-9c7d-e6cc3773b0a9\" id=\"b636d063-90cb-4b41-9c7d-e6cc3773b0a9-link\">438<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los m\u00e9todos de investigaci\u00f3n no invasivos y basados en la biolog\u00eda humana est\u00e1n proporcionando respuestas a preguntas que son imposibles de resolver por medio de experimentos en animales. Investigadores de la Universidad Rutgers publicaron recientemente un art\u00edculo en el que se\u00f1alan que el uso de hiPSC puede ofrecer una \u201coportunidad \u00fanica para modelar trastornos neuropsiqui\u00e1tricos como [los trastornos por consumo de alcohol] de una forma que\u2026 refleja fielmente los complejos contextos gen\u00e9ticos humanos. Las c\u00e9lulas neuronales espec\u00edficas de cada paciente derivadas de c\u00e9lulas [madre pluripotentes inducidas] pueden usarse para el descubrimiento de f\u00e1rmacos y la medicina de precisi\u00f3n\u201d.<sup data-fn=\"d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924\" class=\"fn\"><a href=\"#d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924\" id=\"d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924-link\">439<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Estos son ejemplos de investigaciones innovadoras, sin animales y relevantes para los humanos sobre el TUS:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Se est\u00e1n usando muestras humanas <em>post mortem<\/em> para modelar los cambios inducidos por el TUS en el cerebro y las c\u00e9lulas cerebrales. Por ejemplo, en el Centro de Ciencias de la Salud de la Universidad de Texas y en la Escuela de Medicina Baylor se cre\u00f3 un novedoso modelo hiPSC de c\u00e9lulas progenitoras neuronales y neuronas a partir de c\u00e9lulas de piel humana <em>post mortem<\/em>, y se compar\u00f3 directamente con tejido cerebral de los mismos donantes para modelar los cambios cerebrales inducidos por opi\u00e1ceos.<sup data-fn=\"3619417a-a9a2-4678-964e-0bed40a474ad\" class=\"fn\"><a href=\"#3619417a-a9a2-4678-964e-0bed40a474ad\" id=\"3619417a-a9a2-4678-964e-0bed40a474ad-link\">440<\/a><\/sup><\/li>\n\n\n\n<li>Un equipo de la Universidad de Heidelberg realiz\u00f3 un estudio epigen\u00f3mico de tejido cerebral <em>post mortem<\/em> de individuos con trastorno por uso de coca\u00edna para comprender c\u00f3mo este trastorno altera la se\u00f1alizaci\u00f3n sin\u00e1ptica y la neuroplasticidad.<sup data-fn=\"55e77e85-7a3c-4aee-abfc-c5dda37b02fb\" class=\"fn\"><a href=\"#55e77e85-7a3c-4aee-abfc-c5dda37b02fb\" id=\"55e77e85-7a3c-4aee-abfc-c5dda37b02fb-link\">441<\/a><\/sup><\/li>\n\n\n\n<li>En la Universidad de Pensilvania se usaron conjuntos de datos gen\u00f3micos en 3D para secuenciar m\u00e1s de 50 tipos de c\u00e9lulas humanas e identificar blancos gen\u00e9ticos y celulares subyacentes al TUS.<sup data-fn=\"ff31f347-198f-4b87-8ea0-d1aa38bcfa2d\" class=\"fn\"><a href=\"#ff31f347-198f-4b87-8ea0-d1aa38bcfa2d\" id=\"ff31f347-198f-4b87-8ea0-d1aa38bcfa2d-link\">442<\/a><\/sup><\/li>\n\n\n\n<li>Como parte del Programa Un Mill\u00f3n de Veteranos, un equipo estadounidense realiz\u00f3 un estudio multi\u00f3mico con biolog\u00eda de sistemas para revelar blancos gen\u00e9ticos clave para desarrollar nuevos medicamentos para tratar el trastorno por uso de opi\u00e1ceos.<sup data-fn=\"74984579-39c9-4770-8f80-96c7e8f1058a\" class=\"fn\"><a href=\"#74984579-39c9-4770-8f80-96c7e8f1058a\" id=\"74984579-39c9-4770-8f80-96c7e8f1058a-link\">443<\/a><\/sup><\/li>\n\n\n\n<li>En la Universidad de Florida Central desarrollaron un modelo de hiPSC para estudiar el trastorno por uso de opi\u00e1ceos y la depresi\u00f3n respiratoria que estos inducen, y combatir la crisis de sobredosis de estas sustancias.<sup data-fn=\"bc8e76f4-47f4-4f53-99d9-7ceffada9f1a\" class=\"fn\"><a href=\"#bc8e76f4-47f4-4f53-99d9-7ceffada9f1a\" id=\"bc8e76f4-47f4-4f53-99d9-7ceffada9f1a-link\">444<\/a><\/sup><\/li>\n\n\n\n<li>En la Universidad Estatal de Carolina del Norte cocultivaron neuronas humanas para formar ensambloides y entender las respuestas moleculares a la coca\u00edna y la morfina en las c\u00e9lulas humanas.<sup data-fn=\"8e44778e-a05c-4d35-bf0a-dc1cf14c8039\" class=\"fn\"><a href=\"#8e44778e-a05c-4d35-bf0a-dc1cf14c8039\" id=\"8e44778e-a05c-4d35-bf0a-dc1cf14c8039-link\">445<\/a><\/sup> Los ensambloides y organoides derivados de humanos \u201cmuestran un potencial \u00fanico para recapitular la respuesta a sustancias de un cerebro humano en desarrollo\u201d<sup data-fn=\"cfe0c7ff-0eed-44e7-a53a-d199a69aaf36\" class=\"fn\"><a href=\"#cfe0c7ff-0eed-44e7-a53a-d199a69aaf36\" id=\"cfe0c7ff-0eed-44e7-a53a-d199a69aaf36-link\">446<\/a><\/sup> y tambi\u00e9n ser\u00e1n \u00fatiles para estudiar la exposici\u00f3n a drogas en el \u00fatero.<\/li>\n\n\n\n<li>La investigaci\u00f3n sobre las mejores formas de tratar el dolor humano es crucial para reducir la incidencia de los trastornos por uso de opi\u00e1ceos y las reca\u00eddas. En Queen\u2019s University Belfast usaron modelos neuronales humanos <em>in vitro<\/em> e <em>in vivo<\/em> para estudiar las bases moleculares de la modulaci\u00f3n de la nocicepci\u00f3n en los nervios perif\u00e9ricos humanos.<sup data-fn=\"1085d05a-5a4b-41c0-84f4-3791acea7fea\" class=\"fn\"><a href=\"#1085d05a-5a4b-41c0-84f4-3791acea7fea\" id=\"1085d05a-5a4b-41c0-84f4-3791acea7fea-link\">447<\/a><\/sup> Empresas biotecnol\u00f3gicas como AxoSim y NETRI, entre otras, han desarrollado modelos neuronales humanos <em>in vitro<\/em> que pueden usarse para la investigaci\u00f3n del dolor en humanos.&nbsp;<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Los recursos que actualmente se desperdician en el financiamiento de estudios ineficaces sobre el TUS en animales podr\u00edan, en su lugar, usarse para apoyar programas eficaces de prevenci\u00f3n del uso de drogas, rehabilitaci\u00f3n y salud mental.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong><strong>Salud de la mujer<\/strong>&nbsp;<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s de los problemas de salud que las mujeres enfrentan independientemente de su sexo o g\u00e9nero, hay condiciones relacionadas de forma estrecha con el ciclo reproductivo que pueden variar a lo largo de la vida.<sup data-fn=\"52e58bd8-78a7-43d7-bec6-0839b991631a\" class=\"fn\"><a href=\"#52e58bd8-78a7-43d7-bec6-0839b991631a\" id=\"52e58bd8-78a7-43d7-bec6-0839b991631a-link\">448<\/a><\/sup> Aunque requieren atenci\u00f3n urgente, la infertilidad, la endometriosis, la adenomiosis y los s\u00edntomas de la menopausia se han estudiado poco y la financiaci\u00f3n en estas \u00e1reas de investigaci\u00f3n ha sido insuficiente.<sup data-fn=\"008ae57d-3281-44aa-9f56-8e2b0a010a6b\" class=\"fn\"><a href=\"#008ae57d-3281-44aa-9f56-8e2b0a010a6b\" id=\"008ae57d-3281-44aa-9f56-8e2b0a010a6b-link\">449<\/a><\/sup><\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-15&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-15-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-15\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-15\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-15-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Un obst\u00e1culo importante en el uso de otras especies para estudiar la salud de la mujer es la anatom\u00eda del aparato reproductor. Por ejemplo, los ratones tienen un sistema reproductor cerrado con oviductos enrollados firmemente que se abren hacia el espacio de la bolsa ov\u00e1rica. En cambio, el aparato reproductor humano se abre hacia la cavidad peritoneal. Esto permite que las c\u00e9lulas endometriales que se desprenden durante la menstruaci\u00f3n fluyan hacia atr\u00e1s (menstruaci\u00f3n retr\u00f3grada) hasta la cavidad peritoneal. Esta menstruaci\u00f3n retr\u00f3grada est\u00e1 relacionada con la aparici\u00f3n y los s\u00edntomas de la endometriosis. \u201c[D]esde una perspectiva morfogen\u00e9tica, el desarrollo del conducto de M\u00fcller difiere sustancialmente entre ratones y humanos\u201d,<sup data-fn=\"d07792ce-cc80-4944-9047-f781eb61f185\" class=\"fn\"><a href=\"#d07792ce-cc80-4944-9047-f781eb61f185\" id=\"d07792ce-cc80-4944-9047-f781eb61f185-link\">450<\/a><\/sup> lo cual resulta en las trompas de Falopio en humanos y en la vagina de M\u00fcller en ratones.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">La endometriosis y la adenomiosis son afecciones ginecol\u00f3gicas estrechamente relacionadas que causan dolor p\u00e9lvico, abortos espont\u00e1neos e infertilidady afectan a alrededor del 10% de las mujeres.<sup data-fn=\"77860b87-2d02-45fe-950e-542b7e6976a7\" class=\"fn\"><a href=\"#77860b87-2d02-45fe-950e-542b7e6976a7\" id=\"77860b87-2d02-45fe-950e-542b7e6976a7-link\">451<\/a><\/sup><sup data-fn=\"da13c77a-4b50-4bf0-b3f8-e180d46a9840\" class=\"fn\"><a href=\"#da13c77a-4b50-4bf0-b3f8-e180d46a9840\" id=\"da13c77a-4b50-4bf0-b3f8-e180d46a9840-link\">452<\/a><\/sup><sup data-fn=\"3d3f09e2-4005-4573-8327-ae4fb8e0d5b0\" class=\"fn\"><a href=\"#3d3f09e2-4005-4573-8327-ae4fb8e0d5b0\" id=\"3d3f09e2-4005-4573-8327-ae4fb8e0d5b0-link\">453<\/a><\/sup> A pesar de haberse descrito por primera vez hace siglos, las importantes lagunas en el diagn\u00f3stico y el tratamiento de estas afecciones se deben a la comprensi\u00f3n limitada de los mecanismos subyacentes<sup>5<\/sup> que se han investigado en modelos animales fallidos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las lesiones propias de la endometriosis humana, que a\u00fan no est\u00e1n completamente caracterizadas, var\u00edan de forma significativa en ubicaci\u00f3n, tama\u00f1o, color y profundidad.<sup data-fn=\"ba7f916f-c723-4b8f-9f5b-f94de2826acc\" class=\"fn\"><a href=\"#ba7f916f-c723-4b8f-9f5b-f94de2826acc\" id=\"ba7f916f-c723-4b8f-9f5b-f94de2826acc-link\">454<\/a><\/sup> Adem\u00e1s, estas lesiones tienen etiolog\u00edas distintas que son imposibles de reproducir por completo en modelos animales, y el intento de imitarlas requiere m\u00e9todos invasivos como injertos quir\u00fargicos e inyecciones intraperitoneales o de tejido aplicadas en el endometrio.<sup data-fn=\"25de1692-e53d-4387-8e61-f145903815de\" class=\"fn\"><a href=\"#25de1692-e53d-4387-8e61-f145903815de\" id=\"25de1692-e53d-4387-8e61-f145903815de-link\">455<\/a><\/sup><sup data-fn=\"e12f1113-f9da-4f8a-b4a3-8c68a10c8349\" class=\"fn\"><a href=\"#e12f1113-f9da-4f8a-b4a3-8c68a10c8349\" id=\"e12f1113-f9da-4f8a-b4a3-8c68a10c8349-link\">456<\/a><\/sup> Estos m\u00e9todos artificiales suelen causar contaminaci\u00f3n celular con tejido no uterino e inflamaci\u00f3n local en los animales.<sup data-fn=\"9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5\" class=\"fn\"><a href=\"#9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5\" id=\"9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5-link\">457<\/a><\/sup> Los modelos de rat\u00f3n transg\u00e9nico <em>de novo<\/em> rara vez logran reproducir la endometriosis con \u00e9xito debido a los fenotipos letales com\u00fanmente asociados con la eliminaci\u00f3n de genes esenciales.<sup>8<\/sup> Adem\u00e1s, el largo per\u00edodo de latencia necesario para que se desarrolle la endometriosis \u2013algo inalcanzable en especies de vida corta como los ratones\u2013 pone de manifiesto las limitaciones fundamentales de los modelos animales.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El proceso de la menopausia y los s\u00edntomas asociados var\u00edan mucho de una mujer a otra y dependen de factores como la cantidad de \u00f3vulos restantes en los ovarios, el estilo de vida, la alimentaci\u00f3n y el origen \u00e9tnico.<sup data-fn=\"2116da25-12d5-4ac8-951e-3cfb07207cd5\" class=\"fn\"><a href=\"#2116da25-12d5-4ac8-951e-3cfb07207cd5\" id=\"2116da25-12d5-4ac8-951e-3cfb07207cd5-link\">458<\/a><\/sup><sup data-fn=\"b7598a6e-7206-440d-94d6-81c3f0c87b5f\" class=\"fn\"><a href=\"#b7598a6e-7206-440d-94d6-81c3f0c87b5f\" id=\"b7598a6e-7206-440d-94d6-81c3f0c87b5f-link\">459<\/a><\/sup><sup data-fn=\"306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3\" class=\"fn\"><a href=\"#306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3\" id=\"306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3-link\">460<\/a><\/sup> Durante la transici\u00f3n a la menopausia, las fluctuaciones en los niveles de estradiol durante la fase perimenop\u00e1usica pueden causar cambios fisiol\u00f3gicos, conductuales y neurol\u00f3gicos espec\u00edficos, complejos y prolongados<sup data-fn=\"74d4082d-5d79-40d4-b9b2-04f408b595e6\" class=\"fn\"><a href=\"#74d4082d-5d79-40d4-b9b2-04f408b595e6\" id=\"74d4082d-5d79-40d4-b9b2-04f408b595e6-link\">461<\/a><\/sup> que los experimentos en animales no pueden replicar.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El ciclo estral de otros primates y roedores difiere de forma considerable del ciclo menstrual humano.<sup data-fn=\"df41a430-4222-46ba-acaa-532e73e42f07\" class=\"fn\"><a href=\"#df41a430-4222-46ba-acaa-532e73e42f07\" id=\"df41a430-4222-46ba-acaa-532e73e42f07-link\">462<\/a><\/sup> La gran mayor\u00eda de los animales no humanos no atraviesa la menopausia y sus patrones de fertilidad discrepan de forma significativa en comparaci\u00f3n con los humanos. La fertilidad de los ratones empieza a disminuir a los 8 meses de vida,<sup data-fn=\"7f530923-1be6-4ece-a394-6f8a02b86347\" class=\"fn\"><a href=\"#7f530923-1be6-4ece-a394-6f8a02b86347\" id=\"7f530923-1be6-4ece-a394-6f8a02b86347-link\">463<\/a><\/sup> o cerca de una sexta parte de su longevidad potencial. En comparaci\u00f3n con los humanos, el ciclo menstrual de otros primates y roedores var\u00eda en duraci\u00f3n, fluctuaci\u00f3n hormonal y las formas en que estas hormonas regulan el eje hipotal\u00e1mico-hipofisario-gonadal.<sup data-fn=\"bef7c181-da06-4a89-921e-1159e270c101\" class=\"fn\"><a href=\"#bef7c181-da06-4a89-921e-1159e270c101\" id=\"bef7c181-da06-4a89-921e-1159e270c101-link\">464<\/a><\/sup><sup data-fn=\"18f8583d-1ac0-47b5-bf8d-872ce931be9d\" class=\"fn\"><a href=\"#18f8583d-1ac0-47b5-bf8d-872ce931be9d\" id=\"18f8583d-1ac0-47b5-bf8d-872ce931be9d-link\">465<\/a><\/sup><sup data-fn=\"68a87a23-d33b-48c1-8eef-23fcc019713b\" class=\"fn\"><a href=\"#68a87a23-d33b-48c1-8eef-23fcc019713b\" id=\"68a87a23-d33b-48c1-8eef-23fcc019713b-link\">466<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Dadas las numerosas limitaciones biol\u00f3gicas descritas anteriormente, los experimentadores intentan reproducir la menopausia y las lesiones uterinas en animales mediante m\u00e9todos artificiales. La ovariectom\u00eda, o la extirpaci\u00f3n quir\u00fargica de los ovarios, es el m\u00e9todo est\u00e1ndar para crear estos s\u00edntomas en animales, pero el procedimiento es invasivo y cl\u00ednicamente irrelevante para inducir la menopausia. La menopausia es una transici\u00f3n gradual (no un acontecimiento abrupto) y los animales no experimentan los mismos s\u00edntomas que los humanos, como la niebla mental o la liberaci\u00f3n continua de andr\u00f3genos por parte de los ovarios.<sup data-fn=\"a70feddf-308f-4f52-bd2c-88b8a1e51226\" class=\"fn\"><a href=\"#a70feddf-308f-4f52-bd2c-88b8a1e51226\" id=\"a70feddf-308f-4f52-bd2c-88b8a1e51226-link\">467<\/a><\/sup> Otros modelos animales creados mediante la inducci\u00f3n qu\u00edmica de la falla ov\u00e1rica prematura pueden resultar en factores de confusi\u00f3n experimental, como discrepancias relacionadas con la dosis y la duraci\u00f3n del tratamiento, el desarrollo de problemas neurol\u00f3gicos no relacionados,<sup data-fn=\"f0c17532-4f7f-48eb-bf59-5507961be65c\" class=\"fn\"><a href=\"#f0c17532-4f7f-48eb-bf59-5507961be65c\" id=\"f0c17532-4f7f-48eb-bf59-5507961be65c-link\">468<\/a><\/sup> y la incapacidad de modelar respuestas a medicamentos que pueden revertir el fallo ov\u00e1rico prematuro en humanos.<sup data-fn=\"692759fe-bf78-4d6c-8afb-fc82a1983401\" class=\"fn\"><a href=\"#692759fe-bf78-4d6c-8afb-fc82a1983401\" id=\"692759fe-bf78-4d6c-8afb-fc82a1983401-link\">469<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En la mayor\u00eda de los experimentos se usan animales j\u00f3venes, como monos tit\u00ed de corta edad, cuya fisiolog\u00eda difiere dr\u00e1sticamente de la de los humanos en proceso de envejecimiento, a los que se pretende imitar. Los patrones gen\u00e9ticos del cerebro de estos animales no coinciden con los de los humanos en la transici\u00f3n menop\u00e1usica, lo que significa que no pueden replicar el deterioro cognoscitivo asociado con la fluctuaci\u00f3n y p\u00e9rdida de estr\u00f3geno durante este per\u00edodo.<sup data-fn=\"0b117682-b74c-4890-8a67-cef1c7188451\" class=\"fn\"><a href=\"#0b117682-b74c-4890-8a67-cef1c7188451\" id=\"0b117682-b74c-4890-8a67-cef1c7188451-link\">470<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Para dise\u00f1ar intervenciones m\u00e1s eficaces, es esencial comprender mejor los mecanismos biol\u00f3gicos humanos espec\u00edficos que afectan la salud de la mujer y financiar las herramientas necesarias para esta investigaci\u00f3n crucial y, a menudo, ignorada.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El trabajo colectivo para la caracterizaci\u00f3n fenot\u00edpica de lesiones endometriales humanas y su almacenamiento en biobancos,<sup data-fn=\"f6f5695b-decf-4141-803d-54b98353b7b2\" class=\"fn\"><a href=\"#f6f5695b-decf-4141-803d-54b98353b7b2\" id=\"f6f5695b-decf-4141-803d-54b98353b7b2-link\">471<\/a><\/sup><sup data-fn=\"68b16e78-1156-465c-9698-bae606256f30\" class=\"fn\"><a href=\"#68b16e78-1156-465c-9698-bae606256f30\" id=\"68b16e78-1156-465c-9698-bae606256f30-link\">472<\/a><\/sup> combinado con herramientas de aprendizaje autom\u00e1tico que analizan datos de pacientes y dispositivos port\u00e1tiles para identificar posibles factores de riesgo, puede generar datos que hist\u00f3ricamente han sido dif\u00edciles de replicar mediante modelos <em>in vitro <\/em>m\u00e1s sencillos. Por ejemplo, se ha desarrollado un modelo predictivo unificado para el diagn\u00f3stico de la endometriosis a trav\u00e9s de un conjunto de datos de m\u00e1s de 5000&nbsp;mujeres. El modelo analiz\u00f3 m\u00e1s de 1000&nbsp;variables, entre ellas el estilo de vida, las variantes gen\u00e9ticas y los antecedentes m\u00e9dicos.<sup data-fn=\"a58cf240-c68a-4985-b771-49f190bbf448\" class=\"fn\"><a href=\"#a58cf240-c68a-4985-b771-49f190bbf448\" id=\"a58cf240-c68a-4985-b771-49f190bbf448-link\">473<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Las limitaciones de los experimentos en animales y los modelos <em>in vitro <\/em>tradicionales han impulsado el desarrollo de plataformas microflu\u00eddicas avanzadas que recapitulan con precisi\u00f3n el sistema reproductor humano,<sup data-fn=\"ce046412-734c-43f7-8bf9-8dfc15360fd3\" class=\"fn\"><a href=\"#ce046412-734c-43f7-8bf9-8dfc15360fd3\" id=\"ce046412-734c-43f7-8bf9-8dfc15360fd3-link\">474<\/a><\/sup> por ejemplo, la placenta humana en chip, que permite el estudio de la interfaz materno-fetal y las afecciones relacionadas con el embarazo,<sup data-fn=\"df47c072-46b9-4a8c-a46a-4e053ef93d3f\" class=\"fn\"><a href=\"#df47c072-46b9-4a8c-a46a-4e053ef93d3f\" id=\"df47c072-46b9-4a8c-a46a-4e053ef93d3f-link\">475<\/a><\/sup><sup data-fn=\"fe49c1a2-7341-4e03-a039-f0c55ce96227\" class=\"fn\"><a href=\"#fe49c1a2-7341-4e03-a039-f0c55ce96227\" id=\"fe49c1a2-7341-4e03-a039-f0c55ce96227-link\">476<\/a><\/sup><sup data-fn=\"bacbf547-9a95-4acb-92a5-1c2d41604472\" class=\"fn\"><a href=\"#bacbf547-9a95-4acb-92a5-1c2d41604472\" id=\"bacbf547-9a95-4acb-92a5-1c2d41604472-link\">477<\/a><\/sup> y protocolos estandarizados de hiPSC.<sup data-fn=\"07c8f50a-88e4-47bd-ae95-61244dcca480\" class=\"fn\"><a href=\"#07c8f50a-88e4-47bd-ae95-61244dcca480\" id=\"07c8f50a-88e4-47bd-ae95-61244dcca480-link\">478<\/a><\/sup> Otro modelo multicelular vascularizado imita con eficacia las fluctuaciones hormonales del ciclo menstrual humano,<sup data-fn=\"055c3df9-2fab-4c7e-b7aa-87ff95070a09\" class=\"fn\"><a href=\"#055c3df9-2fab-4c7e-b7aa-87ff95070a09\" id=\"055c3df9-2fab-4c7e-b7aa-87ff95070a09-link\">479<\/a><\/sup> lo que permite estudiar la permeabilidad del endometrio a los anticonceptivos y sirve como prueba de concepto para estudiar la implantaci\u00f3n del embri\u00f3n humano, que es imposible de reproducir en modelos animales. Los datos ultrasonogr\u00e1ficos se han usado para construir un endometrio bioimpreso en 3D y diagnosticar anomal\u00edas uterinas cong\u00e9nitas.<sup data-fn=\"3d2e7353-3e96-4adc-b3a9-c937bf39b9be\" class=\"fn\"><a href=\"#3d2e7353-3e96-4adc-b3a9-c937bf39b9be\" id=\"3d2e7353-3e96-4adc-b3a9-c937bf39b9be-link\">480<\/a><\/sup> Recientemente, se ha publicado el <em>Human Endometrial Cell Atlas<\/em> como una nueva referencia para estudiar la transcript\u00f3mica endometrial y guiar el desarrollo de sistemas humanos <em>in vitro<\/em>.<sup data-fn=\"fe92fc63-2954-4c0e-aa35-a3963d989f88\" class=\"fn\"><a href=\"#fe92fc63-2954-4c0e-aa35-a3963d989f88\" id=\"fe92fc63-2954-4c0e-aa35-a3963d989f88-link\">481<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Destinar recursos a mejorar el servicio de salud en lugar de financiar modelos animales imprecisos tendr\u00eda un gran impacto en las personas que requieren atenci\u00f3n. Un estudio reciente concluy\u00f3 que la interpretaci\u00f3n err\u00f3nea de los s\u00edntomas de la endometriosis contribuye en gran medida a retrasar su diagn\u00f3stico y propuso un enfoque integral que incluya capacitar a los m\u00e9dicos, ofrecer cursos especializados para estudiantes de medicina e integrar a otros profesionales de la salud en los procesos de diagn\u00f3stico y atenci\u00f3n m\u00e9dica.<sup data-fn=\"b84aeb83-a894-4425-a40f-aeda76725731\" class=\"fn\"><a href=\"#b84aeb83-a894-4425-a40f-aeda76725731\" id=\"b84aeb83-a894-4425-a40f-aeda76725731-link\">482<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">El ciclo menstrual humano y el endometrio son din\u00e1micos y \u00fanicos en cada individuo, lo quesubrayala necesidad de priorizar enfoques personalizados mediante modelos derivados de pacientes. Los m\u00e9todos sin animales pueden revolucionar la investigaci\u00f3n sobre la salud de la mujer, ya que brindan modelos m\u00e1s precisos para estudiar enfermedades, evaluar medicamentos y desarrollar intervenciones con medicina de precisi\u00f3n.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Xenotransplantes<\/strong><\/h2>\n\n\n\n<p class=\"wp-block-paragraph\">A medida que crece la demanda de \u00f3rganos, la idea alguna vez experimental de usar animales para trasplantes se ha convertido en una pol\u00e9mica apuesta por reproducir cerdos exclusivamente para la extracci\u00f3n de \u00f3rganos, una pr\u00e1ctica conocida como xenotrasplante. Existen m\u00faltiples formas de mejorar nuestro sistema actual para aumentar el acceso a \u00f3rganos humanos viables sin xenotrasplantes.<\/p>\n\n\n\n<div data-wp-context=\"{ &quot;autoclose&quot;: false, &quot;accordionItems&quot;: [] }\" data-wp-interactive=\"core\/accordion\" role=\"group\" class=\"wp-block-accordion is-layout-flow wp-block-accordion-is-layout-flow\">\n<div data-wp-class--is-open=\"state.isOpen\" data-wp-context=\"{ &quot;id&quot;: &quot;accordion-item-16&quot;, &quot;openByDefault&quot;: false }\" data-wp-init=\"callbacks.initAccordionItems\" data-wp-on-window--hashchange=\"callbacks.hashChange\" class=\"wp-block-accordion-item is-layout-flow wp-block-accordion-item-is-layout-flow\">\n<h3 class=\"wp-block-accordion-heading\"><button aria-expanded=\"false\" aria-controls=\"accordion-item-16-panel\" data-wp-bind--aria-expanded=\"state.isOpen\" data-wp-on--click=\"actions.toggle\" data-wp-on--keydown=\"actions.handleKeyDown\" id=\"accordion-item-16\" type=\"button\" class=\"wp-block-accordion-heading__toggle\"><span class=\"wp-block-accordion-heading__toggle-title\">Lee m\u00e1s<\/span><span class=\"wp-block-accordion-heading__toggle-icon\" aria-hidden=\"true\">+<\/span><\/button><\/h3>\n\n\n\n<div inert aria-labelledby=\"accordion-item-16\" data-wp-bind--inert=\"!state.isOpen\" id=\"accordion-item-16-panel\" role=\"region\" class=\"wp-block-accordion-panel is-layout-flow wp-block-accordion-panel-is-layout-flow\">\n<p class=\"wp-block-paragraph\">De acuerdo con la Red Unida para Compartir \u00d3rganos de EE. UU. (UNOS), a junio de 2025, cerca de 106 mil personas en dicho pa\u00eds esperaban un trasplante de \u00f3rganos.<sup data-fn=\"27183fb0-b6df-4e54-bc41-626d7ef77b7c\" class=\"fn\"><a href=\"#27183fb0-b6df-4e54-bc41-626d7ef77b7c\" id=\"27183fb0-b6df-4e54-bc41-626d7ef77b7c-link\">483<\/a><\/sup> En 2024, en M\u00e9xico hubo cerca de 20 mil personas en lista de espera para un trasplante<sup data-fn=\"df06caa6-0e33-4ad0-adab-3e840e52e528\" class=\"fn\"><a href=\"#df06caa6-0e33-4ad0-adab-3e840e52e528\" id=\"df06caa6-0e33-4ad0-adab-3e840e52e528-link\">484<\/a><\/sup> y en Colombia hubo m\u00e1s de 4000.<sup data-fn=\"88446638-ca05-441f-a811-4ced4aec01e4\" class=\"fn\"><a href=\"#88446638-ca05-441f-a811-4ced4aec01e4\" id=\"88446638-ca05-441f-a811-4ced4aec01e4-link\">485<\/a><\/sup> A pesar de esta enorme y urgente necesidad, el sistema actual de gesti\u00f3n, extracci\u00f3n y transporte de \u00f3rganos humanos es muy ineficiente. Los \u00f3rganos humanos siguen siendo la opci\u00f3n m\u00e1s compatible y eficaz para los trasplantes, pero las ineficiencias del sistema hacen que se desechen muchos \u00f3rganos viables. En lugar de recurrir a la ingenier\u00eda gen\u00e9tica, la reproducci\u00f3n y el asesinato de cerdos para la extracci\u00f3n de \u00f3rganos, habr\u00eda que centrarse en perfeccionar los sistemas de obtenci\u00f3n y trasplante de \u00f3rganos en cada pa\u00eds. La creaci\u00f3n de una red independiente de xenotrasplantes exigir\u00eda mecanismos p\u00fablicos de supervisi\u00f3n y financiaci\u00f3n considerables, lo que har\u00eda m\u00e1s complejo e ineficiente un sistema ya problem\u00e1tico. En su lugar, la soluci\u00f3n m\u00e1s responsable y eficaz consiste en reforzar el proceso de donaci\u00f3n de \u00f3rganos humanos para garantizar que los pacientes reciban las mejores opciones posibles de trasplante.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En EE. UU., la UNOS, que hasta hace poco era la \u00fanica organizaci\u00f3n que gestionaba la obtenci\u00f3n y el trasplante de \u00f3rganos, ha enfrentado cr\u00edticas por mala gesti\u00f3n durante d\u00e9cadas. En 2022, una investigaci\u00f3n de la Comisi\u00f3n de Finanzas del Senado de EE. UU. revel\u00f3 que, con frecuencia, los \u00f3rganos obtenidos por la UNOS se perd\u00edan, da\u00f1aban, retrasaban o nunca se recog\u00edan.<sup data-fn=\"fbceca82-c6dc-4dab-94f9-1cfdb7eb736d\" class=\"fn\"><a href=\"#fbceca82-c6dc-4dab-94f9-1cfdb7eb736d\" id=\"fbceca82-c6dc-4dab-94f9-1cfdb7eb736d-link\">486<\/a><\/sup> Un informe del mismo a\u00f1o, realizado por las Academias Nacionales de Ciencias, Ingenier\u00eda y Medicina de EE. UU., concluy\u00f3 que el sistema de trasplantes de \u00f3rganos en ese pa\u00eds es ineficaz, desigual e inconsistente y requiere mejoras significativas.<sup data-fn=\"212e2190-692b-4520-b625-c07ff4cdd228\" class=\"fn\"><a href=\"#212e2190-692b-4520-b625-c07ff4cdd228\" id=\"212e2190-692b-4520-b625-c07ff4cdd228-link\">487<\/a><\/sup> El trasplante de \u00f3rganos humanos es un recurso crucial que salva vidas y que, por su propia naturaleza, es escaso. A\u00fan as\u00ed, en 2022, &nbsp;por ejemplo, uno de cada cinco ri\u00f1ones y uno de cada diez h\u00edgados donados nunca se trasplantaron debido a estos problemas sist\u00e9micos.<sup data-fn=\"1754ebd7-0154-42f9-9cac-f63d7bdab721\" class=\"fn\"><a href=\"#1754ebd7-0154-42f9-9cac-f63d7bdab721\" id=\"1754ebd7-0154-42f9-9cac-f63d7bdab721-link\">488<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s, el sistema actual de EE. UU. suele desperdiciar \u00f3rganos ya disponibles. Un estudio de los trasplantes de ri\u00f1\u00f3n entre 2000 y 2015 encontr\u00f3 que, en casi 8.000 casos, se utiliz\u00f3 un ri\u00f1\u00f3n del donante mientras que el otro se descart\u00f3, a menudo, debido a peque\u00f1as diferencias con respecto a los criterios ideales de donaci\u00f3n.<sup data-fn=\"aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8\" class=\"fn\"><a href=\"#aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8\" id=\"aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8-link\">489<\/a><\/sup> Estos ri\u00f1ones descartados probablemente funcionar\u00edan bien, en particular si se comparan con la di\u00e1lisis a largo plazo.<sup data-fn=\"3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae\" class=\"fn\"><a href=\"#3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae\" id=\"3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae-link\">490<\/a><\/sup> De acuerdo con &nbsp;Dalvin Roth, profesor de Stanford y Premio Nobel por su trabajo en programas de intercambio de ri\u00f1ones, los centros de trasplantes se ven presionados para rechazar ri\u00f1ones porque se les penaliza por trasplantes fallidos.<sup data-fn=\"873d9338-5037-4160-8adf-dc9f53a2fc52\" class=\"fn\"><a href=\"#873d9338-5037-4160-8adf-dc9f53a2fc52\" id=\"873d9338-5037-4160-8adf-dc9f53a2fc52-link\">491<\/a><\/sup> Sin embargo, los centros de trasplantes no son penalizados por <em>rechazar<\/em> ri\u00f1ones.<sup data-fn=\"4dcee4ec-65c8-425c-84d8-fc37baa923f0\" class=\"fn\"><a href=\"#4dcee4ec-65c8-425c-84d8-fc37baa923f0\" id=\"4dcee4ec-65c8-425c-84d8-fc37baa923f0-link\">492<\/a><\/sup> Este sistema perpet\u00faa la escasez de \u00f3rganos, ya que los ri\u00f1ones rechazados pueden no alcanzar un umbral poco realista. Teniendo en cuenta que la morbilidad y la mortalidad de la di\u00e1lisis de larga duraci\u00f3n son significativas, los trasplantes ofrecen muchas m\u00e1s ventajas a los pacientes.<sup data-fn=\"050927b4-6a8f-4ef0-86e5-eea3ce9c49d0\" class=\"fn\"><a href=\"#050927b4-6a8f-4ef0-86e5-eea3ce9c49d0\" id=\"050927b4-6a8f-4ef0-86e5-eea3ce9c49d0-link\">493<\/a><\/sup> Reformar estos criterios podr\u00eda aumentar considerablemente el n\u00famero de ri\u00f1ones disponibles, entre otros \u00f3rganos.&nbsp;<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Como respuesta a esto, en 2023 se aprob\u00f3 la ley para garantizar la red de obtenci\u00f3n y trasplante de \u00f3rganos (<em>Securing the U.S. Organ Procurement and Transplantation Network Act<\/em>) para modernizar el sistema nacional de trasplantes.<sup data-fn=\"dde7c07f-5389-4951-ad34-7d58940c62b3\" class=\"fn\"><a href=\"#dde7c07f-5389-4951-ad34-7d58940c62b3\" id=\"dde7c07f-5389-4951-ad34-7d58940c62b3-link\">494<\/a><\/sup> Esta legislaci\u00f3n pretende garantizar que los pacientes reciban \u00f3rganos humanos de alta calidad,<sup data-fn=\"8dabffcc-0193-4ebe-ac3a-8e5b93828ae3\" class=\"fn\"><a href=\"#8dabffcc-0193-4ebe-ac3a-8e5b93828ae3\" id=\"8dabffcc-0193-4ebe-ac3a-8e5b93828ae3-link\">495<\/a><\/sup> en contraste con los \u00f3rganos animales, que plantean riesgos de rechazo, infecciones zoon\u00f3ticas y problemas \u00e9ticos. Asimismo, en agosto de 2024, se anunci\u00f3 que la instancia que rige la pol\u00edtica nacional de asignaci\u00f3n de \u00f3rganos se constituir\u00eda por separado y ser\u00eda independiente de la UNOS,<sup data-fn=\"44331a34-2ab3-481c-bd67-490e385fd02f\" class=\"fn\"><a href=\"#44331a34-2ab3-481c-bd67-490e385fd02f\" id=\"44331a34-2ab3-481c-bd67-490e385fd02f-link\">496<\/a><\/sup> un paso fundamental para mejorar la eficiencia. Sin embargo, ya que los \u00f3rganos humanos siguen siendo la mejor opci\u00f3n para las personas que necesitan un trasplante, se debe hacer mucho m\u00e1s para ampliar y mejorar el sistema para su obtenci\u00f3n y trasplante.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Los xenotrasplantes implican riesgos adicionales, como la transmisi\u00f3n de pat\u00f3genos de animales a humanos, un fen\u00f3meno conocido como xenozoonosis. La FDA ha reconocido que se trata de un riesgo importante, sobre todo para los pacientes trasplantados que est\u00e1n inherente y m\u00e9dicamente inmunodeprimidos.<sup data-fn=\"d96e5f24-7d5c-4391-ba1c-f3cdffaffd47\" class=\"fn\"><a href=\"#d96e5f24-7d5c-4391-ba1c-f3cdffaffd47\" id=\"d96e5f24-7d5c-4391-ba1c-f3cdffaffd47-link\">497<\/a><\/sup> Estas infecciones podr\u00edan propagarse a los contactos cercanos y a la comunidad en general, lo que plantea un dilema \u00e9tico entre el deber de proteger la salud p\u00fablica y la necesidad de proporcionar trasplantes de \u00f3rganos a pacientes con insuficiencia terminal.<sup>10<\/sup> A pesar de someter a los animales a ingenier\u00eda gen\u00e9tica, de reproducirlos en instalaciones sin agentes pat\u00f3genos y de practicarles pruebas para su detecci\u00f3n, se han identificado el citomegalovirus y el roseolovirus porcinos, incluso despu\u00e9s de la evaluaci\u00f3n &nbsp;previa al trasplante.<sup data-fn=\"92ef33d3-34b5-4d4c-83d9-e534c52863f9\" class=\"fn\"><a href=\"#92ef33d3-34b5-4d4c-83d9-e534c52863f9\" id=\"92ef33d3-34b5-4d4c-83d9-e534c52863f9-link\">498<\/a><\/sup> En mayo de 2022, el receptor de un trasplante de coraz\u00f3n de cerdo falleci\u00f3 dos meses despu\u00e9s de su operaci\u00f3n.<sup data-fn=\"a1a9b500-2c79-4576-ac13-dd869b9cba47\" class=\"fn\"><a href=\"#a1a9b500-2c79-4576-ac13-dd869b9cba47\" id=\"a1a9b500-2c79-4576-ac13-dd869b9cba47-link\">499<\/a><\/sup> La autopsia revel\u00f3 que el coraz\u00f3n del cerdo era portador de citomegalovirus porcino no detectado y pudo haber contribuido a una muerte imprevista y prematura en un individuo inmunodeprimido.<sup data-fn=\"8b838035-0ed2-44fe-8c5d-a5ba6cf41b76\" class=\"fn\"><a href=\"#8b838035-0ed2-44fe-8c5d-a5ba6cf41b76\" id=\"8b838035-0ed2-44fe-8c5d-a5ba6cf41b76-link\">500<\/a><\/sup><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Hist\u00f3ricamente, los estudios que involucraban \u00f3rganos xenotrasplantados en participantes humanos vivos se aprobaban mediante el Protocolo de Acceso Expandido, conocido coloquialmente como uso compasivo, y aun este enfoque ha sido objeto de cr\u00edticas. Algunos acad\u00e9micos han sostenido que la FDA hizo un uso indebido del acceso expandido en este contexto, ya que este programa nunca fue concebido para generar evidencia de seguridad o eficacia destinada a respaldar el inicio de un ensayo cl\u00ednico.<sup data-fn=\"727a251d-c956-4310-a9b1-7b744bbc155c\" class=\"fn\"><a href=\"#727a251d-c956-4310-a9b1-7b744bbc155c\" id=\"727a251d-c956-4310-a9b1-7b744bbc155c-link\">501<\/a><\/sup> Sin embargo, desde febrero de 2025, la FDA ha permitido el uso de \u00f3rganos xenotrasplantados en estudios cl\u00ednicos bajo una solicitud de nuevo f\u00e1rmaco en investigaci\u00f3n.<sup data-fn=\"e7b6b9bb-960f-4f8e-9633-a208b336ecc0\" class=\"fn\"><a href=\"#e7b6b9bb-960f-4f8e-9633-a208b336ecc0\" id=\"e7b6b9bb-960f-4f8e-9633-a208b336ecc0-link\">502<\/a><\/sup> Esta v\u00eda permite la realizaci\u00f3n de pruebas cl\u00ednicas formales m\u00e1s all\u00e1 del uso compasivo y refleja una transici\u00f3n hacia investigaciones estructuradas dise\u00f1adas para respaldar una posible aprobaci\u00f3n regulatoria de los \u00f3rganos xenotrasplantados como alternativa a los \u00f3rganos humanos.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En lugar de invertir en ensayos cl\u00ednicos que exploran el xenotrasplante, deber\u00edan destinarse m\u00e1s recursos a otras estrategias para aumentar la disponibilidad de \u00f3rganos humanos aptos para alotrasplantes.&nbsp;En 2025, la Administraci\u00f3n de Recursos y Servicios de Salud de EE. UU. (HRSA) le solicit\u00f3 a la Red de Obtenci\u00f3n y Transplante de \u00d3rganos (OPTN)&nbsp;que propusiera una pol\u00edtica para fortalecer el proceso de donaci\u00f3n tras muerte circulatoria (DCD).<sup data-fn=\"5c485b5d-b65d-4fef-a7a3-2338e570fa69\" class=\"fn\"><a href=\"#5c485b5d-b65d-4fef-a7a3-2338e570fa69\" id=\"5c485b5d-b65d-4fef-a7a3-2338e570fa69-link\">503<\/a><\/sup> Las futuras investigaciones sobre DCD deber\u00edan examinar c\u00f3mo implementar pr\u00e1cticas que promuevan la transparencia y fortalezcan la confianza p\u00fablica, favoreciendo en \u00faltima instancia una mayor aceptaci\u00f3n de la DCD como una estrategia \u00e9tica y eficaz para incrementar la disponibilidad de \u00f3rganos humanos.  Adem\u00e1s, deber\u00edan destinarse m\u00e1s recursos a la evaluaci\u00f3n de tecnolog\u00edas avanzadas de preservaci\u00f3n de \u00f3rganos, como la perfusi\u00f3n normot\u00e9rmica <em>ex vivo<\/em>, con el fin de reducir las tasas de descarte de \u00f3rganos y mejorar la funci\u00f3n de los injertos despu\u00e9s del trasplante.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">En enero de 2026, el Departamento de Salud y Servicios Humanos de EE. UU. anunci\u00f3 nuevas convocatorias para equipos de investigaci\u00f3n que utilizan tecnolog\u00edas de bioimpresi\u00f3n y medicina regenerativa para crear \u00f3rganos humanos personalizados y disponibles bajo demanda que no requieran medicamentos inmunosupresores.<sup data-fn=\"44444a99-e1a7-408d-a9a7-9af3ad4ea167\" class=\"fn\"><a href=\"#44444a99-e1a7-408d-a9a7-9af3ad4ea167\" id=\"44444a99-e1a7-408d-a9a7-9af3ad4ea167-link\">504<\/a><\/sup> El objetivo de esta tecnolog\u00eda es utilizar las c\u00e9lulas del paciente o provenientes de un banco de c\u00e9lulas para producir r\u00e1pidamente \u00f3rganos de reemplazo inmunol\u00f3gicamente compatibles. Existe una gran expectativa de que esta tecnolog\u00eda permita ir m\u00e1s all\u00e1 de considerar el xenotrasplante como una alternativa e incluso reducir la dependencia del sistema actual de alotrasplantes.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Adem\u00e1s de financiar investigaciones orientadas a identificar formas de aumentar la disponibilidad de \u00f3rganos humanos, los gobiernos deber\u00edan implementar reformas sistem\u00e1ticas para fortalecer su sistema actual de alotrasplantes. Por ejemplo, un estudio publicado en 2019 sugiere adoptar una pol\u00edtica de \u201cconsentimiento presunto\u201d, donde la donaci\u00f3n de \u00f3rganos es el \u201cvalor por defecto\u201d, a menos que los individuos opten por no hacerlo, una pr\u00e1ctica que ya ha aumentado las tasas de donaci\u00f3n en pa\u00edses como Austria y B\u00e9lgica.<sup data-fn=\"5efee13d-1326-4987-b97c-067db919a717\" class=\"fn\"><a href=\"#5efee13d-1326-4987-b97c-067db919a717\" id=\"5efee13d-1326-4987-b97c-067db919a717-link\">505<\/a><\/sup>  En Am\u00e9rica Latina, el sistema de donaci\u00f3n presunta existe en Argentina,<sup data-fn=\"c8ae5797-2caa-4f71-891a-d929ddbf7a34\" class=\"fn\"><a href=\"#c8ae5797-2caa-4f71-891a-d929ddbf7a34\" id=\"c8ae5797-2caa-4f71-891a-d929ddbf7a34-link\">506<\/a><\/sup> Colombia,<sup data-fn=\"96e80953-165b-49c4-8687-722f3d804a91\" class=\"fn\"><a href=\"#96e80953-165b-49c4-8687-722f3d804a91\" id=\"96e80953-165b-49c4-8687-722f3d804a91-link\">507<\/a><\/sup> Chile,<sup data-fn=\"c421c8d5-b39c-459c-b739-75d1a67aaf35\" class=\"fn\"><a href=\"#c421c8d5-b39c-459c-b739-75d1a67aaf35\" id=\"c421c8d5-b39c-459c-b739-75d1a67aaf35-link\">508<\/a><\/sup> Per\u00fa<sup data-fn=\"ac49ad9e-9993-4907-8c29-ece6de164c79\" class=\"fn\"><a href=\"#ac49ad9e-9993-4907-8c29-ece6de164c79\" id=\"ac49ad9e-9993-4907-8c29-ece6de164c79-link\">509<\/a><\/sup> y Uruguay.<sup data-fn=\"b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c\" class=\"fn\"><a href=\"#b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c\" id=\"b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c-link\">510<\/a><\/sup> Asimismo, pueden implementarse pol\u00edticas que priorizan un amplio acceso a \u00f3rganos humanos y maximizan la eficiencia de sus sistemas de donaci\u00f3n y trasplante de \u00f3rganos,<sup data-fn=\"09deb376-7863-4fe7-bd62-3a07bdae478c\" class=\"fn\"><a href=\"#09deb376-7863-4fe7-bd62-3a07bdae478c\" id=\"09deb376-7863-4fe7-bd62-3a07bdae478c-link\">511<\/a><\/sup> cuyo \u00e9xito radica en el compromiso gubernamental, un sistema de donaci\u00f3n con consentimiento presunto, el fomento de una cultura de confianza en el sistema y el establecimiento de instituciones especializadas en m\u00faltiples niveles. Adem\u00e1s, una compensaci\u00f3n adecuada a los hospitales garantiza que las barreras financieras no obstaculicen la participaci\u00f3n en el sistema.<sup data-fn=\"457e59c2-127e-4a61-96aa-ff1a293836d4\" class=\"fn\"><a href=\"#457e59c2-127e-4a61-96aa-ff1a293836d4\" id=\"457e59c2-127e-4a61-96aa-ff1a293836d4-link\">512<\/a><\/sup> Estas medidas ampl\u00edan el acceso a los \u00f3rganos humanos y mejoran la eficiencia del sistema de trasplantes. Con un compromiso para mejorar los sistemas de donaci\u00f3n de \u00f3rganos, los legisladores y tomadores de decisiones pueden ampliar el acceso a \u00f3rganos humanos que salvan vidas sin recurrir a los xenotrasplantes, una pr\u00e1ctica arriesgada, innecesaria y con serias limitaciones \u00e9ticas.<\/p>\n<\/div>\n<\/div>\n<\/div>\n\n\n\n<div class=\"wp-block-columns footnotes is-layout-flex wp-container-core-columns-is-layout-8f761849 wp-block-columns-is-layout-flex\">\n<div class=\"wp-block-column is-layout-flow wp-block-column-is-layout-flow\">\n<h5 class=\"wp-block-heading\">ReferencIAS<\/h5>\n\n\n<ol class=\"wp-block-footnotes\"><li id=\"b5d1e717-bfa3-4939-9c1a-04301e350ee5\">Wender RC, Brawley OW, Fedewa SA, Gansler T, Smith RA. A blueprint for cancer screening and early detection: advancing screening\u2019s contribution to cancer control. <em>CA Cancer J Clin<\/em>. 2019;69(1):50-79. doi:10.3322\/caac.21550\u00a0 <a href=\"#b5d1e717-bfa3-4939-9c1a-04301e350ee5-link\" aria-label=\"Jump to footnote reference 1\">\u21a9\ufe0e<\/a><\/li><li id=\"3532e163-51af-49b6-b56e-6ad0e9bc691c\">Loud JT, Murphy J. Cancer screening and early detection in the 21<sup>st <\/sup>century. <em>Semin Oncol Nurs<\/em>. 2017;33(2):121-128. doi:10.1016\/j.soncn.2017.02.002 <a href=\"#3532e163-51af-49b6-b56e-6ad0e9bc691c-link\" aria-label=\"Jump to footnote reference 2\">\u21a9\ufe0e<\/a><\/li><li id=\"35e17b68-cd0c-4261-a697-47ece3fc8cf3\">National Cancer Institute. Cancer statistics. Cancer.gov. May 9, 2024. Accessed October 1, 2024. <a href=\"https:\/\/www.cancer.gov\/about-cancer\/understanding\/statistics\">https:\/\/www.cancer.gov\/about-cancer\/understanding\/statistics<\/a>\u00a0 <a href=\"#35e17b68-cd0c-4261-a697-47ece3fc8cf3-link\" aria-label=\"Jump to footnote reference 3\">\u21a9\ufe0e<\/a><\/li><li id=\"156dd4d7-6f00-4510-8b02-e0748c64e448\">Chen SLF, N\u00f8st TH, Botteri E, et al. Overall lifestyle changes in adulthood are associated with cancer incidence in the Norwegian Women and Cancer Study (NOWAC)\u2014a prospective cohort study. <em>BMC Public Health<\/em>. 2023;23(1):633. doi:10.1186\/s12889-023-15476-3 <a href=\"#156dd4d7-6f00-4510-8b02-e0748c64e448-link\" aria-label=\"Jump to footnote reference 4\">\u21a9\ufe0e<\/a><\/li><li id=\"49977b17-baec-430d-830f-599d34cf61f0\">Cronin KA, Scott S, Firth AU, et al. Annual report to the nation on the status of cancer, part 1: national cancer statistics. <em>Cancer<\/em>. 2022;128(24):4251-4284. doi:10.1002\/cncr.34479\u00a0 <a href=\"#49977b17-baec-430d-830f-599d34cf61f0-link\" aria-label=\"Jump to footnote reference 5\">\u21a9\ufe0e<\/a><\/li><li id=\"4d2bcedf-235e-45eb-b2c2-aa074f90968d\">Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. <em>Biostatistics<\/em>. 2019;20(2):273-286. doi:10.1093\/biostatistics\/kxx069\u00a0 <a href=\"#4d2bcedf-235e-45eb-b2c2-aa074f90968d-link\" aria-label=\"Jump to footnote reference 6\">\u21a9\ufe0e<\/a><\/li><li id=\"649ff382-081f-46b1-9e2d-ed90a9afca45\">Errington TM, Mathur M, Soderberg CK, et al. Investigating the replicability of preclinical cancer biology. Pasqualini R, Franco E, eds. <em>eLife<\/em>. 2021;10:e71601. doi:10.7554\/eLife.71601\u00a0 <a href=\"#649ff382-081f-46b1-9e2d-ed90a9afca45-link\" aria-label=\"Jump to footnote reference 7\">\u21a9\ufe0e<\/a><\/li><li id=\"a5157d53-deb5-4531-a934-3b02f2288a3d\">Mak IW, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. <em>Am J Transl Res<\/em>. 2014;6(2):114-118.\u00a0 <a href=\"#a5157d53-deb5-4531-a934-3b02f2288a3d-link\" aria-label=\"Jump to footnote reference 8\">\u21a9\ufe0e<\/a><\/li><li id=\"42a19a54-55f0-4de6-b5ca-dfe280ac45ef\">Cimons M, Getlin J, Maugh II T. Cancer drugs face long road from mice to men. <em>Los Angeles Times<\/em>. May 6, 1998. Accessed October 23, 2021. <a href=\"https:\/\/www.latimes.com\/archives\/la-xpm-1998-may-06-mn-46795-story.html.\">https:\/\/www.latimes.com\/archives\/la-xpm-1998-may-06-mn-46795-story.html.<\/a>\u00a0 <a href=\"#42a19a54-55f0-4de6-b5ca-dfe280ac45ef-link\" aria-label=\"Jump to footnote reference 9\">\u21a9\ufe0e<\/a><\/li><li id=\"27ff85ba-0983-4744-a4fc-ef4fccbbf5ed\">Ormandy EH, Dale J, Griffin G. Genetic engineering of animals: ethical issues, including welfare concerns. <em>Can Vet J<\/em>. 2011;52(5):544-550.\u00a0 <a href=\"#27ff85ba-0983-4744-a4fc-ef4fccbbf5ed-link\" aria-label=\"Jump to footnote reference 10\">\u21a9\ufe0e<\/a><\/li><li id=\"d9823697-d716-43f2-8d32-bffeeb2a7e4f\">Wewetzer H, Wagenknecht T, Bert B, Sch\u00f6nfelder G. The fate of surplus laboratory animals: minimizing the production of surplus animals has greatest potential to reduce the number of laboratory animals. <em>EMBO Rep<\/em>. 2023;24(3):e56551. doi:10.15252\/embr.202256551 <a href=\"#d9823697-d716-43f2-8d32-bffeeb2a7e4f-link\" aria-label=\"Jump to footnote reference 11\">\u21a9\ufe0e<\/a><\/li><li id=\"e6504616-eeff-4478-8418-807f98d84778\">Li Z, Zheng W, Wang H, et al. Application of animal models in cancer research: recent progress and future prospects. <em>Cancer Manag Res<\/em>. 2021;13:2455-2475. doi:10.2147\/CMAR.S302565\u00a0 <a href=\"#e6504616-eeff-4478-8418-807f98d84778-link\" aria-label=\"Jump to footnote reference 12\">\u21a9\ufe0e<\/a><\/li><li id=\"7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320\">Zhou Y, Xia J, Xu S, et al. Experimental mouse models for translational human cancer research. <em>Front Immunol<\/em>. 2023;14. doi:10.3389\/fimmu.2023.1095388\u00a0 <a href=\"#7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320-link\" aria-label=\"Jump to footnote reference 13\">\u21a9\ufe0e<\/a><\/li><li id=\"c72f94bc-8970-434b-a1f0-c875b4a80fd6\">Ben-David U, Ha G, Tseng YY, et al. Patient-derived xenografts undergo mouse-specific tumor evolution. <em>Nat Genet<\/em>. 2017;49:1567-1575. doi:10.1038\/ng.3967\u00a0 <a href=\"#c72f94bc-8970-434b-a1f0-c875b4a80fd6-link\" aria-label=\"Jump to footnote reference 14\">\u21a9\ufe0e<\/a><\/li><li id=\"60918212-9812-4989-97ec-69df548590b0\">Cheon DJ, Orsulic S. Mouse models of cancer. <em>Annu Rev Pathol<\/em>. 2011;6:95-119. doi:10.1146\/annurev.pathol.3.121806.154244\u00a0 <a href=\"#60918212-9812-4989-97ec-69df548590b0-link\" aria-label=\"Jump to footnote reference 15\">\u21a9\ufe0e<\/a><\/li><li id=\"d3031221-f943-4eed-b6c1-5d8f812f961e\">Ormandy et al., <em>Genetic Engineering of Animals<\/em>, 2011 <a href=\"#d3031221-f943-4eed-b6c1-5d8f812f961e-link\" aria-label=\"Jump to footnote reference 16\">\u21a9\ufe0e<\/a><\/li><li id=\"85c1ed46-9d65-4969-861d-9ab0e5e84484\">Romania P, Folgiero V, Nic M, et al. <em>Advanced Non-Animal Models in Biomedical Research: Immuno-Oncology<\/em>. Publications Office of the European Union; 2021:46. doi:10.2760\/393670 <a href=\"#85c1ed46-9d65-4969-861d-9ab0e5e84484-link\" aria-label=\"Jump to footnote reference 17\">\u21a9\ufe0e<\/a><\/li><li id=\"9708627f-2772-43aa-8bdd-465c51d8e6af\">Tricinci O, De Pasquale D, Marino A, Battaglini M, Pucci C, Ciofani G. A 3D biohybrid real-scale model of the brain cancer microenvironment for advanced in vitro testing. <em>Adv Mater Technol<\/em>. 2020;5(10):2000540. doi:10.1002\/admt.202000540 <a href=\"#9708627f-2772-43aa-8bdd-465c51d8e6af-link\" aria-label=\"Jump to footnote reference 18\">\u21a9\ufe0e<\/a><\/li><li id=\"ea5e7dd5-be13-4fe5-b608-97f12f2049db\">Sun H, Sun L, Ke X, et al. Prediction of clinical precision chemotherapy by patient-derived 3D bioprinting models of colorectal cancer and its liver metastases. <em>Adv Sci (Weinh)<\/em>. 2024;11(2):2304460. doi:10.1002\/advs.202304460\u00a0 <a href=\"#ea5e7dd5-be13-4fe5-b608-97f12f2049db-link\" aria-label=\"Jump to footnote reference 19\">\u21a9\ufe0e<\/a><\/li><li id=\"d472cc93-352a-4415-a8d6-41d3acd94809\">Asciak L, Gilmour L, Williams JA, et al. Investigating multi-material hydrogel three-dimensional printing for in vitro representation of the neo-vasculature of solid tumours: a comprehensive mechanical analysis and assessment of nitric oxide release from human umbilical vein endothelial cells. <em>R Soc Open Sci<\/em>. 2023;10(8):230929. doi:10.1098\/rsos.230929 <a href=\"#d472cc93-352a-4415-a8d6-41d3acd94809-link\" aria-label=\"Jump to footnote reference 20\">\u21a9\ufe0e<\/a><\/li><li id=\"fb72839a-f026-462a-952d-8761e9613ae7\">Dey M, Kim MH, Dogan M, et al. Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model. <em>Adv Funct Mater<\/em>. 2022;32(52):2203966. doi:10.1002\/adfm.202203966\u00a0 <a href=\"#fb72839a-f026-462a-952d-8761e9613ae7-link\" aria-label=\"Jump to footnote reference 21\">\u21a9\ufe0e<\/a><\/li><li id=\"f8b870f3-62c4-4953-87f4-65ac056998ad\">Polidoro MA, Ferrari E, Soldani C, et al. Cholangiocarcinoma-on-a-chip: a human 3D platform for personalised medicine. <em>JHEP Report<\/em>. 2024;6(1). doi:10.1016\/j.jhepr.2023.100910\u00a0 <a href=\"#f8b870f3-62c4-4953-87f4-65ac056998ad-link\" aria-label=\"Jump to footnote reference 22\">\u21a9\ufe0e<\/a><\/li><li id=\"73670505-ba59-4f3b-99b9-d4a8bf64ef8f\">Kim Y, Lee J, Lee S, Jung HI, Kwak B. Anisotropic tumor spheroid remission with binary tumor-microenvironment-on-a-chip. <em>Biosens Bioelectron<\/em>. 2024;243:115787. doi:10.1016\/j.bios.2023.115787\u00a0 <a href=\"#73670505-ba59-4f3b-99b9-d4a8bf64ef8f-link\" aria-label=\"Jump to footnote reference 23\">\u21a9\ufe0e<\/a><\/li><li id=\"9a3cd416-6989-4a15-b090-d41239bc6fed\">Sontheimer-Phelps A, Hassell BA, Ingber DE. Modelling cancer in microfluidic human organs-on-chips. <em>Nat Rev Cancer<\/em>. 2019;19(2):65-81. doi:10.1038\/s41568-018-0104-6 <a href=\"#9a3cd416-6989-4a15-b090-d41239bc6fed-link\" aria-label=\"Jump to footnote reference 24\">\u21a9\ufe0e<\/a><\/li><li id=\"1eb45f77-2665-440c-aab1-9b3f9885ada3\">McAleer CW, Long CJ, Elbrecht D, et al. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. <em>Sci Transl Med<\/em>. 2019;11(497):eaav1386. doi:10.1126\/scitranslmed.aav1386\u00a0 <a href=\"#1eb45f77-2665-440c-aab1-9b3f9885ada3-link\" aria-label=\"Jump to footnote reference 25\">\u21a9\ufe0e<\/a><\/li><li id=\"c1002ca2-b660-4b53-b87a-804b0fb1ea37\">Lim J, Rhee S, Choi H, et al. Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis. <em>Mater Today Bio<\/em>. 2023;22:100773. doi:10.1016\/j.mtbio.2023.100773\u00a0 <a href=\"#c1002ca2-b660-4b53-b87a-804b0fb1ea37-link\" aria-label=\"Jump to footnote reference 26\">\u21a9\ufe0e<\/a><\/li><li id=\"9f007b5a-8eae-4c12-9820-3c76c6617c69\">Millen R, De Kort WWB, Koomen M, et al. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification. <em>Med<\/em>. 2023;4(5):290-310.e12. doi:10.1016\/j.medj.2023.04.003\u00a0 <a href=\"#9f007b5a-8eae-4c12-9820-3c76c6617c69-link\" aria-label=\"Jump to footnote reference 27\">\u21a9\ufe0e<\/a><\/li><li id=\"af0cbef2-46ce-4c7c-9597-235e3fe5b056\">Tan T, Mouradov D, Lee M, et al. Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer. <em>Cell Rep Med<\/em>. 2023;4(12). doi:10.1016\/j.xcrm.2023.101335\u00a0 <a href=\"#af0cbef2-46ce-4c7c-9597-235e3fe5b056-link\" aria-label=\"Jump to footnote reference 28\">\u21a9\ufe0e<\/a><\/li><li id=\"a88c7153-224b-4804-9440-0e87416cea3e\">Raffo-Romero A, Ziane-Chaouche L, Salom\u00e9-Desnoulez S, et al. A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses. <em>Cell Rep Methods<\/em>. 2024;4(6). doi:10.1016\/j.crmeth.2024.100792\u00a0 <a href=\"#a88c7153-224b-4804-9440-0e87416cea3e-link\" aria-label=\"Jump to footnote reference 29\">\u21a9\ufe0e<\/a><\/li><li id=\"4fd24010-f6b8-4123-bf87-cb49796b6ebe\">Ethier SP, Guest ST, Garrett-Mayer E, et al. Development and implementation of the SUM breast cancer cell line functional genomics knowledge base. <em>NPJ Breast Cancer<\/em>. 2020;6(1):1-14. doi:10.1038\/s41523-020-0173-z\u00a0 <a href=\"#4fd24010-f6b8-4123-bf87-cb49796b6ebe-link\" aria-label=\"Jump to footnote reference 30\">\u21a9\ufe0e<\/a><\/li><li id=\"141fc7e4-6182-4414-abfe-3f2ffb60bbb7\">Campbell P, Getz G, Korbel J, et al. Pan-cancer analysis of whole genomes. <em>Nature<\/em>. 2020;578:82-93. doi:10.1038\/s41586-020-1969-6\u00a0 <a href=\"#141fc7e4-6182-4414-abfe-3f2ffb60bbb7-link\" aria-label=\"Jump to footnote reference 31\">\u21a9\ufe0e<\/a><\/li><li id=\"80be0c70-14ca-4a2f-bbc3-897bd0d042b6\">Dong X, Ding L, Thrasher A, et al. NetBID2 provides comprehensive hidden driver analysis. <em>Nat Commun<\/em>. 2023;14(1):2581. doi:10.1038\/s41467-023-38335-6\u00a0 <a href=\"#80be0c70-14ca-4a2f-bbc3-897bd0d042b6-link\" aria-label=\"Jump to footnote reference 32\">\u21a9\ufe0e<\/a><\/li><li id=\"c05b6008-28cc-4c3b-8d4c-28963c57275e\">Yang H, Zhao L, Li D, et al. Subtype-WGME enables whole-genome-wide multi-omics cancer subtyping. <em>Cell Rep Methods<\/em>. 2024;4(6):100781. doi:10.1016\/j.crmeth.2024.100781 <a href=\"#c05b6008-28cc-4c3b-8d4c-28963c57275e-link\" aria-label=\"Jump to footnote reference 33\">\u21a9\ufe0e<\/a><\/li><li id=\"15ee1a33-89ca-4d05-9f01-02aa6a8c5123\">Meric-Bernstam F, Ford JM, O\u2019Dwyer PJ, et al. National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH). <em>Clin Cancer Res<\/em>. 2023;29(8):1412-1422. doi:10.1158\/1078-0432.CCR-22-3334\u00a0 <a href=\"#15ee1a33-89ca-4d05-9f01-02aa6a8c5123-link\" aria-label=\"Jump to footnote reference 34\">\u21a9\ufe0e<\/a><\/li><li id=\"f90baee9-90cb-4311-b5df-2486ae499638\">Landhuis E. Deep learning takes on tumours. <em>Nature<\/em>. 2020;580(7804):551-553. doi:10.1038\/D41586-020-01128-8\u00a0 <a href=\"#f90baee9-90cb-4311-b5df-2486ae499638-link\" aria-label=\"Jump to footnote reference 35\">\u21a9\ufe0e<\/a><\/li><li id=\"d86bb19e-05b3-4fcf-97d9-21ec5593a362\">Acanda De La Rocha AM, Berlow NE, Fader M, et al. Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers. <em>Nat Med<\/em>. 2024;30(4):990-1000. doi:10.1038\/s41591-024-02848-4\u00a0 <a href=\"#d86bb19e-05b3-4fcf-97d9-21ec5593a362-link\" aria-label=\"Jump to footnote reference 36\">\u21a9\ufe0e<\/a><\/li><li id=\"39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c\">Meaney C, Das S, Colak E, Kohandel M. Deep learning characterization of brain tumours with diffusion weighted imaging. <em>J Theor Biol<\/em>. 2023;557:111342. doi:10.1016\/j.jtbi.2022.111342 <a href=\"#39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c-link\" aria-label=\"Jump to footnote reference 37\">\u21a9\ufe0e<\/a><\/li><li id=\"20f51e18-62a3-49d6-80ca-f5303d7d27e6\">Tan CL, Lindner K, Boschert T, et al. Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. <em>Nat Biotechnol<\/em>. Published online 2024:1-9. doi:10.1038\/s41587-024-02161-y\u00a0 <a href=\"#20f51e18-62a3-49d6-80ca-f5303d7d27e6-link\" aria-label=\"Jump to footnote reference 38\">\u21a9\ufe0e<\/a><\/li><li id=\"8276aa67-b7ba-478f-8708-a88fda55c8a7\">Jean-Quartier C, Jeanquartier F, Jurisica I, Holzinger A. In silico cancer research towards 3R. <em>BMC Cancer<\/em>. 2018;18(1):408. doi:10.1186\/s12885-018-4302-0 <a href=\"#8276aa67-b7ba-478f-8708-a88fda55c8a7-link\" aria-label=\"Jump to footnote reference 39\">\u21a9\ufe0e<\/a><\/li><li id=\"f63e9cf1-a54a-494e-a5de-c104dda7e778\">World Health Organization. Cardiovascular diseases. 2024. Accessed November 3, 2024. <a href=\"https:\/\/www.who.int\/health-topics\/cardiovascular-diseases\">https:\/\/www.who.int\/health-topics\/cardiovascular-diseases<\/a> <a href=\"#f63e9cf1-a54a-494e-a5de-c104dda7e778-link\" aria-label=\"Jump to footnote reference 40\">\u21a9\ufe0e<\/a><\/li><li id=\"e3fbad9e-65f3-4067-804a-b3f3f693c075\">Joint Research Centre (European Commission). World Heart Day: Non-animal models as promising tools to fight cardiovascular diseases\u2014European Commission. September 28, 2022. Accessed November 3, 2024. <a href=\"https:\/\/joint-research-centre.ec.europa.eu\/jrc-news-and-updates\/world-heart-day-non-animal-models-promising-tools-fight-cardiovascular-diseases-2022-09-28_en\">https:\/\/joint-research-centre.ec.europa.eu\/jrc-news-and-updates\/world-heart-day-non-animal-models-promising-tools-fight-cardiovascular-diseases-2022-09-28_en<\/a> <a href=\"#e3fbad9e-65f3-4067-804a-b3f3f693c075-link\" aria-label=\"Jump to footnote reference 41\">\u21a9\ufe0e<\/a><\/li><li id=\"05798e28-e21b-4414-9ce7-fb8679906d4d\">Vyas MV, Gros R, Hackam DG. Translation of cardiovascular animal models to human randomized trials. <em>Am J Cardiol<\/em>. 2020;137:141. doi:10.1016\/j.amjcard.2020.10.027 <a href=\"#05798e28-e21b-4414-9ce7-fb8679906d4d-link\" aria-label=\"Jump to footnote reference 42\">\u21a9\ufe0e<\/a><\/li><li id=\"84249d2d-5f00-4f4e-9473-bfd3c656c5df\">Joint Research Centre, <em>World Heart Day<\/em>, 2022. <a href=\"#84249d2d-5f00-4f4e-9473-bfd3c656c5df-link\" aria-label=\"Jump to footnote reference 43\">\u21a9\ufe0e<\/a><\/li><li id=\"b07c0d63-d807-429b-b44b-bcc74cbb1da2\">Zaragoza C, Gomez-Guerrero C, Martin-Ventura JL, et al. Animal models of cardiovascular diseases. <em>J Biomed Biotechnol<\/em>. 2011;2011(1):497841. doi:10.1155\/2011\/497841 <a href=\"#b07c0d63-d807-429b-b44b-bcc74cbb1da2-link\" aria-label=\"Jump to footnote reference 44\">\u21a9\ufe0e<\/a><\/li><li id=\"14a6ac36-8a42-4782-8319-cdc0b7a2f6d8\">Gintant G, Sager PT, Stockbridge N. Evolution of strategies to improve preclinical cardiac safety testing. <em>Nat Rev Drug Discov<\/em>. 2016;15(7):457-471. doi:10.1038\/nrd.2015.34 <a href=\"#14a6ac36-8a42-4782-8319-cdc0b7a2f6d8-link\" aria-label=\"Jump to footnote reference 45\">\u21a9\ufe0e<\/a><\/li><li id=\"1c48bfe9-c016-4967-b5dd-d613944fa130\">Milani-Nejad N, Janssen PML. Small and large animal models in cardiac contraction research: advantages and disadvantages. <em>Pharmacol Ther<\/em>. 2014;141(3):235-249. doi:10.1016\/j.pharmthera.2013.10.007 <a href=\"#1c48bfe9-c016-4967-b5dd-d613944fa130-link\" aria-label=\"Jump to footnote reference 46\">\u21a9\ufe0e<\/a><\/li><li id=\"75144ee4-253c-4014-9ae4-4667488fb05f\">Janssen PM, Elnakish MT. Modeling heart failure in animal models for novel drug discovery and development. <em>Expert Opin Drug Discov<\/em>. 2019;14(4):355. doi:10.1080\/17460441.2019.1582636 <a href=\"#75144ee4-253c-4014-9ae4-4667488fb05f-link\" aria-label=\"Jump to footnote reference 47\">\u21a9\ufe0e<\/a><\/li><li id=\"e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880\">Zaragoza et al., <em>Animal Models of Cardiovascular Diseases<\/em>, 2011. <a href=\"#e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880-link\" aria-label=\"Jump to footnote reference 48\">\u21a9\ufe0e<\/a><\/li><li id=\"72fd6b41-02d1-4590-b1c3-a77f531923a2\">Chorro FJ, Such-Belenguer L, L\u00f3pez-Merino V. Modelos animales de enfermedad cardiovascular. <em>Rev Esp Cardiol<\/em>. 2009;62(1):69-84. doi:10.1016\/S0300-8932(09)70023-5 <a href=\"#72fd6b41-02d1-4590-b1c3-a77f531923a2-link\" aria-label=\"Jump to footnote reference 49\">\u21a9\ufe0e<\/a><\/li><li id=\"bbaa06a9-31bc-4c16-8050-6e6597eaf437\">Del \u00c1lamo JC, Lemons D, Serrano R, et al. High throughput physiological screening of iPSC-derived cardiomyocytes for drug development. <em>Biochim Biophys Acta<\/em>. 2016;1863(7 Pt B):1717-1727. doi:10.1016\/j.bbamcr.2016.03.003 <a href=\"#bbaa06a9-31bc-4c16-8050-6e6597eaf437-link\" aria-label=\"Jump to footnote reference 50\">\u21a9\ufe0e<\/a><\/li><li id=\"7b91ef3a-c5c0-4e38-9db8-d40d699edac2\">Barter P, Rye KA. Cholesteryl ester transfer protein inhibition to reduce cardiovascular risk: where are we now? <em>Trends Pharmacol Sci<\/em>. 2011;32(12):694-699. doi:10.1016\/j.tips.2011.07.004\u00a0 <a href=\"#7b91ef3a-c5c0-4e38-9db8-d40d699edac2-link\" aria-label=\"Jump to footnote reference 51\">\u21a9\ufe0e<\/a><\/li><li id=\"8a669361-e64f-44e4-b564-4e243ed88c76\">Celi S, Cioffi M, Capellini K, et al. <em>Advanced Non-Animal Models in Biomedical Research: Cardiovascular Diseases<\/em>. European Commission Joint Research Centre; 2022. doi:10.2760\/94608 <a href=\"#8a669361-e64f-44e4-b564-4e243ed88c76-link\" aria-label=\"Jump to footnote reference 52\">\u21a9\ufe0e<\/a><\/li><li id=\"989f960c-b634-4f16-b294-474fa48fd78b\">World Health Organization. Cardiovascular diseases. 2024. Accessed November 3, 2024.\u00a0<a href=\"https:\/\/www.who.int\/health-topics\/cardiovascular-diseases\">https:\/\/www.who.int\/health-topics\/cardiovascular-diseases<\/a> <a href=\"#989f960c-b634-4f16-b294-474fa48fd78b-link\" aria-label=\"Jump to footnote reference 53\">\u21a9\ufe0e<\/a><\/li><li id=\"37d9bf7d-1dbf-43d4-a6db-e02c246fd526\">van Doorn ECH, Amesz JH, Sadeghi AH, de Groot NMS, Manintveld OC, Taverne YJHJ. Preclinical models of cardiac disease: a comprehensive overview for clinical scientists. <em>Cardiovasc Eng Tech<\/em>. 2024;15(2):232-249. doi:10.1007\/s13239-023-00707-w\u00a0 <a href=\"#37d9bf7d-1dbf-43d4-a6db-e02c246fd526-link\" aria-label=\"Jump to footnote reference 54\">\u21a9\ufe0e<\/a><\/li><li id=\"a78ed81d-1af3-4074-b6c2-28881e7a4f50\">Ho BX, Pang JKS, Chen Y, et al. Robust generation of human-chambered cardiac organoids from pluripotent stem cells for improved modelling of cardiovascular diseases. <em>Stem Cell Res Ther<\/em>. 2022;13(1):529. doi:10.1186\/s13287-022-03215-1\u00a0 <a href=\"#a78ed81d-1af3-4074-b6c2-28881e7a4f50-link\" aria-label=\"Jump to footnote reference 55\">\u21a9\ufe0e<\/a><\/li><li id=\"d2ac872c-a177-485e-a2e9-86c6e6a44d94\">Yang J, Lei W, Xiao Y, et al. Generation of human vascularized and chambered cardiac organoids for cardiac disease modelling and drug evaluation. <em>Cell Prolif<\/em>. 2024;57(8):e13631. doi:10.1111\/cpr.13631 <a href=\"#d2ac872c-a177-485e-a2e9-86c6e6a44d94-link\" aria-label=\"Jump to footnote reference 56\">\u21a9\ufe0e<\/a><\/li><li id=\"017577c0-c43a-4056-add0-716f3b2577cd\">Song M, Choi DB, Im JS, et al. Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell\u2013derived multi-cellular heart organoids. <em>Cell Death Dis<\/em>. 2024;15(5):308. doi:10.1038\/s41419-024-06703-9 <a href=\"#017577c0-c43a-4056-add0-716f3b2577cd-link\" aria-label=\"Jump to footnote reference 57\">\u21a9\ufe0e<\/a><\/li><li id=\"a79f293e-21a0-47ce-9a8e-3dae9ecd32b1\">Li PR, Kiran Boilla S, Wang CH, et al. A self-driven, microfluidic, integrated-circuit biosensing chip for detecting four cardiovascular disease biomarkers. <em>Biosens Bioelectron<\/em>. 2024;249:115931. doi:10.1016\/j.bios.2023.115931 <a href=\"#a79f293e-21a0-47ce-9a8e-3dae9ecd32b1-link\" aria-label=\"Jump to footnote reference 58\">\u21a9\ufe0e<\/a><\/li><li id=\"9059e30b-faf7-4ca2-bbc6-f01ca65bf884\">van Doorn et al., <em>Preclinical Models of Cardiac Disease<\/em>, 2024. <a href=\"#9059e30b-faf7-4ca2-bbc6-f01ca65bf884-link\" aria-label=\"Jump to footnote reference 59\">\u21a9\ufe0e<\/a><\/li><li id=\"6e8aa3b6-b816-4f9c-ac4b-b7309b218341\">Williams K, Liang T, Mass\u00e9 S, et al. A 3-D human model of complex cardiac arrhythmias. <em>Acta Biomaterialia<\/em>. 2021;132:149-161. doi:10.1016\/j.actbio.2021.03.004 <a href=\"#6e8aa3b6-b816-4f9c-ac4b-b7309b218341-link\" aria-label=\"Jump to footnote reference 60\">\u21a9\ufe0e<\/a><\/li><li id=\"f5699161-2a50-42f2-b785-204a6d1b7e3b\">Dalal S, Goel P, Onyema EM, et al. Application of machine learning for cardiovascular disease risk prediction. Bhardwaj A, ed. <em>Comput Intell Neurosci<\/em>. 2023;2023(1):9418666. doi:10.1155\/2023\/9418666 <a href=\"#f5699161-2a50-42f2-b785-204a6d1b7e3b-link\" aria-label=\"Jump to footnote reference 61\">\u21a9\ufe0e<\/a><\/li><li id=\"86c9eda2-bf94-428c-a230-dc3d6a869166\">Baghdadi NA, Farghaly Abdelaliem SM, Malki A, Gad I, Ewis A, Atlam E. Advanced machine learning techniques for cardiovascular disease early detection and diagnosis. <em>J Big Data<\/em>. 2023;10(1):144. doi:10.1186\/s40537-023-00817-1 <a href=\"#86c9eda2-bf94-428c-a230-dc3d6a869166-link\" aria-label=\"Jump to footnote reference 62\">\u21a9\ufe0e<\/a><\/li><li id=\"6657df79-120c-47f1-8a40-4ffe5128bfb1\">Pal M, Parija S, Panda G, Dhama K, Mohapatra RK. Risk prediction of cardiovascular disease using machine learning classifiers. <em>Open Med (Wars)<\/em>. 2022;17(1):1100-1113. doi:10.1515\/med-2022-0508 <a href=\"#6657df79-120c-47f1-8a40-4ffe5128bfb1-link\" aria-label=\"Jump to footnote reference 63\">\u21a9\ufe0e<\/a><\/li><li id=\"db08ab77-1578-4ba9-81a6-c439ac2d78cb\">Pi\u010dulin M, Smole T, \u017dunkovi\u010d B, et al. Disease progression of hypertrophic cardiomyopathy: modeling using machine learning. <em>JMIR Med Inform<\/em>. 2022;10(2):e30483. doi:10.2196\/30483 <a href=\"#db08ab77-1578-4ba9-81a6-c439ac2d78cb-link\" aria-label=\"Jump to footnote reference 64\">\u21a9\ufe0e<\/a><\/li><li id=\"7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b\">Margara F, Wang ZJ, Levrero-Florencio F, et al. In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment. <em>Prog Biophys Mol Biol<\/em>. 2021;159:58-74. doi:10.1016\/j.pbiomolbio.2020.06.007 <a href=\"#7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b-link\" aria-label=\"Jump to footnote reference 65\">\u21a9\ufe0e<\/a><\/li><li id=\"7ca34966-87e6-437e-9220-395c39ad6de5\">Milani-Nejad &amp; Janssen, 2014 <a href=\"#7ca34966-87e6-437e-9220-395c39ad6de5-link\" aria-label=\"Jump to footnote reference 66\">\u21a9\ufe0e<\/a><\/li><li id=\"ee8810ef-3b00-4aa2-8f48-9c90b69523cf\">van Doorn et al., <em>Preclinical Models of Cardiac Disease<\/em>, 2024 <a href=\"#ee8810ef-3b00-4aa2-8f48-9c90b69523cf-link\" aria-label=\"Jump to footnote reference 67\">\u21a9\ufe0e<\/a><\/li><li id=\"992d3102-c04c-4130-a926-f5d84a8fc8b5\">Ram R. Extrapolation of animal research data to humans: an analysis of the evidence. In: Herrmann K, Jayne K, eds. <em>Animal Experimentation: Working Towards a Paradigm Change<\/em>. BRILL; 2019:341-375. doi:10.1163\/9789004391192_016 <a href=\"#992d3102-c04c-4130-a926-f5d84a8fc8b5-link\" aria-label=\"Jump to footnote reference 68\">\u21a9\ufe0e<\/a><\/li><li id=\"c38c9aba-b804-4236-a611-1810ebc6ebc0\">Whiting R, Sander E, Conway C, Vaughan TJ. In silico modelling of aortic valve implants\u2014predicting in vitro performance using finite element analysis. <em>J Med Eng Technol<\/em>. 2022;46(3):220-230. doi:10.1080\/03091902.2022.2026506 <a href=\"#c38c9aba-b804-4236-a611-1810ebc6ebc0-link\" aria-label=\"Jump to footnote reference 69\">\u21a9\ufe0e<\/a><\/li><li id=\"14d49a8b-5a9c-4fa1-bdde-da3bf47c459c\">Abbassy M, Ali MZ, Sharma RM, et al. Biosensors with left ventricular assist devices. <em>Heart Fail Rev<\/em>. 2024;29(5):957-967. doi:10.1007\/s10741-024-10413-x <a href=\"#14d49a8b-5a9c-4fa1-bdde-da3bf47c459c-link\" aria-label=\"Jump to footnote reference 70\">\u21a9\ufe0e<\/a><\/li><li id=\"24ad7787-9c22-4326-ad63-c12f686c7a19\">American Association for the Advancement of Blood &amp; Biotherapies. Facts about cellular therapies. www.aabb.org. 2024. Accessed October 1, 2024. https:\/\/www.aabb.org\/news-resources\/resources\/cellular-therapies\/facts-about-cellular-therapies <a href=\"#24ad7787-9c22-4326-ad63-c12f686c7a19-link\" aria-label=\"Jump to footnote reference 71\">\u21a9\ufe0e<\/a><\/li><li id=\"2c63ece2-3530-40f5-bda7-915aff52a346\">American Society of Gene + Cell Therapy. Cell therapy basics. asgct.org. December 18, 2023. Accessed October 1, 2024. https:\/\/patienteducation.asgct.org\/gene-therapy-101\/cell-therapy-basics <a href=\"#2c63ece2-3530-40f5-bda7-915aff52a346-link\" aria-label=\"Jump to footnote reference 72\">\u21a9\ufe0e<\/a><\/li><li id=\"6d385ef5-32fc-44a7-84be-471ce649c370\">American Association for the Advancement of Blood &amp; Biotherapies, 2024 <a href=\"#6d385ef5-32fc-44a7-84be-471ce649c370-link\" aria-label=\"Jump to footnote reference 73\">\u21a9\ufe0e<\/a><\/li><li id=\"8002d682-8084-422f-b6a1-6e5d5b4ae89b\">Dey M, Kim MH, Dogan M, et al. Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model. <em>Adv Funct Mater<\/em>. 2022;32(52):2203966. doi:10.1002\/adfm.202203966 <a href=\"#8002d682-8084-422f-b6a1-6e5d5b4ae89b-link\" aria-label=\"Jump to footnote reference 74\">\u21a9\ufe0e<\/a><\/li><li id=\"fdf2504d-5830-4398-981a-6e3f9fd554d8\">Ying Li CM, Li R, Drew P, et al. Clinical application of cytokine-induced killer (CIK) cell therapy in colorectal cancer: current strategies and future challenges. <em>Cancer Treat Rev<\/em>. 2024;122:102665. doi:10.1016\/j.ctrv.2023.102665 <a href=\"#fdf2504d-5830-4398-981a-6e3f9fd554d8-link\" aria-label=\"Jump to footnote reference 75\">\u21a9\ufe0e<\/a><\/li><li id=\"f5a6c26c-c887-4758-8be1-55e1b55bbc46\">U.S. Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. FDA.gov. June 28, 2023. Accessed October 1, 2024. <a href=\"https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes\">https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes<\/a> <a href=\"#f5a6c26c-c887-4758-8be1-55e1b55bbc46-link\" aria-label=\"Jump to footnote reference 76\">\u21a9\ufe0e<\/a><\/li><li id=\"5de69205-f37b-4989-8692-2b22ad62ce4b\">Thai VL, Ramos-Rodriguez DH, Mesfin M, Leach JK. Hydrogel degradation promotes angiogenic and regenerative potential of cell spheroids for wound healing. <em>Mater Today Bio<\/em>. 2023;22:100769. doi:10.1016\/j.mtbio.2023.100769 <a href=\"#5de69205-f37b-4989-8692-2b22ad62ce4b-link\" aria-label=\"Jump to footnote reference 77\">\u21a9\ufe0e<\/a><\/li><li id=\"c83ae1eb-5b9d-440e-89dc-9b0948a54047\">Harding J, Roberts RM, Mirochnitchenko O. Large animal models for stem cell therapy. <em>Stem Cell Res Ther<\/em>. 2013;4(2):23. doi:10.1186\/scrt171 <a href=\"#c83ae1eb-5b9d-440e-89dc-9b0948a54047-link\" aria-label=\"Jump to footnote reference 78\">\u21a9\ufe0e<\/a><\/li><li id=\"70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf\">Hu C, Liu M, Li Y, et al. Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer. <em>Front Immunol<\/em>. 2023;14. doi:10.3389\/fimmu.2023.1213716 <a href=\"#70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf-link\" aria-label=\"Jump to footnote reference 79\">\u21a9\ufe0e<\/a><\/li><li id=\"efaeede9-a56c-4eb9-8c54-391507b8f2ed\">Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. <em>Clin Cancer Res<\/em>. 2006;12(20):6106-6115. doi:10.1158\/1078-0432.CCR-06-1183 <a href=\"#efaeede9-a56c-4eb9-8c54-391507b8f2ed-link\" aria-label=\"Jump to footnote reference 80\">\u21a9\ufe0e<\/a><\/li><li id=\"5a7a5765-6c73-4366-92b6-5c46c2f16195\">Lamers CHJ, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. <em>J Clin Oncol<\/em>. 2006;24(13):e20-e22. doi:10.1200\/JCO.2006.05.9964 <a href=\"#5a7a5765-6c73-4366-92b6-5c46c2f16195-link\" aria-label=\"Jump to footnote reference 81\">\u21a9\ufe0e<\/a><\/li><li id=\"bb130843-5efa-436c-914b-0bca564799cd\">Seattle Children\u2019s. Mouse model for CAR-T therapy. seattlechildrens.org. 2024. Accessed October 2, 2024. https:\/\/www.seattlechildrens.org\/research\/centers-programs\/science-industry-partnerships\/partnership-opportunities\/cancer-mouse-model-for-car-t-therapy\/ <a href=\"#bb130843-5efa-436c-914b-0bca564799cd-link\" aria-label=\"Jump to footnote reference 82\">\u21a9\ufe0e<\/a><\/li><li id=\"c5f12286-b96f-448c-90b7-7a1d9be301ed\">Harding et al., 2013 <a href=\"#c5f12286-b96f-448c-90b7-7a1d9be301ed-link\" aria-label=\"Jump to footnote reference 83\">\u21a9\ufe0e<\/a><\/li><li id=\"06c453ea-95ab-4dac-93ad-196e72f41bf7\">Kleiman RJ, Engle SJ. Human inducible pluripotent stem cells: realization of initial promise in drug discovery. <em>Cell Stem Cell<\/em>. 2021;28(9):1507-1515. doi:10.1016\/j.stem.2021.08.002 <a href=\"#06c453ea-95ab-4dac-93ad-196e72f41bf7-link\" aria-label=\"Jump to footnote reference 84\">\u21a9\ufe0e<\/a><\/li><li id=\"402d9886-6f97-4a17-a8df-0d763b43373d\">Cerneckis J, Cai H, Shi Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. <em>Sig Transduct Target Ther<\/em>. 2024;9(1):1-26. doi:10.1038\/s41392-024-01809-0 <a href=\"#402d9886-6f97-4a17-a8df-0d763b43373d-link\" aria-label=\"Jump to footnote reference 85\">\u21a9\ufe0e<\/a><\/li><li id=\"f872aa91-c354-42c6-b6e4-1949b2a33933\">Maulana TI, Teufel C, Cipriano M, et al. Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells. <em>Cell Stem Cell<\/em>. 2024;31(7):989-1002.e9. doi:10.1016\/j.stem.2024.04.018 <a href=\"#f872aa91-c354-42c6-b6e4-1949b2a33933-link\" aria-label=\"Jump to footnote reference 86\">\u21a9\ufe0e<\/a><\/li><li id=\"48bbc6e3-e783-4a97-91ff-9f2125362f3f\">Dees S, Ganesan R, Singh S, Grewal IS. Emerging CAR-T cell therapy for the treatment of triple-negative breast cancer. <em>Mol Cancer Ther<\/em>. 2020;19(12):2409-2421. doi:10.1158\/1535-7163.MCT-20-0385 <a href=\"#48bbc6e3-e783-4a97-91ff-9f2125362f3f-link\" aria-label=\"Jump to footnote reference 87\">\u21a9\ufe0e<\/a><\/li><li id=\"54799e1e-00dd-48c5-98d6-17eca4dcdda9\">Zaib T, Cheng K, Liu T, et al. Expression of CD22 in triple-negative breast cancer: a novel prognostic biomarker and potential target for CAR therapy. <em>Int J Mol Sci<\/em>. 2023;24(3):2152. doi:10.3390\/ijms24032152 <a href=\"#54799e1e-00dd-48c5-98d6-17eca4dcdda9-link\" aria-label=\"Jump to footnote reference 88\">\u21a9\ufe0e<\/a><\/li><li id=\"5452aaab-df18-450c-8107-5b7c9667ad44\">Singh R, Gholipourmalekabadi M, Shafikhani SH. Animal models for type 1 and type 2 diabetes: advantages and limitations. <em>Front Endocrinol (Lausanne)<\/em>. 2024;15:1359685. doi:10.3389\/fendo.2024.1359685 <a href=\"#5452aaab-df18-450c-8107-5b7c9667ad44-link\" aria-label=\"Jump to footnote reference 89\">\u21a9\ufe0e<\/a><\/li><li id=\"fe87a148-e467-4639-97e2-3d5685a06099\">Pandey S, Chmelir T, Chottova Dvorakova M. Animal models in diabetic research\u2014history, presence, and future perspectives. <em>Biomedicines<\/em>. 2023;11(10):2852. doi:10.3390\/biomedicines11102852 <a href=\"#fe87a148-e467-4639-97e2-3d5685a06099-link\" aria-label=\"Jump to footnote reference 90\">\u21a9\ufe0e<\/a><\/li><li id=\"a68fbfca-e143-4937-bf1f-cd16c9b716fc\">Kottaisamy CPD, Raj DS, Prasanth Kumar V, Sankaran U. Experimental animal models for diabetes and its related complications\u2014a review. <em>Lab Anim Res<\/em>. 2021;37(1):23. doi:10.1186\/s42826-021-00101-4 <a href=\"#a68fbfca-e143-4937-bf1f-cd16c9b716fc-link\" aria-label=\"Jump to footnote reference 91\">\u21a9\ufe0e<\/a><\/li><li id=\"f22ea257-0ab6-4bd2-ad29-c59d32cdda61\">Bunner AE, Chandrasekera PC, Barnard ND. Knockout mouse models of insulin signaling: relevance past and future. <em>World J Diabetes<\/em>. 2014;5(2):146-159. doi:10.4239\/wjd.v5.i2.146 <a href=\"#f22ea257-0ab6-4bd2-ad29-c59d32cdda61-link\" aria-label=\"Jump to footnote reference 92\">\u21a9\ufe0e<\/a><\/li><li id=\"d711ff14-8e6d-4927-9f65-cb0d2b9d86d0\">Rogal J, Zbinden A, Schenke-Layland K, Loskill P. Stem-cell based organ-on-a-chip models for diabetes research. <em>Adv Drug Deliv Rev<\/em>. 2019;140:101-128. doi:10.1016\/j.addr.2018.10.010 <a href=\"#d711ff14-8e6d-4927-9f65-cb0d2b9d86d0-link\" aria-label=\"Jump to footnote reference 93\">\u21a9\ufe0e<\/a><\/li><li id=\"e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5\">Chandrasekera PC, Pippin JJ. Of rodents and men: species-specific glucose regulation and type 2 diabetes research. <em>ALTEX<\/em>. 2014;31(2):157-176. doi:10.14573\/altex.1309231 <a href=\"#e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5-link\" aria-label=\"Jump to footnote reference 94\">\u21a9\ufe0e<\/a><\/li><li id=\"3f6d07cb-9410-46e3-9a25-a8c25a6c58a4\">Wang B, P. CC, Pippin JJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. <em>Curr Diabetes Rev<\/em>. 2014;10(2):131-145. doi:10.2174\/1573399810666140508121012 <a href=\"#3f6d07cb-9410-46e3-9a25-a8c25a6c58a4-link\" aria-label=\"Jump to footnote reference 95\">\u21a9\ufe0e<\/a><\/li><li id=\"86a9999f-a017-4225-b2c2-8c5d4a064658\">Singh et al., 2024 <a href=\"#86a9999f-a017-4225-b2c2-8c5d4a064658-link\" aria-label=\"Jump to footnote reference 96\">\u21a9\ufe0e<\/a><\/li><li id=\"60fde9d7-47ed-4c25-b2b3-8e8111108b61\">Arndt T, J\u00f6rns A, Hedrich HJ, Lenzen S, Wedekind D. Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddm rats over time compared to other congenic LEW strains. <em>Clin Exp Immunol<\/em>. 2014;177(1):168-178. doi:10.1111\/cei.12323 <a href=\"#60fde9d7-47ed-4c25-b2b3-8e8111108b61-link\" aria-label=\"Jump to footnote reference 97\">\u21a9\ufe0e<\/a><\/li><li id=\"858c6af8-fa4d-44f6-ae85-3336dfd17bb1\">Mir-Coll J, Moede T, Paschen M, et al. Human islet microtissues as an in vitro and an in vivo model system for diabetes. <em>Int J Mol Sci<\/em>. 2021;22(4):1813. doi:10.3390\/ijms22041813 <a href=\"#858c6af8-fa4d-44f6-ae85-3336dfd17bb1-link\" aria-label=\"Jump to footnote reference 98\">\u21a9\ufe0e<\/a><\/li><li id=\"acf07f13-22a1-4619-afe8-fb37b99097c8\">Joksimovic SL, Jevtovic-Todorovic V, Todorovic SM. The mechanisms of plasticity of nociceptive ion channels in painful diabetic neuropathy. <em>Front Pain Res (Lausanne)<\/em>. 2022;3:869735. doi:10.3389\/fpain.2022.869735 <a href=\"#acf07f13-22a1-4619-afe8-fb37b99097c8-link\" aria-label=\"Jump to footnote reference 99\">\u21a9\ufe0e<\/a><\/li><li id=\"209c7d6c-df7b-4e18-92c8-18f002c33c97\">Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. <em>Eur J Heart Fail<\/em>. 2017;19(1):43-53. doi:10.1002\/ejhf.633 <a href=\"#209c7d6c-df7b-4e18-92c8-18f002c33c97-link\" aria-label=\"Jump to footnote reference 100\">\u21a9\ufe0e<\/a><\/li><li id=\"dae01dad-95d5-483f-8ebf-b28c079f2477\">Lieschke GJ, Currie PD. Animal models of human disease: zebrafish swim into view. <em>Nat Rev Genet<\/em>. 2007;8(5):353-367. doi:10.1038\/nrg2091 <a href=\"#dae01dad-95d5-483f-8ebf-b28c079f2477-link\" aria-label=\"Jump to footnote reference 101\">\u21a9\ufe0e<\/a><\/li><li id=\"42239f74-e967-4ed1-bd7c-70e1639735f8\">Covington BA, Chen W. Animal models for understanding the mechanisms of beta cell death during type 2 diabetes pathogenesis. <em>Biomedicines<\/em>. 2024;12(3):473. doi:10.3390\/biomedicines12030473 <a href=\"#42239f74-e967-4ed1-bd7c-70e1639735f8-link\" aria-label=\"Jump to footnote reference 102\">\u21a9\ufe0e<\/a><\/li><li id=\"685997dc-6304-499a-9e46-2e6382171a0c\">Inaishi J, Saisho Y. Ethnic similarities and differences in the relationship between beta cell mass and diabetes. <em>J Clin Med<\/em>. 2017;6(12):113. doi:10.3390\/jcm6120113 <a href=\"#685997dc-6304-499a-9e46-2e6382171a0c-link\" aria-label=\"Jump to footnote reference 103\">\u21a9\ufe0e<\/a><\/li><li id=\"a31634e4-a5ff-42b3-bf9b-f472ca10c627\">Kusuyama J, Alves-Wagner AB, Makarewicz NS, Goodyear LJ. Effects of maternal and paternal exercise on offspring metabolism. <em>Nat Metab<\/em>. 2020;2(9):858-872. doi:10.1038\/s42255-020-00274-7 <a href=\"#a31634e4-a5ff-42b3-bf9b-f472ca10c627-link\" aria-label=\"Jump to footnote reference 104\">\u21a9\ufe0e<\/a><\/li><li id=\"d44f1095-ad37-48c6-967e-912592204bda\">Pandey et al., <em>Animal Models in Diabetic Research<\/em>, 2023 <a href=\"#d44f1095-ad37-48c6-967e-912592204bda-link\" aria-label=\"Jump to footnote reference 105\">\u21a9\ufe0e<\/a><\/li><li id=\"921b9db1-bf0e-4e98-aecb-3de96684dba3\">Rogal et al., 2019 <a href=\"#921b9db1-bf0e-4e98-aecb-3de96684dba3-link\" aria-label=\"Jump to footnote reference 106\">\u21a9\ufe0e<\/a><\/li><li id=\"0c743c36-f712-4726-a55a-ddc534ef96e1\">Pandey et al., <em>Animal Models in Diabetic Research<\/em>, 2023 <a href=\"#0c743c36-f712-4726-a55a-ddc534ef96e1-link\" aria-label=\"Jump to footnote reference 107\">\u21a9\ufe0e<\/a><\/li><li id=\"c04e205f-e2b8-4bc6-9f38-21a1597456b0\">Bunner et al., 2014 <a href=\"#c04e205f-e2b8-4bc6-9f38-21a1597456b0-link\" aria-label=\"Jump to footnote reference 108\">\u21a9\ufe0e<\/a><\/li><li id=\"5302ab5c-8233-42c1-af54-5381f693f4ab\">Ali Z, Chandrasekera PC, Pippin JJ. Animal research for type 2 diabetes mellitus, its limited translation for clinical benefit, and the way forward. <em>Altern Lab Anim<\/em>. 2018;46(1):13-22. doi:10.1177\/026119291804600101 <a href=\"#5302ab5c-8233-42c1-af54-5381f693f4ab-link\" aria-label=\"Jump to footnote reference 109\">\u21a9\ufe0e<\/a><\/li><li id=\"44692265-c894-4db3-b4aa-3b0aee4d9e56\">Petrosyan A, Cravedi P, Villani V, et al. A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier. <em>Nat Commun<\/em>. 2019;10(1):3656. doi:10.1038\/s41467-019-11577-z <a href=\"#44692265-c894-4db3-b4aa-3b0aee4d9e56-link\" aria-label=\"Jump to footnote reference 110\">\u21a9\ufe0e<\/a><\/li><li id=\"f0043d28-9f95-48de-9e1c-adc9f5c2e405\">Perin L, Da Sacco S. Generation of a glomerular filtration barrier on a glomerulus-on-a-chip platform. <em>Methods Mol Biol<\/em>. 2022;2373:121-131. doi:10.1007\/978-1-0716-1693-2_8 <a href=\"#f0043d28-9f95-48de-9e1c-adc9f5c2e405-link\" aria-label=\"Jump to footnote reference 111\">\u21a9\ufe0e<\/a><\/li><li id=\"c2cb5737-725a-4f48-a58d-1b41b153f68e\">Glieberman AL, Pope BD, Zimmerman JF, et al. Synchronized stimulation and continuous insulin sensing in a microfluidic human islet on a chip designed for scalable manufacturing. <em>Lab Chip<\/em>. 2019;19(18):2993-3010. doi:10.1039\/C9LC00253G <a href=\"#c2cb5737-725a-4f48-a58d-1b41b153f68e-link\" aria-label=\"Jump to footnote reference 112\">\u21a9\ufe0e<\/a><\/li><li id=\"30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e\">Riyaphan J, Pham DC, Leong MK, Weng CF. In silico approaches to identify polyphenol compounds as \u03b1-glucosidase and \u03b1-amylase inhibitors against type-II diabetes. <em>Biomolecules<\/em>. 2021;11(12):1877. doi:10.3390\/biom11121877 <a href=\"#30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e-link\" aria-label=\"Jump to footnote reference 113\">\u21a9\ufe0e<\/a><\/li><li id=\"3be906f0-c3e3-4cc2-a495-175ffe626fd8\">Moinul M, Amin SA, Kumar P, et al. Exploring sodium glucose cotransporter (SGLT2) inhibitors with machine learning approach: a novel hope in anti-diabetes drug discovery. <em>J Mol Graph Model<\/em>. 2022;111:108106. doi:10.1016\/j.jmgm.2021.108106 <a href=\"#3be906f0-c3e3-4cc2-a495-175ffe626fd8-link\" aria-label=\"Jump to footnote reference 114\">\u21a9\ufe0e<\/a><\/li><li id=\"39d47f23-c7e6-402c-9d28-918904685942\">Han K, Ma S, Sun J, et al. In silico modeling of patient-specific blood rheology in type 2 diabetes mellitus. <em>Biophys J<\/em>. 2023;122(8):1445-1458. doi:10.1016\/j.bpj.2023.03.010 <a href=\"#39d47f23-c7e6-402c-9d28-918904685942-link\" aria-label=\"Jump to footnote reference 115\">\u21a9\ufe0e<\/a><\/li><li id=\"cd041d9e-460a-427c-a29d-a1857d5be948\">Piersanti A, Pacini G, Tura A, D\u2019Argenio DZ, Morettini M. An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin. <em>Sci Rep<\/em>. 2024;14(1):10936. doi:10.1038\/s41598-024-61293-y <a href=\"#cd041d9e-460a-427c-a29d-a1857d5be948-link\" aria-label=\"Jump to footnote reference 116\">\u21a9\ufe0e<\/a><\/li><li id=\"0771f530-192a-499d-b750-ffb500715fbd\">Pandey et al., 2023 <a href=\"#0771f530-192a-499d-b750-ffb500715fbd-link\" aria-label=\"Jump to footnote reference 117\">\u21a9\ufe0e<\/a><\/li><li id=\"c64b7c17-a34d-40fb-866d-61d5f747cd76\">Saiding Q, Ma J, Ke C, Cui W. From \u201corgans on a chip\u201d to \u201cpatient on a chip.\u201d <em>Innovation<\/em>. 2022;3(5). doi:10.1016\/j.xinn.2022.100282 <a href=\"#c64b7c17-a34d-40fb-866d-61d5f747cd76-link\" aria-label=\"Jump to footnote reference 118\">\u21a9\ufe0e<\/a><\/li><li id=\"6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a\">Rogal et al., 2019 <a href=\"#6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a-link\" aria-label=\"Jump to footnote reference 119\">\u21a9\ufe0e<\/a><\/li><li id=\"aa7808d1-ccd1-4cf3-9b63-e04658b8bbde\">Tao T, Wang Y, Chen W, et al. Engineering human islet organoids from iPSCs using an organ-on-chip platform. <em>Lab Chip<\/em>. 2019;19(6):948-958. doi:10.1039\/C8LC01298A <a href=\"#aa7808d1-ccd1-4cf3-9b63-e04658b8bbde-link\" aria-label=\"Jump to footnote reference 120\">\u21a9\ufe0e<\/a><\/li><li id=\"41bcd3ad-1d97-4d89-ad10-21e0e4c93145\">Rodr\u00edguez-Comas J, Ram\u00f3n-Azc\u00f3n J. Islet-on-a-chip for the study of pancreatic \u03b2-cell function. <em>In vitro models<\/em>. 2022;1(1):41-57. doi:10.1007\/s44164-021-00005-6 <a href=\"#41bcd3ad-1d97-4d89-ad10-21e0e4c93145-link\" aria-label=\"Jump to footnote reference 121\">\u21a9\ufe0e<\/a><\/li><li id=\"f63c9ded-49b5-4b46-869f-a65bba1c8876\">Abadpour S, Aizenshtadt A, Olsen PA, et al. Pancreas-on-a-chip technology for transplantation applications. <em>Curr Diab Rep<\/em>. 2020;20(12):72. doi:10.1007\/s11892-020-01357-1 <a href=\"#f63c9ded-49b5-4b46-869f-a65bba1c8876-link\" aria-label=\"Jump to footnote reference 122\">\u21a9\ufe0e<\/a><\/li><li id=\"5504406f-3b1e-44b7-9184-fa1f6b68e63c\">Sokolowska P, Zukowski K, Janikiewicz J, Jastrzebska E, Dobrzyn A, Brzozka Z. Islet-on-a-chip: biomimetic micropillar-based microfluidic system for three-dimensional pancreatic islet cell culture. <em>Biosens Bioelectron<\/em>. 2021;183:113215. doi:10.1016\/j.bios.2021.113215 <a href=\"#5504406f-3b1e-44b7-9184-fa1f6b68e63c-link\" aria-label=\"Jump to footnote reference 123\">\u21a9\ufe0e<\/a><\/li><li id=\"7f0642c5-e462-4edd-aea0-04bea6a930f0\">Kim M, Jang J. Construction of 3D hierarchical tissue platforms for modeling diabetes. <em>APL Bioeng<\/em>. 2021;5(4):041506. doi:10.1063\/5.0055128 <a href=\"#7f0642c5-e462-4edd-aea0-04bea6a930f0-link\" aria-label=\"Jump to footnote reference 124\">\u21a9\ufe0e<\/a><\/li><li id=\"ed855932-6197-4ca0-95fd-5db032564172\">Kottaisamy et al., 2021 <a href=\"#ed855932-6197-4ca0-95fd-5db032564172-link\" aria-label=\"Jump to footnote reference 125\">\u21a9\ufe0e<\/a><\/li><li id=\"5bbf758b-f16c-41a4-bfec-460eaa861d89\">Antony JM, MacDonald KS. A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1\/SIV vaccine efficacy. <em>Vaccine<\/em>. 2015;33(27):3073-3083. doi:10.1016\/j.vaccine.2014.12.004 <a href=\"#5bbf758b-f16c-41a4-bfec-460eaa861d89-link\" aria-label=\"Jump to footnote reference 126\">\u21a9\ufe0e<\/a><\/li><li id=\"691a380a-a5dc-4ecd-8e3a-26aea1b9a26c\">Centlivre M, Combadi\u00e8re B. New challenges in modern vaccinology. <em>BMC Immunol<\/em>. 2015;16(1):18. doi:10.1186\/s12865-015-0075-2 <a href=\"#691a380a-a5dc-4ecd-8e3a-26aea1b9a26c-link\" aria-label=\"Jump to footnote reference 127\">\u21a9\ufe0e<\/a><\/li><li id=\"fd011132-72e5-4599-a105-4b865c846131\">Haigwood NL. Update on animal models for HIV research. <em>Eur J Immunol<\/em>. 2009;39(8):1994-1999. doi:10.1002\/eji.200939576 <a href=\"#fd011132-72e5-4599-a105-4b865c846131-link\" aria-label=\"Jump to footnote reference 128\">\u21a9\ufe0e<\/a><\/li><li id=\"947ee380-bf77-458a-b11a-1b73f8bb08d5\">J\u00fclg B, Barouch DH. Novel immunological strategies for HIV-1 eradication. <em>J Virus Erad<\/em>. 2015;1(4):232-236. <a href=\"#947ee380-bf77-458a-b11a-1b73f8bb08d5-link\" aria-label=\"Jump to footnote reference 129\">\u21a9\ufe0e<\/a><\/li><li id=\"e0d2d497-a11e-42e8-9028-cfb2005abeaf\">Girard M, Habel A, Chanel C. New prospects for the development of a vaccine against human immunodeficiency virus type 1. An overview. <em>Comptes Rendus de l\u2019Acad\u00e9mie des Sciences &#8211; Series III &#8211; Sciences de la Vie<\/em>. 1999;322(11):959-966. doi:10.1016\/S0764-4469(00)87193-0 <a href=\"#e0d2d497-a11e-42e8-9028-cfb2005abeaf-link\" aria-label=\"Jump to footnote reference 130\">\u21a9\ufe0e<\/a><\/li><li id=\"fd9ccee5-d94b-4975-99ba-ce0dcfabe145\">Hu SL. Non-human primate models for AIDS vaccine research. <em>Curr Drug Targets Infect Disord<\/em>. 2005;5(2):193-201. doi:10.2174\/1568005054201508 <a href=\"#fd9ccee5-d94b-4975-99ba-ce0dcfabe145-link\" aria-label=\"Jump to footnote reference 131\">\u21a9\ufe0e<\/a><\/li><li id=\"31c78c72-a1e4-4e0b-932c-21417c7a9342\">National Institute of Allergy and Infectious Diseases. History of HIV vaccine research. niaid.nih.gov. October 22, 2018. Accessed December 5, 2024. https:\/\/www.niaid.nih.gov\/diseases-conditions\/hiv-vaccine-research-history <a href=\"#31c78c72-a1e4-4e0b-932c-21417c7a9342-link\" aria-label=\"Jump to footnote reference 132\">\u21a9\ufe0e<\/a><\/li><li id=\"bd0ef70e-9918-40b3-8774-34b0c6524cc7\">PreEPVacc. HIV vaccines tested in PrEPVacc fail to reduce infections. July 23, 2024. Accessed October 18, 2024. https:\/\/www.prepvacc.org\/news\/hiv-vaccines-tested-in-prepvacc-fail-to-reduce-infections-23-july-news-release <a href=\"#bd0ef70e-9918-40b3-8774-34b0c6524cc7-link\" aria-label=\"Jump to footnote reference 133\">\u21a9\ufe0e<\/a><\/li><li id=\"ff5ca556-0244-440a-baf3-b8228abd4389\">Sekaly RP. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? <em>J Exp Med<\/em>. 2008;205(1):7-12. doi:10.1084\/jem.20072681 <a href=\"#ff5ca556-0244-440a-baf3-b8228abd4389-link\" aria-label=\"Jump to footnote reference 134\">\u21a9\ufe0e<\/a><\/li><li id=\"6c940557-c7ae-4372-ae6a-4062a7bd3747\">Cohen J. \u201cIt\u2019s sobering\u201d: a once-exciting HIV cure strategy fails its test in people. <em>Science<\/em>. July 25, 2018. Accessed February 7, 2022. https:\/\/www.science.org\/content\/article\/it-s-sobering-once-exciting-hiv-curestrategy-fails-its-test-people <a href=\"#6c940557-c7ae-4372-ae6a-4062a7bd3747-link\" aria-label=\"Jump to footnote reference 135\">\u21a9\ufe0e<\/a><\/li><li id=\"7e5d28ab-b432-4efe-85ba-a9de952787f3\">Matthews H, Hanison J, Nirmalan N. \u201cOmics\u201d-informed drug and biomarker discovery: opportunities, challenges and future perspectives. <em>Proteomes<\/em>. 2016;4(3):28. doi:10.3390\/proteomes4030028 <a href=\"#7e5d28ab-b432-4efe-85ba-a9de952787f3-link\" aria-label=\"Jump to footnote reference 136\">\u21a9\ufe0e<\/a><\/li><li id=\"ccf58197-a4c7-42e7-9c73-5076bd8a7326\">Haigwood, 2009 <a href=\"#ccf58197-a4c7-42e7-9c73-5076bd8a7326-link\" aria-label=\"Jump to footnote reference 137\">\u21a9\ufe0e<\/a><\/li><li id=\"212aba32-9855-4565-9282-e0f815170d8b\">Antony &amp; MacDonald, 2015 <a href=\"#212aba32-9855-4565-9282-e0f815170d8b-link\" aria-label=\"Jump to footnote reference 138\">\u21a9\ufe0e<\/a><\/li><li id=\"8b7df6e5-f6b4-4699-aab7-fc4b152fd96e\">O\u2019Dell R. Sickness and death at Mesa-area monkey farm threaten primate center viability. <em>azcentral.com<\/em>. October 5, 2021. Accessed March 2, 2022. <a href=\"https:\/\/www.peta.org\/wp-content\/uploads\/2021\/10\/202110-04-Sickness-and-death-at-Mesa-area-monkey-farm-threaten-primate-center-viability.pdf\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.peta.org\/wp-content\/uploads\/2021\/10\/202110-04-Sickness-and-death-at-Mesa-area-monkey-farm-threaten-primate-center-viability.pdf<\/a>\u202f <a href=\"#8b7df6e5-f6b4-4699-aab7-fc4b152fd96e-link\" aria-label=\"Jump to footnote reference 139\">\u21a9\ufe0e<\/a><\/li><li id=\"ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b\">Rao M, Alving CR. Adjuvants for HIV vaccines. <em>Curr Opin HIV AIDS<\/em>. 2016;11(6):585-592. doi:10.1097\/COH.0000000000000315 <a href=\"#ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b-link\" aria-label=\"Jump to footnote reference 140\">\u21a9\ufe0e<\/a><\/li><li id=\"e950dc7d-ba59-4fe2-88c9-7b4c37297cfb\">Tonks A. Quest for the AIDS vaccine. <em>BMJ<\/em>. 2007;334(7608):1346-1348. doi:10.1136\/bmj.39240.416968.AD <a href=\"#e950dc7d-ba59-4fe2-88c9-7b4c37297cfb-link\" aria-label=\"Jump to footnote reference 141\">\u21a9\ufe0e<\/a><\/li><li id=\"de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52\">Kumar N, Chahroudi A, Silvestri G. Animal models to achieve an HIV cure. <em>Curr Opin HIV AIDS<\/em>. 2016;11(4):432-441. doi:10.1097\/COH.0000000000000290\u00a0 <a href=\"#de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52-link\" aria-label=\"Jump to footnote reference 142\">\u21a9\ufe0e<\/a><\/li><li id=\"fea94a25-6186-4382-b9dc-6b93c88abc08\">Deeks HM, Walters RK, Hare SR, O\u2019Connor MB, Mulholland AJ, Glowacki DR. Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking. Paci E, ed. <em>PLoS One<\/em>. 2020;15(3):e0228461. doi:10.1371\/journal.pone.0228461 <a href=\"#fea94a25-6186-4382-b9dc-6b93c88abc08-link\" aria-label=\"Jump to footnote reference 143\">\u21a9\ufe0e<\/a><\/li><li id=\"a532aecc-0fa7-4532-bca6-5398c1f8b21e\">Baassi M, Moussaoui M, Soufi H, et al. Towards designing of a potential new HIV-1 protease inhibitor using QSAR study in combination with molecular docking and molecular dynamics simulations. Ghosh A, ed. <em>PLoS One<\/em>. 2023;18(4):e0284539. doi:10.1371\/journal.pone.0284539\u00a0 <a href=\"#a532aecc-0fa7-4532-bca6-5398c1f8b21e-link\" aria-label=\"Jump to footnote reference 144\">\u21a9\ufe0e<\/a><\/li><li id=\"a30c0a94-ff81-4a61-a8de-26889bb06ad2\">Zhang YJ, Chen L, Xu J, et al. Evaluation of novel HIV-1 protease inhibitors with DRV-resistance by utilizing 3D-QSAR molecular docking and molecular dynamics simulation. <em>New J Chem<\/em>. 2022;46(45):21885-21897. doi:10.1039\/D2NJ04492G\u00a0 <a href=\"#a30c0a94-ff81-4a61-a8de-26889bb06ad2-link\" aria-label=\"Jump to footnote reference 145\">\u21a9\ufe0e<\/a><\/li><li id=\"4bff9792-36f1-4f95-b5d2-5272f4353e62\">Wang R, Zheng Q. Multiple molecular dynamics simulations and energy analysis unravel the dynamic properties and binding mechanism of mutants HIV-1 protease with DRV and CA-p2. <em>Microbiol Spectr<\/em>. 2022;10(2):e0074821. doi:10.1128\/spectrum.00748-21 <a href=\"#4bff9792-36f1-4f95-b5d2-5272f4353e62-link\" aria-label=\"Jump to footnote reference 146\">\u21a9\ufe0e<\/a><\/li><li id=\"3cf51db2-8e6a-4609-83db-3b54784af073\">Saha I, Saffarian S. Dynamics of the HIV Gag lattice detected by localization correlation analysis and time-lapse iPALM. <em>Biophys J<\/em>. 2020;119(3):581-592. doi:10.1016\/j.bpj.2020.06.023 <a href=\"#3cf51db2-8e6a-4609-83db-3b54784af073-link\" aria-label=\"Jump to footnote reference 147\">\u21a9\ufe0e<\/a><\/li><li id=\"8d9b0e43-f194-42aa-85cb-88836a341fcf\">Xie G, Luo X, Ma T, et al. Characterization of HIV-induced remodeling reveals differences in infection susceptibility of memory CD4+ T cell subsets in vivo. <em>Cell Rep<\/em>. 2021;35(4):109038. doi:10.1016\/J.CELREP.2021.109038\/ATTACHMENT\/DD9335E3-A2AE-4B21-B703-B888B3ACCC05\/MMC1.PDF\u00a0 <a href=\"#8d9b0e43-f194-42aa-85cb-88836a341fcf-link\" aria-label=\"Jump to footnote reference 148\">\u21a9\ufe0e<\/a><\/li><li id=\"8624236b-267a-4a8e-80e5-273f333c9ad3\">Collora JA, Liu R, Pinto-Santini D, et al. Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones. <em>Immunity<\/em>. 2022;55(6):1013-1031.e7. doi:10.1016\/j.immuni.2022.03.004\u00a0 <a href=\"#8624236b-267a-4a8e-80e5-273f333c9ad3-link\" aria-label=\"Jump to footnote reference 149\">\u21a9\ufe0e<\/a><\/li><li id=\"9e2d8fee-c83a-4b26-ab43-4a9675673e2b\">Ma T, McGregor M, Giron L, et al. Single-cell glycomics analysis by CyTOF-Lec reveals glycan features defining cells differentially susceptible to HIV. <em>eLife<\/em>. 2022;11:e78870. doi:10.7554\/eLife.78870\u00a0 <a href=\"#9e2d8fee-c83a-4b26-ab43-4a9675673e2b-link\" aria-label=\"Jump to footnote reference 150\">\u21a9\ufe0e<\/a><\/li><li id=\"95da9a6a-fe0c-4619-a12f-e5e223b7cca4\">Wang XM, Zhang JY, Xing X, et al. Global transcriptomic characterization of T cells in individuals with chronic HIV-1 infection. <em>Cell Discov<\/em>. 2022;8(1):29. doi:10.1038\/s41421-021-00367-x\u00a0 <a href=\"#95da9a6a-fe0c-4619-a12f-e5e223b7cca4-link\" aria-label=\"Jump to footnote reference 151\">\u21a9\ufe0e<\/a><\/li><li id=\"17bab855-46cc-4186-85db-e09a2ac641ef\">Galperin M, Farenc C, Mukhopadhyay M, et al. CD4 <sup>+<\/sup> T cell\u2013mediated HLA class II cross-restriction in HIV controllers. <em>Sci Immunol<\/em>. 2018;3(24):eaat0687. doi:10.1126\/sciimmunol.aat0687 <a href=\"#17bab855-46cc-4186-85db-e09a2ac641ef-link\" aria-label=\"Jump to footnote reference 152\">\u21a9\ufe0e<\/a><\/li><li id=\"162ead82-a6d8-45d6-ab0a-d8492e7eb17b\">Claireaux M, Robinot R, Kervevan J, et al. Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry. <em>Nat Commun<\/em>. 2022;13(1):521. doi:10.1038\/s41467-022-28130-0\u00a0 <a href=\"#162ead82-a6d8-45d6-ab0a-d8492e7eb17b-link\" aria-label=\"Jump to footnote reference 153\">\u21a9\ufe0e<\/a><\/li><li id=\"b3fa3635-ec79-4fe9-83d1-aec0141aeb80\">Etemad B, Sun X, Li Y, et al. HIV post-treatment controllers have distinct immunological and virological features. <em>Proc Natl Acad Sci USA<\/em>. 2023;120(11):e2218960120. doi:10.1073\/pnas.2218960120\u00a0 <a href=\"#b3fa3635-ec79-4fe9-83d1-aec0141aeb80-link\" aria-label=\"Jump to footnote reference 154\">\u21a9\ufe0e<\/a><\/li><li id=\"4584cf68-2da0-4527-af9a-d61666458ccf\">Real LM, S\u00e1ez ME, Corma-G\u00f3mez A, et al. A metagenome-wide association study of HIV disease progression in HIV controllers. <em>iScience<\/em>. 2023;26(7):107214. doi:10.1016\/j.isci.2023.107214 <a href=\"#4584cf68-2da0-4527-af9a-d61666458ccf-link\" aria-label=\"Jump to footnote reference 155\">\u21a9\ufe0e<\/a><\/li><li id=\"13a969ed-7287-4251-8d6a-f8c4fac36b15\">Kennedy BD, Blazkova J, Justement JS, et al. Comprehensive analysis of HIV reservoirs in elite controllers. <em>J Clin Invest<\/em>. 2023;133(3):e165446. doi:10.1172\/JCI165446\u00a0 <a href=\"#13a969ed-7287-4251-8d6a-f8c4fac36b15-link\" aria-label=\"Jump to footnote reference 156\">\u21a9\ufe0e<\/a><\/li><li id=\"ba0d86e2-86bd-43d0-8fa8-23f00d79134e\">Shi Y, Su J, Chen R, et al. The role of innate immunity in natural elite controllers of HIV-1 infection. <em>Front Immunol<\/em>. 2022;13:780922. doi:10.3389\/fimmu.2022.780922\u00a0 <a href=\"#ba0d86e2-86bd-43d0-8fa8-23f00d79134e-link\" aria-label=\"Jump to footnote reference 157\">\u21a9\ufe0e<\/a><\/li><li id=\"e68a59c6-dff5-4701-8d42-94d0ca8d05bd\">Cait J, Cait A, Scott RW, Winder CB, Mason GJ. Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis. <em>BMC Biol<\/em>. 2022;20(1):1-22. doi:10.1186\/S12915-021-01184-0\/TABLES\/2\u00a0 <a href=\"#e68a59c6-dff5-4701-8d42-94d0ca8d05bd-link\" aria-label=\"Jump to footnote reference 158\">\u21a9\ufe0e<\/a><\/li><li id=\"64baf987-b033-4d02-8057-d48a8eb446d0\">Maulana TI, Kromidas E, Wallstabe L, et al. Immunocompetent cancer-on-chip models to assess immuno-oncology therapy. <em>Adv Drug Deliv Rev<\/em>. 2021;173:281-305. doi:10.1016\/j.addr.2021.03.015 <a href=\"#64baf987-b033-4d02-8057-d48a8eb446d0-link\" aria-label=\"Jump to footnote reference 159\">\u21a9\ufe0e<\/a><\/li><li id=\"acdc8a1f-7ba2-48e5-8092-6c7e288ab443\">Mestas J, Hughes CCW. Of mice and not men: differences between mouse and human immunology. <em>J Immunol<\/em>. 2004;172(5):2731-2738. doi:10.4049\/jimmunol.172.5.2731 <a href=\"#acdc8a1f-7ba2-48e5-8092-6c7e288ab443-link\" aria-label=\"Jump to footnote reference 160\">\u21a9\ufe0e<\/a><\/li><li id=\"29d5a1f1-893f-4c4c-80bd-9aba0e053b89\">Zschaler J, Schlorke D, Arnhold J. Differences in innate immune response between man and mouse. <em>Crit Rev Immunol<\/em>. 2014;34(5):433-454. <a href=\"#29d5a1f1-893f-4c4c-80bd-9aba0e053b89-link\" aria-label=\"Jump to footnote reference 161\">\u21a9\ufe0e<\/a><\/li><li id=\"9c3301e1-207e-4f94-8881-7bd7acfc9c4e\">Johnson MD, Witherden DA, Havran WL. The role of tissue-resident T cells in stress surveillance and tissue maintenance. <em>Cells<\/em>. 2020;9(3):686. doi:10.3390\/cells9030686 <a href=\"#9c3301e1-207e-4f94-8881-7bd7acfc9c4e-link\" aria-label=\"Jump to footnote reference 162\">\u21a9\ufe0e<\/a><\/li><li id=\"8d031a6b-6b2b-4a42-afa6-7a58fdf651b0\">Leukemia &amp; Lymphoma Society. Understanding blood counts. LLS.org. Accessed October 3, 2024. <a href=\"https:\/\/www.lls.org\/treatment\/lab-and-imaging-tests\/understanding-blood-counts\">https:\/\/www.lls.org\/treatment\/lab-and-imaging-tests\/understanding-blood-counts<\/a> <a href=\"#8d031a6b-6b2b-4a42-afa6-7a58fdf651b0-link\" aria-label=\"Jump to footnote reference 163\">\u21a9\ufe0e<\/a><\/li><li id=\"afe94fd7-d6f8-4eca-961c-c223e14a0f92\">Provencher Bolliger A, Everds N, Zimmerman K, Moore D, Smith S, Barnhart K. Hematology of laboratory animals. In: <em>Schalm\u2019s Veterinary Hematology<\/em>. Wiley-Blackwell; 2010:852-887 <a href=\"#afe94fd7-d6f8-4eca-961c-c223e14a0f92-link\" aria-label=\"Jump to footnote reference 164\">\u21a9\ufe0e<\/a><\/li><li id=\"41356df1-cf70-4255-8db9-775bc9d5e936\">Medetgul-Ernar K, Davis MM. Standing on the shoulders of mice. <em>Immunity<\/em>. 2022;55(8):1343-1353. doi:10.1016\/j.immuni.2022.07.008 <a href=\"#41356df1-cf70-4255-8db9-775bc9d5e936-link\" aria-label=\"Jump to footnote reference 165\">\u21a9\ufe0e<\/a><\/li><li id=\"f8f0a535-012a-4e7e-a266-1e483e7e1a05\">Bjornson-Hooper ZB, Fragiadakis GK, Spitzer MH, et al. A comprehensive atlas of immunological differences between humans, mice, and non-human primates. <em>Front Immunol<\/em>. 2022;13. doi:10.3389\/fimmu.2022.867015 <a href=\"#f8f0a535-012a-4e7e-a266-1e483e7e1a05-link\" aria-label=\"Jump to footnote reference 166\">\u21a9\ufe0e<\/a><\/li><li id=\"7a6e3743-f714-4639-852f-c4c3a825e969\">Leist M, Hartung T. Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. <em>Arch Toxicol<\/em>. 2013;87(4):563-567. doi:10.1007\/s00204-013-1038-0 <a href=\"#7a6e3743-f714-4639-852f-c4c3a825e969-link\" aria-label=\"Jump to footnote reference 167\">\u21a9\ufe0e<\/a><\/li><li id=\"9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e\">Mestas &amp; Hughes, 2004 <a href=\"#9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e-link\" aria-label=\"Jump to footnote reference 168\">\u21a9\ufe0e<\/a><\/li><li id=\"37da492c-af45-490c-9b6a-8543467fa9d1\">Bjornson-Hooper et al., 2022 <a href=\"#37da492c-af45-490c-9b6a-8543467fa9d1-link\" aria-label=\"Jump to footnote reference 169\">\u21a9\ufe0e<\/a><\/li><li id=\"72afd8b1-3651-4048-ae5d-46e24ea94224\">Gros P, Casanova JL. Reconciling mouse and human immunology at the altar of genetics. <em>Ann Rev Immunol<\/em>. 2023;41:39-71. doi:10.1146\/annurev-immunol-101721-065201 <a href=\"#72afd8b1-3651-4048-ae5d-46e24ea94224-link\" aria-label=\"Jump to footnote reference 170\">\u21a9\ufe0e<\/a><\/li><li id=\"3f10983f-1bc6-4461-a24b-9fc31d40be7f\">B\u00e9ziat V, Rapaport F, Hu J, et al. Humans with inherited T\u202fcell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy. <em>Cell<\/em>. 2021;184(14):3812-3828.e30. doi:10.1016\/j.cell.2021.06.004 <a href=\"#3f10983f-1bc6-4461-a24b-9fc31d40be7f-link\" aria-label=\"Jump to footnote reference 171\">\u21a9\ufe0e<\/a><\/li><li id=\"5ce45f89-9bd1-4c46-8635-d55770c8ff27\">Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. <em>Br J Pharmacol<\/em>. 2010;161(3):512-526. doi:10.1111\/j.1476-5381.2010.00922.x <a href=\"#5ce45f89-9bd1-4c46-8635-d55770c8ff27-link\" aria-label=\"Jump to footnote reference 172\">\u21a9\ufe0e<\/a><\/li><li id=\"62fbf8f3-2558-491e-8747-4d16ac1714a5\">Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. <em>Gut Microbes<\/em>. 2012;3(1):4-14. doi:10.4161\/gmic.19320 <a href=\"#62fbf8f3-2558-491e-8747-4d16ac1714a5-link\" aria-label=\"Jump to footnote reference 173\">\u21a9\ufe0e<\/a><\/li><li id=\"d1644946-e86d-4e6c-8efa-1e1482d09199\">Nguyen TLA, Vieira-Silva S, Liston A, Raes J. How informative is the mouse for human gut microbiota research? <em>Dis Model Mech<\/em>. 2015;8(1):1-16. doi:10.1242\/dmm.017400 <a href=\"#d1644946-e86d-4e6c-8efa-1e1482d09199-link\" aria-label=\"Jump to footnote reference 174\">\u21a9\ufe0e<\/a><\/li><li id=\"51ddb5d0-b90f-4a76-9321-f4ea28d14631\">Beresford-Jones BS, Forster SC, Stares MD, et al. The Mouse Gastrointestinal Bacteria Catalogue enables translation between the mouse and human gut microbiotas via functional mapping.\u00a0<em>Cell Host Microbe<\/em>. 2022;30(1):124-138.e8. doi:10.1016\/j.chom.2021.12.003 <a href=\"#51ddb5d0-b90f-4a76-9321-f4ea28d14631-link\" aria-label=\"Jump to footnote reference 175\">\u21a9\ufe0e<\/a><\/li><li id=\"1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1\">Gros &amp; Casanova, 2023 <a href=\"#1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1-link\" aria-label=\"Jump to footnote reference 176\">\u21a9\ufe0e<\/a><\/li><li id=\"8d3ff126-87fa-4f93-9e8d-f9610aed9d9d\">Pulendran B, Davis MM. The science and medicine of human immunology. <em>Science<\/em>. 2020;369(6511):eaay4014. doi:10.1126\/science.aay4014 <a href=\"#8d3ff126-87fa-4f93-9e8d-f9610aed9d9d-link\" aria-label=\"Jump to footnote reference 177\">\u21a9\ufe0e<\/a><\/li><li id=\"53fabe99-4180-4bd8-8807-a1bf300156ff\">Pulendran &amp; Davis, 2020 <a href=\"#53fabe99-4180-4bd8-8807-a1bf300156ff-link\" aria-label=\"Jump to footnote reference 178\">\u21a9\ufe0e<\/a><\/li><li id=\"348f49f5-b9c6-4923-ab8d-5f5b7841f538\">Martin MD, Sompallae R, Winborn CS, Harty JT, Badovinac VP. Diverse CD8 T cell responses to viral infection revealed by the collaborative cross. <em>Cell Rep<\/em>. 2020;31(2). doi:10.1016\/j.celrep.2020.03.072 <a href=\"#348f49f5-b9c6-4923-ab8d-5f5b7841f538-link\" aria-label=\"Jump to footnote reference 179\">\u21a9\ufe0e<\/a><\/li><li id=\"51876190-2d5e-4c7d-acbe-3769bf0fe093\">Ehling P, Meuth P, Eichinger P, et al. Human T cells in silico: modelling their electrophysiological behaviour in health and disease. <em>J Theor Biol<\/em>. 2016;404:236-250. doi:10.1016\/j.jtbi.2016.06.001 <a href=\"#51876190-2d5e-4c7d-acbe-3769bf0fe093-link\" aria-label=\"Jump to footnote reference 180\">\u21a9\ufe0e<\/a><\/li><li id=\"a89d3e28-3bfb-4c44-a100-f2a2e1677392\">Cappuccio A, Tieri P, Castiglione F. Multiscale modelling in immunology: a review. <em>Brief Bioinform<\/em>. 2016;17(3):408-418. doi:10.1093\/bib\/bbv012 <a href=\"#a89d3e28-3bfb-4c44-a100-f2a2e1677392-link\" aria-label=\"Jump to footnote reference 181\">\u21a9\ufe0e<\/a><\/li><li id=\"b98a3765-1a86-4ed5-b8fe-7e37032bdf87\">Day JD, Metes DM, Vodovotz Y. Mathematical modeling of early cellular innate and adaptive immune responses to ischemia\/reperfusion injury and solid organ allotransplantation. <em>Front Immunol<\/em>. 2015;6. doi:10.3389\/fimmu.2015.00484 <a href=\"#b98a3765-1a86-4ed5-b8fe-7e37032bdf87-link\" aria-label=\"Jump to footnote reference 182\">\u21a9\ufe0e<\/a><\/li><li id=\"15d069ae-4d90-4281-9805-7f389cfff709\">Wagar LE, Salahudeen A, Constantz CM, et al. Modeling human adaptive immune responses with tonsil organoids. <em>Nat Med<\/em>. 2021;27(1):125-135. doi:10.1038\/s41591-020-01145-0 <a href=\"#15d069ae-4d90-4281-9805-7f389cfff709-link\" aria-label=\"Jump to footnote reference 183\">\u21a9\ufe0e<\/a><\/li><li id=\"5694b598-9785-41ba-a37f-8db92f3ff39f\">Halliley JL, Tipton CM, Liesveld J, et al. Long-lived plasma cells are contained within the CD19\u2212CD38hiCD138+ subset in human bone marrow. <em>Immunity<\/em>. 2015;43(1):132-145. doi:10.1016\/j.immuni.2015.06.016 <a href=\"#5694b598-9785-41ba-a37f-8db92f3ff39f-link\" aria-label=\"Jump to footnote reference 184\">\u21a9\ufe0e<\/a><\/li><li id=\"e0d7d79e-4b97-455e-8e44-0d3de37c47bc\">Shou Y, Johnson SC, Quek YJ, Li X, Tay A. Integrative lymph node\u2013mimicking models created with biomaterials and computational tools to study the immune system. <em>Mater Today Bio<\/em>. 2022;14:100269. doi:10.1016\/j.mtbio.2022.100269 <a href=\"#e0d7d79e-4b97-455e-8e44-0d3de37c47bc-link\" aria-label=\"Jump to footnote reference 185\">\u21a9\ufe0e<\/a><\/li><li id=\"c3d97ba9-469d-4167-b365-67ca8fb1c792\">Wagar et al., 2021 <a href=\"#c3d97ba9-469d-4167-b365-67ca8fb1c792-link\" aria-label=\"Jump to footnote reference 186\">\u21a9\ufe0e<\/a><\/li><li id=\"e2dc6cd4-424e-497e-b88b-a250becceaac\">Gill US, Pallett LJ, Thomas N, et al. Fine needle aspirates comprehensively sample intrahepatic immunity. <em>Gut<\/em>. 2019;68(8):1493-1503. doi:10.1136\/gutjnl-2018-317071 <a href=\"#e2dc6cd4-424e-497e-b88b-a250becceaac-link\" aria-label=\"Jump to footnote reference 187\">\u21a9\ufe0e<\/a><\/li><li id=\"2a37d948-a323-4dc5-b596-86514b8f1a23\">Bergers LIJC, Reijnders CMA, van den Broek LJ, et al. Immune-competent human skin disease models. <em>Drug Discov Today<\/em>. 2016;21(9):1479-1488. doi:10.1016\/j.drudis.2016.05.008 <a href=\"#2a37d948-a323-4dc5-b596-86514b8f1a23-link\" aria-label=\"Jump to footnote reference 188\">\u21a9\ufe0e<\/a><\/li><li id=\"c5328c41-0091-4932-acf1-c8f07f2de141\">Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study. <em>Lancet<\/em>. 2020;395(10219):200-211. doi:10.1016\/S0140-6736(19)32989-7 <a href=\"#c5328c41-0091-4932-acf1-c8f07f2de141-link\" aria-label=\"Jump to footnote reference 189\">\u21a9\ufe0e<\/a><\/li><li id=\"ae392600-303c-49f5-8594-71f8a226f3fb\">Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. <em>JAMA<\/em>. 2014;312(1):90-92. doi:10.1001\/jama.2014.5804 <a href=\"#ae392600-303c-49f5-8594-71f8a226f3fb-link\" aria-label=\"Jump to footnote reference 190\">\u21a9\ufe0e<\/a><\/li><li id=\"84c2ad96-b605-47c4-a395-b818d8ca66a8\">Torio CM, Moore BJ. National inpatient hospital costs: the most expensive conditions by payer, 2013. In: <em>Healthcare Cost and Utilization Project (HCUP) Statistical Briefs<\/em>. Agency for Healthcare Research and Quality (U.S.); 2006. Accessed December 5, 2024. <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK368492\/\">http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK368492\/<\/a> <a href=\"#84c2ad96-b605-47c4-a395-b818d8ca66a8-link\" aria-label=\"Jump to footnote reference 191\">\u21a9\ufe0e<\/a><\/li><li id=\"5e2a6c80-3559-4ff8-8bbf-fe90dc470af5\">Azevedo LCP, Cavalcanti AB, Lisboa T, et al. Sepsis is an important healthcare burden in Latin America: A call to action! A sepse \u00e9 um grave problema de sa\u00fade na Am\u00e9rica Latina: uma chamada \u00e0 a\u00e7\u00e3o!.\u00a0<em>Rev Bras Ter Intensiva<\/em>. 2018;30(4):402-404. doi:10.5935\/0103-507X.20180061 <a href=\"#5e2a6c80-3559-4ff8-8bbf-fe90dc470af5-link\" aria-label=\"Jump to footnote reference 192\">\u21a9\ufe0e<\/a><\/li><li id=\"4ab6ecbd-f4d7-4917-857e-81da0f368917\">Verma S. Laboratory animal models to mimic human sepsis: a review. <em>Res Rev J Zool Sci<\/em>. May 28, 2016. Accessed December 5, 2024. <a href=\"https:\/\/www.semanticscholar.org\/paper\/Laboratory-Animal-Models-to-Mimic-Human-Sepsis%3A-A-Verma\/8d933dca987c3db1a9e29c960416b07a47b7105a\">https:\/\/www.semanticscholar.org\/paper\/Laboratory-Animal-Models-to-Mimic-Human-Sepsis%3A-A-Verma\/8d933dca987c3db1a9e29c960416b07a47b7105a<\/a> <a href=\"#4ab6ecbd-f4d7-4917-857e-81da0f368917-link\" aria-label=\"Jump to footnote reference 193\">\u21a9\ufe0e<\/a><\/li><li id=\"71a2860c-9e9c-47eb-a34a-ea38fdbed8d9\">Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. <em>Proc Natl Acad Sci U S A<\/em>. 2013;110(9):3507-3512. doi:10.1073\/pnas.1222878110 <a href=\"#71a2860c-9e9c-47eb-a34a-ea38fdbed8d9-link\" aria-label=\"Jump to footnote reference 194\">\u21a9\ufe0e<\/a><\/li><li id=\"fa11862a-51c6-4904-9fee-bf1e3a30dd10\">Collins F. Of mice, men, and medicine. NIH. February 19, 2013. Accessed October 31, 2022.\u00a0https:\/\/us.pagefreezer.com\/en-US\/wa\/browse\/c530da90-f454-461b-9a86-959c53acb16c?url=https:%2F%2Fdirectorsblog.nih.gov%2F2013%2F02%2F19%2Fof-mice-men-and-medicine%2F&amp;timestamp=2025-05-27T10:13:51Z <a href=\"#fa11862a-51c6-4904-9fee-bf1e3a30dd10-link\" aria-label=\"Jump to footnote reference 195\">\u21a9\ufe0e<\/a><\/li><li id=\"5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb\">Collins, <em>Of Mice, Men, and Medicine<\/em>, 2013. <a href=\"#5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb-link\" aria-label=\"Jump to footnote reference 196\">\u21a9\ufe0e<\/a><\/li><li id=\"672a37b7-a8d4-4e08-b77c-255ce0951cce\">Esmon CT. Why do animal models (sometimes) fail to mimic human sepsis? <em>Crit Care Med<\/em>. 2004;32(5 Suppl):S219-222. doi:10.1097\/01.ccm.0000127036.27343.48 <a href=\"#672a37b7-a8d4-4e08-b77c-255ce0951cce-link\" aria-label=\"Jump to footnote reference 197\">\u21a9\ufe0e<\/a><\/li><li id=\"144dc1e0-30e2-42ff-ba10-3d82d0598aa4\">Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of sepsis and human sepsis. <em>J Leukoc Biol<\/em>. 2007;81(1):137-143. doi:10.1189\/jlb.0806542 <a href=\"#144dc1e0-30e2-42ff-ba10-3d82d0598aa4-link\" aria-label=\"Jump to footnote reference 198\">\u21a9\ufe0e<\/a><\/li><li id=\"7a2f7943-7793-41b5-81c3-6720fe4b887e\">Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. <em>Nat Rev Drug Discov<\/em>. 2005;4(10):854-865. doi:10.1038\/nrd1854 <a href=\"#7a2f7943-7793-41b5-81c3-6720fe4b887e-link\" aria-label=\"Jump to footnote reference 199\">\u21a9\ufe0e<\/a><\/li><li id=\"fc538274-1545-45d8-8ed6-b2c2475b7c93\">Nemzek JA, Hugunin KMS, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. <em>Comp Med<\/em>. 2008;58(2):120-128. <a href=\"#fc538274-1545-45d8-8ed6-b2c2475b7c93-link\" aria-label=\"Jump to footnote reference 200\">\u21a9\ufe0e<\/a><\/li><li id=\"ce8396bc-62be-40fe-8690-93373242d41f\">Joffre J. Preclinical model in sepsis: should we abandon the CLP? <em>J Inflamm Res<\/em>. 2023;16:1757-1759. doi:10.2147\/JIR.S415972 <a href=\"#ce8396bc-62be-40fe-8690-93373242d41f-link\" aria-label=\"Jump to footnote reference 201\">\u21a9\ufe0e<\/a><\/li><li id=\"c343fa9a-015b-49ac-813f-a808eb1ce42a\">Buras et al., <em>Animal Models of Sepsis: Setting the Stage<\/em>, 2005. <a href=\"#c343fa9a-015b-49ac-813f-a808eb1ce42a-link\" aria-label=\"Jump to footnote reference 202\">\u21a9\ufe0e<\/a><\/li><li id=\"fd240d66-c2c2-4fb0-a50b-802b9bea1af6\">Redl H, Bahrami S. Large animal models: baboons for trauma, shock, and sepsis studies. <em>Shock<\/em>. 2005;24 Suppl 1:88-93. doi:10.1097\/01.shk.0000191339.46777.63 <a href=\"#fd240d66-c2c2-4fb0-a50b-802b9bea1af6-link\" aria-label=\"Jump to footnote reference 203\">\u21a9\ufe0e<\/a><\/li><li id=\"2aff7613-3913-4cef-9984-f332596cae38\">Fink MP. Animal models of sepsis. <em>Virulence<\/em>. 2014;5(1):143-153. doi:10.4161\/viru.26083 <a href=\"#2aff7613-3913-4cef-9984-f332596cae38-link\" aria-label=\"Jump to footnote reference 204\">\u21a9\ufe0e<\/a><\/li><li id=\"84ac3132-fe9e-46d3-b53c-e564dd62fe49\">Hawash MBF, Sanz-Rem\u00f3n J, Grenier JC, et al. Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity. <em>Proc Natl Acad Sci U S A<\/em>. 2021;118(13):e2015855118. doi:10.1073\/pnas.2015855118 <a href=\"#84ac3132-fe9e-46d3-b53c-e564dd62fe49-link\" aria-label=\"Jump to footnote reference 205\">\u21a9\ufe0e<\/a><\/li><li id=\"cba825d9-a6b9-4d8d-ae79-4aa3a4572f23\">NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022 <a href=\"#cba825d9-a6b9-4d8d-ae79-4aa3a4572f23-link\" aria-label=\"Jump to footnote reference 206\">\u21a9\ufe0e<\/a><\/li><li id=\"306e53ee-17f2-4d95-8e3e-5edd158d9d9c\">NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022. <a href=\"#306e53ee-17f2-4d95-8e3e-5edd158d9d9c-link\" aria-label=\"Jump to footnote reference 207\">\u21a9\ufe0e<\/a><\/li><li id=\"2ee291f7-7a8a-477d-b14a-24143e4ea365\">Hays A. Major health agency slashes funding for sepsis experiments on animals after push from PETA. PETA. June 18, 2024. Accessed December 5, 2024. <a href=\"https:\/\/www.peta.org\/blog\/major-health-agency-slashes-funding-for-sepsis-experiments-on-animals\/\">https:\/\/www.peta.org\/blog\/major-health-agency-slashes-funding-for-sepsis-experiments-on-animals\/<\/a> <a href=\"#2ee291f7-7a8a-477d-b14a-24143e4ea365-link\" aria-label=\"Jump to footnote reference 208\">\u21a9\ufe0e<\/a><\/li><li id=\"0a687cc1-d57c-4d56-9940-a307ce2b6be5\">NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022 <a href=\"#0a687cc1-d57c-4d56-9940-a307ce2b6be5-link\" aria-label=\"Jump to footnote reference 209\">\u21a9\ufe0e<\/a><\/li><li id=\"4e40a7d9-f652-4dc0-ad61-7351938898d9\">Lilley E, Armstrong R, Clark N, et al. Refinement of animal models of sepsis and septic shock. <em>Shock<\/em>. 2015;43(4):304-316. doi:10.1097\/SHK.0000000000000318 <a href=\"#4e40a7d9-f652-4dc0-ad61-7351938898d9-link\" aria-label=\"Jump to footnote reference 210\">\u21a9\ufe0e<\/a><\/li><li id=\"74c35407-82d3-429a-9170-646e670bc3ba\">Li Y, Nie Y, Yang X, et al. Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis. <em>Cell Rep<\/em>. 2024;43(3):113918. doi:10.1016\/j.celrep.2024.113918 <a href=\"#74c35407-82d3-429a-9170-646e670bc3ba-link\" aria-label=\"Jump to footnote reference 211\">\u21a9\ufe0e<\/a><\/li><li id=\"0502e20c-9f16-4f09-baa2-c922aa359819\">Yang Q, Langston JC, Prosniak R, et al. Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity. <em>Front Immunol<\/em>. 2024;15:1341752. doi:10.3389\/fimmu.2024.1341752 <a href=\"#0502e20c-9f16-4f09-baa2-c922aa359819-link\" aria-label=\"Jump to footnote reference 212\">\u21a9\ufe0e<\/a><\/li><li id=\"a09f042c-a14e-4a37-af85-c44bd8698691\">Yang X, Pu X, Xu Y, et al. A novel prognosis evaluation indicator of patients with sepsis created by integrating six microfluidic-based neutrophil chemotactic migration parameters. <em>Talanta<\/em>. 2024;281:126801. doi:10.1016\/j.talanta.2024.126801 <a href=\"#a09f042c-a14e-4a37-af85-c44bd8698691-link\" aria-label=\"Jump to footnote reference 213\">\u21a9\ufe0e<\/a><\/li><li id=\"6be35304-9b3f-460e-8555-01e234414b60\">Sakuma M, Wang X, Ellett F, et al. Microfluidic capture of chromatin fibres measures neutrophil extracellular traps (NETs) released in a drop of human blood. <em>Lab Chip<\/em>. 2022;22(5):936-944. doi:10.1039\/d1lc01123e <a href=\"#6be35304-9b3f-460e-8555-01e234414b60-link\" aria-label=\"Jump to footnote reference 214\">\u21a9\ufe0e<\/a><\/li><li id=\"b2091492-ceda-4d8e-a415-5fd9bf06d708\">Marik PE, Farkas JD. The changing paradigm of sepsis: early diagnosis, early antibiotics, early pressors, and early adjuvant treatment. <em>Crit Care Med<\/em>. 2018;46(10):1690-1692. doi:10.1097\/CCM.0000000000003310 <a href=\"#b2091492-ceda-4d8e-a415-5fd9bf06d708-link\" aria-label=\"Jump to footnote reference 215\">\u21a9\ufe0e<\/a><\/li><li id=\"13bd5a62-32f4-4841-bcda-510cc4c7b9e2\">Goh KH, Wang L, Yeow AYK, et al. Artificial intelligence in sepsis early prediction and diagnosis using unstructured data in healthcare. <em>Nat Commun<\/em>. 2021;12(1):711. doi:10.1038\/s41467-021-20910-4 <a href=\"#13bd5a62-32f4-4841-bcda-510cc4c7b9e2-link\" aria-label=\"Jump to footnote reference 216\">\u21a9\ufe0e<\/a><\/li><li id=\"6e0849ea-9eed-40fa-acb8-f9c6aa853a74\">Rosnati M, Fortuin V. MGP-AttTCN: An interpretable machine learning model for the prediction of sepsis. <em>PLoS One<\/em>. 2021;16(5):e0251248. doi:10.1371\/journal.pone.0251248 <a href=\"#6e0849ea-9eed-40fa-acb8-f9c6aa853a74-link\" aria-label=\"Jump to footnote reference 217\">\u21a9\ufe0e<\/a><\/li><li id=\"675d4f40-91d5-4534-88b2-1c69d5ebe7c6\">Honor\u00e9 A, Forsberg D, Adolphson K, Chatterjee S, Jost K, Herlenius E. Vital sign-based detection of sepsis in neonates using machine learning. <em>Acta Paediatr Oslo Nor 1992<\/em>. 2023;112(4):686-696. doi:10.1111\/apa.16660 <a href=\"#675d4f40-91d5-4534-88b2-1c69d5ebe7c6-link\" aria-label=\"Jump to footnote reference 218\">\u21a9\ufe0e<\/a><\/li><li id=\"e2ae2e42-2c61-421f-b49e-4863b4dda374\">Sun B, Lei M, Wang L, et al. Prediction of sepsis among patients with major trauma using artificial intelligence: a multicenter validated cohort study. <em>Int J Surg Lond Engl<\/em>. Published online June 26, 2024. doi:10.1097\/JS9.0000000000001866 <a href=\"#e2ae2e42-2c61-421f-b49e-4863b4dda374-link\" aria-label=\"Jump to footnote reference 219\">\u21a9\ufe0e<\/a><\/li><li id=\"f601e191-3068-4a7d-a051-45baad3853f3\">Gao J, Lu Y, Ashrafi N, Domingo I, Alaei K, Pishgar M. Prediction of sepsis mortality in ICU patients using machine learning methods. <em>BMC Med Inform Decis Mak<\/em>. 2024;24(1):228. doi:10.1186\/s12911-024-02630-z <a href=\"#f601e191-3068-4a7d-a051-45baad3853f3-link\" aria-label=\"Jump to footnote reference 220\">\u21a9\ufe0e<\/a><\/li><li id=\"3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef\">Hang Y, Qu H, Yang J, et al. Exploration of programmed cell death-associated characteristics and immune infiltration in neonatal sepsis: new insights from bioinformatics analysis and machine learning. <em>BMC Pediatr<\/em>. 2024;24(1):67. doi:10.1186\/s12887-024-04555-y <a href=\"#3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef-link\" aria-label=\"Jump to footnote reference 221\">\u21a9\ufe0e<\/a><\/li><li id=\"3ebe7abf-ede3-473e-89d1-4b489da97faa\">Boussina A, Shashikumar SP, Malhotra A, et al. Impact of a deep learning sepsis prediction model on quality of care and survival. <em>NPJ Digit Med<\/em>. 2024;7(1):14. doi:10.1038\/s41746-023-00986-6 <a href=\"#3ebe7abf-ede3-473e-89d1-4b489da97faa-link\" aria-label=\"Jump to footnote reference 222\">\u21a9\ufe0e<\/a><\/li><li id=\"97719922-c79b-4289-8c50-2ba0350fd80f\">Giacobbe DR, Signori A, Del Puente F, et al. Early detection of sepsis with machine learning techniques: a brief clinical perspective. <em>Front Med<\/em>. 2021;8:617486. doi:10.3389\/fmed.2021.617486 <a href=\"#97719922-c79b-4289-8c50-2ba0350fd80f-link\" aria-label=\"Jump to footnote reference 223\">\u21a9\ufe0e<\/a><\/li><li id=\"3e860dc8-2651-4f71-bce7-062a90e5f08c\">Steinbach D, Ahrens PC, Schmidt M, et al. Applying machine learning to blood count data predicts sepsis with ICU admission. <em>Clin Chem<\/em>. 2024;70(3):506-515. doi:10.1093\/clinchem\/hvae001 <a href=\"#3e860dc8-2651-4f71-bce7-062a90e5f08c-link\" aria-label=\"Jump to footnote reference 224\">\u21a9\ufe0e<\/a><\/li><li id=\"59a178f8-8781-4a3e-b606-99413f1d07e4\">Peery AF, Murphy CC, Anderson C, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2024. <em>Gastroenterology<\/em>. 2025;168(5):1000-1024. doi:10.1053\/j.gastro.2024.12.029 <a href=\"#59a178f8-8781-4a3e-b606-99413f1d07e4-link\" aria-label=\"Jump to footnote reference 225\">\u21a9\ufe0e<\/a><\/li><li id=\"ad910464-1694-4ecd-966c-bf099cde1281\">Almario CV, Ballal ML, Chey WD, Nordstrom C, Khanna D, Spiegel BMR. Burden of gastrointestinal symptoms in the United States: results of a nationally representative survey of over 71,000 Americans. <em>Am J Gastroenterol<\/em>. 2018;113(11):1701-1710. doi:10.1038\/s41395-018-0256-8 <a href=\"#ad910464-1694-4ecd-966c-bf099cde1281-link\" aria-label=\"Jump to footnote reference 226\">\u21a9\ufe0e<\/a><\/li><li id=\"e075402e-a5aa-407f-8089-f2b5fa1c1117\">Mayer EA, Bradesi S, Chang L, Spiegel BMR, Bueller JA, Naliboff BD. Functional GI disorders: from animal models to drug development. <em>Gut<\/em>. 2008;57(3):384-404. doi:10.1136\/gut.2006.101675 <a href=\"#e075402e-a5aa-407f-8089-f2b5fa1c1117-link\" aria-label=\"Jump to footnote reference 227\">\u21a9\ufe0e<\/a><\/li><li id=\"9c724b9f-77e8-409a-b187-45541bbf2e9f\">Sciascia Q, Da\u015f G, Metges CC. REVIEW: The pig as a model for humans: effects of nutritional factors on intestinal function and health1. <em>J Anim Sci<\/em>. 2016;94(suppl_3):441-452. doi:10.2527\/jas.2015-9788 <a href=\"#9c724b9f-77e8-409a-b187-45541bbf2e9f-link\" aria-label=\"Jump to footnote reference 228\">\u21a9\ufe0e<\/a><\/li><li id=\"62db0c02-6bf4-4d4b-926f-9dc9352759c7\">DeSesso JM, Jacobson CF. Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. <em>Food Chem Toxicol<\/em>. 2001;39(3):209-228. doi:10.1016\/S0278-6915(00)00136-8\u00a0 <a href=\"#62db0c02-6bf4-4d4b-926f-9dc9352759c7-link\" aria-label=\"Jump to footnote reference 229\">\u21a9\ufe0e<\/a><\/li><li id=\"1151c5a8-61f7-48b9-a909-7a55c593ad07\">DeSesso &amp; Jacobson, 2001 <a href=\"#1151c5a8-61f7-48b9-a909-7a55c593ad07-link\" aria-label=\"Jump to footnote reference 230\">\u21a9\ufe0e<\/a><\/li><li id=\"377f6f1c-6e54-423d-89e1-e284c6a54e5b\">Higashiyama H, Uemura M, Igarashi H, Kurohmaru M, Kanai\u2010Azuma M, Kanai Y. Anatomy and development of the extrahepatic biliary system in mouse and rat: a perspective on the evolutionary loss of the gallbladder. <em>J Anat<\/em>. 2018;232(1):134-145. doi:10.1111\/joa.12707\u00a0 <a href=\"#377f6f1c-6e54-423d-89e1-e284c6a54e5b-link\" aria-label=\"Jump to footnote reference 231\">\u21a9\ufe0e<\/a><\/li><li id=\"a81ace1f-686c-4d29-b812-d6189aa29796\">Gonzalez LM, Moeser AJ, Blikslager AT. Porcine models of digestive disease: the future of large animal translational research. <em>Transl Res<\/em>. 2015;166(1):12-27. doi:10.1016\/j.trsl.2015.01.004 <a href=\"#a81ace1f-686c-4d29-b812-d6189aa29796-link\" aria-label=\"Jump to footnote reference 232\">\u21a9\ufe0e<\/a><\/li><li id=\"8f9ff7f5-d1ce-4590-bdff-06d8d8302610\">Clifton P. Meal patterning in rodents: psychopharmacological and neuroanatomical studies. <em>Neurosci Biobehav Rev<\/em>. 2000;24(2):213-222. doi:10.1016\/S0149-7634(99)00074-3 <a href=\"#8f9ff7f5-d1ce-4590-bdff-06d8d8302610-link\" aria-label=\"Jump to footnote reference 233\">\u21a9\ufe0e<\/a><\/li><li id=\"171f7ced-d186-43aa-b299-fe4c470f9f55\">Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016. <a href=\"#171f7ced-d186-43aa-b299-fe4c470f9f55-link\" aria-label=\"Jump to footnote reference 234\">\u21a9\ufe0e<\/a><\/li><li id=\"0314f180-05d5-4f7d-8122-53497f394f6f\">Han A, Hudson-Paz C, Robinson BG, et al. Temperature-dependent differences in mouse gut motility are mediated by stress. <em>Lab Anim<\/em>. 2024;53(6):148-159. doi:10.1038\/s41684-024-01376-5 <a href=\"#0314f180-05d5-4f7d-8122-53497f394f6f-link\" aria-label=\"Jump to footnote reference 235\">\u21a9\ufe0e<\/a><\/li><li id=\"08d2402a-efc6-4987-9d14-ced355060954\">Harley ITW, Giles DA, Pfluger PT, et al. Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL\/6 mice. <em>Mol Metab<\/em>. 2013;2(3):171-183. doi:10.1016\/j.molmet.2013.04.004 <a href=\"#08d2402a-efc6-4987-9d14-ced355060954-link\" aria-label=\"Jump to footnote reference 236\">\u21a9\ufe0e<\/a><\/li><li id=\"5bdedddb-9ab0-4ed4-b7ab-e75196205472\">Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016. <a href=\"#5bdedddb-9ab0-4ed4-b7ab-e75196205472-link\" aria-label=\"Jump to footnote reference 237\">\u21a9\ufe0e<\/a><\/li><li id=\"96f15b44-e375-4442-b63a-c86c95a3584a\">Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. <em>Cell<\/em>. 2014;157(1):121-141. doi:10.1016\/j.cell.2014.03.011 <a href=\"#96f15b44-e375-4442-b63a-c86c95a3584a-link\" aria-label=\"Jump to footnote reference 238\">\u21a9\ufe0e<\/a><\/li><li id=\"c1564d1c-e472-4030-8d4e-416f469d4f96\">Kriaa A, Mariaule V, De Rudder C, et al. From animal models to gut-on-chip: the challenging journey to capture inter-individual variability in chronic digestive disorders. <em>Gut Microbes<\/em>. 2024;16(1):2333434. doi:10.1080\/19490976.2024.2333434 <a href=\"#c1564d1c-e472-4030-8d4e-416f469d4f96-link\" aria-label=\"Jump to footnote reference 239\">\u21a9\ufe0e<\/a><\/li><li id=\"087348ee-2cae-4458-8053-02a0561223a4\">Ram\u00edrez Aranda JM, Mart\u00ednez Guti\u00e9rrez CM, Fuentes Ram\u00edrez MM, et al. Agregaci\u00f3n familiar en el s\u00edndrome de colon irritable en pacientes mexicanos. Un estudio de casos y controles.\u00a0<em>Aten Primaria<\/em>. 2024;56(2):102794. doi:10.1016\/j.aprim.2023.102794 <a href=\"#087348ee-2cae-4458-8053-02a0561223a4-link\" aria-label=\"Jump to footnote reference 240\">\u21a9\ufe0e<\/a><\/li><li id=\"8564b728-bf71-4475-aae9-cb890d58ca7b\">Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016 <a href=\"#8564b728-bf71-4475-aae9-cb890d58ca7b-link\" aria-label=\"Jump to footnote reference 241\">\u21a9\ufe0e<\/a><\/li><li id=\"548eb557-1e85-4626-9aa2-43c24e47c8b2\">Accarie A, Vanuytsel T. Animal models for functional gastrointestinal disorders. <em>Front Psychiatry<\/em>. 2020;11:509681. doi:10.3389\/fpsyt.2020.509681 <a href=\"#548eb557-1e85-4626-9aa2-43c24e47c8b2-link\" aria-label=\"Jump to footnote reference 242\">\u21a9\ufe0e<\/a><\/li><li id=\"6a5e556e-aad5-44ad-aa57-aa0ab2c9333c\">Johnson AC, Farmer AD, Ness TJ, Greenwood\u2010Van Meerveld B. Critical evaluation of animal models of visceral pain for therapeutics development: a focus on irritable bowel syndrome. <em>Neurogastroenterol Motil<\/em>. 2020;32(4):e13776. doi:10.1111\/nmo.13776 <a href=\"#6a5e556e-aad5-44ad-aa57-aa0ab2c9333c-link\" aria-label=\"Jump to footnote reference 243\">\u21a9\ufe0e<\/a><\/li><li id=\"71426e73-b382-415c-ba77-755bcd43b89b\">Weisman MH, Oleg S, Seok Kim H, Hou JK, Miller FW, Dillon CF. Inflammatory bowel disease prevalence: surveillance data from the U.S. National Health and Nutrition Examination Survey. <em>Prev Med Rep<\/em>. 2023;33:102173. doi:10.1016\/j.pmedr.2023.102173 <a href=\"#71426e73-b382-415c-ba77-755bcd43b89b-link\" aria-label=\"Jump to footnote reference 244\">\u21a9\ufe0e<\/a><\/li><li id=\"1d13560e-c572-410e-98bc-b2356753fdbc\">. Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. <em>Gastroenterology<\/em>. 2023;165(5):1197-1205.e2. doi:10.1053\/j.gastro.2023.07.003 <a href=\"#1d13560e-c572-410e-98bc-b2356753fdbc-link\" aria-label=\"Jump to footnote reference 245\">\u21a9\ufe0e<\/a><\/li><li id=\"49282ffc-ff3e-4b12-aff9-7579f364abd0\">Flynn S, Eisenstein S. Inflammatory bowel disease presentation and diagnosis. <em>Surg Clin North Am<\/em>. 2019;99(6):1051-1062. doi:10.1016\/j.suc.2019.08.001 <a href=\"#49282ffc-ff3e-4b12-aff9-7579f364abd0-link\" aria-label=\"Jump to footnote reference 246\">\u21a9\ufe0e<\/a><\/li><li id=\"310d60a1-e143-4d41-aaed-33bc1773bbdd\">Baydi Z, Limami Y, Khalki L, et al. An update of research animal models of inflammatory bowel disease. Chiba T, ed. <em>Sci World J<\/em>. 2021;2021:1-12. doi:10.1155\/2021\/7479540 <a href=\"#310d60a1-e143-4d41-aaed-33bc1773bbdd-link\" aria-label=\"Jump to footnote reference 247\">\u21a9\ufe0e<\/a><\/li><li id=\"8da8a509-f25e-4cff-917e-1217f360f79e\">Pizarro TT, Stappenbeck TS, Rieder F, et al. Challenges in IBD research: preclinical human IBD mechanisms. <em>Inflamm Bowel Dis<\/em>. 2019;25(Suppl 2):S5-S12. doi:10.1093\/ibd\/izz075 <a href=\"#8da8a509-f25e-4cff-917e-1217f360f79e-link\" aria-label=\"Jump to footnote reference 248\">\u21a9\ufe0e<\/a><\/li><li id=\"8a1cd113-0fb9-492f-8888-ebe6a1ed55ab\">Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn\u2019s disease: unexpected results of a randomised, double-blind placebo-controlled trial. <em>Gut<\/em>. 2012;61(12):1693-1700. doi:10.1136\/gutjnl-2011-301668 <a href=\"#8a1cd113-0fb9-492f-8888-ebe6a1ed55ab-link\" aria-label=\"Jump to footnote reference 249\">\u21a9\ufe0e<\/a><\/li><li id=\"063369f1-af67-4c51-86c5-e2251d086e58\">Targan SR, Feagan B, Vermeire S, et al. A randomized, double-blind, placebo-controlled phase 2 study of Brodalumab in patients with moderate-to-severe Crohn\u2019s disease. <em>Am J Gastroenterol<\/em>. 2016;111(11):1599-1607. doi:10.1038\/ajg.2016.298 <a href=\"#063369f1-af67-4c51-86c5-e2251d086e58-link\" aria-label=\"Jump to footnote reference 250\">\u21a9\ufe0e<\/a><\/li><li id=\"f7e4a5f8-bf6f-4985-81c1-db6ec619038f\">Pizarro et al., 2019 <a href=\"#f7e4a5f8-bf6f-4985-81c1-db6ec619038f-link\" aria-label=\"Jump to footnote reference 251\">\u21a9\ufe0e<\/a><\/li><li id=\"9a1694a8-8c0d-4ac4-ad13-35237b1b96cc\">Verstockt B, Salas A, Sands BE, et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. <em>Nat Rev Gastroenterol Hepatol<\/em>. 2023;20(7):433-446. doi:10.1038\/s41575-023-00768-1 <a href=\"#9a1694a8-8c0d-4ac4-ad13-35237b1b96cc-link\" aria-label=\"Jump to footnote reference 252\">\u21a9\ufe0e<\/a><\/li><li id=\"4c5278ca-4c4b-42a6-a4b9-48cd2a3261be\">Lewis JD, Chen EZ, Baldassano RN, et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn\u2019s disease. <em>Cell Host Microbe<\/em>. 2015;18(4):489-500. doi:10.1016\/j.chom.2015.09.008 <a href=\"#4c5278ca-4c4b-42a6-a4b9-48cd2a3261be-link\" aria-label=\"Jump to footnote reference 253\">\u21a9\ufe0e<\/a><\/li><li id=\"d01b8e18-0a80-449e-88af-3dc1cee8820f\">Trapecar M, Communal C, Velazquez J, et al. Gut-liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids. <em>Cell Syst<\/em>. 2020;10(3):223-239.e9. doi:10.1016\/j.cels.2020.02.008 <a href=\"#d01b8e18-0a80-449e-88af-3dc1cee8820f-link\" aria-label=\"Jump to footnote reference 254\">\u21a9\ufe0e<\/a><\/li><li id=\"436d4997-bdca-45d4-8405-d2e4e9f5136b\">Stankey CT, Bourges C, Haag LM, et al. A disease-associated gene desert directs macrophage inflammation through ETS2. <em>Nature<\/em>. 2024;630(8016):447-456. doi:10.1038\/s41586-024-07501-1 <a href=\"#436d4997-bdca-45d4-8405-d2e4e9f5136b-link\" aria-label=\"Jump to footnote reference 255\">\u21a9\ufe0e<\/a><\/li><li id=\"6731e81f-03c9-4b2f-b172-b33a839fd671\">Lanik WE, Luke CJ, Nolan LS, et al. Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis\u2013on-a-chip. <em>JCI Insight<\/em>. 2023;8(8):e146496. doi:10.1172\/jci.insight.146496 <a href=\"#6731e81f-03c9-4b2f-b172-b33a839fd671-link\" aria-label=\"Jump to footnote reference 256\">\u21a9\ufe0e<\/a><\/li><li id=\"77162fdb-fe27-449c-b7dc-844e721c53da\">IBDMDB Investigators, Lloyd-Price J, Arze C, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. <em>Nature<\/em>. 2019;569(7758):655-662. doi:10.1038\/s41586-019-1237-9 <a href=\"#77162fdb-fe27-449c-b7dc-844e721c53da-link\" aria-label=\"Jump to footnote reference 257\">\u21a9\ufe0e<\/a><\/li><li id=\"04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3\">Chakravarti D, Lee R, Multani AS, et al. Telomere dysfunction instigates inflammation in inflammatory bowel disease. <em>Proc Natl Acad Sci U S A<\/em>. 2021;118(29):e2024853118. doi:10.1073\/pnas.2024853118 <a href=\"#04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3-link\" aria-label=\"Jump to footnote reference 258\">\u21a9\ufe0e<\/a><\/li><li id=\"78b363a5-f936-4123-a1d9-213d1a962421\">Lee A. Animal models of gastroduodenal ulcer disease. <em>Best Pract Res Clin Gastroenterol<\/em>. 2000;14(1):75-96. doi:10.1053\/bega.2000.0060 <a href=\"#78b363a5-f936-4123-a1d9-213d1a962421-link\" aria-label=\"Jump to footnote reference 259\">\u21a9\ufe0e<\/a><\/li><li id=\"7aaf2d99-918c-415f-a2dc-d25e9e1af49c\">Kazachkov M, Marcus M, Vaynblat M, Nino G, Pagala M. The effect of surgically created gastroesophageal reflux on intrapleural pressures in dogs. <em>Transl Res<\/em>. 2008;151(6):315-321. doi:10.1016\/j.trsl.2008.04.005\u00a0 <a href=\"#7aaf2d99-918c-415f-a2dc-d25e9e1af49c-link\" aria-label=\"Jump to footnote reference 260\">\u21a9\ufe0e<\/a><\/li><li id=\"3f691159-1b47-45d1-87e1-97dde4fd0db7\">Hu Y, Xu X, Chen S, et al. Laryngoscopy findings and histological results in a rabbit gastroesophageal reflux model. <em>Eur Arch Otorhinolaryngol<\/em>. 2012;269(8):1939-1944. doi:10.1007\/s00405-012-1968-9 <a href=\"#3f691159-1b47-45d1-87e1-97dde4fd0db7-link\" aria-label=\"Jump to footnote reference 261\">\u21a9\ufe0e<\/a><\/li><li id=\"165bfb66-d7ee-4bb7-8fe0-fbf660f9f961\">Kanai S, Mukaisho K, Yoshida S, Taniura N, Sugihara H. Host factors influence Barrett\u2019s carcinogenesis: findings from a mouse gastroduodenal reflux model. <em>Esophagus<\/em>. 2019;16(3):264-271. doi:10.1007\/s10388-019-00660-5 <a href=\"#165bfb66-d7ee-4bb7-8fe0-fbf660f9f961-link\" aria-label=\"Jump to footnote reference 262\">\u21a9\ufe0e<\/a><\/li><li id=\"eb4dddb0-2df2-4376-8359-4cf6fdf8e502\">He J, Fang Y, Chen X. Surgical models of gastroesophageal reflux with mice. <em>J Vis Exp<\/em>. 2015;(102):e53012. doi:10.3791\/53012 <a href=\"#eb4dddb0-2df2-4376-8359-4cf6fdf8e502-link\" aria-label=\"Jump to footnote reference 263\">\u21a9\ufe0e<\/a><\/li><li id=\"efc86773-d02d-4337-a80f-6d06cde91197\">Akhtar AZ, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: a review.\u00a0<em>Rev\u00a0Neurosci<\/em>. 2008;19(1):47-60. doi:10.1515\/REVNEURO.2008.19.1.47 <a href=\"#efc86773-d02d-4337-a80f-6d06cde91197-link\" aria-label=\"Jump to footnote reference 264\">\u21a9\ufe0e<\/a><\/li><li id=\"be726af9-0da0-47f9-a010-d1ac77843d1a\">Angius\u00a0D, Wang H, Spinner RJ, Gutierrez-Cotto Y,\u00a0Yaszemski\u00a0MJ, Windebank AJ. A systematic review of animal models used to study nerve regeneration in tissue-engineered scaffolds.\u00a0<em>Biomaterials<\/em>. 2012;33(32):8034-8039.\u00a0doi:10.1016\/j.biomaterials.2012.07.056 <a href=\"#be726af9-0da0-47f9-a010-d1ac77843d1a-link\" aria-label=\"Jump to footnote reference 265\">\u21a9\ufe0e<\/a><\/li><li id=\"1605ad63-928f-4b4a-8a0c-c569f1083844\">Akhtar AZ, Pippin JJ, Sandusky CB. Animal studies in spinal cord injury: a systematic review of methylprednisolone.\u00a0<em>Altern Lab Anim<\/em>. 2009;37(1):43-62. doi:10.1177\/026119290903700108 <a href=\"#1605ad63-928f-4b4a-8a0c-c569f1083844-link\" aria-label=\"Jump to footnote reference 266\">\u21a9\ufe0e<\/a><\/li><li id=\"da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de\">Kaplan HM, Mishra P, Kohn J. The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans.\u00a0<em>J Mater Sci: Mater Med<\/em>. 2015;26(8):226. doi:10.1007\/s10856-015-5558-4 <a href=\"#da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de-link\" aria-label=\"Jump to footnote reference 267\">\u21a9\ufe0e<\/a><\/li><li id=\"c132c9d7-6067-45ab-be00-8fde1d671af4\">Gliksten\u00a0L, Yip PK. Current spinal cord injury animal models are too simplistic for clinical translation.\u00a0<em>J\u00a0Exp\u00a0Neurol<\/em>.\u00a02023;4(1):6-10.\u00a0doi:10.33696\/Neurol.4.068 <a href=\"#c132c9d7-6067-45ab-be00-8fde1d671af4-link\" aria-label=\"Jump to footnote reference 268\">\u21a9\ufe0e<\/a><\/li><li id=\"7ad6b49c-da20-4530-9577-47928b199909\">Kaplan HM, et al. (2015). Rat models may limit human nerve conduit design. <em>J Mater Sci Mater Med,<\/em> 26(8), 226. <a href=\"#7ad6b49c-da20-4530-9577-47928b199909-link\" aria-label=\"Jump to footnote reference 269\">\u21a9\ufe0e<\/a><\/li><li id=\"5237fd46-854a-41a8-b5aa-44ad772b1fae\">Cheriyan\u00a0T, Ryan DJ,\u00a0Weinreb\u00a0JH, et al.\u00a0Spinal cord injury models: a review.\u00a0<em>Spinal Cord<\/em>. 2014;52(8):588-595. doi:10.1038\/sc.2014.91 <a href=\"#5237fd46-854a-41a8-b5aa-44ad772b1fae-link\" aria-label=\"Jump to footnote reference 270\">\u21a9\ufe0e<\/a><\/li><li id=\"d22b862d-a56b-41d0-8cd7-ffe63a301648\">Cheriyan T, et al. (2014). Spinal cord injury models. <em>Spinal Cord,<\/em> 52(8), 588\u2013595. <a href=\"#d22b862d-a56b-41d0-8cd7-ffe63a301648-link\" aria-label=\"Jump to footnote reference 271\">\u21a9\ufe0e<\/a><\/li><li id=\"544d66a2-622b-40c6-95e3-e53bc3b44279\">Mobini\u00a0S, Song YH, McCrary MW, Schmidt CE. Advances in ex vivo models and lab-on-a-chip devices for neural tissue engineering.\u00a0<em>Biomaterials<\/em>.\u00a02019;198:146-166.\u00a0doi:10.1016\/J.BIOMATERIALS.2018.05.012 <a href=\"#544d66a2-622b-40c6-95e3-e53bc3b44279-link\" aria-label=\"Jump to footnote reference 272\">\u21a9\ufe0e<\/a><\/li><li id=\"328d07cb-d0e7-45f7-9a24-7aea35715d34\">Mobini S, et al. (2019). Ex vivo models and lab-on-a-chip for neural tissue engineering. <em>Biomaterials,<\/em> 198, 146\u2013166. <a href=\"#328d07cb-d0e7-45f7-9a24-7aea35715d34-link\" aria-label=\"Jump to footnote reference 273\">\u21a9\ufe0e<\/a><\/li><li id=\"a5dc6b9d-7af7-4290-94e3-de4a81215f6a\">Zhuang P, Sun AX,\u00a0An\u00a0J, Chua CK, Chew SY. 3D neural tissue models: from spheroids to bioprinting.\u00a0<em>Biomaterials<\/em>.\u00a02018;154:113-133.\u00a0doi:10.1016\/J.BIOMATERIALS.2017.10.002 <a href=\"#a5dc6b9d-7af7-4290-94e3-de4a81215f6a-link\" aria-label=\"Jump to footnote reference 274\">\u21a9\ufe0e<\/a><\/li><li id=\"e9c5f67b-bcbc-4ac5-8e83-776367874baa\">Angius D, et al. (2012). Animal models for nerve regeneration in tissue-engineered scaffolds. <em>Biomaterials,<\/em> 33(32), 8034\u20138039. <a href=\"#e9c5f67b-bcbc-4ac5-8e83-776367874baa-link\" aria-label=\"Jump to footnote reference 275\">\u21a9\ufe0e<\/a><\/li><li id=\"c85d3c45-a0be-481e-9789-1ee224b265a5\">Beltr\u00e1n SM, Bobo J, Habib A, et al. Characterization of neural\u00a0mechanotransduction\u00a0response in human traumatic brain injury organoid model.\u00a0<em>Sci Rep<\/em>. 2023;13(1):13536. doi:10.1038\/s41598-023-40431-y <a href=\"#c85d3c45-a0be-481e-9789-1ee224b265a5-link\" aria-label=\"Jump to footnote reference 276\">\u21a9\ufe0e<\/a><\/li><li id=\"afa9e3ab-8b66-436e-8bf5-4d25a1903ebd\">Xue W, Li B, Liu H, et al. Generation of dorsoventral human spinal cord organoids via functionalizing composite scaffold for drug testing.\u00a0<em>iScience<\/em>. 2023;26(1):105898.\u00a0doi:10.1016\/j.isci.2022.105898 <a href=\"#afa9e3ab-8b66-436e-8bf5-4d25a1903ebd-link\" aria-label=\"Jump to footnote reference 277\">\u21a9\ufe0e<\/a><\/li><li id=\"e827147a-3b4f-4c97-a902-a70ce9541ba5\">Shrirao\u00a0AB, Kung FH, Omelchenko A, et al. Microfluidic platforms for the study of neuronal injury in vitro.\u00a0<em>Biotechnol\u00a0Bioeng<\/em>. 2018;115(4):830. doi:10.1002\/BIT.26519 <a href=\"#e827147a-3b4f-4c97-a902-a70ce9541ba5-link\" aria-label=\"Jump to footnote reference 278\">\u21a9\ufe0e<\/a><\/li><li id=\"e0c3e4c2-7d04-4e9d-ab3c-a18053304776\">Amirifar\u00a0L, Shamloo A, Nasiri R, et al. Brain-on-a-chip: recent advances in design and techniques for microfluidic models of the brain in health and disease.\u00a0<em>Biomaterials<\/em>.\u00a02022;285:121531.\u00a0doi:10.1016\/j.biomaterials.2022.121531 <a href=\"#e0c3e4c2-7d04-4e9d-ab3c-a18053304776-link\" aria-label=\"Jump to footnote reference 279\">\u21a9\ufe0e<\/a><\/li><li id=\"794dc1ae-894a-40c7-a53e-8172f45c8508\">Pan X, Li J, Li W, et al. Axons-on-a-chip for mimicking non-disruptive diffuse axonal injury underlying traumatic brain injury.\u00a0<em>Lab Chip<\/em>. 2022;22(23):4541-4555. doi:10.1039\/D2LC00730D <a href=\"#794dc1ae-894a-40c7-a53e-8172f45c8508-link\" aria-label=\"Jump to footnote reference 280\">\u21a9\ufe0e<\/a><\/li><li id=\"c162ec0f-5ec1-460b-b69d-601bebdda678\">Mobini S, et al. (2019). Ex vivo models and lab-on-a-chip for neural tissue engineering. <em>Biomaterials,<\/em> 198, 146\u2013166. <a href=\"#c162ec0f-5ec1-460b-b69d-601bebdda678-link\" aria-label=\"Jump to footnote reference 281\">\u21a9\ufe0e<\/a><\/li><li id=\"873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2\">Potashkin\u00a0JA, Blume SR, Runkle NK. Limitations of animal models of Parkinson\u2032s disease.\u00a0<em>Parkinsons Dis<\/em>. 2011;2011(1):658083. doi:10.4061\/2011\/658083 <a href=\"#873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2-link\" aria-label=\"Jump to footnote reference 282\">\u21a9\ufe0e<\/a><\/li><li id=\"8d0db68d-494d-426c-bafb-4462c61c8fa9\">Cummings JL,\u00a0Morstorf\u00a0T, Zhong K. Alzheimer\u2019s disease drug-development pipeline: few candidates, frequent failures.\u00a0<em>Alzheimers\u00a0Res Ther<\/em>. 2014;6(4):37. doi:10.1186\/alzrt269 <a href=\"#8d0db68d-494d-426c-bafb-4462c61c8fa9-link\" aria-label=\"Jump to footnote reference 283\">\u21a9\ufe0e<\/a><\/li><li id=\"01aa3885-6f22-4e4d-9242-74e389eef972\">Mullane K, Williams M. Preclinical models of Alzheimer\u2019s disease: relevance and translational validity.\u00a0<em>Curr\u00a0Protoc\u00a0Pharmacol<\/em>. 2019;84(1):e57. doi:10.1002\/cpph.57 <a href=\"#01aa3885-6f22-4e4d-9242-74e389eef972-link\" aria-label=\"Jump to footnote reference 284\">\u21a9\ufe0e<\/a><\/li><li id=\"ef4cc749-ce97-44df-809f-e4d92142b681\">Burke JF, Kerber KA, Langa KM, Albin RL,\u00a0Kotagal\u00a0V.\u00a0Lecanemab: looking before we leap.\u00a0<em>Neurology<\/em>. 2023;101(15):661-665. doi:10.1212\/WNL.0000000000207505 <a href=\"#ef4cc749-ce97-44df-809f-e4d92142b681-link\" aria-label=\"Jump to footnote reference 285\">\u21a9\ufe0e<\/a><\/li><li id=\"fa6531b8-bdce-4349-8b91-a601f9ddc566\">H\u00f8ilund-Carlsen PF, Alavi A, Barrio JR, et al. Donanemab, another anti-Alzheimer\u2019s drug with risk and uncertain benefit.\u00a0<em>Ageing Res Rev<\/em>.\u00a02024;99:102348.\u00a0doi:10.1016\/j.arr.2024.102348 <a href=\"#fa6531b8-bdce-4349-8b91-a601f9ddc566-link\" aria-label=\"Jump to footnote reference 286\">\u21a9\ufe0e<\/a><\/li><li id=\"e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa\">Burns TC, Li MD, Mehta S, Awad AJ, Morgan AA. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: a systematic bioinformatics-based critique of preclinical models.\u00a0<em>Eur\u00a0J\u00a0Pharmacol<\/em>.\u00a02015;759:101-117.\u00a0doi:10.1016\/j.ejphar.2015.03.021 <a href=\"#e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa-link\" aria-label=\"Jump to footnote reference 287\">\u21a9\ufe0e<\/a><\/li><li id=\"50be7246-a3b2-4332-a69d-c850094ed9cf\">Lane E, Dunnett S. Animal models of Parkinson\u2019s disease and L-dopa induced dyskinesia: how close are we to the clinic?\u00a0<em>Psychopharmacology\u00a0(Berl)<\/em>.\u00a02008;199(3):303-312.\u00a0doi:10.1007\/s00213-007-0931-8 <a href=\"#50be7246-a3b2-4332-a69d-c850094ed9cf-link\" aria-label=\"Jump to footnote reference 288\">\u21a9\ufe0e<\/a><\/li><li id=\"4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d\">Granzotto\u00a0A,\u00a0Vissel\u00a0B,\u00a0Sensi\u00a0SL.\u00a0Lost in translation: inconvenient truths on the utility of mouse models in Alzheimer\u2019s disease research. Behrens TE, ed.\u00a0<em>eLife<\/em>. 2024;13:e90633. doi:10.7554\/eLife.90633 <a href=\"#4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d-link\" aria-label=\"Jump to footnote reference 289\">\u21a9\ufe0e<\/a><\/li><li id=\"75e7b8bd-fd91-4959-98f0-03ac53c32781\">Ehrnhoefer\u00a0DE, Butland SL,\u00a0Pouladi\u00a0MA, Hayden MR. Mouse models of Huntington disease: variations on a theme.\u00a0<em>Dis Model Mech<\/em>. 2009;2(3-4):123-129. doi:10.1242\/dmm.002451 <a href=\"#75e7b8bd-fd91-4959-98f0-03ac53c32781-link\" aria-label=\"Jump to footnote reference 290\">\u21a9\ufe0e<\/a><\/li><li id=\"18c0e15a-3d08-4195-a498-6d3c582b1afb\">Aghaizu\u00a0ND, Jolly S, Samra SK, et al. Microglial expression of the\u00a0Wnt\u00a0signaling modulator DKK2 differs between human Alzheimer\u2019s disease brains and mouse neurodegeneration models.\u00a0<em>eNeuro<\/em>. 2023;10(1). doi:10.1523\/ENEURO.0306-22.2022 <a href=\"#18c0e15a-3d08-4195-a498-6d3c582b1afb-link\" aria-label=\"Jump to footnote reference 291\">\u21a9\ufe0e<\/a><\/li><li id=\"81b4d110-03b6-450e-a0c0-d55e188a391f\">Menache\u00a0A, Beuter A. Lessons from the analysis of non-human primates for understanding human aging and neurodegenerative diseases.\u00a0<em>Front Hum\u00a0Neurosci<\/em>. 2016;10. doi:10.3389\/fnhum.2016.00033 <a href=\"#81b4d110-03b6-450e-a0c0-d55e188a391f-link\" aria-label=\"Jump to footnote reference 292\">\u21a9\ufe0e<\/a><\/li><li id=\"ae257fdb-8274-4389-aa88-91390084c54f\">\u00a0Olsson IAS, Hansen AK, Sand\u00f8e P. Animal welfare and the refinement of neuroscience research methods\u2014a case study of Huntington\u2019s disease models.\u00a0<em>Lab Anim<\/em>. 2008;42(3):277-283. doi:10.1258\/la.2008.007147 <a href=\"#ae257fdb-8274-4389-aa88-91390084c54f-link\" aria-label=\"Jump to footnote reference 293\">\u21a9\ufe0e<\/a><\/li><li id=\"1e763afc-bab0-4d38-93d0-3137846469dc\">Pistollato\u00a0F, Ohayon EL, Lam A, et al. Alzheimer disease research in the 21<sup>st<\/sup>\u00a0century: past and current failures, new\u00a0perspectives\u00a0and funding priorities.\u00a0<em>Oncotarget<\/em>. 2016;7(26):38999-39016. doi:10.18632\/oncotarget.9175 <a href=\"#1e763afc-bab0-4d38-93d0-3137846469dc-link\" aria-label=\"Jump to footnote reference 294\">\u21a9\ufe0e<\/a><\/li><li id=\"1eb3a4e0-8cb3-4530-af51-be7f6183eaac\">Shrirao AB, Kung FH, Omelchenko A, et al. Microfluidic platforms for the study of neuronal injury in vitro. <em>Biotechnol Bioeng<\/em>. 2018;115(4):830. doi:10.1002\/BIT.26519 <a href=\"#1eb3a4e0-8cb3-4530-af51-be7f6183eaac-link\" aria-label=\"Jump to footnote reference 295\">\u21a9\ufe0e<\/a><\/li><li id=\"0b986690-ffac-45d4-82d3-660badf2ce23\">Amirifar L, et al. (2022). Brain-on-a-chip advances for microfluidic brain models. <em>Biomaterials,<\/em> 285, 121531. <a href=\"#0b986690-ffac-45d4-82d3-660badf2ce23-link\" aria-label=\"Jump to footnote reference 296\">\u21a9\ufe0e<\/a><\/li><li id=\"ff9ccac2-2850-434a-b2c7-139a8eeb0f98\">Amirifar L, Shamloo A, Nasiri R, et al. Brain-on-a-chip: recent advances in design and techniques for microfluidic models of the brain in health and disease. <em>Biomaterials<\/em>. 2022;285:121531. doi:10.1016\/j.biomaterials.2022.121531 <a href=\"#ff9ccac2-2850-434a-b2c7-139a8eeb0f98-link\" aria-label=\"Jump to footnote reference 297\">\u21a9\ufe0e<\/a><\/li><li id=\"cec7dce4-7bcf-4c87-87bc-501ca3f2f565\">Pan X, Li J, Li W, et al. Axons-on-a-chip for mimicking non-disruptive diffuse axonal injury underlying traumatic brain injury. <em>Lab Chip<\/em>. 2022;22(23):4541-4555. doi:10.1039\/D2LC00730D <a href=\"#cec7dce4-7bcf-4c87-87bc-501ca3f2f565-link\" aria-label=\"Jump to footnote reference 298\">\u21a9\ufe0e<\/a><\/li><li id=\"61053cdb-d3e1-49e0-93d3-338c3f79c215\">Lam I, Ndayisaba A, Lewis AJ, et al. Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of \u03b1-synuclein inclusions. <em>Neuron<\/em>. 2024;112(17):2886-2909.e16. doi:10.1016\/j.neuron.2024.06.002 <a href=\"#61053cdb-d3e1-49e0-93d3-338c3f79c215-link\" aria-label=\"Jump to footnote reference 299\">\u21a9\ufe0e<\/a><\/li><li id=\"32013bed-278a-45ce-abec-6bd25e3aaa24\">Sun Z, Kwon JS, Ren Y, et al. Modeling late-onset Alzheimer\u2019s disease neuropathology via direct neuronal reprogramming. <em>Science<\/em>. 2024;385(6708):adl2992. doi:10.1126\/science.adl2992 <a href=\"#32013bed-278a-45ce-abec-6bd25e3aaa24-link\" aria-label=\"Jump to footnote reference 300\">\u21a9\ufe0e<\/a><\/li><li id=\"6b631497-7d4a-4306-99cd-6999f25b3b6e\">Shen Y, Timsina J, Heo G, et al. CSF proteomics identifies early changes in autosomal dominant Alzheimer\u2019s disease. <em>Cell<\/em>. 2024;187(22):6309-6326.e15. doi:10.1016\/j.cell.2024.08.049 <a href=\"#6b631497-7d4a-4306-99cd-6999f25b3b6e-link\" aria-label=\"Jump to footnote reference 301\">\u21a9\ufe0e<\/a><\/li><li id=\"fbdab90e-1fa8-4ee4-9e3b-04368b8eb397\">Palma-Florez S, L\u00f3pez-Canosa A, Moralez-Zavala F, et al. BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer\u2019s disease. <em>J Nanobiotechnology<\/em>. 2023;21:115. doi:10.1186\/s12951-023-01798-2 <a href=\"#fbdab90e-1fa8-4ee4-9e3b-04368b8eb397-link\" aria-label=\"Jump to footnote reference 302\">\u21a9\ufe0e<\/a><\/li><li id=\"f43fdfcb-49bf-4b80-86e5-3f049aa8ce59\">Reumann D, Krauditsch C, Novatchkova M, et al. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain\u2013striatum\u2013cortex assembloids. <em>Nat Methods<\/em>. 2023;20(12):2034-2047. doi:10.1038\/s41592-023-02080-x <a href=\"#f43fdfcb-49bf-4b80-86e5-3f049aa8ce59-link\" aria-label=\"Jump to footnote reference 303\">\u21a9\ufe0e<\/a><\/li><li id=\"507b2c90-f1ed-4995-b00c-ea58a2759f7f\">Rosety I, Zagare A, Saraiva C, et al. Impaired neuron differentiation in GBA-associated Parkinson\u2019s disease is linked to cell cycle defects in organoids. <em>NPJ Parkinsons Dis<\/em>. 2023;9(1):1-16. doi:10.1038\/s41531-023-00616-8\u00a0 <a href=\"#507b2c90-f1ed-4995-b00c-ea58a2759f7f-link\" aria-label=\"Jump to footnote reference 304\">\u21a9\ufe0e<\/a><\/li><li id=\"55b207c4-27c2-4ef5-b1d0-36758b72c1c1\">Barmpa K, Saraiva C, Lopez-Pigozzi D, et al. Modeling early phenotypes of Parkinson\u2019s disease by age-induced midbrain-striatum assembloids. <em>Commun Biol<\/em>. 2024;7(1):1-19. doi:10.1038\/s42003-024-07273-4 <a href=\"#55b207c4-27c2-4ef5-b1d0-36758b72c1c1-link\" aria-label=\"Jump to footnote reference 305\">\u21a9\ufe0e<\/a><\/li><li id=\"18463416-0bda-47d8-aae6-d0f9c5bf3a87\">Pediaditakis I, Kodella KR, Manatakis DV, et al. Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption. <em>Nat Commun<\/em>. 2021;12(1):5907. doi:10.1038\/s41467-021-26066-5 <a href=\"#18463416-0bda-47d8-aae6-d0f9c5bf3a87-link\" aria-label=\"Jump to footnote reference 306\">\u21a9\ufe0e<\/a><\/li><li id=\"4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7\">Lisowski P, Lickfett S, Rybak-Wolf A, et al. Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure. <em>Nat Commun<\/em>. 2024;15(1):7027. doi:10.1038\/s41467-024-51216-w <a href=\"#4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7-link\" aria-label=\"Jump to footnote reference 307\">\u21a9\ufe0e<\/a><\/li><li id=\"ee570513-5ef3-4945-9b8f-ed59f2e72a54\">Badu-Mensah A, Guo X, Mendez R, Parsaud H, Hickman JJ. The effect of skeletal muscle-specific creatine treatment on ALS NMJ integrity and function. <em>Int J Mol Sci<\/em>. 2023;24(17):13519. doi:10.3390\/ijms241713519 <a href=\"#ee570513-5ef3-4945-9b8f-ed59f2e72a54-link\" aria-label=\"Jump to footnote reference 308\">\u21a9\ufe0e<\/a><\/li><li id=\"fcf754ae-f526-4abd-b088-8533715b34b6\">van der Geest AT, Jakobs CE, Ljubikj T, et al. Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS\/FTD cerebral organoids. <em>Acta Neuropathol Commun<\/em>. 2024;12(1):152. doi:10.1186\/s40478-024-01857-1 <a href=\"#fcf754ae-f526-4abd-b088-8533715b34b6-link\" aria-label=\"Jump to footnote reference 309\">\u21a9\ufe0e<\/a><\/li><li id=\"53b3febe-7a31-444c-900d-e1b1de9a4329\">Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. <em>Nat Neurosci<\/em>. 2010;13(10):1161-1169. doi:10.1038\/nn.2647 <a href=\"#53b3febe-7a31-444c-900d-e1b1de9a4329-link\" aria-label=\"Jump to footnote reference 310\">\u21a9\ufe0e<\/a><\/li><li id=\"15bcc946-dbc4-4285-b449-0a1e3ed20de1\">Molendijk ML, de Kloet ER. Immobility in the forced swim test is adaptive and does not reflect depression. <em>Psychoneuroendocrinology<\/em>. 2015;62:389-391. doi:10.1016\/j.psyneuen.2015.08.028 <a href=\"#15bcc946-dbc4-4285-b449-0a1e3ed20de1-link\" aria-label=\"Jump to footnote reference 311\">\u21a9\ufe0e<\/a><\/li><li id=\"ec47efa9-5e69-4f9b-ad87-966051395383\">De Pablo JM, Parra A, Segovia S, Guillam\u00f3n A. Learned immobility explains the behavior of rats in the forced swimming test. <em>Physiol Behav<\/em>. 1989;46(2):229-237. doi:10.1016\/0031-9384(89)90261-8 <a href=\"#ec47efa9-5e69-4f9b-ad87-966051395383-link\" aria-label=\"Jump to footnote reference 312\">\u21a9\ufe0e<\/a><\/li><li id=\"48383639-ef56-4724-b89f-5402cee096f4\">Jefferys D, Funder J. The effect of water temperature on immobility in the forced swimming test in rats. <em>Eur J Pharmacol<\/em>. 1994;253(1-2):91-94. doi:10.1016\/0014-2999(94)90761-7 <a href=\"#48383639-ef56-4724-b89f-5402cee096f4-link\" aria-label=\"Jump to footnote reference 313\">\u21a9\ufe0e<\/a><\/li><li id=\"f300d69f-1114-4fe9-b89b-10e73b590a95\">Lucki I, Dalvi A, Mayorga AJ. Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. <em>Psychopharmacology (Berl)<\/em>. 2001;155(3):315-322. doi:10.1007\/s002130100694 <a href=\"#f300d69f-1114-4fe9-b89b-10e73b590a95-link\" aria-label=\"Jump to footnote reference 314\">\u21a9\ufe0e<\/a><\/li><li id=\"3af7fa0f-c28a-4f4d-b696-8b7806493522\">Rosas-S\u00e1nchez GU, German-Ponciano LJ, Rodr\u00edguez-Landa JF. Considerations of pool dimensions in the forced swim test in predicting the potential antidepressant activity of drugs. <em>Front Behav Neurosci<\/em>. 2022;15:757348. doi:10.3389\/fnbeh.2021.757348 <a href=\"#3af7fa0f-c28a-4f4d-b696-8b7806493522-link\" aria-label=\"Jump to footnote reference 315\">\u21a9\ufe0e<\/a><\/li><li id=\"a1c96c7c-308b-44c2-9d9c-a94f356c01cd\">Trunnell ER, Carvalho C. The forced swim test has poor accuracy for identifying novel antidepressants. <em>Drug Discov Today<\/em>. 2021;26(12):2898-2904. doi:10.1016\/j.drudis.2021.08.003 <a href=\"#a1c96c7c-308b-44c2-9d9c-a94f356c01cd-link\" aria-label=\"Jump to footnote reference 316\">\u21a9\ufe0e<\/a><\/li><li id=\"8baafa78-0984-4108-afe4-8ff9cd7de325\">Trunnell ER, Baines J, Farghali S, et al. The need for guidance in antidepressant drug development: revisiting the role of the forced swim test and tail suspension test. <em>Regul Toxicol Pharmacol<\/em>. 2024;151:105666. doi:10.1016\/j.yrtph.2024.105666 <a href=\"#8baafa78-0984-4108-afe4-8ff9cd7de325-link\" aria-label=\"Jump to footnote reference 317\">\u21a9\ufe0e<\/a><\/li><li id=\"105f4c65-2212-4260-a890-1bc13b938a42\">Berrio JP, Hestehave S, Kalliokoski O. Reliability of sucrose preference testing following short or no food and water deprivation\u2014a systematic review and meta-analysis of rat models of chronic unpredictable stress. <em>Transl Psychiatry<\/em>. 2024;14(1):1-10. doi:10.1038\/s41398-024-02742-0 <a href=\"#105f4c65-2212-4260-a890-1bc13b938a42-link\" aria-label=\"Jump to footnote reference 318\">\u21a9\ufe0e<\/a><\/li><li id=\"dfd3ec4d-2db6-46f5-a353-1843757c62c2\">Scheggi S. Still controversial issues on assessing anhedonia in experimental modeling of depression. <em>Transl Psychiatry<\/em>. 2024;14(1):1-2. doi:10.1038\/s41398-024-03057-w <a href=\"#dfd3ec4d-2db6-46f5-a353-1843757c62c2-link\" aria-label=\"Jump to footnote reference 319\">\u21a9\ufe0e<\/a><\/li><li id=\"7f85a86e-aab3-4876-ad19-d4f43354a2c5\">Verharen JPH, de Jong JW, Zhu Y, Lammel S. A computational analysis of mouse behavior in the sucrose preference test. <em>Nat Commun<\/em>. 2023;14(1):2419. doi:10.1038\/s41467-023-38028-0 <a href=\"#7f85a86e-aab3-4876-ad19-d4f43354a2c5-link\" aria-label=\"Jump to footnote reference 320\">\u21a9\ufe0e<\/a><\/li><li id=\"9d722a92-a161-4ccf-a8bf-8ec463094268\">V\u00f5ikar V, Stanford SC. The open field test. In: Harro J, ed. <em>Psychiatric Vulnerability, Mood, and Anxiety Disorders: Tests and Models in Mice and Rats<\/em>. Springer US; 2023:9-29. doi:10.1007\/978-1-0716-2748-8_2 <a href=\"#9d722a92-a161-4ccf-a8bf-8ec463094268-link\" aria-label=\"Jump to footnote reference 321\">\u21a9\ufe0e<\/a><\/li><li id=\"bd273750-7c2d-41a3-b1b2-799ae3f50da5\">Rosso M, Wirz R, Loretan AV, et al. Reliability of common mouse behavioural tests of anxiety: a systematic review and meta-analysis on the effects of anxiolytics. <em>Neurosci Biobehav Rev<\/em>. 2022;143:104928. doi:10.1016\/j.neubiorev.2022.104928 <a href=\"#bd273750-7c2d-41a3-b1b2-799ae3f50da5-link\" aria-label=\"Jump to footnote reference 322\">\u21a9\ufe0e<\/a><\/li><li id=\"7114cae6-10c1-4c92-b0e9-6c525c15b1b6\">Dixit PV, Sahu R, Mishra DK. Marble-burying behavior test as a murine model of compulsive-like behavior. <em>J Pharmacol Toxicol Methods<\/em>. 2020;102:106676. doi:10.1016\/j.vascn.2020.106676 <a href=\"#7114cae6-10c1-4c92-b0e9-6c525c15b1b6-link\" aria-label=\"Jump to footnote reference 323\">\u21a9\ufe0e<\/a><\/li><li id=\"cbbb1555-7416-4d5e-8cf5-545ca8e5ace7\">Markov DD, Novosadova EV. Chronic unpredictable mild stress model of depression: possible sources of poor reproducibility and latent variables. <em>Biology (Basel)<\/em>. 2022;11(11):1621. doi:10.3390\/biology11111621 <a href=\"#cbbb1555-7416-4d5e-8cf5-545ca8e5ace7-link\" aria-label=\"Jump to footnote reference 324\">\u21a9\ufe0e<\/a><\/li><li id=\"73c43d59-914d-45af-9856-e8e3fb27b829\">Silverman JL. Animal models for psychiatric research: novel directions for behavioral neuroscience in translation. <em>Neurosci Biobehav Rev<\/em>. 2023;152:105309. doi:10.1016\/j.neubiorev.2023.105309 <a href=\"#73c43d59-914d-45af-9856-e8e3fb27b829-link\" aria-label=\"Jump to footnote reference 325\">\u21a9\ufe0e<\/a><\/li><li id=\"2cbc6467-404a-40a5-a811-4cafa6e7323c\">Carvalho C, Varela SAM, Marques TA, Knight A, Vicente L. Are in vitro and in silico approaches used appropriately for animal-based major depressive disorder research? <em>PLoS One<\/em>. 2020;15(6):e0233954. doi:10.1371\/journal.pone.0233954 <a href=\"#2cbc6467-404a-40a5-a811-4cafa6e7323c-link\" aria-label=\"Jump to footnote reference 326\">\u21a9\ufe0e<\/a><\/li><li id=\"19c00b04-2260-4382-b5c4-0ec626ca2cf0\">Carvalho C, Peste F, Marques TA, Knight A, Vicente LM. The contribution of rat studies to current knowledge of major depressive disorder: results from citation analysis. <em>Front Psychol<\/em>. 2020;11:1486. doi:10.3389\/fpsyg.2020.01486 <a href=\"#19c00b04-2260-4382-b5c4-0ec626ca2cf0-link\" aria-label=\"Jump to footnote reference 327\">\u21a9\ufe0e<\/a><\/li><li id=\"a3d63714-be52-43f5-b22f-067ac761d110\">Carvalho C, Herrmann K, Marques TA, Knight A. Time to abolish the forced swim test in rats for depression research? <em>JAAE<\/em>. 2021;4(2):170-178. doi:10.1163\/25889567-BJA10026 <a href=\"#a3d63714-be52-43f5-b22f-067ac761d110-link\" aria-label=\"Jump to footnote reference 328\">\u21a9\ufe0e<\/a><\/li><li id=\"f7b711be-9c6e-473b-8f65-f1ffaa1a52df\">Kato T, Kasahara T, Kubota-Sakashita M, Kato TM, Nakajima K. Animal models of recurrent or bipolar depression. <em>Neuroscience<\/em>. 2016;321:189-196. doi:10.1016\/j.neuroscience.2015.08.016 <a href=\"#f7b711be-9c6e-473b-8f65-f1ffaa1a52df-link\" aria-label=\"Jump to footnote reference 329\">\u21a9\ufe0e<\/a><\/li><li id=\"10cd95b2-cd00-4032-9a50-00a8e4ac720b\">Garner JP. The significance of meaning: why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? <em>ILAR J<\/em>. 2014;55(3):438-456. doi:10.1093\/ilar\/ilu047 <a href=\"#10cd95b2-cd00-4032-9a50-00a8e4ac720b-link\" aria-label=\"Jump to footnote reference 330\">\u21a9\ufe0e<\/a><\/li><li id=\"461ca1ab-6fb9-4155-b15b-a75736395edc\">Molendijk ML, de Kloet ER. Forced swim stressor: trends in usage and mechanistic consideration. <em>Eur J Neurosci<\/em>. 2022;55(9-10):2813-2831. doi:10.1111\/EJN.15139 <a href=\"#461ca1ab-6fb9-4155-b15b-a75736395edc-link\" aria-label=\"Jump to footnote reference 331\">\u21a9\ufe0e<\/a><\/li><li id=\"ffb83547-3d7b-46ac-8ff0-4c6a15a9993c\">Trunnell et al., 2024 <a href=\"#ffb83547-3d7b-46ac-8ff0-4c6a15a9993c-link\" aria-label=\"Jump to footnote reference 332\">\u21a9\ufe0e<\/a><\/li><li id=\"66d85322-bc6a-4931-9993-e0e3fb65598c\">Jin H, Romano G, Marshall C, Donaldson AE, Suon S, Iacovitti L. Tyrosine hydroxylase gene regulation in human neuronal progenitor cells does not depend on Nurr1 as in the murine and rat systems. <em>J Cell Physiol<\/em>. 2006;207(1):49-57. doi:10.1002\/jcp.20534 <a href=\"#66d85322-bc6a-4931-9993-e0e3fb65598c-link\" aria-label=\"Jump to footnote reference 333\">\u21a9\ufe0e<\/a><\/li><li id=\"e2e0f43d-54d5-44a7-823e-2828119473d8\">Hodge RD, Bakken TE, Miller JA, et al. Conserved cell types with divergent features in human versus mouse cortex. <em>Nature<\/em>. 2019;573(7772):61-68. doi:10.1038\/s41586-019-1506-7 <a href=\"#e2e0f43d-54d5-44a7-823e-2828119473d8-link\" aria-label=\"Jump to footnote reference 334\">\u21a9\ufe0e<\/a><\/li><li id=\"ad0c603b-47da-4e3b-8c00-382ab2cc7884\">Dixon TA, Muotri AR. Advancing preclinical models of psychiatric disorders with human brain organoid cultures. <em>Mol Psychiatry<\/em>. 2023;28(1):83-95. doi:10.1038\/s41380-022-01708-2 <a href=\"#ad0c603b-47da-4e3b-8c00-382ab2cc7884-link\" aria-label=\"Jump to footnote reference 335\">\u21a9\ufe0e<\/a><\/li><li id=\"56c06caf-27d2-45d6-bd6f-96d9c7e23157\">Figdor C. Animal models in neuropsychiatry: do the benefits outweigh the moral costs? <em>Camb Q Healthc Ethics<\/em>. 2022;31(4):530-535. doi:10.1017\/S0963180122000147 <a href=\"#56c06caf-27d2-45d6-bd6f-96d9c7e23157-link\" aria-label=\"Jump to footnote reference 336\">\u21a9\ufe0e<\/a><\/li><li id=\"cf80c8c8-283b-4b42-b9c1-83914b277c9e\">Dixon &amp; Muotri, 2023 <a href=\"#cf80c8c8-283b-4b42-b9c1-83914b277c9e-link\" aria-label=\"Jump to footnote reference 337\">\u21a9\ufe0e<\/a><\/li><li id=\"cfaa5c04-0e1d-49c9-ab46-3478a46d5055\">Urenda JP, Dosso AD, Birtele M, Quadrato G. Present and future modeling of human psychiatric connectopathies with brain organoids. <em>Biol Psychiatry<\/em>. 2023;93(7):606-615. doi:10.1016\/j.biopsych.2022.12.017 <a href=\"#cfaa5c04-0e1d-49c9-ab46-3478a46d5055-link\" aria-label=\"Jump to footnote reference 338\">\u21a9\ufe0e<\/a><\/li><li id=\"40f25b41-71f5-487c-8a09-557d3a7239bf\">Levy RJ, Pa\u015fca SP. What have organoids and assembloids taught us about the pathophysiology of neuropsychiatric disorders? <em>Biol Psychiatry<\/em>. 2023;93(7):632-641. doi:10.1016\/j.biopsych.2022.11.01 <a href=\"#40f25b41-71f5-487c-8a09-557d3a7239bf-link\" aria-label=\"Jump to footnote reference 339\">\u21a9\ufe0e<\/a><\/li><li id=\"62aaba4c-f8dd-4c16-a08d-a9291860872b\">Li C, Fleck JS, Martins-Costa C, et al. Single-cell brain organoid screening identifies developmental defects in autism. <em>Nature<\/em>. 2023;621(7978):373-380. doi:10.1038\/s41586-023-06473-y <a href=\"#62aaba4c-f8dd-4c16-a08d-a9291860872b-link\" aria-label=\"Jump to footnote reference 340\">\u21a9\ufe0e<\/a><\/li><li id=\"04c6d376-007b-4984-a980-ea0c394298ef\">Onesto MM, Kim JI, Pasca SP. Assembloid models of cell-cell interaction to study tissue and disease biology. <em>Cell Stem Cell<\/em>. 2024;31(11):1563-1573. doi:10.1016\/j.stem.2024.09.017 <a href=\"#04c6d376-007b-4984-a980-ea0c394298ef-link\" aria-label=\"Jump to footnote reference 341\">\u21a9\ufe0e<\/a><\/li><li id=\"49701689-071a-469a-8f89-96348f80a41a\">Levy &amp; Pa\u015fca, 2023 <a href=\"#49701689-071a-469a-8f89-96348f80a41a-link\" aria-label=\"Jump to footnote reference 342\">\u21a9\ufe0e<\/a><\/li><li id=\"eff889ea-73f1-4833-b314-b41ce2e4872b\">Miura Y, Kim JI, Jurju\u021b O, et al. Assembloid model to study loop circuits of the human nervous system. <em>bioRxiv. <\/em>Preprint posted online October 14, 2024 <a href=\"#eff889ea-73f1-4833-b314-b41ce2e4872b-link\" aria-label=\"Jump to footnote reference 343\">\u21a9\ufe0e<\/a><\/li><li id=\"645fe329-137e-4c03-93a9-57491fdef324\">Kim JI, Miura Y, Li MY, et al. Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. <em>Neuron<\/em>. 2024;0(0). doi:10.1016\/j.neuron.2024.09.020 <a href=\"#645fe329-137e-4c03-93a9-57491fdef324-link\" aria-label=\"Jump to footnote reference 344\">\u21a9\ufe0e<\/a><\/li><li id=\"9f130a40-a0ec-4328-81ed-3b0324dffba4\">Courchesne E, Taluja V, Nazari S, et al. Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms. <em>Mol Autism<\/em>. 2024;15(1):22. doi:10.1186\/s13229-024-00602-8 <a href=\"#9f130a40-a0ec-4328-81ed-3b0324dffba4-link\" aria-label=\"Jump to footnote reference 345\">\u21a9\ufe0e<\/a><\/li><li id=\"72ee992e-0472-41b7-ae34-82d3a862dc9a\">Papes F, Camargo AP, de Souza JS, et al. Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content. <em>Nat Commun<\/em>. 2022;13(1):2387. doi:10.1038\/s41467-022-29942-w <a href=\"#72ee992e-0472-41b7-ae34-82d3a862dc9a-link\" aria-label=\"Jump to footnote reference 346\">\u21a9\ufe0e<\/a><\/li><li id=\"3910c00c-f1db-422f-a179-6bfd160a9cee\">Sebastian R, Jin K, Pavon N, et al. Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids. <em>Nat Commun<\/em>. 2023;14(1):3770. doi:10.1038\/s41467-023-39420-6 <a href=\"#3910c00c-f1db-422f-a179-6bfd160a9cee-link\" aria-label=\"Jump to footnote reference 347\">\u21a9\ufe0e<\/a><\/li><li id=\"75310f32-3c8b-493a-8f8f-e724cbd50d97\">Science. PsychENCODE2. AAAS. 2024. Accessed December 2, 2024. https:\/\/www.science.org\/collections\/psychencode2 <a href=\"#75310f32-3c8b-493a-8f8f-e724cbd50d97-link\" aria-label=\"Jump to footnote reference 348\">\u21a9\ufe0e<\/a><\/li><li id=\"b5a77dda-c499-4768-9dd3-9444735b707a\">Lynall ME, Soskic B, Hayhurst J, et al. Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells. <em>Nat Commun<\/em>. 2022;13(1):6102. doi:10.1038\/s41467-022-33885-7 <a href=\"#b5a77dda-c499-4768-9dd3-9444735b707a-link\" aria-label=\"Jump to footnote reference 349\">\u21a9\ufe0e<\/a><\/li><li id=\"e95708ec-9c5c-499a-af7d-d97da684ee59\">Kundu S, Sair H, Sherr EH, Mukherjee P, Rohde GK. Discovering the gene-brain-behavior link in autism via generative machine learning. <em>Sci Adv<\/em>. 2024;10(24):eadl5307. doi:10.1126\/sciadv.adl5307 <a href=\"#e95708ec-9c5c-499a-af7d-d97da684ee59-link\" aria-label=\"Jump to footnote reference 350\">\u21a9\ufe0e<\/a><\/li><li id=\"52842d9d-5897-4519-8652-6238040bd79c\">Gaudfernau F, Lefebvre A, Engemann DA, et al. Cortico-cerebellar neurodynamics during social interaction in autism spectrum disorders. <em>NeuroImage Clin<\/em>. 2023;39:103465. doi:10.1016\/j.nicl.2023.103465 <a href=\"#52842d9d-5897-4519-8652-6238040bd79c-link\" aria-label=\"Jump to footnote reference 351\">\u21a9\ufe0e<\/a><\/li><li id=\"a62f2103-16d6-4119-bf8c-6ef909497ce4\">Wang M, Barker PB, Cascella NG, et al. Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study. <em>Mol Psychiatry<\/em>. 2023;28(5):2018-2029. doi:10.1038\/s41380-023-01969-5 <a href=\"#a62f2103-16d6-4119-bf8c-6ef909497ce4-link\" aria-label=\"Jump to footnote reference 352\">\u21a9\ufe0e<\/a><\/li><li id=\"fb25b73c-00f8-4933-8aa3-fea428d33690\">Nour MM, McNamee DC, Liu Y, Dolan RJ. Trajectories through semantic spaces in schizophrenia and the relationship to ripple bursts. <em>Proc Natl Acad Sci U S A<\/em>. 2023;120(42):e2305290120. doi:10.1073\/pnas.2305290120 <a href=\"#fb25b73c-00f8-4933-8aa3-fea428d33690-link\" aria-label=\"Jump to footnote reference 353\">\u21a9\ufe0e<\/a><\/li><li id=\"3d0b3e37-06b7-409d-bbb1-1edad662cca2\">Tozzi L, Zhang X, Pines A, et al. Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. <em>Nat Med<\/em>. 2024;30(7):2076-2087. doi:10.1038\/s41591-024-03057-9 <a href=\"#3d0b3e37-06b7-409d-bbb1-1edad662cca2-link\" aria-label=\"Jump to footnote reference 354\">\u21a9\ufe0e<\/a><\/li><li id=\"f755388f-8bb7-4686-8c1a-010a06c3b97a\">Arnold C. Discovering how environment affects autism. <em>Hopkins Bloomberg Public Health<\/em>. November 3, 2023. Accessed December 2, 2024. <a href=\"https:\/\/magazine.publichealth.jhu.edu\/2023\/discovering-how-environment-affects-autism\">https:\/\/magazine.publichealth.jhu.edu\/2023\/discovering-how-environment-affects-autism<\/a> <a href=\"#f755388f-8bb7-4686-8c1a-010a06c3b97a-link\" aria-label=\"Jump to footnote reference 355\">\u21a9\ufe0e<\/a><\/li><li id=\"9b6f7cbc-b839-4867-b28c-37af2caa2714\">Ahrens AP, Hy\u00f6tyl\u00e4inen T, Petrone JR, et al. Infant microbes and metabolites point to childhood neurodevelopmental disorders. <em>Cell<\/em>. 2024;187(8):1853-1873.e15. doi:10.1016\/j.cell.2024.02.035 <a href=\"#9b6f7cbc-b839-4867-b28c-37af2caa2714-link\" aria-label=\"Jump to footnote reference 356\">\u21a9\ufe0e<\/a><\/li><li id=\"44c88bc5-46b1-41b6-8636-2d25573e24e1\">Guti\u00e9rrez-Casares JR, Quintero J, Seg\u00fa-Verg\u00e9s C, et al. In silico clinical trial evaluating lisdexamfetamine\u2019s and methylphenidate\u2019s mechanism of action computational models in an attention-deficit\/hyperactivity disorder virtual patients\u2019 population. <em>Front Psychiatry<\/em>. 2023;14:939650. doi:10.3389\/fpsyt.2023.939650 <a href=\"#44c88bc5-46b1-41b6-8636-2d25573e24e1-link\" aria-label=\"Jump to footnote reference 357\">\u21a9\ufe0e<\/a><\/li><li id=\"635c7069-655c-4a7a-b847-a653310086b0\">Siekmeier PJ. An in silico, biomarker-based method for the evaluation of virtual neuropsychiatric drug effects. <em>Neural Comput<\/em>. 2017;29(4):1021-1052. doi:10.1162\/NECO_a_00944 <a href=\"#635c7069-655c-4a7a-b847-a653310086b0-link\" aria-label=\"Jump to footnote reference 358\">\u21a9\ufe0e<\/a><\/li><li id=\"631ed052-332a-4871-a503-304085e05104\">Boodman E. Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals. STAT. March 11, 2020. Accessed December 3, 2024. <a href=\"https:\/\/www.statnews.com\/2020\/03\/11\/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing\/\">https:\/\/www.statnews.com\/2020\/03\/11\/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing\/<\/a> <a href=\"#631ed052-332a-4871-a503-304085e05104-link\" aria-label=\"Jump to footnote reference 359\">\u21a9\ufe0e<\/a><\/li><li id=\"bb996f9c-ea71-434b-afd1-4dfad51260c3\">Zimmer C. Prototype vaccine protects monkeys from coronavirus. <em>The New York Times<\/em>. May 20, 2020. Accessed December 3, 2024.\u00a0<br><a href=\"https:\/\/www.nytimes.com\/2020\/05\/20\/health\/coronavirus-vaccine-harvard.html.\">https:\/\/www.nytimes.com\/2020\/05\/20\/health\/coronavirus-vaccine-harvard.html<\/a>. <a href=\"#bb996f9c-ea71-434b-afd1-4dfad51260c3-link\" aria-label=\"Jump to footnote reference 360\">\u21a9\ufe0e<\/a><\/li><li id=\"144630d0-7843-4f94-8ad5-fefb0694d349\">Zimmer C. (2020). Prototype vaccine protects monkeys. <em>The New York Times.<\/em> Retrieved December 3, 2024. <a href=\"#144630d0-7843-4f94-8ad5-fefb0694d349-link\" aria-label=\"Jump to footnote reference 361\">\u21a9\ufe0e<\/a><\/li><li id=\"9d652e52-1ad6-4e0b-8357-2cf52c9512c7\">Hwang KS, Seo EU, Choi N, Kim J, Kim HN. 3D engineered tissue models for studying human-specific infectious viral diseases. <em>Bioact Mater<\/em>. 2023;21:576-594. doi:10.1016\/j.bioactmat.2022.09.010 <a href=\"#9d652e52-1ad6-4e0b-8357-2cf52c9512c7-link\" aria-label=\"Jump to footnote reference 362\">\u21a9\ufe0e<\/a><\/li><li id=\"373448ee-683a-4b04-9597-572c1b5a7de2\">Hwang et al., 2023 <a href=\"#373448ee-683a-4b04-9597-572c1b5a7de2-link\" aria-label=\"Jump to footnote reference 363\">\u21a9\ufe0e<\/a><\/li><li id=\"e6dea537-908f-4b0c-9480-14f5795949b1\">Alonso-Roman R, Mosig AS, Figge MT, et al. Organ-on-chip models for infectious disease research. <em>Nat Microbiol<\/em>. 2024;9(4):891-904. doi:10.1038\/s41564-024-01645-6 <a href=\"#e6dea537-908f-4b0c-9480-14f5795949b1-link\" aria-label=\"Jump to footnote reference 364\">\u21a9\ufe0e<\/a><\/li><li id=\"8ff615ed-1d18-4610-a1c2-42ad26a70a9f\">Hwang KS, Seo EU, Choi N, Kim J, Kim HN. 3D engineered tissue models for studying human-specific infectious viral diseases. <em>Bioact Mater<\/em>. 2023;21:576-594. doi:10.1016\/j.bioactmat.2022.09.010 <a href=\"#8ff615ed-1d18-4610-a1c2-42ad26a70a9f-link\" aria-label=\"Jump to footnote reference 365\">\u21a9\ufe0e<\/a><\/li><li id=\"64e35358-f1e7-4f80-af2e-272dfc96e0e4\">Morrocchi E, Haren S van, Palma P, Levy O. Modeling human immune responses to vaccination in vitro. <em>Trends Immunol<\/em>. 2024;45(1):32-47. doi:10.1016\/j.it.2023.11.002 <a href=\"#64e35358-f1e7-4f80-af2e-272dfc96e0e4-link\" aria-label=\"Jump to footnote reference 366\">\u21a9\ufe0e<\/a><\/li><li id=\"9beaf43b-f224-4306-80f6-cd7c8bf4e721\">Flagg M, de Wit E. Advancing zoonotic respiratory virus research through the use of organoids. <em>Curr Opin Virol<\/em>. 2024;68-69:101435. doi:10.1016\/j.coviro.2024.101435 <a href=\"#9beaf43b-f224-4306-80f6-cd7c8bf4e721-link\" aria-label=\"Jump to footnote reference 367\">\u21a9\ufe0e<\/a><\/li><li id=\"ed152674-6dd3-453c-adfb-bd758ba65b96\">Gebert JT, Scribano F, Engevik KA, Perry JL, Hyser JM. Gastrointestinal organoids in the study of viral infections. <em>Am J Physiol Gastrointest Liver Physiol<\/em>. 2023;324(1):G51-G59. doi:10.1152\/ajpgi.00152.2022\u00a0 <a href=\"#ed152674-6dd3-453c-adfb-bd758ba65b96-link\" aria-label=\"Jump to footnote reference 368\">\u21a9\ufe0e<\/a><\/li><li id=\"ff49183b-ccbc-41df-a8bf-d41dfe7273b6\">Tang X, Xue D, Zhang T, et al. A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection. <em>Nat Cell Biol<\/em>. 2023;25(3):381-389. doi:10.1038\/s41556-023-01095-y <a href=\"#ff49183b-ccbc-41df-a8bf-d41dfe7273b6-link\" aria-label=\"Jump to footnote reference 369\">\u21a9\ufe0e<\/a><\/li><li id=\"2df06206-65b6-4a16-b541-341b1b1c7b36\">Leibel SL, McVicar RN, Murad R, et al. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response. <em>Proc Natl Acad Sci U S A<\/em>. 2024;121(30):e2408109121. doi:10.1073\/pnas.2408109121 <a href=\"#2df06206-65b6-4a16-b541-341b1b1c7b36-link\" aria-label=\"Jump to footnote reference 370\">\u21a9\ufe0e<\/a><\/li><li id=\"6c9ebdf4-5dba-40a3-b243-7d7fd4339558\">Ng JH, Sun A, Je HS, Tan EK. Unravelling pathophysiology of neurological and psychiatric complications of COVID-19 using brain organoids. <em>Neuroscientist<\/em>. 2023;29(1):30-40. doi:10.1177\/10738584211015136 <a href=\"#6c9ebdf4-5dba-40a3-b243-7d7fd4339558-link\" aria-label=\"Jump to footnote reference 371\">\u21a9\ufe0e<\/a><\/li><li id=\"755591bc-12f5-47c4-9707-611b12bbd782\">Shaker MR, Slonchak A, Al-mhanawi B, et al. Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2. <em>Sci Adv<\/em>. 2024;10(23):eadj4735. doi:10.1126\/sciadv.adj4735 <a href=\"#755591bc-12f5-47c4-9707-611b12bbd782-link\" aria-label=\"Jump to footnote reference 372\">\u21a9\ufe0e<\/a><\/li><li id=\"c39857f0-1282-4745-9fe0-6d880890f7f5\">Mesci P, Souza JS de, Martin-Sancho L, et al. SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir. <em>PLoS Biol<\/em>. 2022;20(11):e3001845. doi:10.1371\/journal.pbio.3001845 <a href=\"#c39857f0-1282-4745-9fe0-6d880890f7f5-link\" aria-label=\"Jump to footnote reference 373\">\u21a9\ufe0e<\/a><\/li><li id=\"10ff12ed-0301-4ed7-b0b0-ece1deaf5a60\">Deguchi S, Kosugi K, Hashimoto R, et al. Elucidation of the liver pathophysiology of COVID-19 patients using liver-on-a-chips. <em>PNAS Nexus<\/em>. 2023;2(3):pgad029. doi:10.1093\/pnasnexus\/pgad029 <a href=\"#10ff12ed-0301-4ed7-b0b0-ece1deaf5a60-link\" aria-label=\"Jump to footnote reference 374\">\u21a9\ufe0e<\/a><\/li><li id=\"3fea169c-56bc-47ad-8a48-9565778ab980\">Flagg M, Williamson BN, Ortiz-Morales JA, Lutterman TR, de Wit E. Comparison of contemporary and historic highly pathogenic avian influenza A(H5N1) virus replication in human lung organoids. <em>Emerg Infect Dis<\/em>. 2025;31(2):318-322. doi:10.3201\/eid3102.241147 <a href=\"#3fea169c-56bc-47ad-8a48-9565778ab980-link\" aria-label=\"Jump to footnote reference 375\">\u21a9\ufe0e<\/a><\/li><li id=\"d224f830-fdf4-4e89-93ec-d969dd1aae7d\">Widerspick L, Steffen JF, Tappe D, Mu\u00f1oz-Fontela C. Animal model alternatives in filovirus and bornavirus research. <em>Viruses<\/em>. 2023;15(1):158. doi:10.3390\/v15010158 <a href=\"#d224f830-fdf4-4e89-93ec-d969dd1aae7d-link\" aria-label=\"Jump to footnote reference 376\">\u21a9\ufe0e<\/a><\/li><li id=\"fa3da7c4-1f25-4fca-9f2f-ef2e38f63491\">Widerspick L, et al. (2023). Animal model alternatives in filovirus and bornavirus research. <em>Viruses,<\/em> 15(1), 158. <a href=\"#fa3da7c4-1f25-4fca-9f2f-ef2e38f63491-link\" aria-label=\"Jump to footnote reference 377\">\u21a9\ufe0e<\/a><\/li><li id=\"c7492489-64fb-4dc4-a070-e35a44606b5d\">Altman MC, Reeves SR, Parker AR, et al. Interferon response to respiratory syncytial virus by bronchial epithelium from children with asthma is inversely correlated with pulmonary function. <em>J Allergy Clin Immunol<\/em>. 2018;142(2):451-459. doi:10.1016\/j.jaci.2017.10.004 <a href=\"#c7492489-64fb-4dc4-a070-e35a44606b5d-link\" aria-label=\"Jump to footnote reference 378\">\u21a9\ufe0e<\/a><\/li><li id=\"c1d71a5d-5536-406e-b897-30f225b653cb\">van Dijk LLA, Rijsbergen LC, Rubio BT, et al. Virus neutralization assays for human respiratory syncytial virus using airway organoids. <em>Cell Mol Life Sci<\/em>. 2024;81(1):267. doi:10.1007\/s00018-024-05307-y <a href=\"#c1d71a5d-5536-406e-b897-30f225b653cb-link\" aria-label=\"Jump to footnote reference 379\">\u21a9\ufe0e<\/a><\/li><li id=\"4551c279-9048-4cb0-84c2-f08a1b31b2d8\">Walitt B, Singh K, LaMunion SR, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis\/chronic fatigue syndrome. <em>Nat Commun<\/em>. 2024;15(1):907. doi:10.1038\/s41467-024-45107-3 <a href=\"#4551c279-9048-4cb0-84c2-f08a1b31b2d8-link\" aria-label=\"Jump to footnote reference 380\">\u21a9\ufe0e<\/a><\/li><li id=\"96a33d3b-142e-4b89-a4d4-914cd3024804\">Maria NI, Rapicavoli RV, Alaimo S, et al. Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing. <em>Heliyon<\/em>. 2023;9(3). doi:10.1016\/j.heliyon.2023.e14115 <a href=\"#96a33d3b-142e-4b89-a4d4-914cd3024804-link\" aria-label=\"Jump to footnote reference 381\">\u21a9\ufe0e<\/a><\/li><li id=\"bd4db79e-2652-4294-aa48-4c8e226cc8f4\">Borsky S, Hennighausen H, Leiter A, Williges K. CITES and the zoonotic disease content in international wildlife trade. <em>Environ Resource Econ (Dordr)<\/em>. 2020;76(4):1001-1017. doi:10.1007\/s10640-020-00456-7\u00a0 <a href=\"#bd4db79e-2652-4294-aa48-4c8e226cc8f4-link\" aria-label=\"Jump to footnote reference 382\">\u21a9\ufe0e<\/a><\/li><li id=\"f57a02e5-7129-49a1-8601-4be949222377\">Johnson CK, Hitchens PL, Pandit PS, et al. Global shifts in mammalian population trends reveal key predictors of virus spillover risk. <em>Proc Biol Sci<\/em>. 2020;287(1924):20192736. doi:10.1098\/rspb.2019.2736 <a href=\"#f57a02e5-7129-49a1-8601-4be949222377-link\" aria-label=\"Jump to footnote reference 383\">\u21a9\ufe0e<\/a><\/li><li id=\"e403585c-97ae-48cb-84ad-f55190da4c36\">United States Department of Justice Southern District of Florida. Cambodian officials and six coconspirators indicted for taking part in primate smuggling scheme. Justice.gov. November 16, 2022. Accessed December 3, 2024. <a href=\"https:\/\/www.justice.gov\/usao-sdfl\/pr\/cambodian-officials-and-six-co-conspirators-indicted-taking-part-primate-smuggling-0\">https:\/\/www.justice.gov\/usao-sdfl\/pr\/cambodian-officials-and-six-co-conspirators-indicted-taking-part-primate-smuggling-0<\/a> <a href=\"#e403585c-97ae-48cb-84ad-f55190da4c36-link\" aria-label=\"Jump to footnote reference 384\">\u21a9\ufe0e<\/a><\/li><li id=\"3bfc99c5-89e1-4a25-986a-a53a30bdae5f\">Taetzsch SJ, Swaney EM, Gee JE, et al. Melioidosis in cynomolgus macaques (Macaca fascicularis) imported to the United States from Cambodia. <em>Comp Med<\/em>. 2022;72(6):394-402. doi:10.30802\/AALAS-CM-22-000024 <a href=\"#3bfc99c5-89e1-4a25-986a-a53a30bdae5f-link\" aria-label=\"Jump to footnote reference 385\">\u21a9\ufe0e<\/a><\/li><li id=\"a6777a7b-9c4f-47f0-bafb-4f077ce56f56\">Swisher SD, Taetzsch SJ, Laughlin ME, et al. Outbreak of Mycobacterium orygis in a shipment of cynomolgus macaques imported from Southeast Asia\u2013<a href=\"#_msocom_1\">[ET1]<\/a>\u00a0United States, February-May 2023. <em>MMWR Morb Mortal Wkly Rep<\/em>. 2024;73(7):145-148. doi:10.15585\/mmwr.mm7307a2 <a href=\"#a6777a7b-9c4f-47f0-bafb-4f077ce56f56-link\" aria-label=\"Jump to footnote reference 386\">\u21a9\ufe0e<\/a><\/li><li id=\"ff8ab1a3-ff0f-41d5-b214-db885d564bfe\">Weber K, Mayoral FJ, Vallejo C, et al. Natural outbreak of Mycobacterium caprae infection in imported laboratory cynomolgus macaques (Macaca fascicularis): diagnostic pitfalls and management of safety precautions. <em>J Toxicol Pathol<\/em>. 2024;37(4):197-206. doi:10.1293\/tox.2024-0048 <a href=\"#ff8ab1a3-ff0f-41d5-b214-db885d564bfe-link\" aria-label=\"Jump to footnote reference 387\">\u21a9\ufe0e<\/a><\/li><li id=\"f993a22d-b249-40ac-8f79-5fa6805de934\">National Center for Emerging and Zoonotic Infectious Diseases. Tuberculosis and nonhuman primates. Published online July 2023. <a href=\"#f993a22d-b249-40ac-8f79-5fa6805de934-link\" aria-label=\"Jump to footnote reference 388\">\u21a9\ufe0e<\/a><\/li><li id=\"0a2f23b5-c867-495b-a162-e9c14045b93e\">Organizaci\u00f3n Panamericana de la Salud. La carga de enfermedades cardiovasculares. Accessed June 2025. https:\/\/www.paho.org\/es\/enlace\/carga-enfermedades-cardiovasculares <a href=\"#0a2f23b5-c867-495b-a162-e9c14045b93e-link\" aria-label=\"Jump to footnote reference 389\">\u21a9\ufe0e<\/a><\/li><li id=\"2d0f7a5d-a3d3-4e54-b29c-ca5388087736\">Ruscu M, Glavan D, Surugiu R, et al. Pharmacological and stem cell therapy of stroke in animal models: do they accurately reflect the response of humans? <em>Exp Neurol<\/em>. 2024;376:114753. doi:10.1016\/j.expneurol.2024.114753 <a href=\"#2d0f7a5d-a3d3-4e54-b29c-ca5388087736-link\" aria-label=\"Jump to footnote reference 390\">\u21a9\ufe0e<\/a><\/li><li id=\"eaeb746d-c222-44f6-b0d4-f4e74075388b\">Crilly S, Zille M, Kasher PR, Modo M. Editorial: Innovative models of stroke pathology. <em>Front Neurol<\/em>. 2023;14. doi:10.3389\/fneur.2023.1266075 <a href=\"#eaeb746d-c222-44f6-b0d4-f4e74075388b-link\" aria-label=\"Jump to footnote reference 391\">\u21a9\ufe0e<\/a><\/li><li id=\"eb60afbf-5adb-4991-b61e-9cc44e9cb661\">Van Breedam E, Ponsaerts P. Promising strategies for the development of advanced in vitro models with high predictive power in ischaemic stroke research. <em>Int J Mol Sci<\/em>. 2022;23(13):7140. doi:10.3390\/ijms23137140 <a href=\"#eb60afbf-5adb-4991-b61e-9cc44e9cb661-link\" aria-label=\"Jump to footnote reference 392\">\u21a9\ufe0e<\/a><\/li><li id=\"5f1a8344-e9fc-4d16-a763-acc54b7f036b\">Ruscu et al., 2024 <a href=\"#5f1a8344-e9fc-4d16-a763-acc54b7f036b-link\" aria-label=\"Jump to footnote reference 393\">\u21a9\ufe0e<\/a><\/li><li id=\"edfdae4a-5ee1-41a1-9330-74975e1d31a5\">Van Breedam &amp; Ponsaerts, 2022 <a href=\"#edfdae4a-5ee1-41a1-9330-74975e1d31a5-link\" aria-label=\"Jump to footnote reference 394\">\u21a9\ufe0e<\/a><\/li><li id=\"5da4d2a4-b809-4100-bad0-5b91ab5214ee\">Nikolakopoulou P, Rauti R, Voulgaris D, Shlomy I, Maoz BM, Herland A. Recent progress in translational engineered in vitro models of the central nervous system. <em>Brain<\/em>. 2020;143(11):3181-3213. doi:10.1093\/brain\/awaa268 <a href=\"#5da4d2a4-b809-4100-bad0-5b91ab5214ee-link\" aria-label=\"Jump to footnote reference 395\">\u21a9\ufe0e<\/a><\/li><li id=\"34edb820-89da-48a7-bf8c-5e0031661029\">Sommer CJ. Ischemic stroke: experimental models and reality. <em>Acta Neuropathol<\/em>. 2017;133(2):245-261. doi:10.1007\/s00401-017-1667-0 <a href=\"#34edb820-89da-48a7-bf8c-5e0031661029-link\" aria-label=\"Jump to footnote reference 396\">\u21a9\ufe0e<\/a><\/li><li id=\"f8092f5e-63fa-44c9-98e1-04e8c02f0acd\">Krafft PR, Bailey EL, Lekic T, et al. Etiology of stroke and choice of models. <em>Int J Stroke<\/em>. 2012;7(5):398-406. doi:10.1111\/j.1747-4949.2012.00838.x <a href=\"#f8092f5e-63fa-44c9-98e1-04e8c02f0acd-link\" aria-label=\"Jump to footnote reference 397\">\u21a9\ufe0e<\/a><\/li><li id=\"e1bacd73-eaf2-4aee-8b27-2218c3de4262\">Chen ZQ, Mou R, Feng D, Wang Z, Chen G. The role of nitric oxide in stroke. <em>Med Gas Res<\/em>. 2017;7(3):194-203. doi:10.4103\/2045-9912.215750 <a href=\"#e1bacd73-eaf2-4aee-8b27-2218c3de4262-link\" aria-label=\"Jump to footnote reference 398\">\u21a9\ufe0e<\/a><\/li><li id=\"da0d54b4-afcf-441d-a62b-38be76628208\">Syv\u00e4nen S, Lindhe O, Palner M, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. <em>Drug Metab Dispos<\/em>. 2009;37(3):635-643. doi:10.1124\/dmd.108.024745 <a href=\"#da0d54b4-afcf-441d-a62b-38be76628208-link\" aria-label=\"Jump to footnote reference 399\">\u21a9\ufe0e<\/a><\/li><li id=\"76b8b5a8-c7c3-4d91-a334-be8b8ebf756d\">Lin S, Lin Y, Nery JR, et al. Comparison of the transcriptional landscapes between human and mouse tissues. <em>Proc Natl Acad Sci U S A<\/em>. 2014;111(48):17224-17229. doi:10.1073\/pnas.1413624111 <a href=\"#76b8b5a8-c7c3-4d91-a334-be8b8ebf756d-link\" aria-label=\"Jump to footnote reference 400\">\u21a9\ufe0e<\/a><\/li><li id=\"0eadcbaf-9db9-4784-b39e-268bd7e45112\">Johnson S, Dwivedi A, Mirza M, McCarthy R, Gilvarry M. A review of the advancements in the in-vitro modelling of acute ischemic stroke and its treatment. <em>Front Med Technol<\/em>. 2022;4. doi:10.3389\/fmedt.2022.879074 <a href=\"#0eadcbaf-9db9-4784-b39e-268bd7e45112-link\" aria-label=\"Jump to footnote reference 401\">\u21a9\ufe0e<\/a><\/li><li id=\"4f3be857-ebad-40e2-a0fa-68d6c55c170b\">Roth S, Liesz A. Stroke research at the crossroads\u2014 where are we heading? <em>Swiss Med Wkly<\/em>. 2016;146:w14329. doi:10.4414\/smw.2016.14329 <a href=\"#4f3be857-ebad-40e2-a0fa-68d6c55c170b-link\" aria-label=\"Jump to footnote reference 402\">\u21a9\ufe0e<\/a><\/li><li id=\"cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d\">Sena ES, Bart van der Worp H, Bath PMW, Howells DW, Macleod MR. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. <em>PLoS Biol<\/em>. 2010;8(3):e1000344. doi:10.1371\/JOURNAL.PBIO.1000344 <a href=\"#cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d-link\" aria-label=\"Jump to footnote reference 403\">\u21a9\ufe0e<\/a><\/li><li id=\"47246d3c-73ca-421f-894a-c2d8eea14a42\">Konduri PR, Marquering HA, van Bavel EE, Hoekstra A, Majoie CBLM, The INSIST Investigators. In-silico trials for treatment of acute ischemic stroke. <em>Front Neurol<\/em>. 2020;11. doi:10.3389\/fneur.2020.558125 <a href=\"#47246d3c-73ca-421f-894a-c2d8eea14a42-link\" aria-label=\"Jump to footnote reference 404\">\u21a9\ufe0e<\/a><\/li><li id=\"dc7f62f1-8e40-4f0d-80e9-2458d3bcb870\">Konduri PR, et al. (2020). In-silico trials for acute ischemic stroke treatment. <em>Frontiers in Neurology,<\/em> 11, 558125. <a href=\"#dc7f62f1-8e40-4f0d-80e9-2458d3bcb870-link\" aria-label=\"Jump to footnote reference 405\">\u21a9\ufe0e<\/a><\/li><li id=\"67b971cc-070b-4611-9bdf-c25b9af6a212\">Sarrami-Foroushani A, Lassila T, MacRaild M, et al. In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials. <em>Nat Commun<\/em>. 2021;12(1):3861. doi:10.1038\/s41467-021-23998-w <a href=\"#67b971cc-070b-4611-9bdf-c25b9af6a212-link\" aria-label=\"Jump to footnote reference 406\">\u21a9\ufe0e<\/a><\/li><li id=\"987c44a0-91a1-4d26-b38c-1c064c57b25d\">KPMG. In silicoregulatory evidence utilisation within the life science sector. InSilicoUK Pro-Innovation Regulations Network; 2024. doi:10.5281\/zenodo.12735158 <a href=\"#987c44a0-91a1-4d26-b38c-1c064c57b25d-link\" aria-label=\"Jump to footnote reference 407\">\u21a9\ufe0e<\/a><\/li><li id=\"a8eea9c0-848b-4cc4-a46f-e4edb52bfb80\">Nikolakopoulou et al., 2020 <a href=\"#a8eea9c0-848b-4cc4-a46f-e4edb52bfb80-link\" aria-label=\"Jump to footnote reference 408\">\u21a9\ufe0e<\/a><\/li><li id=\"40b042b5-436a-48b6-8849-12d4892046b9\">Ruscu et al., 2024 <a href=\"#40b042b5-436a-48b6-8849-12d4892046b9-link\" aria-label=\"Jump to footnote reference 409\">\u21a9\ufe0e<\/a><\/li><li id=\"9588dbd0-4cab-4b03-ae82-7d53c390f868\">He JQ, Sussman ES, Steinberg GK. Revisiting stem cell-based clinical trials for ischemic stroke. <em>Front Aging Neurosci<\/em>. 2020;12. doi:10.3389\/fnagi.2020.575990 <a href=\"#9588dbd0-4cab-4b03-ae82-7d53c390f868-link\" aria-label=\"Jump to footnote reference 410\">\u21a9\ufe0e<\/a><\/li><li id=\"be6adede-e5bd-40c6-ba43-8b7ce3c7b774\">Laskowitz DT, Bennett ER, Durham RJ, et al. Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase I safety study. <em>Stem Cells Transl Med<\/em>. 2018;7(7):521-529. doi:10.1002\/sctm.18-0008 <a href=\"#be6adede-e5bd-40c6-ba43-8b7ce3c7b774-link\" aria-label=\"Jump to footnote reference 411\">\u21a9\ufe0e<\/a><\/li><li id=\"7778f291-1832-432e-af97-ef5fd26513a2\">Boncoraglio GB, Ranieri M, Bersano A, Parati EA, Giovane CD. Stem cell transplantation for ischemic stroke. <em>Cochrane Database Syst Rev<\/em>. 2019;2019(5):CD007231 <a href=\"#7778f291-1832-432e-af97-ef5fd26513a2-link\" aria-label=\"Jump to footnote reference 412\">\u21a9\ufe0e<\/a><\/li><li id=\"01d5c1f8-bd1a-4a87-99ef-5443d725d910\">Van Breedam &amp; Ponsaerts, 2022 <a href=\"#01d5c1f8-bd1a-4a87-99ef-5443d725d910-link\" aria-label=\"Jump to footnote reference 413\">\u21a9\ufe0e<\/a><\/li><li id=\"22a9b601-88ca-4b7f-96f9-5eb244a7f379\">Giorgi C, Castelli V, d\u2019Angelo M, Cimini A. Organoids modeling stroke in a petri dish. <em>Biomedicines<\/em>. 2024;12(4):877. doi:10.3390\/biomedicines12040877 <a href=\"#22a9b601-88ca-4b7f-96f9-5eb244a7f379-link\" aria-label=\"Jump to footnote reference 414\">\u21a9\ufe0e<\/a><\/li><li id=\"73ad396d-6e18-4f1d-ad65-3022472d9492\">Shakeri A, Wang Y, Zhao Y, et al. Engineering organ-on-a-chip systems for vascular diseases. <em>Arterioscler Thromb Vasc Biol<\/em>. 2023;43(12):2241-2255. doi:10.1161\/ATVBAHA.123.318233 <a href=\"#73ad396d-6e18-4f1d-ad65-3022472d9492-link\" aria-label=\"Jump to footnote reference 415\">\u21a9\ufe0e<\/a><\/li><li id=\"d3c0265e-e376-4e92-a35f-c440a168ac95\">Kofman S, Mohan N, Sun X, Ibric L, Piermarini E, Qiang L. Human mini brains and spinal cords in a dish: modeling strategies, current challenges, and prospective advances. <em>J Tissue Eng<\/em>. 2022;13:20417314221113391. doi:10.1177\/20417314221113391 <a href=\"#d3c0265e-e376-4e92-a35f-c440a168ac95-link\" aria-label=\"Jump to footnote reference 416\">\u21a9\ufe0e<\/a><\/li><li id=\"435807fc-b9b6-404c-92d9-34cbbe802784\">Jochumsen M, Janjua TAM, Arceo JC, Lauber J, Buessinger ES, K\u00e6seler RL. Induction of neural plasticity using a low-cost open source brain-computer interface and a 3D-printed wrist exoskeleton. <em>Sensors (Basel)<\/em>. 2021;21(2):572. doi:10.3390\/s21020572 <a href=\"#435807fc-b9b6-404c-92d9-34cbbe802784-link\" aria-label=\"Jump to footnote reference 417\">\u21a9\ufe0e<\/a><\/li><li id=\"b8d85711-7480-4aaa-9a8f-6031e19eac86\">Kook MG, Lee SE, Shin N, et al. Generation of cortical brain organoid with vascularization by assembling with vascular spheroid. <em>Int J Stem Cells<\/em>. 2022;15(1):85-94 <a href=\"#b8d85711-7480-4aaa-9a8f-6031e19eac86-link\" aria-label=\"Jump to footnote reference 418\">\u21a9\ufe0e<\/a><\/li><li id=\"fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee\">Xu R, Boreland AJ, Li X, et al. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. <em>Stem Cell Rep<\/em>. 2021;16(8):1923-1937. doi:10.1016\/j.stemcr.2021.06.011 <a href=\"#fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee-link\" aria-label=\"Jump to footnote reference 419\">\u21a9\ufe0e<\/a><\/li><li id=\"f15c3464-da52-4c68-84cb-66b0383cec7f\">National Centre for the Replacement, Refinement and Reduction of Animals in Research. Research round-up: replacing animals in stroke research. www.nc3rs.org.uk. August 14, 2023. Accessed October 14, 2024. https:\/\/nc3rs.org.uk\/news\/research-round-replacing-animals-stroke-research <a href=\"#f15c3464-da52-4c68-84cb-66b0383cec7f-link\" aria-label=\"Jump to footnote reference 420\">\u21a9\ufe0e<\/a><\/li><li id=\"731a0be8-829f-4336-8472-6c2684b488f0\">Syv\u00e4nen et al., 2009 <a href=\"#731a0be8-829f-4336-8472-6c2684b488f0-link\" aria-label=\"Jump to footnote reference 421\">\u21a9\ufe0e<\/a><\/li><li id=\"478686f0-319a-44fe-bd19-0829119c4017\">Tzschentke TM. Where do we stand in the field of anti-abuse drug discovery? <em>Expert Opin Drug Discov<\/em>. 2014;9(11):1255-1258. doi:10.1517\/17460441.2014.948415 <a href=\"#478686f0-319a-44fe-bd19-0829119c4017-link\" aria-label=\"Jump to footnote reference 422\">\u21a9\ufe0e<\/a><\/li><li id=\"4ffd49eb-cd83-4da1-99d2-77724138687b\">Stephens DN, Crombag HS, Duka T. The challenge of studying parallel behaviors in humans and animal models. In: Sommer WH, Spanagel R, eds. <em>Behavioral Neurobiology of Alcohol Addiction<\/em>. Springer; 2013:611-645. doi:10.1007\/978-3-642-28720-6_133 <a href=\"#4ffd49eb-cd83-4da1-99d2-77724138687b-link\" aria-label=\"Jump to footnote reference 423\">\u21a9\ufe0e<\/a><\/li><li id=\"a874773c-626e-4576-bb3c-925a46ff2b18\">Li K, Gu L, Cai H, Lu HC, Mackie K, Guo F. Human brain organoids for understanding substance use disorders. <em>Drug Metab Pharmacokinet<\/em>. 2024;58:101036. doi:10.1016\/j.dmpk.2024.101036 <a href=\"#a874773c-626e-4576-bb3c-925a46ff2b18-link\" aria-label=\"Jump to footnote reference 424\">\u21a9\ufe0e<\/a><\/li><li id=\"b9a896ec-9700-4f0b-bb7e-638cc9246093\">Field M, Kersbergen I. Are animal models of addiction useful? <em>Addiction<\/em>. 2020;115(1):6-12. doi:10.1111\/add.14764 <a href=\"#b9a896ec-9700-4f0b-bb7e-638cc9246093-link\" aria-label=\"Jump to footnote reference 425\">\u21a9\ufe0e<\/a><\/li><li id=\"b6b0acbe-0757-4016-b380-d819e2b85bfb\">Green AR, King MV, Shortall SE, Fone KCF. Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans. <em>Br J Pharmacol<\/em>. 2012;166(5):1523-1536. doi:10.1111\/j.1476-5381.2011.01819.x <a href=\"#b6b0acbe-0757-4016-b380-d819e2b85bfb-link\" aria-label=\"Jump to footnote reference 426\">\u21a9\ufe0e<\/a><\/li><li id=\"a694aa88-dc92-4fec-b9a8-66d976b91025\">Green AR, et al. (2012). MDMA preclinical studies and limits in predicting human adverse events. <em>Br J Pharmacol,<\/em> 166(5), 1523\u20131536. <a href=\"#a694aa88-dc92-4fec-b9a8-66d976b91025-link\" aria-label=\"Jump to footnote reference 427\">\u21a9\ufe0e<\/a><\/li><li id=\"b496e41f-7fcc-495e-af35-a45e56e7832d\">Ahmed SH. Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. <em>Neurosci Biobehav Rev<\/em>. 2010;35(2):172-184. doi:10.1016\/j.neubiorev.2010.04.005 <a href=\"#b496e41f-7fcc-495e-af35-a45e56e7832d-link\" aria-label=\"Jump to footnote reference 428\">\u21a9\ufe0e<\/a><\/li><li id=\"348c6826-d221-4ec6-9129-4c289fd386b9\">Ramsden E. Making animals alcoholic: shifting laboratory models of addiction. <em>J Hist Behav Sci<\/em>. 2015;51(2):164-194. doi:10.1002\/jhbs.21715\u00a0 <a href=\"#348c6826-d221-4ec6-9129-4c289fd386b9-link\" aria-label=\"Jump to footnote reference 429\">\u21a9\ufe0e<\/a><\/li><li id=\"15626447-9ea8-43ed-8451-a26a46b599c5\">Ahmed, 2010 <a href=\"#15626447-9ea8-43ed-8451-a26a46b599c5-link\" aria-label=\"Jump to footnote reference 430\">\u21a9\ufe0e<\/a><\/li><li id=\"ada753d0-5ec6-43ee-a4cc-09214894de11\">Ahmed, 2010 <a href=\"#ada753d0-5ec6-43ee-a4cc-09214894de11-link\" aria-label=\"Jump to footnote reference 431\">\u21a9\ufe0e<\/a><\/li><li id=\"3e6ce804-260d-40c5-b2a8-07978bef88f8\">Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. <em>Nat Rev Neurosci<\/em>. 2001;2(10):695-703. doi:10.1038\/35094560\u00a0 <a href=\"#3e6ce804-260d-40c5-b2a8-07978bef88f8-link\" aria-label=\"Jump to footnote reference 432\">\u21a9\ufe0e<\/a><\/li><li id=\"e9519310-ad76-4394-89e6-6f8b3fe3cb62\">Whitten A. Developing new drugs to treat addiction. <em>Drug Discovery News<\/em>. September 3, 2024. Accessed December 3, 2024. https:\/\/www.drugdiscoverynews.com\/developing-new-drugs-to-treat-addiction-16033 <a href=\"#e9519310-ad76-4394-89e6-6f8b3fe3cb62-link\" aria-label=\"Jump to footnote reference 433\">\u21a9\ufe0e<\/a><\/li><li id=\"92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886\">Whitten, 2024 <a href=\"#92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886-link\" aria-label=\"Jump to footnote reference 434\">\u21a9\ufe0e<\/a><\/li><li id=\"b16b4a49-22b5-47f0-bdad-df89d194f80a\">Montoya ID, Volkow ND. IUPHAR Review: New strategies for medications to treat substance use disorders. <em>Pharmacol Res<\/em>. 2024;200:107078. doi:10.1016\/j.phrs.2024.107078 <a href=\"#b16b4a49-22b5-47f0-bdad-df89d194f80a-link\" aria-label=\"Jump to footnote reference 435\">\u21a9\ufe0e<\/a><\/li><li id=\"c057a541-01c5-4388-a74b-5f415c0d56a0\">Montoya &amp; Volkow, 2024 <a href=\"#c057a541-01c5-4388-a74b-5f415c0d56a0-link\" aria-label=\"Jump to footnote reference 436\">\u21a9\ufe0e<\/a><\/li><li id=\"049c4d00-2dc8-4a1d-97bc-90abb269f266\">Field &amp; Kersbergen, 2020<br> <a href=\"#049c4d00-2dc8-4a1d-97bc-90abb269f266-link\" aria-label=\"Jump to footnote reference 437\">\u21a9\ufe0e<\/a><\/li><li id=\"b636d063-90cb-4b41-9c7d-e6cc3773b0a9\">Field &amp; Kersbergen, 2020 <a href=\"#b636d063-90cb-4b41-9c7d-e6cc3773b0a9-link\" aria-label=\"Jump to footnote reference 438\">\u21a9\ufe0e<\/a><\/li><li id=\"d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924\">Scarnati MS, Halikere A, Pang ZP. Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: current status and outlook. <em>Alcohol<\/em>. 2019;74:83-93. doi:10.1016\/j.alcohol.2018.03.008 <a href=\"#d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924-link\" aria-label=\"Jump to footnote reference 439\">\u21a9\ufe0e<\/a><\/li><li id=\"3619417a-a9a2-4678-964e-0bed40a474ad\">Mendez EF, Grimm SL, Stertz L, et al. A human stem cell-derived neuronal model of morphine exposure reflects brain dysregulation in opioid use disorder: transcriptomic and epigenetic characterization of postmortem-derived iPSC neurons. <em>Front Psychiatry<\/em>. 2023;14. doi:10.3389\/fpsyt.2023.1070556 <a href=\"#3619417a-a9a2-4678-964e-0bed40a474ad-link\" aria-label=\"Jump to footnote reference 440\">\u21a9\ufe0e<\/a><\/li><li id=\"55e77e85-7a3c-4aee-abfc-c5dda37b02fb\">Poisel E, Zillich L, Streit F, et al. DNA methylation in cocaine use disorder\u2014 an epigenome-wide approach in the human prefrontal cortex. <em>Front Psychiatry<\/em>. 2023;14. doi:10.3389\/fpsyt.2023.1075250 <a href=\"#55e77e85-7a3c-4aee-abfc-c5dda37b02fb-link\" aria-label=\"Jump to footnote reference 441\">\u21a9\ufe0e<\/a><\/li><li id=\"ff31f347-198f-4b87-8ea0-d1aa38bcfa2d\">Trang KB, Chesi A, Toikumo S, et al. Shared and unique 3D genomic features of substance use disorders across multiple cell types. <em>medRxiv. <\/em>Preprint posted online July 19, 2024. \u00a0doi:10.1101\/2024.07.18.24310649 <a href=\"#ff31f347-198f-4b87-8ea0-d1aa38bcfa2d-link\" aria-label=\"Jump to footnote reference 442\">\u21a9\ufe0e<\/a><\/li><li id=\"74984579-39c9-4770-8f80-96c7e8f1058a\">Sullivan KA, Kainer D, Lane M, et al. Multi-omic network analysis identifies dysregulated neurobiological pathways in opioid addiction. <em>Biol Psychiatry<\/em>. 2024;(24). doi:10.1016\/j.biopsych.2024.11.013 <a href=\"#74984579-39c9-4770-8f80-96c7e8f1058a-link\" aria-label=\"Jump to footnote reference 443\">\u21a9\ufe0e<\/a><\/li><li id=\"bc8e76f4-47f4-4f53-99d9-7ceffada9f1a\">Guo X, Akanda N, Fiorino G, et al. Human iPSC-derived PreB\u00f6tC-like neurons and development of an opiate overdose and recovery model. <em>Adv Biol (Weinh)<\/em>. 2024;8(8):2300276. doi:10.1002\/adbi.202300276 <a href=\"#bc8e76f4-47f4-4f53-99d9-7ceffada9f1a-link\" aria-label=\"Jump to footnote reference 444\">\u21a9\ufe0e<\/a><\/li><li id=\"8e44778e-a05c-4d35-bf0a-dc1cf14c8039\">Rudibaugh TP, Tam RW, Estridge RC, Stuppy SR, Keung AJ. Single-cell assessment of human stem cell-derived mesolimbic models and their responses to substances of abuse. <em>Organoids<\/em>. 2024;3(2):126-147. doi:10.3390\/organoids3020009 <a href=\"#8e44778e-a05c-4d35-bf0a-dc1cf14c8039-link\" aria-label=\"Jump to footnote reference 445\">\u21a9\ufe0e<\/a><\/li><li id=\"cfe0c7ff-0eed-44e7-a53a-d199a69aaf36\">Li et al., 2024 <a href=\"#cfe0c7ff-0eed-44e7-a53a-d199a69aaf36-link\" aria-label=\"Jump to footnote reference 446\">\u21a9\ufe0e<\/a><\/li><li id=\"1085d05a-5a4b-41c0-84f4-3791acea7fea\">McMillan H, Lundy FT, Dunne OM, et al. Endogenous Mas-related G-protein-coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves. <em>FASEB J<\/em>. 2021;35(5):e21492. doi:10.1096\/fj.202001667RR <a href=\"#1085d05a-5a4b-41c0-84f4-3791acea7fea-link\" aria-label=\"Jump to footnote reference 447\">\u21a9\ufe0e<\/a><\/li><li id=\"52e58bd8-78a7-43d7-bec6-0839b991631a\">Mayo Clinic Staff. Women\u2019s health. Mayo Clinic. September 28, 2022. Accessed October 9, 2024. https:\/\/www.mayoclinic.org\/healthy-lifestyle\/womens-health\/basics\/womens-health\/hlv-20049411 <a href=\"#52e58bd8-78a7-43d7-bec6-0839b991631a-link\" aria-label=\"Jump to footnote reference 448\">\u21a9\ufe0e<\/a><\/li><li id=\"008ae57d-3281-44aa-9f56-8e2b0a010a6b\">Carneiro MM. Women\u2019s health in 2024: change now for tomorrow will be too late. <em>Women &amp; Health<\/em>. 2024;64(1):1-4. doi:10.1080\/03630242.2024.2292320 <a href=\"#008ae57d-3281-44aa-9f56-8e2b0a010a6b-link\" aria-label=\"Jump to footnote reference 449\">\u21a9\ufe0e<\/a><\/li><li id=\"d07792ce-cc80-4944-9047-f781eb61f185\">Cunha GR, Sinclair A, Ricke WA, Robboy SJ, Cao M, Baskin LS. Reproductive tract biology: of mice and men. <em>Differentiation<\/em>. 2019;110:49-63. doi:10.1016\/j.diff.2019.07.004 <a href=\"#d07792ce-cc80-4944-9047-f781eb61f185-link\" aria-label=\"Jump to footnote reference 450\">\u21a9\ufe0e<\/a><\/li><li id=\"77860b87-2d02-45fe-950e-542b7e6976a7\">Vercellini P, Vigan\u00f2 P, Bandini V, Buggio L, Berlanda N, Somigliana E. Association of endometriosis and adenomyosis with pregnancy and infertility. <em>Fertil Steril<\/em>. 2023;119(5):727-740. doi:10.1016\/j.fertnstert.2023.03.018 <a href=\"#77860b87-2d02-45fe-950e-542b7e6976a7-link\" aria-label=\"Jump to footnote reference 451\">\u21a9\ufe0e<\/a><\/li><li id=\"da13c77a-4b50-4bf0-b3f8-e180d46a9840\">Smolarz B, Szy\u0142\u0142o K, Romanowicz H. Endometriosis: epidemiology, classification, pathogenesis, treatment and genetics (review of literature). <em>Int J Mol Sci<\/em>. 2021;22(19):10554. doi:10.3390\/ijms221910554 <a href=\"#da13c77a-4b50-4bf0-b3f8-e180d46a9840-link\" aria-label=\"Jump to footnote reference 452\">\u21a9\ufe0e<\/a><\/li><li id=\"3d3f09e2-4005-4573-8327-ae4fb8e0d5b0\">World Health Organization. Endometriosis. WHO.int. March 24, 2023. Accessed October 9, 2024. <a href=\"https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/endometriosis\">https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/endometriosis<\/a> <a href=\"#3d3f09e2-4005-4573-8327-ae4fb8e0d5b0-link\" aria-label=\"Jump to footnote reference 453\">\u21a9\ufe0e<\/a><\/li><li id=\"ba7f916f-c723-4b8f-9f5b-f94de2826acc\">Burns KA, Pearson AM, Slack JL, et al. Endometriosis in the mouse: challenges and progress toward a \u2018best fit\u2019 murine model. <em>Front Physiol<\/em>. 2022;12. Accessed January 17, 2024. <a href=\"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.806574\">https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.806574<\/a> <a href=\"#ba7f916f-c723-4b8f-9f5b-f94de2826acc-link\" aria-label=\"Jump to footnote reference 454\">\u21a9\ufe0e<\/a><\/li><li id=\"25de1692-e53d-4387-8e61-f145903815de\">Burns et al., 2022 <a href=\"#25de1692-e53d-4387-8e61-f145903815de-link\" aria-label=\"Jump to footnote reference 455\">\u21a9\ufe0e<\/a><\/li><li id=\"e12f1113-f9da-4f8a-b4a3-8c68a10c8349\">Zhao Y, Wang Y, Gu P, Tuo L, Wang L, Jiang SW. Transgenic mice applications in the study of endometriosis pathogenesis. <em>Front Cell Dev Biol<\/em>. 2024;12. doi:10.3389\/fcell.2024.1376414 <a href=\"#e12f1113-f9da-4f8a-b4a3-8c68a10c8349-link\" aria-label=\"Jump to footnote reference 456\">\u21a9\ufe0e<\/a><\/li><li id=\"9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5\">Feng D, Menger MD, Wang H, Laschke MW. Luminal epithelium in endometrial fragments affects their vascularization, growth and morphological development into endometriosis-like lesions in mice. <em>Dis Model Mech<\/em>. 2014;7(2):225-232. doi:10.1242\/dmm.013664 <a href=\"#9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5-link\" aria-label=\"Jump to footnote reference 457\">\u21a9\ufe0e<\/a><\/li><li id=\"2116da25-12d5-4ac8-951e-3cfb07207cd5\">Chalouhi S. Menopause: a complex and controversial journey. <em>Post Reprod Health<\/em>. 2017;23(3):128-131. doi:10.1177\/2053369117711346 <a href=\"#2116da25-12d5-4ac8-951e-3cfb07207cd5-link\" aria-label=\"Jump to footnote reference 458\">\u21a9\ufe0e<\/a><\/li><li id=\"b7598a6e-7206-440d-94d6-81c3f0c87b5f\">Bansal R, Aggarwal N. Menopausal hot flashes: a concise review. <em>J Midlife Health<\/em>. 2019;10(1):6. doi:10.4103\/jmh.JMH_7_19 <a href=\"#b7598a6e-7206-440d-94d6-81c3f0c87b5f-link\" aria-label=\"Jump to footnote reference 459\">\u21a9\ufe0e<\/a><\/li><li id=\"306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3\">Todorova L, Bonassi R, Guerrero Carre\u00f1o FJ, et al. Prevalence and impact of vasomotor symptoms due to menopause among women in Brazil, Canada, Mexico, and Nordic Europe: a cross-sectional survey. <em>Menopause<\/em>. 2023;30(12):1179. doi:10.1097\/GME.0000000000002265 <a href=\"#306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3-link\" aria-label=\"Jump to footnote reference 460\">\u21a9\ufe0e<\/a><\/li><li id=\"74d4082d-5d79-40d4-b9b2-04f408b595e6\">Chalouhi, 2017 <a href=\"#74d4082d-5d79-40d4-b9b2-04f408b595e6-link\" aria-label=\"Jump to footnote reference 461\">\u21a9\ufe0e<\/a><\/li><li id=\"df41a430-4222-46ba-acaa-532e73e42f07\">Acevedo-Rodriguez A, Kauffman AS, Cherrington BD, Borges CS, Roepke TA, Laconi M. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. <em>J Neuroendocrinol<\/em>. 2018;30(10):e12590. doi:10.1111\/jne.12590 <a href=\"#df41a430-4222-46ba-acaa-532e73e42f07-link\" aria-label=\"Jump to footnote reference 462\">\u21a9\ufe0e<\/a><\/li><li id=\"7f530923-1be6-4ece-a394-6f8a02b86347\">Zhang Z, He C, Gao Y, et al. \u03b1-ketoglutarate delays age-related fertility decline in mammals. <em>Aging Cell<\/em>. 2021;20(2):e13291. doi:10.1111\/acel.13291 <a href=\"#7f530923-1be6-4ece-a394-6f8a02b86347-link\" aria-label=\"Jump to footnote reference 463\">\u21a9\ufe0e<\/a><\/li><li id=\"bef7c181-da06-4a89-921e-1159e270c101\">Acevedo-Rodriguez et al., 2018 <a href=\"#bef7c181-da06-4a89-921e-1159e270c101-link\" aria-label=\"Jump to footnote reference 464\">\u21a9\ufe0e<\/a><\/li><li id=\"18f8583d-1ac0-47b5-bf8d-872ce931be9d\">Koebele SV, Bimonte-Nelson HA. Modeling menopause: the utility of rodents in translational behavioral endocrinology research. <em>Maturitas<\/em>. 2016;87:5-17. doi:10.1016\/j.maturitas.2016.01.015 <a href=\"#18f8583d-1ac0-47b5-bf8d-872ce931be9d-link\" aria-label=\"Jump to footnote reference 465\">\u21a9\ufe0e<\/a><\/li><li id=\"68a87a23-d33b-48c1-8eef-23fcc019713b\">Wood BM, Negrey JD, Brown JL, et al. Demographic and hormonal evidence for menopause in wild chimpanzees. <em>Science<\/em>. 2023;382(6669):eadd5473. doi:10.1126\/science.add5473 <a href=\"#68a87a23-d33b-48c1-8eef-23fcc019713b-link\" aria-label=\"Jump to footnote reference 466\">\u21a9\ufe0e<\/a><\/li><li id=\"a70feddf-308f-4f52-bd2c-88b8a1e51226\">Whitton K, Baber R. Androgen-based therapies in women. <em>Best Pract Res Clin Endocrinol Metab<\/em>. 2024;38(1):101783. doi:10.1016\/j.beem.2023.101783 <a href=\"#a70feddf-308f-4f52-bd2c-88b8a1e51226-link\" aria-label=\"Jump to footnote reference 467\">\u21a9\ufe0e<\/a><\/li><li id=\"f0c17532-4f7f-48eb-bf59-5507961be65c\">Cao LB, Leung CK, Law PWN, et al. Systemic changes in a mouse model of VCD-induced premature ovarian failure. <em>Life Sci<\/em>. 2020;262:118543. doi:10.1016\/j.lfs.2020.118543 <a href=\"#f0c17532-4f7f-48eb-bf59-5507961be65c-link\" aria-label=\"Jump to footnote reference 468\">\u21a9\ufe0e<\/a><\/li><li id=\"692759fe-bf78-4d6c-8afb-fc82a1983401\">Lee EH, Han SE, Park MJ, et al. Establishment of effective mouse model of premature ovarian failure considering treatment duration of anticancer drugs and natural recovery time. <em>J Menopausal Med<\/em>. 2018;24(3):196-203. doi:10.6118\/jmm.2018.24.3.196 <a href=\"#692759fe-bf78-4d6c-8afb-fc82a1983401-link\" aria-label=\"Jump to footnote reference 469\">\u21a9\ufe0e<\/a><\/li><li id=\"0b117682-b74c-4890-8a67-cef1c7188451\">Russell JK, Jones CK, Newhouse PA. The role of estrogen in brain and cognitive aging. <em>Neurotherapeutics<\/em>. 2019;16(3):649-665. doi:10.1007\/s13311-019-00766-9 <a href=\"#0b117682-b74c-4890-8a67-cef1c7188451-link\" aria-label=\"Jump to footnote reference 470\">\u21a9\ufe0e<\/a><\/li><li id=\"f6f5695b-decf-4141-803d-54b98353b7b2\">Col\u00f3n-Caraballo M, Garc\u00eda M, Mendoza A, Flores I. Human endometriosis tissue microarray reveals site-specific expression of estrogen receptors, progesterone receptor, and Ki67. <em>Appl Immunohistochem Mol Morphol<\/em>. 2019;27(7):491-500. doi:10.1097\/PAI.0000000000000663 <a href=\"#f6f5695b-decf-4141-803d-54b98353b7b2-link\" aria-label=\"Jump to footnote reference 471\">\u21a9\ufe0e<\/a><\/li><li id=\"68b16e78-1156-465c-9698-bae606256f30\">Becker CM, Laufer MR, Stratton P, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. <em>Fertil Steril<\/em>. 2014;102(5). doi:10.1016\/j.fertnstert.2014.07.709 <a href=\"#68b16e78-1156-465c-9698-bae606256f30-link\" aria-label=\"Jump to footnote reference 472\">\u21a9\ufe0e<\/a><\/li><li id=\"a58cf240-c68a-4985-b771-49f190bbf448\">Blass I, Sahar T, Shraibman A, Ofer D, Rappoport N, Linial M. Revisiting the risk factors for endometriosis: a machine learning approach. <em>J Pers Med<\/em>. 2022;12(7):1114. doi:10.3390\/jpm12071114 <a href=\"#a58cf240-c68a-4985-b771-49f190bbf448-link\" aria-label=\"Jump to footnote reference 473\">\u21a9\ufe0e<\/a><\/li><li id=\"ce046412-734c-43f7-8bf9-8dfc15360fd3\">Deng ZM, Dai FF, Wang RQ, et al. Organ-on-a-chip: future of female reproductive pathophysiological models. <em>J Nanobiotechnology<\/em>. 2024;22(1):455. doi:10.1186\/s12951-024-02651-w <a href=\"#ce046412-734c-43f7-8bf9-8dfc15360fd3-link\" aria-label=\"Jump to footnote reference 474\">\u21a9\ufe0e<\/a><\/li><li id=\"df47c072-46b9-4a8c-a46a-4e053ef93d3f\">Blundell C, Tess ER, Schanzer ASR, et al. A microphysiological model of the human placental barrier. <em>Lab Chip<\/em>. 2016;16(16):3065-3073. doi:10.1039\/c6lc00259e <a href=\"#df47c072-46b9-4a8c-a46a-4e053ef93d3f-link\" aria-label=\"Jump to footnote reference 475\">\u21a9\ufe0e<\/a><\/li><li id=\"fe49c1a2-7341-4e03-a039-f0c55ce96227\">Ghorbanpour SM, Richards C, Pienaar D, et al. A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia. <em>Cell Mol Life Sci<\/em>. 2023;80(2):44. doi:10.1007\/s00018-022-04648-w <a href=\"#fe49c1a2-7341-4e03-a039-f0c55ce96227-link\" aria-label=\"Jump to footnote reference 476\">\u21a9\ufe0e<\/a><\/li><li id=\"bacbf547-9a95-4acb-92a5-1c2d41604472\">Lee JS, Romero R, Han YM, et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. <em>J Matern Fetal Neonatal Med<\/em>. 2016;29(7):1046-1054. doi:10.3109\/14767058.2015.1038518 <a href=\"#bacbf547-9a95-4acb-92a5-1c2d41604472-link\" aria-label=\"Jump to footnote reference 477\">\u21a9\ufe0e<\/a><\/li><li id=\"07c8f50a-88e4-47bd-ae95-61244dcca480\">. Lermant A, Rabussier G, Davidson L, Lanz HL, Murdoch CE. Protocol for a placenta-on-a-chip model using trophoblasts differentiated from human induced pluripotent stem cells. <em>STAR Protoc<\/em>. 2024;5(1):102879. doi:10.1016\/j.xpro.2024.102879\u00a0 <a href=\"#07c8f50a-88e4-47bd-ae95-61244dcca480-link\" aria-label=\"Jump to footnote reference 478\">\u21a9\ufe0e<\/a><\/li><li id=\"055c3df9-2fab-4c7e-b7aa-87ff95070a09\">Ahn J, Yoon MJ, Hong SH, et al. Three-dimensional microengineered vascularised endometrium-on-a-chip. <em>Hum Reprod<\/em>. 2021;36(10):2720-2731. doi:10.1093\/humrep\/deab186 <a href=\"#055c3df9-2fab-4c7e-b7aa-87ff95070a09-link\" aria-label=\"Jump to footnote reference 479\">\u21a9\ufe0e<\/a><\/li><li id=\"3d2e7353-3e96-4adc-b3a9-c937bf39b9be\">Wang L, Chen XJ, Liang JH, Zhang ZK, Cao TS, Zhang L. Preliminary application of three-dimensional printing in congenital uterine anomalies based on three-dimensional transvaginal ultrasonographic data. <em>BMC Women\u2019s Health<\/em>. 2022;22(1):290. doi:10.1186\/s12905-022-01873-0 <a href=\"#3d2e7353-3e96-4adc-b3a9-c937bf39b9be-link\" aria-label=\"Jump to footnote reference 480\">\u21a9\ufe0e<\/a><\/li><li id=\"fe92fc63-2954-4c0e-aa35-a3963d989f88\">Mare\u010dkov\u00e1 M, Garcia-Alonso L, Moullet M, et al. An integrated single-cell reference atlas of the human endometrium. <em>Nat Genet<\/em>. 2024;56(9):1925-1937. doi:10.1038\/s41588-024-01873-w <a href=\"#fe92fc63-2954-4c0e-aa35-a3963d989f88-link\" aria-label=\"Jump to footnote reference 481\">\u21a9\ufe0e<\/a><\/li><li id=\"b84aeb83-a894-4425-a40f-aeda76725731\">Lukac S, Hancke K, Janni W, et al. Three-dimensional model for improvement of endometriosis care (3D-E). <em>Int J Gynaecol Obstet<\/em>. 2024;165(2):416-423. doi:10.1002\/ijgo.15165 <a href=\"#b84aeb83-a894-4425-a40f-aeda76725731-link\" aria-label=\"Jump to footnote reference 482\">\u21a9\ufe0e<\/a><\/li><li id=\"27183fb0-b6df-4e54-bc41-626d7ef77b7c\">United Network for Organ Sharing. Data and trends. October 15, 2024. Accessed June 26, 2025. <a href=\"https:\/\/unos.org\/data\/\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/unos.org\/data\/<\/a> <a href=\"#27183fb0-b6df-4e54-bc41-626d7ef77b7c-link\" aria-label=\"Jump to footnote reference 483\">\u21a9\ufe0e<\/a><\/li><li id=\"df06caa6-0e33-4ad0-adab-3e840e52e528\">Gobierno de M\u00e9xico. Estado actual de receptores, donaci\u00f3n y trasplantes en M\u00e9xico 2024. Accessed June 26, 2025. <a href=\"https:\/\/www.gob.mx\/cms\/uploads\/attachment\/file\/967152\/ESTADISTICAS_ANUAL_2024.pdf\">https:\/\/www.gob.mx\/cms\/uploads\/attachment\/file\/967152\/ESTADISTICAS_ANUAL_2024.pdf<\/a> <a href=\"#df06caa6-0e33-4ad0-adab-3e840e52e528-link\" aria-label=\"Jump to footnote reference 484\">\u21a9\ufe0e<\/a><\/li><li id=\"88446638-ca05-441f-a811-4ced4aec01e4\">Ministerio de Salud y Protecci\u00f3n Social. MinSalud e INS conmemoran el D\u00eda Mundial del Donante de \u00d3rganos y Tejidos. Accessed June 26, 2025. <a href=\"https:\/\/www.minsalud.gov.co\/Paginas\/minsalud-e-ins-conmemoran-el-dia-mundial-del-donante-de-organos-y-tejidos.aspx\">https:\/\/www.minsalud.gov.co\/Paginas\/minsalud-e-ins-conmemoran-el-dia-mundial-del-donante-de-organos-y-tejidos.aspx<\/a> <a href=\"#88446638-ca05-441f-a811-4ced4aec01e4-link\" aria-label=\"Jump to footnote reference 485\">\u21a9\ufe0e<\/a><\/li><li id=\"fbceca82-c6dc-4dab-94f9-1cfdb7eb736d\">United States Senate Committee on Finance. A system in need of repair: addressing organizational failures of the U.S.\u2019s Organ Procurement and Transplantation Network. August 3, 2022. Accessed October 15, 2024. <a href=\"https:\/\/www.finance.senate.gov\/hearings\/a-system-in-need-of-repair-addressing-organizational-failures-of-the-uss-organ-procurement-and-transplantation-network\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.finance.senate.gov\/hearings\/a-system-in-need-of-repair-addressing-organizational-failures-of-the-uss-organ-procurement-and-transplantation-network<\/a> <a href=\"#fbceca82-c6dc-4dab-94f9-1cfdb7eb736d-link\" aria-label=\"Jump to footnote reference 486\">\u21a9\ufe0e<\/a><\/li><li id=\"212e2190-692b-4520-b625-c07ff4cdd228\">Kizer KW, English RA, Hackmann M, eds. <em>Realizing the Promise of Equity in the Organ Transplantation System<\/em>. National Academies Press; 2022. <a href=\"#212e2190-692b-4520-b625-c07ff4cdd228-link\" aria-label=\"Jump to footnote reference 487\">\u21a9\ufe0e<\/a><\/li><li id=\"1754ebd7-0154-42f9-9cac-f63d7bdab721\">In America, lots of usable organs go unrecovered or get binned. <em>The Economist<\/em>. September 16, 2023. Accessed October 15, 2024. <a href=\"https:\/\/www.economist.com\/united-states\/2023\/09\/16\/in-america-lots-of-usable-organs-go-unrecovered-or-get-binned\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.economist.com\/united-states\/2023\/09\/16\/in-america-lots-of-usable-organs-go-unrecovered-or-get-binned<\/a> <a href=\"#1754ebd7-0154-42f9-9cac-f63d7bdab721-link\" aria-label=\"Jump to footnote reference 488\">\u21a9\ufe0e<\/a><\/li><li id=\"aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8\">Mohan S, Chiles MC, Patzer RE, et al. Factors leading to the discard of deceased donor kidneys in the United States.\u202f<em>Kidney Int<\/em>. 2018;94(1):187-198. <a href=\"#aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8-link\" aria-label=\"Jump to footnote reference 489\">\u21a9\ufe0e<\/a><\/li><li id=\"3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae\">Jena B. Why do so many donated kidneys end up in the trash? <em>Freakonomics<\/em>. November 11, 2021. Accessed October 24, 2024. <a href=\"https:\/\/freakonomics.com\/podcast\/why-do-so-many-donated-kidneys-end-up-in-the-trash\/\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/freakonomics.com\/podcast\/why-do-so-many-donated-kidneys-end-up-in-the-trash\/<\/a> <a href=\"#3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae-link\" aria-label=\"Jump to footnote reference 490\">\u21a9\ufe0e<\/a><\/li><li id=\"873d9338-5037-4160-8adf-dc9f53a2fc52\">Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024. <a href=\"#873d9338-5037-4160-8adf-dc9f53a2fc52-link\" aria-label=\"Jump to footnote reference 491\">\u21a9\ufe0e<\/a><\/li><li id=\"4dcee4ec-65c8-425c-84d8-fc37baa923f0\">Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024. <a href=\"#4dcee4ec-65c8-425c-84d8-fc37baa923f0-link\" aria-label=\"Jump to footnote reference 492\">\u21a9\ufe0e<\/a><\/li><li id=\"050927b4-6a8f-4ef0-86e5-eea3ce9c49d0\">Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024. <a href=\"#050927b4-6a8f-4ef0-86e5-eea3ce9c49d0-link\" aria-label=\"Jump to footnote reference 493\">\u21a9\ufe0e<\/a><\/li><li id=\"dde7c07f-5389-4951-ad34-7d58940c62b3\">Health Resource and Services Administration. Organ Procurement and Transplantation Network (OPTN) modernization initiative. Updated November 2024. Accessed December 6, 2024. <a href=\"https:\/\/www.hrsa.gov\/optn-modernization\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.hrsa.gov\/optn-modernization<\/a> <a href=\"#dde7c07f-5389-4951-ad34-7d58940c62b3-link\" aria-label=\"Jump to footnote reference 494\">\u21a9\ufe0e<\/a><\/li><li id=\"8dabffcc-0193-4ebe-ac3a-8e5b93828ae3\">HRSA. (2024). OPTN modernization initiative. Retrieved December 6, 2024. <a href=\"#8dabffcc-0193-4ebe-ac3a-8e5b93828ae3-link\" aria-label=\"Jump to footnote reference 495\">\u21a9\ufe0e<\/a><\/li><li id=\"44331a34-2ab3-481c-bd67-490e385fd02f\">U.S. Department of Health and Human Services. In historic step, HRSA makes first ever multi-vendor awards to modernize the nation\u2019s organ transplant system and end the current contract monopoly. September 19, 2024. Accessed October 15, 2024. <a href=\"https:\/\/www.hhs.gov\/about\/news\/2024\/09\/19\/hrsa-makes-first-ever-multi-vendor-awards-to-modernize-the-nations-organ-transplant-system.html\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.hhs.gov\/about\/news\/2024\/09\/19\/hrsa-makes-first-ever-multi-vendor-awards-to-modernize-the-nations-organ-transplant-system.html<\/a> <a href=\"#44331a34-2ab3-481c-bd67-490e385fd02f-link\" aria-label=\"Jump to footnote reference 496\">\u21a9\ufe0e<\/a><\/li><li id=\"d96e5f24-7d5c-4391-ba1c-f3cdffaffd47\">FDA Center for Biologics Evaluation and Research. Source animal, product, preclinical, and clinical issues concerning the use of xenotransplantation products in humans. December 2016. Accessed October 15, 2024. <a href=\"https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/source-animal-product-preclinical-and-clinical-issues-concerning-use-xenotransplantation-products\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/source-animal-product-preclinical-and-clinical-issues-concerning-use-xenotransplantation-products<\/a> <a href=\"#d96e5f24-7d5c-4391-ba1c-f3cdffaffd47-link\" aria-label=\"Jump to footnote reference 497\">\u21a9\ufe0e<\/a><\/li><li id=\"92ef33d3-34b5-4d4c-83d9-e534c52863f9\">Hawthorne WJ. Ethical and legislative advances in xenotransplantation for clinical translation: focusing on cardiac, kidney and islet cell xenotransplantation.<em> Front Immunol. <\/em>2024;15:1355609 <a href=\"#92ef33d3-34b5-4d4c-83d9-e534c52863f9-link\" aria-label=\"Jump to footnote reference 498\">\u21a9\ufe0e<\/a><\/li><li id=\"a1a9b500-2c79-4576-ac13-dd869b9cba47\">Regalado A. The xenotransplant patient who died received a heart infected with a pig virus. <em>MIT Technology Review<\/em>. May 4, 2022. Accessed October 15, 2024. <a href=\"https:\/\/www.technologyreview.com\/2022\/05\/04\/1051725\/xenotransplant-patient-died-received-heart-infected-with-pig-virus\/\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.technologyreview.com\/2022\/05\/04\/1051725\/xenotransplant-patient-died-received-heart-infected-with-pig-virus\/<\/a> <a href=\"#a1a9b500-2c79-4576-ac13-dd869b9cba47-link\" aria-label=\"Jump to footnote reference 499\">\u21a9\ufe0e<\/a><\/li><li id=\"8b838035-0ed2-44fe-8c5d-a5ba6cf41b76\">Regalado A. (2022). Xenotransplant patient received heart infected with pig virus. <em>MIT Technology Review.<\/em> Retrieved October 15, 2024. <a href=\"#8b838035-0ed2-44fe-8c5d-a5ba6cf41b76-link\" aria-label=\"Jump to footnote reference 500\">\u21a9\ufe0e<\/a><\/li><li id=\"727a251d-c956-4310-a9b1-7b744bbc155c\">Bobier C, Hurst DJ, Rodger D. Should Xenotransplantation Surgeries Be Authorized Under the Food and Drug Administration&#8217;s Expanded Access\u00a0Pathway?.\u00a0<em>AMA J Ethics<\/em>. 2025;27(3):E197-E200.\u00a0doi:10.1001\/amajethics.2025.197 <a href=\"#727a251d-c956-4310-a9b1-7b744bbc155c-link\" aria-label=\"Jump to footnote reference 501\">\u21a9\ufe0e<\/a><\/li><li id=\"e7b6b9bb-960f-4f8e-9633-a208b336ecc0\">Healey\u00a0N. World-first pig kidney trials mark turning point for xenotransplantation.\u00a0<em>Nat Med<\/em>. 2025. doi:10.1038\/d41591-025-00020-0 <a href=\"#e7b6b9bb-960f-4f8e-9633-a208b336ecc0-link\" aria-label=\"Jump to footnote reference 502\">\u21a9\ufe0e<\/a><\/li><li id=\"5c485b5d-b65d-4fef-a7a3-2338e570fa69\">Health Resources &amp; Services Administration. HRSA directive for OPTN donation after circulatory death policy development.\u00a0HRSA.gov. May 28, 2025. Accessed February 6, 2026.\u00a0<a href=\"https:\/\/www.hrsa.gov\/optn\/policies-bylaws\/public-comment\/hrsa-directive-optn-donation-after-circulatory-death-policy-\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/www.hrsa.gov\/optn\/policies-bylaws\/public-comment\/hrsa-directive-optn-donation-after-circulatory-death-policy-<\/a>development <a href=\"#5c485b5d-b65d-4fef-a7a3-2338e570fa69-link\" aria-label=\"Jump to footnote reference 503\">\u21a9\ufe0e<\/a><\/li><li id=\"44444a99-e1a7-408d-a9a7-9af3ad4ea167\">Advanced Research Projects Agency for Health. ARPA-H awards teams set to\u00a0bioprint\u00a0universally matched organs on demand.\u00a0ARPA-H.gov. January 12, 2026. Accessed February 6, 2026.\u00a0<a href=\"https:\/\/arpa-h.gov\/news-and-events\/arpa-h-awards-teams-set-bioprint-universally-matched-organs-demand\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/arpa-h.gov\/news-and-events\/arpa-h-awards-teams-set-bioprint-universally-matched-organs-demand<\/a> <a href=\"#44444a99-e1a7-408d-a9a7-9af3ad4ea167-link\" aria-label=\"Jump to footnote reference 504\">\u21a9\ufe0e<\/a><\/li><li id=\"5efee13d-1326-4987-b97c-067db919a717\">DeRoos LJ, Marrero WJ, Tapper EB, et al. Estimated association between organ availability and presumed consent in solid organ transplant. <em>JAMA Netw Open<\/em>. 2019;2(10):e1912431 <a href=\"#5efee13d-1326-4987-b97c-067db919a717-link\" aria-label=\"Jump to footnote reference 505\">\u21a9\ufe0e<\/a><\/li><li id=\"c8ae5797-2caa-4f71-891a-d929ddbf7a34\">Ministerio de Salud. INCUCAI. Accessed June 26, 2025.\u00a0 <a href=\"https:\/\/www.argentina.gob.ar\/salud\/donarorganos\">https:\/\/www.argentina.gob.ar\/salud\/donarorganos<\/a> <a href=\"#c8ae5797-2caa-4f71-891a-d929ddbf7a34-link\" aria-label=\"Jump to footnote reference 506\">\u21a9\ufe0e<\/a><\/li><li id=\"96e80953-165b-49c4-8687-722f3d804a91\">Ministerio de Salud y Protecci\u00f3n Social. Enlace Minsalud, 16 de febrero de 2017. Accessed July 2, 2026. https:\/\/www.minsalud.gov.co\/sites\/rid\/Lists\/BibliotecaDigital\/RIDE\/DE\/COM\/enlace-minsalud-92-donacion.pdf <a href=\"#96e80953-165b-49c4-8687-722f3d804a91-link\" aria-label=\"Jump to footnote reference 507\">\u21a9\ufe0e<\/a><\/li><li id=\"c421c8d5-b39c-459c-b739-75d1a67aaf35\">Instituto de Salud P\u00fablica. Lo que tienes que saber sobre la donaci\u00f3n de \u00f3rganos en Chile. Accessed June 26, 2025. <a href=\"https:\/\/www.ispch.gob.cl\/noticia\/lo-que-tienes-que-saber-sobre-la-donacion-de-organos-en-chile\/\">https:\/\/www.ispch.gob.cl\/noticia\/lo-que-tienes-que-saber-sobre-la-donacion-de-organos-en-chile\/<\/a> <a href=\"#c421c8d5-b39c-459c-b739-75d1a67aaf35-link\" aria-label=\"Jump to footnote reference 508\">\u21a9\ufe0e<\/a><\/li><li id=\"ac49ad9e-9993-4907-8c29-ece6de164c79\">Gobierno de Per\u00fa. Donaci\u00f3n de \u00f3rganos y tejidos: preguntas frecuentes. Accessed November 14, 2025. <a href=\"https:\/\/www.gob.pe\/100384-donacion-de-organos-y-tejidos-preguntas-frecuentes\">https:\/\/www.gob.pe\/100384-donacion-de-organos-y-tejidos-preguntas-frecuentes<\/a> <a href=\"#ac49ad9e-9993-4907-8c29-ece6de164c79-link\" aria-label=\"Jump to footnote reference 509\">\u21a9\ufe0e<\/a><\/li><li id=\"b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c\">Gobierno de Uruguay. Expresi\u00f3n de voluntad de donaci\u00f3n (positiva o negativa). Accessed June 26, 2025. <a href=\"https:\/\/www.gub.uy\/tramites\/expresion-voluntad-donacion-positiva-negativa\">https:\/\/www.gub.uy\/tramites\/expresion-voluntad-donacion-positiva-negativa<\/a> <a href=\"#b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c-link\" aria-label=\"Jump to footnote reference 510\">\u21a9\ufe0e<\/a><\/li><li id=\"09deb376-7863-4fe7-bd62-3a07bdae478c\">Streit S, Johnston-Webber C, Mah J, et al. Ten lessons from the Spanish model of organ donation and transplantation. <em>Transpl Int.<\/em> 2023;36:11009 <a href=\"#09deb376-7863-4fe7-bd62-3a07bdae478c-link\" aria-label=\"Jump to footnote reference 511\">\u21a9\ufe0e<\/a><\/li><li id=\"457e59c2-127e-4a61-96aa-ff1a293836d4\">Streit S, et al. (2023). Ten lessons from the Spanish model of organ donation and transplantation. <em>Transpl Int,<\/em> 36, 11009. <a href=\"#457e59c2-127e-4a61-96aa-ff1a293836d4-link\" aria-label=\"Jump to footnote reference 512\">\u21a9\ufe0e<\/a><\/li><\/ol><\/div>\n<\/div>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n","protected":false},"excerpt":{"rendered":"<p>C\u00e1ncer Aunque las mejoras en los programas de detecci\u00f3n han permitido un avance significativo en el diagn\u00f3stico temprano del c\u00e1ncer y la reducci\u00f3n de las tasas de mortalidad, esta enfermedad sigue siendo una de las principales causas de muerte en el continente americano y en 2022 caus\u00f3 1,4 millones de fallecimientos. La disminuci\u00f3n de la&#8230;<\/p>\n","protected":false},"author":4,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":"[{\"id\":\"b5d1e717-bfa3-4939-9c1a-04301e350ee5\",\"content\":\"Wender RC, Brawley OW, Fedewa SA, Gansler T, Smith RA. A blueprint for cancer screening and early detection: advancing screening\u2019s contribution to cancer control. <em>CA Cancer J Clin<\/em>. 2019;69(1):50-79. doi:10.3322\/caac.21550\u00a0\"},{\"id\":\"3532e163-51af-49b6-b56e-6ad0e9bc691c\",\"content\":\"Loud JT, Murphy J. Cancer screening and early detection in the 21<sup>st <\/sup>century. <em>Semin Oncol Nurs<\/em>. 2017;33(2):121-128. doi:10.1016\/j.soncn.2017.02.002\"},{\"id\":\"35e17b68-cd0c-4261-a697-47ece3fc8cf3\",\"content\":\"National Cancer Institute. Cancer statistics. Cancer.gov. May 9, 2024. Accessed October 1, 2024. <a href=\\\"https:\/\/www.cancer.gov\/about-cancer\/understanding\/statistics\\\">https:\/\/www.cancer.gov\/about-cancer\/understanding\/statistics<\/a>\u00a0\"},{\"id\":\"156dd4d7-6f00-4510-8b02-e0748c64e448\",\"content\":\"Chen SLF, N\u00f8st TH, Botteri E, et al. Overall lifestyle changes in adulthood are associated with cancer incidence in the Norwegian Women and Cancer Study (NOWAC)\u2014a prospective cohort study. <em>BMC Public Health<\/em>. 2023;23(1):633. doi:10.1186\/s12889-023-15476-3\"},{\"id\":\"49977b17-baec-430d-830f-599d34cf61f0\",\"content\":\"Cronin KA, Scott S, Firth AU, et al. Annual report to the nation on the status of cancer, part 1: national cancer statistics. <em>Cancer<\/em>. 2022;128(24):4251-4284. doi:10.1002\/cncr.34479\u00a0\"},{\"id\":\"4d2bcedf-235e-45eb-b2c2-aa074f90968d\",\"content\":\"Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. <em>Biostatistics<\/em>. 2019;20(2):273-286. doi:10.1093\/biostatistics\/kxx069\u00a0\"},{\"id\":\"649ff382-081f-46b1-9e2d-ed90a9afca45\",\"content\":\"Errington TM, Mathur M, Soderberg CK, et al. Investigating the replicability of preclinical cancer biology. Pasqualini R, Franco E, eds. <em>eLife<\/em>. 2021;10:e71601. doi:10.7554\/eLife.71601\u00a0\"},{\"id\":\"a5157d53-deb5-4531-a934-3b02f2288a3d\",\"content\":\"Mak IW, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. <em>Am J Transl Res<\/em>. 2014;6(2):114-118.\u00a0\"},{\"id\":\"42a19a54-55f0-4de6-b5ca-dfe280ac45ef\",\"content\":\"Cimons M, Getlin J, Maugh II T. Cancer drugs face long road from mice to men. <em>Los Angeles Times<\/em>. May 6, 1998. Accessed October 23, 2021. <a href=\\\"https:\/\/www.latimes.com\/archives\/la-xpm-1998-may-06-mn-46795-story.html.\\\">https:\/\/www.latimes.com\/archives\/la-xpm-1998-may-06-mn-46795-story.html.<\/a>\u00a0\"},{\"id\":\"27ff85ba-0983-4744-a4fc-ef4fccbbf5ed\",\"content\":\"Ormandy EH, Dale J, Griffin G. Genetic engineering of animals: ethical issues, including welfare concerns. <em>Can Vet J<\/em>. 2011;52(5):544-550.\u00a0\"},{\"id\":\"d9823697-d716-43f2-8d32-bffeeb2a7e4f\",\"content\":\"Wewetzer H, Wagenknecht T, Bert B, Sch\u00f6nfelder G. The fate of surplus laboratory animals: minimizing the production of surplus animals has greatest potential to reduce the number of laboratory animals. <em>EMBO Rep<\/em>. 2023;24(3):e56551. doi:10.15252\/embr.202256551\"},{\"id\":\"e6504616-eeff-4478-8418-807f98d84778\",\"content\":\"Li Z, Zheng W, Wang H, et al. Application of animal models in cancer research: recent progress and future prospects. <em>Cancer Manag Res<\/em>. 2021;13:2455-2475. doi:10.2147\/CMAR.S302565\u00a0\"},{\"id\":\"7ab8aefa-97a3-4ee9-bf9e-ffbdd1df5320\",\"content\":\"Zhou Y, Xia J, Xu S, et al. Experimental mouse models for translational human cancer research. <em>Front Immunol<\/em>. 2023;14. doi:10.3389\/fimmu.2023.1095388\u00a0\"},{\"id\":\"c72f94bc-8970-434b-a1f0-c875b4a80fd6\",\"content\":\"Ben-David U, Ha G, Tseng YY, et al. Patient-derived xenografts undergo mouse-specific tumor evolution. <em>Nat Genet<\/em>. 2017;49:1567-1575. doi:10.1038\/ng.3967\u00a0\"},{\"id\":\"60918212-9812-4989-97ec-69df548590b0\",\"content\":\"Cheon DJ, Orsulic S. Mouse models of cancer. <em>Annu Rev Pathol<\/em>. 2011;6:95-119. doi:10.1146\/annurev.pathol.3.121806.154244\u00a0\"},{\"id\":\"d3031221-f943-4eed-b6c1-5d8f812f961e\",\"content\":\"Ormandy et al., <em>Genetic Engineering of Animals<\/em>, 2011\"},{\"id\":\"85c1ed46-9d65-4969-861d-9ab0e5e84484\",\"content\":\"Romania P, Folgiero V, Nic M, et al. <em>Advanced Non-Animal Models in Biomedical Research: Immuno-Oncology<\/em>. Publications Office of the European Union; 2021:46. doi:10.2760\/393670\"},{\"id\":\"9708627f-2772-43aa-8bdd-465c51d8e6af\",\"content\":\"Tricinci O, De Pasquale D, Marino A, Battaglini M, Pucci C, Ciofani G. A 3D biohybrid real-scale model of the brain cancer microenvironment for advanced in vitro testing. <em>Adv Mater Technol<\/em>. 2020;5(10):2000540. doi:10.1002\/admt.202000540\"},{\"id\":\"ea5e7dd5-be13-4fe5-b608-97f12f2049db\",\"content\":\"Sun H, Sun L, Ke X, et al. Prediction of clinical precision chemotherapy by patient-derived 3D bioprinting models of colorectal cancer and its liver metastases. <em>Adv Sci (Weinh)<\/em>. 2024;11(2):2304460. doi:10.1002\/advs.202304460\u00a0\"},{\"id\":\"d472cc93-352a-4415-a8d6-41d3acd94809\",\"content\":\"Asciak L, Gilmour L, Williams JA, et al. Investigating multi-material hydrogel three-dimensional printing for in vitro representation of the neo-vasculature of solid tumours: a comprehensive mechanical analysis and assessment of nitric oxide release from human umbilical vein endothelial cells. <em>R Soc Open Sci<\/em>. 2023;10(8):230929. doi:10.1098\/rsos.230929\"},{\"id\":\"fb72839a-f026-462a-952d-8761e9613ae7\",\"content\":\"Dey M, Kim MH, Dogan M, et al. Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model. <em>Adv Funct Mater<\/em>. 2022;32(52):2203966. doi:10.1002\/adfm.202203966\u00a0\"},{\"id\":\"f8b870f3-62c4-4953-87f4-65ac056998ad\",\"content\":\"Polidoro MA, Ferrari E, Soldani C, et al. Cholangiocarcinoma-on-a-chip: a human 3D platform for personalised medicine. <em>JHEP Report<\/em>. 2024;6(1). doi:10.1016\/j.jhepr.2023.100910\u00a0\"},{\"id\":\"73670505-ba59-4f3b-99b9-d4a8bf64ef8f\",\"content\":\"Kim Y, Lee J, Lee S, Jung HI, Kwak B. Anisotropic tumor spheroid remission with binary tumor-microenvironment-on-a-chip. <em>Biosens Bioelectron<\/em>. 2024;243:115787. doi:10.1016\/j.bios.2023.115787\u00a0\"},{\"id\":\"9a3cd416-6989-4a15-b090-d41239bc6fed\",\"content\":\"Sontheimer-Phelps A, Hassell BA, Ingber DE. Modelling cancer in microfluidic human organs-on-chips. <em>Nat Rev Cancer<\/em>. 2019;19(2):65-81. doi:10.1038\/s41568-018-0104-6\"},{\"id\":\"1eb45f77-2665-440c-aab1-9b3f9885ada3\",\"content\":\"McAleer CW, Long CJ, Elbrecht D, et al. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. <em>Sci Transl Med<\/em>. 2019;11(497):eaav1386. doi:10.1126\/scitranslmed.aav1386\u00a0\"},{\"id\":\"c1002ca2-b660-4b53-b87a-804b0fb1ea37\",\"content\":\"Lim J, Rhee S, Choi H, et al. Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis. <em>Mater Today Bio<\/em>. 2023;22:100773. doi:10.1016\/j.mtbio.2023.100773\u00a0\"},{\"id\":\"9f007b5a-8eae-4c12-9820-3c76c6617c69\",\"content\":\"Millen R, De Kort WWB, Koomen M, et al. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification. <em>Med<\/em>. 2023;4(5):290-310.e12. doi:10.1016\/j.medj.2023.04.003\u00a0\"},{\"id\":\"af0cbef2-46ce-4c7c-9597-235e3fe5b056\",\"content\":\"Tan T, Mouradov D, Lee M, et al. Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer. <em>Cell Rep Med<\/em>. 2023;4(12). doi:10.1016\/j.xcrm.2023.101335\u00a0\"},{\"id\":\"a88c7153-224b-4804-9440-0e87416cea3e\",\"content\":\"Raffo-Romero A, Ziane-Chaouche L, Salom\u00e9-Desnoulez S, et al. A co-culture system of macrophages with breast cancer tumoroids to study cell interactions and therapeutic responses. <em>Cell Rep Methods<\/em>. 2024;4(6). doi:10.1016\/j.crmeth.2024.100792\u00a0\"},{\"id\":\"4fd24010-f6b8-4123-bf87-cb49796b6ebe\",\"content\":\"Ethier SP, Guest ST, Garrett-Mayer E, et al. Development and implementation of the SUM breast cancer cell line functional genomics knowledge base. <em>NPJ Breast Cancer<\/em>. 2020;6(1):1-14. doi:10.1038\/s41523-020-0173-z\u00a0\"},{\"id\":\"141fc7e4-6182-4414-abfe-3f2ffb60bbb7\",\"content\":\"Campbell P, Getz G, Korbel J, et al. Pan-cancer analysis of whole genomes. <em>Nature<\/em>. 2020;578:82-93. doi:10.1038\/s41586-020-1969-6\u00a0\"},{\"id\":\"80be0c70-14ca-4a2f-bbc3-897bd0d042b6\",\"content\":\"Dong X, Ding L, Thrasher A, et al. NetBID2 provides comprehensive hidden driver analysis. <em>Nat Commun<\/em>. 2023;14(1):2581. doi:10.1038\/s41467-023-38335-6\u00a0\"},{\"id\":\"c05b6008-28cc-4c3b-8d4c-28963c57275e\",\"content\":\"Yang H, Zhao L, Li D, et al. Subtype-WGME enables whole-genome-wide multi-omics cancer subtyping. <em>Cell Rep Methods<\/em>. 2024;4(6):100781. doi:10.1016\/j.crmeth.2024.100781\"},{\"id\":\"15ee1a33-89ca-4d05-9f01-02aa6a8c5123\",\"content\":\"Meric-Bernstam F, Ford JM, O\u2019Dwyer PJ, et al. National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH). <em>Clin Cancer Res<\/em>. 2023;29(8):1412-1422. doi:10.1158\/1078-0432.CCR-22-3334\u00a0\"},{\"id\":\"f90baee9-90cb-4311-b5df-2486ae499638\",\"content\":\"Landhuis E. Deep learning takes on tumours. <em>Nature<\/em>. 2020;580(7804):551-553. doi:10.1038\/D41586-020-01128-8\u00a0\"},{\"id\":\"d86bb19e-05b3-4fcf-97d9-21ec5593a362\",\"content\":\"Acanda De La Rocha AM, Berlow NE, Fader M, et al. Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers. <em>Nat Med<\/em>. 2024;30(4):990-1000. doi:10.1038\/s41591-024-02848-4\u00a0\"},{\"id\":\"39e52c8c-1b7e-4f59-9bf0-c8ba95f7366c\",\"content\":\"Meaney C, Das S, Colak E, Kohandel M. Deep learning characterization of brain tumours with diffusion weighted imaging. <em>J Theor Biol<\/em>. 2023;557:111342. doi:10.1016\/j.jtbi.2022.111342\"},{\"id\":\"20f51e18-62a3-49d6-80ca-f5303d7d27e6\",\"content\":\"Tan CL, Lindner K, Boschert T, et al. Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. <em>Nat Biotechnol<\/em>. Published online 2024:1-9. doi:10.1038\/s41587-024-02161-y\u00a0\"},{\"id\":\"8276aa67-b7ba-478f-8708-a88fda55c8a7\",\"content\":\"Jean-Quartier C, Jeanquartier F, Jurisica I, Holzinger A. In silico cancer research towards 3R. <em>BMC Cancer<\/em>. 2018;18(1):408. doi:10.1186\/s12885-018-4302-0\"},{\"id\":\"f63e9cf1-a54a-494e-a5de-c104dda7e778\",\"content\":\"World Health Organization. Cardiovascular diseases. 2024. Accessed November 3, 2024. <a href=\\\"https:\/\/www.who.int\/health-topics\/cardiovascular-diseases\\\">https:\/\/www.who.int\/health-topics\/cardiovascular-diseases<\/a>\"},{\"id\":\"e3fbad9e-65f3-4067-804a-b3f3f693c075\",\"content\":\"Joint Research Centre (European Commission). World Heart Day: Non-animal models as promising tools to fight cardiovascular diseases\u2014European Commission. September 28, 2022. Accessed November 3, 2024. <a href=\\\"https:\/\/joint-research-centre.ec.europa.eu\/jrc-news-and-updates\/world-heart-day-non-animal-models-promising-tools-fight-cardiovascular-diseases-2022-09-28_en\\\">https:\/\/joint-research-centre.ec.europa.eu\/jrc-news-and-updates\/world-heart-day-non-animal-models-promising-tools-fight-cardiovascular-diseases-2022-09-28_en<\/a>\"},{\"id\":\"05798e28-e21b-4414-9ce7-fb8679906d4d\",\"content\":\"Vyas MV, Gros R, Hackam DG. Translation of cardiovascular animal models to human randomized trials. <em>Am J Cardiol<\/em>. 2020;137:141. doi:10.1016\/j.amjcard.2020.10.027\"},{\"id\":\"84249d2d-5f00-4f4e-9473-bfd3c656c5df\",\"content\":\"Joint Research Centre, <em>World Heart Day<\/em>, 2022.\"},{\"id\":\"b07c0d63-d807-429b-b44b-bcc74cbb1da2\",\"content\":\"Zaragoza C, Gomez-Guerrero C, Martin-Ventura JL, et al. Animal models of cardiovascular diseases. <em>J Biomed Biotechnol<\/em>. 2011;2011(1):497841. doi:10.1155\/2011\/497841\"},{\"id\":\"14a6ac36-8a42-4782-8319-cdc0b7a2f6d8\",\"content\":\"Gintant G, Sager PT, Stockbridge N. Evolution of strategies to improve preclinical cardiac safety testing. <em>Nat Rev Drug Discov<\/em>. 2016;15(7):457-471. doi:10.1038\/nrd.2015.34\"},{\"id\":\"1c48bfe9-c016-4967-b5dd-d613944fa130\",\"content\":\"Milani-Nejad N, Janssen PML. Small and large animal models in cardiac contraction research: advantages and disadvantages. <em>Pharmacol Ther<\/em>. 2014;141(3):235-249. doi:10.1016\/j.pharmthera.2013.10.007\"},{\"id\":\"75144ee4-253c-4014-9ae4-4667488fb05f\",\"content\":\"Janssen PM, Elnakish MT. Modeling heart failure in animal models for novel drug discovery and development. <em>Expert Opin Drug Discov<\/em>. 2019;14(4):355. doi:10.1080\/17460441.2019.1582636\"},{\"id\":\"e24d2ecf-ef87-4ccd-b07a-cc1fd6e32880\",\"content\":\"Zaragoza et al., <em>Animal Models of Cardiovascular Diseases<\/em>, 2011.\"},{\"id\":\"72fd6b41-02d1-4590-b1c3-a77f531923a2\",\"content\":\"Chorro FJ, Such-Belenguer L, L\u00f3pez-Merino V. Modelos animales de enfermedad cardiovascular. <em>Rev Esp Cardiol<\/em>. 2009;62(1):69-84. doi:10.1016\/S0300-8932(09)70023-5\"},{\"id\":\"bbaa06a9-31bc-4c16-8050-6e6597eaf437\",\"content\":\"Del \u00c1lamo JC, Lemons D, Serrano R, et al. High throughput physiological screening of iPSC-derived cardiomyocytes for drug development. <em>Biochim Biophys Acta<\/em>. 2016;1863(7 Pt B):1717-1727. doi:10.1016\/j.bbamcr.2016.03.003\"},{\"id\":\"7b91ef3a-c5c0-4e38-9db8-d40d699edac2\",\"content\":\"Barter P, Rye KA. Cholesteryl ester transfer protein inhibition to reduce cardiovascular risk: where are we now? <em>Trends Pharmacol Sci<\/em>. 2011;32(12):694-699. doi:10.1016\/j.tips.2011.07.004\u00a0\"},{\"id\":\"8a669361-e64f-44e4-b564-4e243ed88c76\",\"content\":\"Celi S, Cioffi M, Capellini K, et al. <em>Advanced Non-Animal Models in Biomedical Research: Cardiovascular Diseases<\/em>. European Commission Joint Research Centre; 2022. doi:10.2760\/94608\"},{\"content\":\"World Health Organization. Cardiovascular diseases. 2024. Accessed November 3, 2024.\u00a0<a href=\\\"https:\/\/www.who.int\/health-topics\/cardiovascular-diseases\\\">https:\/\/www.who.int\/health-topics\/cardiovascular-diseases<\/a>\",\"id\":\"989f960c-b634-4f16-b294-474fa48fd78b\"},{\"id\":\"37d9bf7d-1dbf-43d4-a6db-e02c246fd526\",\"content\":\"van Doorn ECH, Amesz JH, Sadeghi AH, de Groot NMS, Manintveld OC, Taverne YJHJ. Preclinical models of cardiac disease: a comprehensive overview for clinical scientists. <em>Cardiovasc Eng Tech<\/em>. 2024;15(2):232-249. doi:10.1007\/s13239-023-00707-w\u00a0\"},{\"id\":\"a78ed81d-1af3-4074-b6c2-28881e7a4f50\",\"content\":\"Ho BX, Pang JKS, Chen Y, et al. Robust generation of human-chambered cardiac organoids from pluripotent stem cells for improved modelling of cardiovascular diseases. <em>Stem Cell Res Ther<\/em>. 2022;13(1):529. doi:10.1186\/s13287-022-03215-1\u00a0\"},{\"id\":\"d2ac872c-a177-485e-a2e9-86c6e6a44d94\",\"content\":\"Yang J, Lei W, Xiao Y, et al. Generation of human vascularized and chambered cardiac organoids for cardiac disease modelling and drug evaluation. <em>Cell Prolif<\/em>. 2024;57(8):e13631. doi:10.1111\/cpr.13631\"},{\"id\":\"017577c0-c43a-4056-add0-716f3b2577cd\",\"content\":\"Song M, Choi DB, Im JS, et al. Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell\u2013derived multi-cellular heart organoids. <em>Cell Death Dis<\/em>. 2024;15(5):308. doi:10.1038\/s41419-024-06703-9\"},{\"id\":\"a79f293e-21a0-47ce-9a8e-3dae9ecd32b1\",\"content\":\"Li PR, Kiran Boilla S, Wang CH, et al. A self-driven, microfluidic, integrated-circuit biosensing chip for detecting four cardiovascular disease biomarkers. <em>Biosens Bioelectron<\/em>. 2024;249:115931. doi:10.1016\/j.bios.2023.115931\"},{\"id\":\"9059e30b-faf7-4ca2-bbc6-f01ca65bf884\",\"content\":\"van Doorn et al., <em>Preclinical Models of Cardiac Disease<\/em>, 2024.\"},{\"id\":\"6e8aa3b6-b816-4f9c-ac4b-b7309b218341\",\"content\":\"Williams K, Liang T, Mass\u00e9 S, et al. A 3-D human model of complex cardiac arrhythmias. <em>Acta Biomaterialia<\/em>. 2021;132:149-161. doi:10.1016\/j.actbio.2021.03.004\"},{\"id\":\"f5699161-2a50-42f2-b785-204a6d1b7e3b\",\"content\":\"Dalal S, Goel P, Onyema EM, et al. Application of machine learning for cardiovascular disease risk prediction. Bhardwaj A, ed. <em>Comput Intell Neurosci<\/em>. 2023;2023(1):9418666. doi:10.1155\/2023\/9418666\"},{\"id\":\"86c9eda2-bf94-428c-a230-dc3d6a869166\",\"content\":\"Baghdadi NA, Farghaly Abdelaliem SM, Malki A, Gad I, Ewis A, Atlam E. Advanced machine learning techniques for cardiovascular disease early detection and diagnosis. <em>J Big Data<\/em>. 2023;10(1):144. doi:10.1186\/s40537-023-00817-1\"},{\"id\":\"6657df79-120c-47f1-8a40-4ffe5128bfb1\",\"content\":\"Pal M, Parija S, Panda G, Dhama K, Mohapatra RK. Risk prediction of cardiovascular disease using machine learning classifiers. <em>Open Med (Wars)<\/em>. 2022;17(1):1100-1113. doi:10.1515\/med-2022-0508\"},{\"id\":\"db08ab77-1578-4ba9-81a6-c439ac2d78cb\",\"content\":\"Pi\u010dulin M, Smole T, \u017dunkovi\u010d B, et al. Disease progression of hypertrophic cardiomyopathy: modeling using machine learning. <em>JMIR Med Inform<\/em>. 2022;10(2):e30483. doi:10.2196\/30483\"},{\"id\":\"7e598fc7-b9fa-4e99-bc0d-d4c1fc02497b\",\"content\":\"Margara F, Wang ZJ, Levrero-Florencio F, et al. In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment. <em>Prog Biophys Mol Biol<\/em>. 2021;159:58-74. doi:10.1016\/j.pbiomolbio.2020.06.007\"},{\"id\":\"7ca34966-87e6-437e-9220-395c39ad6de5\",\"content\":\"Milani-Nejad &amp; Janssen, 2014\"},{\"id\":\"ee8810ef-3b00-4aa2-8f48-9c90b69523cf\",\"content\":\"van Doorn et al., <em>Preclinical Models of Cardiac Disease<\/em>, 2024\"},{\"id\":\"992d3102-c04c-4130-a926-f5d84a8fc8b5\",\"content\":\"Ram R. Extrapolation of animal research data to humans: an analysis of the evidence. In: Herrmann K, Jayne K, eds. <em>Animal Experimentation: Working Towards a Paradigm Change<\/em>. BRILL; 2019:341-375. doi:10.1163\/9789004391192_016\"},{\"id\":\"c38c9aba-b804-4236-a611-1810ebc6ebc0\",\"content\":\"Whiting R, Sander E, Conway C, Vaughan TJ. In silico modelling of aortic valve implants\u2014predicting in vitro performance using finite element analysis. <em>J Med Eng Technol<\/em>. 2022;46(3):220-230. doi:10.1080\/03091902.2022.2026506\"},{\"id\":\"14d49a8b-5a9c-4fa1-bdde-da3bf47c459c\",\"content\":\"Abbassy M, Ali MZ, Sharma RM, et al. Biosensors with left ventricular assist devices. <em>Heart Fail Rev<\/em>. 2024;29(5):957-967. doi:10.1007\/s10741-024-10413-x\"},{\"id\":\"24ad7787-9c22-4326-ad63-c12f686c7a19\",\"content\":\"American Association for the Advancement of Blood &amp; Biotherapies. Facts about cellular therapies. www.aabb.org. 2024. Accessed October 1, 2024. https:\/\/www.aabb.org\/news-resources\/resources\/cellular-therapies\/facts-about-cellular-therapies\"},{\"id\":\"2c63ece2-3530-40f5-bda7-915aff52a346\",\"content\":\"American Society of Gene + Cell Therapy. Cell therapy basics. asgct.org. December 18, 2023. Accessed October 1, 2024. https:\/\/patienteducation.asgct.org\/gene-therapy-101\/cell-therapy-basics\"},{\"id\":\"6d385ef5-32fc-44a7-84be-471ce649c370\",\"content\":\"American Association for the Advancement of Blood &amp; Biotherapies, 2024\"},{\"id\":\"8002d682-8084-422f-b6a1-6e5d5b4ae89b\",\"content\":\"Dey M, Kim MH, Dogan M, et al. Chemotherapeutics and CAR-T cell-based immunotherapeutics screening on a 3D bioprinted vascularized breast tumor model. <em>Adv Funct Mater<\/em>. 2022;32(52):2203966. doi:10.1002\/adfm.202203966\"},{\"id\":\"fdf2504d-5830-4398-981a-6e3f9fd554d8\",\"content\":\"Ying Li CM, Li R, Drew P, et al. Clinical application of cytokine-induced killer (CIK) cell therapy in colorectal cancer: current strategies and future challenges. <em>Cancer Treat Rev<\/em>. 2024;122:102665. doi:10.1016\/j.ctrv.2023.102665\"},{\"id\":\"f5a6c26c-c887-4758-8be1-55e1b55bbc46\",\"content\":\"U.S. Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes. FDA.gov. June 28, 2023. Accessed October 1, 2024. <a href=\\\"https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes\\\">https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes<\/a>\"},{\"id\":\"5de69205-f37b-4989-8692-2b22ad62ce4b\",\"content\":\"Thai VL, Ramos-Rodriguez DH, Mesfin M, Leach JK. Hydrogel degradation promotes angiogenic and regenerative potential of cell spheroids for wound healing. <em>Mater Today Bio<\/em>. 2023;22:100769. doi:10.1016\/j.mtbio.2023.100769\"},{\"id\":\"c83ae1eb-5b9d-440e-89dc-9b0948a54047\",\"content\":\"Harding J, Roberts RM, Mirochnitchenko O. Large animal models for stem cell therapy. <em>Stem Cell Res Ther<\/em>. 2013;4(2):23. doi:10.1186\/scrt171\"},{\"id\":\"70b6633b-cf8c-4a4f-b840-b3fe15f2ffaf\",\"content\":\"Hu C, Liu M, Li Y, et al. Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer. <em>Front Immunol<\/em>. 2023;14. doi:10.3389\/fimmu.2023.1213716\"},{\"id\":\"efaeede9-a56c-4eb9-8c54-391507b8f2ed\",\"content\":\"Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. <em>Clin Cancer Res<\/em>. 2006;12(20):6106-6115. doi:10.1158\/1078-0432.CCR-06-1183\"},{\"id\":\"5a7a5765-6c73-4366-92b6-5c46c2f16195\",\"content\":\"Lamers CHJ, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. <em>J Clin Oncol<\/em>. 2006;24(13):e20-e22. doi:10.1200\/JCO.2006.05.9964\"},{\"id\":\"bb130843-5efa-436c-914b-0bca564799cd\",\"content\":\"Seattle Children\u2019s. Mouse model for CAR-T therapy. seattlechildrens.org. 2024. Accessed October 2, 2024. https:\/\/www.seattlechildrens.org\/research\/centers-programs\/science-industry-partnerships\/partnership-opportunities\/cancer-mouse-model-for-car-t-therapy\/\"},{\"id\":\"c5f12286-b96f-448c-90b7-7a1d9be301ed\",\"content\":\"Harding et al., 2013\"},{\"id\":\"06c453ea-95ab-4dac-93ad-196e72f41bf7\",\"content\":\"Kleiman RJ, Engle SJ. Human inducible pluripotent stem cells: realization of initial promise in drug discovery. <em>Cell Stem Cell<\/em>. 2021;28(9):1507-1515. doi:10.1016\/j.stem.2021.08.002\"},{\"id\":\"402d9886-6f97-4a17-a8df-0d763b43373d\",\"content\":\"Cerneckis J, Cai H, Shi Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. <em>Sig Transduct Target Ther<\/em>. 2024;9(1):1-26. doi:10.1038\/s41392-024-01809-0\"},{\"id\":\"f872aa91-c354-42c6-b6e4-1949b2a33933\",\"content\":\"Maulana TI, Teufel C, Cipriano M, et al. Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells. <em>Cell Stem Cell<\/em>. 2024;31(7):989-1002.e9. doi:10.1016\/j.stem.2024.04.018\"},{\"id\":\"48bbc6e3-e783-4a97-91ff-9f2125362f3f\",\"content\":\"Dees S, Ganesan R, Singh S, Grewal IS. Emerging CAR-T cell therapy for the treatment of triple-negative breast cancer. <em>Mol Cancer Ther<\/em>. 2020;19(12):2409-2421. doi:10.1158\/1535-7163.MCT-20-0385\"},{\"id\":\"54799e1e-00dd-48c5-98d6-17eca4dcdda9\",\"content\":\"Zaib T, Cheng K, Liu T, et al. Expression of CD22 in triple-negative breast cancer: a novel prognostic biomarker and potential target for CAR therapy. <em>Int J Mol Sci<\/em>. 2023;24(3):2152. doi:10.3390\/ijms24032152\"},{\"id\":\"5452aaab-df18-450c-8107-5b7c9667ad44\",\"content\":\"Singh R, Gholipourmalekabadi M, Shafikhani SH. Animal models for type 1 and type 2 diabetes: advantages and limitations. <em>Front Endocrinol (Lausanne)<\/em>. 2024;15:1359685. doi:10.3389\/fendo.2024.1359685\"},{\"id\":\"fe87a148-e467-4639-97e2-3d5685a06099\",\"content\":\"Pandey S, Chmelir T, Chottova Dvorakova M. Animal models in diabetic research\u2014history, presence, and future perspectives. <em>Biomedicines<\/em>. 2023;11(10):2852. doi:10.3390\/biomedicines11102852\"},{\"id\":\"a68fbfca-e143-4937-bf1f-cd16c9b716fc\",\"content\":\"Kottaisamy CPD, Raj DS, Prasanth Kumar V, Sankaran U. Experimental animal models for diabetes and its related complications\u2014a review. <em>Lab Anim Res<\/em>. 2021;37(1):23. doi:10.1186\/s42826-021-00101-4\"},{\"id\":\"f22ea257-0ab6-4bd2-ad29-c59d32cdda61\",\"content\":\"Bunner AE, Chandrasekera PC, Barnard ND. Knockout mouse models of insulin signaling: relevance past and future. <em>World J Diabetes<\/em>. 2014;5(2):146-159. doi:10.4239\/wjd.v5.i2.146\"},{\"id\":\"d711ff14-8e6d-4927-9f65-cb0d2b9d86d0\",\"content\":\"Rogal J, Zbinden A, Schenke-Layland K, Loskill P. Stem-cell based organ-on-a-chip models for diabetes research. <em>Adv Drug Deliv Rev<\/em>. 2019;140:101-128. doi:10.1016\/j.addr.2018.10.010\"},{\"id\":\"e30f9cd2-cdf2-467a-b4cd-26c17c99fcc5\",\"content\":\"Chandrasekera PC, Pippin JJ. Of rodents and men: species-specific glucose regulation and type 2 diabetes research. <em>ALTEX<\/em>. 2014;31(2):157-176. doi:10.14573\/altex.1309231\"},{\"id\":\"3f6d07cb-9410-46e3-9a25-a8c25a6c58a4\",\"content\":\"Wang B, P. CC, Pippin JJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. <em>Curr Diabetes Rev<\/em>. 2014;10(2):131-145. doi:10.2174\/1573399810666140508121012\"},{\"id\":\"86a9999f-a017-4225-b2c2-8c5d4a064658\",\"content\":\"Singh et al., 2024\"},{\"id\":\"60fde9d7-47ed-4c25-b2b3-8e8111108b61\",\"content\":\"Arndt T, J\u00f6rns A, Hedrich HJ, Lenzen S, Wedekind D. Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddm rats over time compared to other congenic LEW strains. <em>Clin Exp Immunol<\/em>. 2014;177(1):168-178. doi:10.1111\/cei.12323\"},{\"id\":\"858c6af8-fa4d-44f6-ae85-3336dfd17bb1\",\"content\":\"Mir-Coll J, Moede T, Paschen M, et al. Human islet microtissues as an in vitro and an in vivo model system for diabetes. <em>Int J Mol Sci<\/em>. 2021;22(4):1813. doi:10.3390\/ijms22041813\"},{\"id\":\"acf07f13-22a1-4619-afe8-fb37b99097c8\",\"content\":\"Joksimovic SL, Jevtovic-Todorovic V, Todorovic SM. The mechanisms of plasticity of nociceptive ion channels in painful diabetic neuropathy. <em>Front Pain Res (Lausanne)<\/em>. 2022;3:869735. doi:10.3389\/fpain.2022.869735\"},{\"id\":\"209c7d6c-df7b-4e18-92c8-18f002c33c97\",\"content\":\"Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. <em>Eur J Heart Fail<\/em>. 2017;19(1):43-53. doi:10.1002\/ejhf.633\"},{\"id\":\"dae01dad-95d5-483f-8ebf-b28c079f2477\",\"content\":\"Lieschke GJ, Currie PD. Animal models of human disease: zebrafish swim into view. <em>Nat Rev Genet<\/em>. 2007;8(5):353-367. doi:10.1038\/nrg2091\"},{\"id\":\"42239f74-e967-4ed1-bd7c-70e1639735f8\",\"content\":\"Covington BA, Chen W. Animal models for understanding the mechanisms of beta cell death during type 2 diabetes pathogenesis. <em>Biomedicines<\/em>. 2024;12(3):473. doi:10.3390\/biomedicines12030473\"},{\"id\":\"685997dc-6304-499a-9e46-2e6382171a0c\",\"content\":\"Inaishi J, Saisho Y. Ethnic similarities and differences in the relationship between beta cell mass and diabetes. <em>J Clin Med<\/em>. 2017;6(12):113. doi:10.3390\/jcm6120113\"},{\"id\":\"a31634e4-a5ff-42b3-bf9b-f472ca10c627\",\"content\":\"Kusuyama J, Alves-Wagner AB, Makarewicz NS, Goodyear LJ. Effects of maternal and paternal exercise on offspring metabolism. <em>Nat Metab<\/em>. 2020;2(9):858-872. doi:10.1038\/s42255-020-00274-7\"},{\"id\":\"d44f1095-ad37-48c6-967e-912592204bda\",\"content\":\"Pandey et al., <em>Animal Models in Diabetic Research<\/em>, 2023\"},{\"id\":\"921b9db1-bf0e-4e98-aecb-3de96684dba3\",\"content\":\"Rogal et al., 2019\"},{\"id\":\"0c743c36-f712-4726-a55a-ddc534ef96e1\",\"content\":\"Pandey et al., <em>Animal Models in Diabetic Research<\/em>, 2023\"},{\"id\":\"c04e205f-e2b8-4bc6-9f38-21a1597456b0\",\"content\":\"Bunner et al., 2014\"},{\"id\":\"5302ab5c-8233-42c1-af54-5381f693f4ab\",\"content\":\"Ali Z, Chandrasekera PC, Pippin JJ. Animal research for type 2 diabetes mellitus, its limited translation for clinical benefit, and the way forward. <em>Altern Lab Anim<\/em>. 2018;46(1):13-22. doi:10.1177\/026119291804600101\"},{\"id\":\"44692265-c894-4db3-b4aa-3b0aee4d9e56\",\"content\":\"Petrosyan A, Cravedi P, Villani V, et al. A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier. <em>Nat Commun<\/em>. 2019;10(1):3656. doi:10.1038\/s41467-019-11577-z\"},{\"id\":\"f0043d28-9f95-48de-9e1c-adc9f5c2e405\",\"content\":\"Perin L, Da Sacco S. Generation of a glomerular filtration barrier on a glomerulus-on-a-chip platform. <em>Methods Mol Biol<\/em>. 2022;2373:121-131. doi:10.1007\/978-1-0716-1693-2_8\"},{\"id\":\"c2cb5737-725a-4f48-a58d-1b41b153f68e\",\"content\":\"Glieberman AL, Pope BD, Zimmerman JF, et al. Synchronized stimulation and continuous insulin sensing in a microfluidic human islet on a chip designed for scalable manufacturing. <em>Lab Chip<\/em>. 2019;19(18):2993-3010. doi:10.1039\/C9LC00253G\"},{\"id\":\"30bcd6ed-3a07-4a9c-84c7-d07ff7d1a03e\",\"content\":\"Riyaphan J, Pham DC, Leong MK, Weng CF. In silico approaches to identify polyphenol compounds as \u03b1-glucosidase and \u03b1-amylase inhibitors against type-II diabetes. <em>Biomolecules<\/em>. 2021;11(12):1877. doi:10.3390\/biom11121877\"},{\"id\":\"3be906f0-c3e3-4cc2-a495-175ffe626fd8\",\"content\":\"Moinul M, Amin SA, Kumar P, et al. Exploring sodium glucose cotransporter (SGLT2) inhibitors with machine learning approach: a novel hope in anti-diabetes drug discovery. <em>J Mol Graph Model<\/em>. 2022;111:108106. doi:10.1016\/j.jmgm.2021.108106\"},{\"id\":\"39d47f23-c7e6-402c-9d28-918904685942\",\"content\":\"Han K, Ma S, Sun J, et al. In silico modeling of patient-specific blood rheology in type 2 diabetes mellitus. <em>Biophys J<\/em>. 2023;122(8):1445-1458. doi:10.1016\/j.bpj.2023.03.010\"},{\"id\":\"cd041d9e-460a-427c-a29d-a1857d5be948\",\"content\":\"Piersanti A, Pacini G, Tura A, D\u2019Argenio DZ, Morettini M. An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin. <em>Sci Rep<\/em>. 2024;14(1):10936. doi:10.1038\/s41598-024-61293-y\"},{\"id\":\"0771f530-192a-499d-b750-ffb500715fbd\",\"content\":\"Pandey et al., 2023\"},{\"id\":\"c64b7c17-a34d-40fb-866d-61d5f747cd76\",\"content\":\"Saiding Q, Ma J, Ke C, Cui W. From \u201corgans on a chip\u201d to \u201cpatient on a chip.\u201d <em>Innovation<\/em>. 2022;3(5). doi:10.1016\/j.xinn.2022.100282\"},{\"id\":\"6ff7d71d-7cdb-48ca-a7df-e20ac4786b6a\",\"content\":\"Rogal et al., 2019\"},{\"id\":\"aa7808d1-ccd1-4cf3-9b63-e04658b8bbde\",\"content\":\"Tao T, Wang Y, Chen W, et al. Engineering human islet organoids from iPSCs using an organ-on-chip platform. <em>Lab Chip<\/em>. 2019;19(6):948-958. doi:10.1039\/C8LC01298A\"},{\"id\":\"41bcd3ad-1d97-4d89-ad10-21e0e4c93145\",\"content\":\"Rodr\u00edguez-Comas J, Ram\u00f3n-Azc\u00f3n J. Islet-on-a-chip for the study of pancreatic \u03b2-cell function. <em>In vitro models<\/em>. 2022;1(1):41-57. doi:10.1007\/s44164-021-00005-6\"},{\"id\":\"f63c9ded-49b5-4b46-869f-a65bba1c8876\",\"content\":\"Abadpour S, Aizenshtadt A, Olsen PA, et al. Pancreas-on-a-chip technology for transplantation applications. <em>Curr Diab Rep<\/em>. 2020;20(12):72. doi:10.1007\/s11892-020-01357-1\"},{\"id\":\"5504406f-3b1e-44b7-9184-fa1f6b68e63c\",\"content\":\"Sokolowska P, Zukowski K, Janikiewicz J, Jastrzebska E, Dobrzyn A, Brzozka Z. Islet-on-a-chip: biomimetic micropillar-based microfluidic system for three-dimensional pancreatic islet cell culture. <em>Biosens Bioelectron<\/em>. 2021;183:113215. doi:10.1016\/j.bios.2021.113215\"},{\"id\":\"7f0642c5-e462-4edd-aea0-04bea6a930f0\",\"content\":\"Kim M, Jang J. Construction of 3D hierarchical tissue platforms for modeling diabetes. <em>APL Bioeng<\/em>. 2021;5(4):041506. doi:10.1063\/5.0055128\"},{\"id\":\"ed855932-6197-4ca0-95fd-5db032564172\",\"content\":\"Kottaisamy et al., 2021\"},{\"id\":\"5bbf758b-f16c-41a4-bfec-460eaa861d89\",\"content\":\"Antony JM, MacDonald KS. A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1\/SIV vaccine efficacy. <em>Vaccine<\/em>. 2015;33(27):3073-3083. doi:10.1016\/j.vaccine.2014.12.004\"},{\"id\":\"691a380a-a5dc-4ecd-8e3a-26aea1b9a26c\",\"content\":\"Centlivre M, Combadi\u00e8re B. New challenges in modern vaccinology. <em>BMC Immunol<\/em>. 2015;16(1):18. doi:10.1186\/s12865-015-0075-2\"},{\"id\":\"fd011132-72e5-4599-a105-4b865c846131\",\"content\":\"Haigwood NL. Update on animal models for HIV research. <em>Eur J Immunol<\/em>. 2009;39(8):1994-1999. doi:10.1002\/eji.200939576\"},{\"id\":\"947ee380-bf77-458a-b11a-1b73f8bb08d5\",\"content\":\"J\u00fclg B, Barouch DH. Novel immunological strategies for HIV-1 eradication. <em>J Virus Erad<\/em>. 2015;1(4):232-236.\"},{\"id\":\"e0d2d497-a11e-42e8-9028-cfb2005abeaf\",\"content\":\"Girard M, Habel A, Chanel C. New prospects for the development of a vaccine against human immunodeficiency virus type 1. An overview. <em>Comptes Rendus de l\u2019Acad\u00e9mie des Sciences - Series III - Sciences de la Vie<\/em>. 1999;322(11):959-966. doi:10.1016\/S0764-4469(00)87193-0\"},{\"id\":\"fd9ccee5-d94b-4975-99ba-ce0dcfabe145\",\"content\":\"Hu SL. Non-human primate models for AIDS vaccine research. <em>Curr Drug Targets Infect Disord<\/em>. 2005;5(2):193-201. doi:10.2174\/1568005054201508\"},{\"id\":\"31c78c72-a1e4-4e0b-932c-21417c7a9342\",\"content\":\"National Institute of Allergy and Infectious Diseases. History of HIV vaccine research. niaid.nih.gov. October 22, 2018. Accessed December 5, 2024. https:\/\/www.niaid.nih.gov\/diseases-conditions\/hiv-vaccine-research-history\"},{\"id\":\"bd0ef70e-9918-40b3-8774-34b0c6524cc7\",\"content\":\"PreEPVacc. HIV vaccines tested in PrEPVacc fail to reduce infections. July 23, 2024. Accessed October 18, 2024. https:\/\/www.prepvacc.org\/news\/hiv-vaccines-tested-in-prepvacc-fail-to-reduce-infections-23-july-news-release\"},{\"id\":\"ff5ca556-0244-440a-baf3-b8228abd4389\",\"content\":\"Sekaly RP. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? <em>J Exp Med<\/em>. 2008;205(1):7-12. doi:10.1084\/jem.20072681\"},{\"id\":\"6c940557-c7ae-4372-ae6a-4062a7bd3747\",\"content\":\"Cohen J. \u201cIt\u2019s sobering\u201d: a once-exciting HIV cure strategy fails its test in people. <em>Science<\/em>. July 25, 2018. Accessed February 7, 2022. https:\/\/www.science.org\/content\/article\/it-s-sobering-once-exciting-hiv-curestrategy-fails-its-test-people\"},{\"id\":\"7e5d28ab-b432-4efe-85ba-a9de952787f3\",\"content\":\"Matthews H, Hanison J, Nirmalan N. \u201cOmics\u201d-informed drug and biomarker discovery: opportunities, challenges and future perspectives. <em>Proteomes<\/em>. 2016;4(3):28. doi:10.3390\/proteomes4030028\"},{\"id\":\"ccf58197-a4c7-42e7-9c73-5076bd8a7326\",\"content\":\"Haigwood, 2009\"},{\"id\":\"212aba32-9855-4565-9282-e0f815170d8b\",\"content\":\"Antony &amp; MacDonald, 2015\"},{\"id\":\"8b7df6e5-f6b4-4699-aab7-fc4b152fd96e\",\"content\":\"O\u2019Dell R. Sickness and death at Mesa-area monkey farm threaten primate center viability. <em>azcentral.com<\/em>. October 5, 2021. Accessed March 2, 2022. <a href=\\\"https:\/\/www.peta.org\/wp-content\/uploads\/2021\/10\/202110-04-Sickness-and-death-at-Mesa-area-monkey-farm-threaten-primate-center-viability.pdf\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.peta.org\/wp-content\/uploads\/2021\/10\/202110-04-Sickness-and-death-at-Mesa-area-monkey-farm-threaten-primate-center-viability.pdf<\/a>\u202f\"},{\"id\":\"ac291439-9fd0-4b7d-a1c4-87bfecfb2f0b\",\"content\":\"Rao M, Alving CR. Adjuvants for HIV vaccines. <em>Curr Opin HIV AIDS<\/em>. 2016;11(6):585-592. doi:10.1097\/COH.0000000000000315\"},{\"id\":\"e950dc7d-ba59-4fe2-88c9-7b4c37297cfb\",\"content\":\"Tonks A. Quest for the AIDS vaccine. <em>BMJ<\/em>. 2007;334(7608):1346-1348. doi:10.1136\/bmj.39240.416968.AD\"},{\"id\":\"de80b1cc-ff4a-4cd6-b0c9-f5c3ff8bfc52\",\"content\":\"Kumar N, Chahroudi A, Silvestri G. Animal models to achieve an HIV cure. <em>Curr Opin HIV AIDS<\/em>. 2016;11(4):432-441. doi:10.1097\/COH.0000000000000290\u00a0\"},{\"id\":\"fea94a25-6186-4382-b9dc-6b93c88abc08\",\"content\":\"Deeks HM, Walters RK, Hare SR, O\u2019Connor MB, Mulholland AJ, Glowacki DR. Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking. Paci E, ed. <em>PLoS One<\/em>. 2020;15(3):e0228461. doi:10.1371\/journal.pone.0228461\"},{\"id\":\"a532aecc-0fa7-4532-bca6-5398c1f8b21e\",\"content\":\"Baassi M, Moussaoui M, Soufi H, et al. Towards designing of a potential new HIV-1 protease inhibitor using QSAR study in combination with molecular docking and molecular dynamics simulations. Ghosh A, ed. <em>PLoS One<\/em>. 2023;18(4):e0284539. doi:10.1371\/journal.pone.0284539\u00a0\"},{\"id\":\"a30c0a94-ff81-4a61-a8de-26889bb06ad2\",\"content\":\"Zhang YJ, Chen L, Xu J, et al. Evaluation of novel HIV-1 protease inhibitors with DRV-resistance by utilizing 3D-QSAR molecular docking and molecular dynamics simulation. <em>New J Chem<\/em>. 2022;46(45):21885-21897. doi:10.1039\/D2NJ04492G\u00a0\"},{\"id\":\"4bff9792-36f1-4f95-b5d2-5272f4353e62\",\"content\":\"Wang R, Zheng Q. Multiple molecular dynamics simulations and energy analysis unravel the dynamic properties and binding mechanism of mutants HIV-1 protease with DRV and CA-p2. <em>Microbiol Spectr<\/em>. 2022;10(2):e0074821. doi:10.1128\/spectrum.00748-21\"},{\"id\":\"3cf51db2-8e6a-4609-83db-3b54784af073\",\"content\":\"Saha I, Saffarian S. Dynamics of the HIV Gag lattice detected by localization correlation analysis and time-lapse iPALM. <em>Biophys J<\/em>. 2020;119(3):581-592. doi:10.1016\/j.bpj.2020.06.023\"},{\"id\":\"8d9b0e43-f194-42aa-85cb-88836a341fcf\",\"content\":\"Xie G, Luo X, Ma T, et al. Characterization of HIV-induced remodeling reveals differences in infection susceptibility of memory CD4+ T cell subsets in vivo. <em>Cell Rep<\/em>. 2021;35(4):109038. doi:10.1016\/J.CELREP.2021.109038\/ATTACHMENT\/DD9335E3-A2AE-4B21-B703-B888B3ACCC05\/MMC1.PDF\u00a0\"},{\"id\":\"8624236b-267a-4a8e-80e5-273f333c9ad3\",\"content\":\"Collora JA, Liu R, Pinto-Santini D, et al. Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones. <em>Immunity<\/em>. 2022;55(6):1013-1031.e7. doi:10.1016\/j.immuni.2022.03.004\u00a0\"},{\"id\":\"9e2d8fee-c83a-4b26-ab43-4a9675673e2b\",\"content\":\"Ma T, McGregor M, Giron L, et al. Single-cell glycomics analysis by CyTOF-Lec reveals glycan features defining cells differentially susceptible to HIV. <em>eLife<\/em>. 2022;11:e78870. doi:10.7554\/eLife.78870\u00a0\"},{\"id\":\"95da9a6a-fe0c-4619-a12f-e5e223b7cca4\",\"content\":\"Wang XM, Zhang JY, Xing X, et al. Global transcriptomic characterization of T cells in individuals with chronic HIV-1 infection. <em>Cell Discov<\/em>. 2022;8(1):29. doi:10.1038\/s41421-021-00367-x\u00a0\"},{\"id\":\"17bab855-46cc-4186-85db-e09a2ac641ef\",\"content\":\"Galperin M, Farenc C, Mukhopadhyay M, et al. CD4 <sup>+<\/sup> T cell\u2013mediated HLA class II cross-restriction in HIV controllers. <em>Sci Immunol<\/em>. 2018;3(24):eaat0687. doi:10.1126\/sciimmunol.aat0687\"},{\"id\":\"162ead82-a6d8-45d6-ab0a-d8492e7eb17b\",\"content\":\"Claireaux M, Robinot R, Kervevan J, et al. Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry. <em>Nat Commun<\/em>. 2022;13(1):521. doi:10.1038\/s41467-022-28130-0\u00a0\"},{\"id\":\"b3fa3635-ec79-4fe9-83d1-aec0141aeb80\",\"content\":\"Etemad B, Sun X, Li Y, et al. HIV post-treatment controllers have distinct immunological and virological features. <em>Proc Natl Acad Sci USA<\/em>. 2023;120(11):e2218960120. doi:10.1073\/pnas.2218960120\u00a0\"},{\"id\":\"4584cf68-2da0-4527-af9a-d61666458ccf\",\"content\":\"Real LM, S\u00e1ez ME, Corma-G\u00f3mez A, et al. A metagenome-wide association study of HIV disease progression in HIV controllers. <em>iScience<\/em>. 2023;26(7):107214. doi:10.1016\/j.isci.2023.107214\"},{\"id\":\"13a969ed-7287-4251-8d6a-f8c4fac36b15\",\"content\":\"Kennedy BD, Blazkova J, Justement JS, et al. Comprehensive analysis of HIV reservoirs in elite controllers. <em>J Clin Invest<\/em>. 2023;133(3):e165446. doi:10.1172\/JCI165446\u00a0\"},{\"id\":\"ba0d86e2-86bd-43d0-8fa8-23f00d79134e\",\"content\":\"Shi Y, Su J, Chen R, et al. The role of innate immunity in natural elite controllers of HIV-1 infection. <em>Front Immunol<\/em>. 2022;13:780922. doi:10.3389\/fimmu.2022.780922\u00a0\"},{\"id\":\"e68a59c6-dff5-4701-8d42-94d0ca8d05bd\",\"content\":\"Cait J, Cait A, Scott RW, Winder CB, Mason GJ. Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis. <em>BMC Biol<\/em>. 2022;20(1):1-22. doi:10.1186\/S12915-021-01184-0\/TABLES\/2\u00a0\"},{\"id\":\"64baf987-b033-4d02-8057-d48a8eb446d0\",\"content\":\"Maulana TI, Kromidas E, Wallstabe L, et al. Immunocompetent cancer-on-chip models to assess immuno-oncology therapy. <em>Adv Drug Deliv Rev<\/em>. 2021;173:281-305. doi:10.1016\/j.addr.2021.03.015\"},{\"id\":\"acdc8a1f-7ba2-48e5-8092-6c7e288ab443\",\"content\":\"Mestas J, Hughes CCW. Of mice and not men: differences between mouse and human immunology. <em>J Immunol<\/em>. 2004;172(5):2731-2738. doi:10.4049\/jimmunol.172.5.2731\"},{\"id\":\"29d5a1f1-893f-4c4c-80bd-9aba0e053b89\",\"content\":\"Zschaler J, Schlorke D, Arnhold J. Differences in innate immune response between man and mouse. <em>Crit Rev Immunol<\/em>. 2014;34(5):433-454.\"},{\"id\":\"9c3301e1-207e-4f94-8881-7bd7acfc9c4e\",\"content\":\"Johnson MD, Witherden DA, Havran WL. The role of tissue-resident T cells in stress surveillance and tissue maintenance. <em>Cells<\/em>. 2020;9(3):686. doi:10.3390\/cells9030686\"},{\"id\":\"8d031a6b-6b2b-4a42-afa6-7a58fdf651b0\",\"content\":\"Leukemia &amp; Lymphoma Society. Understanding blood counts. LLS.org. Accessed October 3, 2024. <a href=\\\"https:\/\/www.lls.org\/treatment\/lab-and-imaging-tests\/understanding-blood-counts\\\">https:\/\/www.lls.org\/treatment\/lab-and-imaging-tests\/understanding-blood-counts<\/a>\"},{\"id\":\"afe94fd7-d6f8-4eca-961c-c223e14a0f92\",\"content\":\"Provencher Bolliger A, Everds N, Zimmerman K, Moore D, Smith S, Barnhart K. Hematology of laboratory animals. In: <em>Schalm\u2019s Veterinary Hematology<\/em>. Wiley-Blackwell; 2010:852-887\"},{\"id\":\"41356df1-cf70-4255-8db9-775bc9d5e936\",\"content\":\"Medetgul-Ernar K, Davis MM. Standing on the shoulders of mice. <em>Immunity<\/em>. 2022;55(8):1343-1353. doi:10.1016\/j.immuni.2022.07.008\"},{\"id\":\"f8f0a535-012a-4e7e-a266-1e483e7e1a05\",\"content\":\"Bjornson-Hooper ZB, Fragiadakis GK, Spitzer MH, et al. A comprehensive atlas of immunological differences between humans, mice, and non-human primates. <em>Front Immunol<\/em>. 2022;13. doi:10.3389\/fimmu.2022.867015\"},{\"id\":\"7a6e3743-f714-4639-852f-c4c3a825e969\",\"content\":\"Leist M, Hartung T. Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. <em>Arch Toxicol<\/em>. 2013;87(4):563-567. doi:10.1007\/s00204-013-1038-0\"},{\"id\":\"9e01d8ef-4e0c-44d3-ba1f-001a6e6d645e\",\"content\":\"Mestas &amp; Hughes, 2004\"},{\"id\":\"37da492c-af45-490c-9b6a-8543467fa9d1\",\"content\":\"Bjornson-Hooper et al., 2022\"},{\"id\":\"72afd8b1-3651-4048-ae5d-46e24ea94224\",\"content\":\"Gros P, Casanova JL. Reconciling mouse and human immunology at the altar of genetics. <em>Ann Rev Immunol<\/em>. 2023;41:39-71. doi:10.1146\/annurev-immunol-101721-065201\"},{\"id\":\"3f10983f-1bc6-4461-a24b-9fc31d40be7f\",\"content\":\"B\u00e9ziat V, Rapaport F, Hu J, et al. Humans with inherited T\u202fcell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy. <em>Cell<\/em>. 2021;184(14):3812-3828.e30. doi:10.1016\/j.cell.2021.06.004\"},{\"id\":\"5ce45f89-9bd1-4c46-8635-d55770c8ff27\",\"content\":\"Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. <em>Br J Pharmacol<\/em>. 2010;161(3):512-526. doi:10.1111\/j.1476-5381.2010.00922.x\"},{\"id\":\"62fbf8f3-2558-491e-8747-4d16ac1714a5\",\"content\":\"Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. <em>Gut Microbes<\/em>. 2012;3(1):4-14. doi:10.4161\/gmic.19320\"},{\"id\":\"d1644946-e86d-4e6c-8efa-1e1482d09199\",\"content\":\"Nguyen TLA, Vieira-Silva S, Liston A, Raes J. How informative is the mouse for human gut microbiota research? <em>Dis Model Mech<\/em>. 2015;8(1):1-16. doi:10.1242\/dmm.017400\"},{\"id\":\"51ddb5d0-b90f-4a76-9321-f4ea28d14631\",\"content\":\"Beresford-Jones BS, Forster SC, Stares MD, et al. The Mouse Gastrointestinal Bacteria Catalogue enables translation between the mouse and human gut microbiotas via functional mapping.\u00a0<em>Cell Host Microbe<\/em>. 2022;30(1):124-138.e8. doi:10.1016\/j.chom.2021.12.003\"},{\"id\":\"1a99fb6b-2fc8-41d1-bbbb-ac48624aefd1\",\"content\":\"Gros &amp; Casanova, 2023\"},{\"id\":\"8d3ff126-87fa-4f93-9e8d-f9610aed9d9d\",\"content\":\"Pulendran B, Davis MM. The science and medicine of human immunology. <em>Science<\/em>. 2020;369(6511):eaay4014. doi:10.1126\/science.aay4014\"},{\"id\":\"53fabe99-4180-4bd8-8807-a1bf300156ff\",\"content\":\"Pulendran &amp; Davis, 2020\"},{\"id\":\"348f49f5-b9c6-4923-ab8d-5f5b7841f538\",\"content\":\"Martin MD, Sompallae R, Winborn CS, Harty JT, Badovinac VP. Diverse CD8 T cell responses to viral infection revealed by the collaborative cross. <em>Cell Rep<\/em>. 2020;31(2). doi:10.1016\/j.celrep.2020.03.072\"},{\"id\":\"51876190-2d5e-4c7d-acbe-3769bf0fe093\",\"content\":\"Ehling P, Meuth P, Eichinger P, et al. Human T cells in silico: modelling their electrophysiological behaviour in health and disease. <em>J Theor Biol<\/em>. 2016;404:236-250. doi:10.1016\/j.jtbi.2016.06.001\"},{\"id\":\"a89d3e28-3bfb-4c44-a100-f2a2e1677392\",\"content\":\"Cappuccio A, Tieri P, Castiglione F. Multiscale modelling in immunology: a review. <em>Brief Bioinform<\/em>. 2016;17(3):408-418. doi:10.1093\/bib\/bbv012\"},{\"id\":\"b98a3765-1a86-4ed5-b8fe-7e37032bdf87\",\"content\":\"Day JD, Metes DM, Vodovotz Y. Mathematical modeling of early cellular innate and adaptive immune responses to ischemia\/reperfusion injury and solid organ allotransplantation. <em>Front Immunol<\/em>. 2015;6. doi:10.3389\/fimmu.2015.00484\"},{\"id\":\"15d069ae-4d90-4281-9805-7f389cfff709\",\"content\":\"Wagar LE, Salahudeen A, Constantz CM, et al. Modeling human adaptive immune responses with tonsil organoids. <em>Nat Med<\/em>. 2021;27(1):125-135. doi:10.1038\/s41591-020-01145-0\"},{\"id\":\"5694b598-9785-41ba-a37f-8db92f3ff39f\",\"content\":\"Halliley JL, Tipton CM, Liesveld J, et al. Long-lived plasma cells are contained within the CD19\u2212CD38hiCD138+ subset in human bone marrow. <em>Immunity<\/em>. 2015;43(1):132-145. doi:10.1016\/j.immuni.2015.06.016\"},{\"id\":\"e0d7d79e-4b97-455e-8e44-0d3de37c47bc\",\"content\":\"Shou Y, Johnson SC, Quek YJ, Li X, Tay A. Integrative lymph node\u2013mimicking models created with biomaterials and computational tools to study the immune system. <em>Mater Today Bio<\/em>. 2022;14:100269. doi:10.1016\/j.mtbio.2022.100269\"},{\"id\":\"c3d97ba9-469d-4167-b365-67ca8fb1c792\",\"content\":\"Wagar et al., 2021\"},{\"id\":\"e2dc6cd4-424e-497e-b88b-a250becceaac\",\"content\":\"Gill US, Pallett LJ, Thomas N, et al. Fine needle aspirates comprehensively sample intrahepatic immunity. <em>Gut<\/em>. 2019;68(8):1493-1503. doi:10.1136\/gutjnl-2018-317071\"},{\"id\":\"2a37d948-a323-4dc5-b596-86514b8f1a23\",\"content\":\"Bergers LIJC, Reijnders CMA, van den Broek LJ, et al. Immune-competent human skin disease models. <em>Drug Discov Today<\/em>. 2016;21(9):1479-1488. doi:10.1016\/j.drudis.2016.05.008\"},{\"id\":\"c5328c41-0091-4932-acf1-c8f07f2de141\",\"content\":\"Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study. <em>Lancet<\/em>. 2020;395(10219):200-211. doi:10.1016\/S0140-6736(19)32989-7\"},{\"id\":\"ae392600-303c-49f5-8594-71f8a226f3fb\",\"content\":\"Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. <em>JAMA<\/em>. 2014;312(1):90-92. doi:10.1001\/jama.2014.5804\"},{\"id\":\"84c2ad96-b605-47c4-a395-b818d8ca66a8\",\"content\":\"Torio CM, Moore BJ. National inpatient hospital costs: the most expensive conditions by payer, 2013. In: <em>Healthcare Cost and Utilization Project (HCUP) Statistical Briefs<\/em>. Agency for Healthcare Research and Quality (U.S.); 2006. Accessed December 5, 2024. <a href=\\\"http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK368492\/\\\">http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK368492\/<\/a>\"},{\"content\":\"Azevedo LCP, Cavalcanti AB, Lisboa T, et al. Sepsis is an important healthcare burden in Latin America: A call to action! A sepse \u00e9 um grave problema de sa\u00fade na Am\u00e9rica Latina: uma chamada \u00e0 a\u00e7\u00e3o!.\u00a0<em>Rev Bras Ter Intensiva<\/em>. 2018;30(4):402-404. doi:10.5935\/0103-507X.20180061\",\"id\":\"5e2a6c80-3559-4ff8-8bbf-fe90dc470af5\"},{\"id\":\"4ab6ecbd-f4d7-4917-857e-81da0f368917\",\"content\":\"Verma S. Laboratory animal models to mimic human sepsis: a review. <em>Res Rev J Zool Sci<\/em>. May 28, 2016. Accessed December 5, 2024. <a href=\\\"https:\/\/www.semanticscholar.org\/paper\/Laboratory-Animal-Models-to-Mimic-Human-Sepsis%3A-A-Verma\/8d933dca987c3db1a9e29c960416b07a47b7105a\\\">https:\/\/www.semanticscholar.org\/paper\/Laboratory-Animal-Models-to-Mimic-Human-Sepsis%3A-A-Verma\/8d933dca987c3db1a9e29c960416b07a47b7105a<\/a>\"},{\"id\":\"71a2860c-9e9c-47eb-a34a-ea38fdbed8d9\",\"content\":\"Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. <em>Proc Natl Acad Sci U S A<\/em>. 2013;110(9):3507-3512. doi:10.1073\/pnas.1222878110\"},{\"id\":\"fa11862a-51c6-4904-9fee-bf1e3a30dd10\",\"content\":\"Collins F. Of mice, men, and medicine. NIH. February 19, 2013. Accessed October 31, 2022.\u00a0https:\/\/us.pagefreezer.com\/en-US\/wa\/browse\/c530da90-f454-461b-9a86-959c53acb16c?url=https:%2F%2Fdirectorsblog.nih.gov%2F2013%2F02%2F19%2Fof-mice-men-and-medicine%2F&amp;timestamp=2025-05-27T10:13:51Z\"},{\"id\":\"5a2071c5-6ef1-496f-9b1e-d5bc2c57e2cb\",\"content\":\"Collins, <em>Of Mice, Men, and Medicine<\/em>, 2013.\"},{\"id\":\"672a37b7-a8d4-4e08-b77c-255ce0951cce\",\"content\":\"Esmon CT. Why do animal models (sometimes) fail to mimic human sepsis? <em>Crit Care Med<\/em>. 2004;32(5 Suppl):S219-222. doi:10.1097\/01.ccm.0000127036.27343.48\"},{\"id\":\"144dc1e0-30e2-42ff-ba10-3d82d0598aa4\",\"content\":\"Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of sepsis and human sepsis. <em>J Leukoc Biol<\/em>. 2007;81(1):137-143. doi:10.1189\/jlb.0806542\"},{\"id\":\"7a2f7943-7793-41b5-81c3-6720fe4b887e\",\"content\":\"Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. <em>Nat Rev Drug Discov<\/em>. 2005;4(10):854-865. doi:10.1038\/nrd1854\"},{\"id\":\"fc538274-1545-45d8-8ed6-b2c2475b7c93\",\"content\":\"Nemzek JA, Hugunin KMS, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. <em>Comp Med<\/em>. 2008;58(2):120-128.\"},{\"id\":\"ce8396bc-62be-40fe-8690-93373242d41f\",\"content\":\"Joffre J. Preclinical model in sepsis: should we abandon the CLP? <em>J Inflamm Res<\/em>. 2023;16:1757-1759. doi:10.2147\/JIR.S415972\"},{\"id\":\"c343fa9a-015b-49ac-813f-a808eb1ce42a\",\"content\":\"Buras et al., <em>Animal Models of Sepsis: Setting the Stage<\/em>, 2005.\"},{\"id\":\"fd240d66-c2c2-4fb0-a50b-802b9bea1af6\",\"content\":\"Redl H, Bahrami S. Large animal models: baboons for trauma, shock, and sepsis studies. <em>Shock<\/em>. 2005;24 Suppl 1:88-93. doi:10.1097\/01.shk.0000191339.46777.63\"},{\"id\":\"2aff7613-3913-4cef-9984-f332596cae38\",\"content\":\"Fink MP. Animal models of sepsis. <em>Virulence<\/em>. 2014;5(1):143-153. doi:10.4161\/viru.26083\"},{\"id\":\"84ac3132-fe9e-46d3-b53c-e564dd62fe49\",\"content\":\"Hawash MBF, Sanz-Rem\u00f3n J, Grenier JC, et al. Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity. <em>Proc Natl Acad Sci U S A<\/em>. 2021;118(13):e2015855118. doi:10.1073\/pnas.2015855118\"},{\"id\":\"cba825d9-a6b9-4d8d-ae79-4aa3a4572f23\",\"content\":\"NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022\"},{\"id\":\"306e53ee-17f2-4d95-8e3e-5edd158d9d9c\",\"content\":\"NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022.\"},{\"id\":\"2ee291f7-7a8a-477d-b14a-24143e4ea365\",\"content\":\"Hays A. Major health agency slashes funding for sepsis experiments on animals after push from PETA. PETA. June 18, 2024. Accessed December 5, 2024. <a href=\\\"https:\/\/www.peta.org\/blog\/major-health-agency-slashes-funding-for-sepsis-experiments-on-animals\/\\\">https:\/\/www.peta.org\/blog\/major-health-agency-slashes-funding-for-sepsis-experiments-on-animals\/<\/a>\"},{\"id\":\"0a687cc1-d57c-4d56-9940-a307ce2b6be5\",\"content\":\"NIGMS. (2019). <em>Priorities for sepsis research.<\/em> Retrieved February 9, 2022\"},{\"id\":\"4e40a7d9-f652-4dc0-ad61-7351938898d9\",\"content\":\"Lilley E, Armstrong R, Clark N, et al. Refinement of animal models of sepsis and septic shock. <em>Shock<\/em>. 2015;43(4):304-316. doi:10.1097\/SHK.0000000000000318\"},{\"id\":\"74c35407-82d3-429a-9170-646e670bc3ba\",\"content\":\"Li Y, Nie Y, Yang X, et al. Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis. <em>Cell Rep<\/em>. 2024;43(3):113918. doi:10.1016\/j.celrep.2024.113918\"},{\"id\":\"0502e20c-9f16-4f09-baa2-c922aa359819\",\"content\":\"Yang Q, Langston JC, Prosniak R, et al. Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity. <em>Front Immunol<\/em>. 2024;15:1341752. doi:10.3389\/fimmu.2024.1341752\"},{\"id\":\"a09f042c-a14e-4a37-af85-c44bd8698691\",\"content\":\"Yang X, Pu X, Xu Y, et al. A novel prognosis evaluation indicator of patients with sepsis created by integrating six microfluidic-based neutrophil chemotactic migration parameters. <em>Talanta<\/em>. 2024;281:126801. doi:10.1016\/j.talanta.2024.126801\"},{\"id\":\"6be35304-9b3f-460e-8555-01e234414b60\",\"content\":\"Sakuma M, Wang X, Ellett F, et al. Microfluidic capture of chromatin fibres measures neutrophil extracellular traps (NETs) released in a drop of human blood. <em>Lab Chip<\/em>. 2022;22(5):936-944. doi:10.1039\/d1lc01123e\"},{\"id\":\"b2091492-ceda-4d8e-a415-5fd9bf06d708\",\"content\":\"Marik PE, Farkas JD. The changing paradigm of sepsis: early diagnosis, early antibiotics, early pressors, and early adjuvant treatment. <em>Crit Care Med<\/em>. 2018;46(10):1690-1692. doi:10.1097\/CCM.0000000000003310\"},{\"id\":\"13bd5a62-32f4-4841-bcda-510cc4c7b9e2\",\"content\":\"Goh KH, Wang L, Yeow AYK, et al. Artificial intelligence in sepsis early prediction and diagnosis using unstructured data in healthcare. <em>Nat Commun<\/em>. 2021;12(1):711. doi:10.1038\/s41467-021-20910-4\"},{\"id\":\"6e0849ea-9eed-40fa-acb8-f9c6aa853a74\",\"content\":\"Rosnati M, Fortuin V. MGP-AttTCN: An interpretable machine learning model for the prediction of sepsis. <em>PLoS One<\/em>. 2021;16(5):e0251248. doi:10.1371\/journal.pone.0251248\"},{\"id\":\"675d4f40-91d5-4534-88b2-1c69d5ebe7c6\",\"content\":\"Honor\u00e9 A, Forsberg D, Adolphson K, Chatterjee S, Jost K, Herlenius E. Vital sign-based detection of sepsis in neonates using machine learning. <em>Acta Paediatr Oslo Nor 1992<\/em>. 2023;112(4):686-696. doi:10.1111\/apa.16660\"},{\"id\":\"e2ae2e42-2c61-421f-b49e-4863b4dda374\",\"content\":\"Sun B, Lei M, Wang L, et al. Prediction of sepsis among patients with major trauma using artificial intelligence: a multicenter validated cohort study. <em>Int J Surg Lond Engl<\/em>. Published online June 26, 2024. doi:10.1097\/JS9.0000000000001866\"},{\"id\":\"f601e191-3068-4a7d-a051-45baad3853f3\",\"content\":\"Gao J, Lu Y, Ashrafi N, Domingo I, Alaei K, Pishgar M. Prediction of sepsis mortality in ICU patients using machine learning methods. <em>BMC Med Inform Decis Mak<\/em>. 2024;24(1):228. doi:10.1186\/s12911-024-02630-z\"},{\"id\":\"3ac7ed50-c8b3-4d15-b499-1f2e4a14e1ef\",\"content\":\"Hang Y, Qu H, Yang J, et al. Exploration of programmed cell death-associated characteristics and immune infiltration in neonatal sepsis: new insights from bioinformatics analysis and machine learning. <em>BMC Pediatr<\/em>. 2024;24(1):67. doi:10.1186\/s12887-024-04555-y\"},{\"id\":\"3ebe7abf-ede3-473e-89d1-4b489da97faa\",\"content\":\"Boussina A, Shashikumar SP, Malhotra A, et al. Impact of a deep learning sepsis prediction model on quality of care and survival. <em>NPJ Digit Med<\/em>. 2024;7(1):14. doi:10.1038\/s41746-023-00986-6\"},{\"id\":\"97719922-c79b-4289-8c50-2ba0350fd80f\",\"content\":\"Giacobbe DR, Signori A, Del Puente F, et al. Early detection of sepsis with machine learning techniques: a brief clinical perspective. <em>Front Med<\/em>. 2021;8:617486. doi:10.3389\/fmed.2021.617486\"},{\"id\":\"3e860dc8-2651-4f71-bce7-062a90e5f08c\",\"content\":\"Steinbach D, Ahrens PC, Schmidt M, et al. Applying machine learning to blood count data predicts sepsis with ICU admission. <em>Clin Chem<\/em>. 2024;70(3):506-515. doi:10.1093\/clinchem\/hvae001\"},{\"id\":\"59a178f8-8781-4a3e-b606-99413f1d07e4\",\"content\":\"Peery AF, Murphy CC, Anderson C, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2024. <em>Gastroenterology<\/em>. 2025;168(5):1000-1024. doi:10.1053\/j.gastro.2024.12.029\"},{\"id\":\"ad910464-1694-4ecd-966c-bf099cde1281\",\"content\":\"Almario CV, Ballal ML, Chey WD, Nordstrom C, Khanna D, Spiegel BMR. Burden of gastrointestinal symptoms in the United States: results of a nationally representative survey of over 71,000 Americans. <em>Am J Gastroenterol<\/em>. 2018;113(11):1701-1710. doi:10.1038\/s41395-018-0256-8\"},{\"id\":\"e075402e-a5aa-407f-8089-f2b5fa1c1117\",\"content\":\"Mayer EA, Bradesi S, Chang L, Spiegel BMR, Bueller JA, Naliboff BD. Functional GI disorders: from animal models to drug development. <em>Gut<\/em>. 2008;57(3):384-404. doi:10.1136\/gut.2006.101675\"},{\"id\":\"9c724b9f-77e8-409a-b187-45541bbf2e9f\",\"content\":\"Sciascia Q, Da\u015f G, Metges CC. REVIEW: The pig as a model for humans: effects of nutritional factors on intestinal function and health1. <em>J Anim Sci<\/em>. 2016;94(suppl_3):441-452. doi:10.2527\/jas.2015-9788\"},{\"id\":\"62db0c02-6bf4-4d4b-926f-9dc9352759c7\",\"content\":\"DeSesso JM, Jacobson CF. Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. <em>Food Chem Toxicol<\/em>. 2001;39(3):209-228. doi:10.1016\/S0278-6915(00)00136-8\u00a0\"},{\"id\":\"1151c5a8-61f7-48b9-a909-7a55c593ad07\",\"content\":\"DeSesso &amp; Jacobson, 2001\"},{\"id\":\"377f6f1c-6e54-423d-89e1-e284c6a54e5b\",\"content\":\"Higashiyama H, Uemura M, Igarashi H, Kurohmaru M, Kanai\u2010Azuma M, Kanai Y. Anatomy and development of the extrahepatic biliary system in mouse and rat: a perspective on the evolutionary loss of the gallbladder. <em>J Anat<\/em>. 2018;232(1):134-145. doi:10.1111\/joa.12707\u00a0\"},{\"id\":\"a81ace1f-686c-4d29-b812-d6189aa29796\",\"content\":\"Gonzalez LM, Moeser AJ, Blikslager AT. Porcine models of digestive disease: the future of large animal translational research. <em>Transl Res<\/em>. 2015;166(1):12-27. doi:10.1016\/j.trsl.2015.01.004\"},{\"id\":\"8f9ff7f5-d1ce-4590-bdff-06d8d8302610\",\"content\":\"Clifton P. Meal patterning in rodents: psychopharmacological and neuroanatomical studies. <em>Neurosci Biobehav Rev<\/em>. 2000;24(2):213-222. doi:10.1016\/S0149-7634(99)00074-3\"},{\"id\":\"171f7ced-d186-43aa-b299-fe4c470f9f55\",\"content\":\"Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016.\"},{\"id\":\"0314f180-05d5-4f7d-8122-53497f394f6f\",\"content\":\"Han A, Hudson-Paz C, Robinson BG, et al. Temperature-dependent differences in mouse gut motility are mediated by stress. <em>Lab Anim<\/em>. 2024;53(6):148-159. doi:10.1038\/s41684-024-01376-5\"},{\"id\":\"08d2402a-efc6-4987-9d14-ced355060954\",\"content\":\"Harley ITW, Giles DA, Pfluger PT, et al. Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL\/6 mice. <em>Mol Metab<\/em>. 2013;2(3):171-183. doi:10.1016\/j.molmet.2013.04.004\"},{\"id\":\"5bdedddb-9ab0-4ed4-b7ab-e75196205472\",\"content\":\"Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016.\"},{\"id\":\"96f15b44-e375-4442-b63a-c86c95a3584a\",\"content\":\"Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. <em>Cell<\/em>. 2014;157(1):121-141. doi:10.1016\/j.cell.2014.03.011\"},{\"id\":\"c1564d1c-e472-4030-8d4e-416f469d4f96\",\"content\":\"Kriaa A, Mariaule V, De Rudder C, et al. From animal models to gut-on-chip: the challenging journey to capture inter-individual variability in chronic digestive disorders. <em>Gut Microbes<\/em>. 2024;16(1):2333434. doi:10.1080\/19490976.2024.2333434\"},{\"content\":\"Ram\u00edrez Aranda JM, Mart\u00ednez Guti\u00e9rrez CM, Fuentes Ram\u00edrez MM, et al. Agregaci\u00f3n familiar en el s\u00edndrome de colon irritable en pacientes mexicanos. Un estudio de casos y controles.\u00a0<em>Aten Primaria<\/em>. 2024;56(2):102794. doi:10.1016\/j.aprim.2023.102794\",\"id\":\"087348ee-2cae-4458-8053-02a0561223a4\"},{\"id\":\"8564b728-bf71-4475-aae9-cb890d58ca7b\",\"content\":\"Sciascia et al., <em>The Pig as a Model for Humans<\/em>, 2016\"},{\"id\":\"548eb557-1e85-4626-9aa2-43c24e47c8b2\",\"content\":\"Accarie A, Vanuytsel T. Animal models for functional gastrointestinal disorders. <em>Front Psychiatry<\/em>. 2020;11:509681. doi:10.3389\/fpsyt.2020.509681\"},{\"id\":\"6a5e556e-aad5-44ad-aa57-aa0ab2c9333c\",\"content\":\"Johnson AC, Farmer AD, Ness TJ, Greenwood\u2010Van Meerveld B. Critical evaluation of animal models of visceral pain for therapeutics development: a focus on irritable bowel syndrome. <em>Neurogastroenterol Motil<\/em>. 2020;32(4):e13776. doi:10.1111\/nmo.13776\"},{\"id\":\"71426e73-b382-415c-ba77-755bcd43b89b\",\"content\":\"Weisman MH, Oleg S, Seok Kim H, Hou JK, Miller FW, Dillon CF. Inflammatory bowel disease prevalence: surveillance data from the U.S. National Health and Nutrition Examination Survey. <em>Prev Med Rep<\/em>. 2023;33:102173. doi:10.1016\/j.pmedr.2023.102173\"},{\"id\":\"1d13560e-c572-410e-98bc-b2356753fdbc\",\"content\":\". Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. <em>Gastroenterology<\/em>. 2023;165(5):1197-1205.e2. doi:10.1053\/j.gastro.2023.07.003\"},{\"id\":\"49282ffc-ff3e-4b12-aff9-7579f364abd0\",\"content\":\"Flynn S, Eisenstein S. Inflammatory bowel disease presentation and diagnosis. <em>Surg Clin North Am<\/em>. 2019;99(6):1051-1062. doi:10.1016\/j.suc.2019.08.001\"},{\"id\":\"310d60a1-e143-4d41-aaed-33bc1773bbdd\",\"content\":\"Baydi Z, Limami Y, Khalki L, et al. An update of research animal models of inflammatory bowel disease. Chiba T, ed. <em>Sci World J<\/em>. 2021;2021:1-12. doi:10.1155\/2021\/7479540\"},{\"id\":\"8da8a509-f25e-4cff-917e-1217f360f79e\",\"content\":\"Pizarro TT, Stappenbeck TS, Rieder F, et al. Challenges in IBD research: preclinical human IBD mechanisms. <em>Inflamm Bowel Dis<\/em>. 2019;25(Suppl 2):S5-S12. doi:10.1093\/ibd\/izz075\"},{\"id\":\"8a1cd113-0fb9-492f-8888-ebe6a1ed55ab\",\"content\":\"Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn\u2019s disease: unexpected results of a randomised, double-blind placebo-controlled trial. <em>Gut<\/em>. 2012;61(12):1693-1700. doi:10.1136\/gutjnl-2011-301668\"},{\"id\":\"063369f1-af67-4c51-86c5-e2251d086e58\",\"content\":\"Targan SR, Feagan B, Vermeire S, et al. A randomized, double-blind, placebo-controlled phase 2 study of Brodalumab in patients with moderate-to-severe Crohn\u2019s disease. <em>Am J Gastroenterol<\/em>. 2016;111(11):1599-1607. doi:10.1038\/ajg.2016.298\"},{\"id\":\"f7e4a5f8-bf6f-4985-81c1-db6ec619038f\",\"content\":\"Pizarro et al., 2019\"},{\"id\":\"9a1694a8-8c0d-4ac4-ad13-35237b1b96cc\",\"content\":\"Verstockt B, Salas A, Sands BE, et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. <em>Nat Rev Gastroenterol Hepatol<\/em>. 2023;20(7):433-446. doi:10.1038\/s41575-023-00768-1\"},{\"id\":\"4c5278ca-4c4b-42a6-a4b9-48cd2a3261be\",\"content\":\"Lewis JD, Chen EZ, Baldassano RN, et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn\u2019s disease. <em>Cell Host Microbe<\/em>. 2015;18(4):489-500. doi:10.1016\/j.chom.2015.09.008\"},{\"id\":\"d01b8e18-0a80-449e-88af-3dc1cee8820f\",\"content\":\"Trapecar M, Communal C, Velazquez J, et al. Gut-liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids. <em>Cell Syst<\/em>. 2020;10(3):223-239.e9. doi:10.1016\/j.cels.2020.02.008\"},{\"id\":\"436d4997-bdca-45d4-8405-d2e4e9f5136b\",\"content\":\"Stankey CT, Bourges C, Haag LM, et al. A disease-associated gene desert directs macrophage inflammation through ETS2. <em>Nature<\/em>. 2024;630(8016):447-456. doi:10.1038\/s41586-024-07501-1\"},{\"id\":\"6731e81f-03c9-4b2f-b172-b33a839fd671\",\"content\":\"Lanik WE, Luke CJ, Nolan LS, et al. Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis\u2013on-a-chip. <em>JCI Insight<\/em>. 2023;8(8):e146496. doi:10.1172\/jci.insight.146496\"},{\"id\":\"77162fdb-fe27-449c-b7dc-844e721c53da\",\"content\":\"IBDMDB Investigators, Lloyd-Price J, Arze C, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. <em>Nature<\/em>. 2019;569(7758):655-662. doi:10.1038\/s41586-019-1237-9\"},{\"id\":\"04eb5a3e-c205-4513-b4ae-fa7daaa6e6b3\",\"content\":\"Chakravarti D, Lee R, Multani AS, et al. Telomere dysfunction instigates inflammation in inflammatory bowel disease. <em>Proc Natl Acad Sci U S A<\/em>. 2021;118(29):e2024853118. doi:10.1073\/pnas.2024853118\"},{\"id\":\"78b363a5-f936-4123-a1d9-213d1a962421\",\"content\":\"Lee A. Animal models of gastroduodenal ulcer disease. <em>Best Pract Res Clin Gastroenterol<\/em>. 2000;14(1):75-96. doi:10.1053\/bega.2000.0060\"},{\"id\":\"7aaf2d99-918c-415f-a2dc-d25e9e1af49c\",\"content\":\"Kazachkov M, Marcus M, Vaynblat M, Nino G, Pagala M. The effect of surgically created gastroesophageal reflux on intrapleural pressures in dogs. <em>Transl Res<\/em>. 2008;151(6):315-321. doi:10.1016\/j.trsl.2008.04.005\u00a0\"},{\"id\":\"3f691159-1b47-45d1-87e1-97dde4fd0db7\",\"content\":\"Hu Y, Xu X, Chen S, et al. Laryngoscopy findings and histological results in a rabbit gastroesophageal reflux model. <em>Eur Arch Otorhinolaryngol<\/em>. 2012;269(8):1939-1944. doi:10.1007\/s00405-012-1968-9\"},{\"id\":\"165bfb66-d7ee-4bb7-8fe0-fbf660f9f961\",\"content\":\"Kanai S, Mukaisho K, Yoshida S, Taniura N, Sugihara H. Host factors influence Barrett\u2019s carcinogenesis: findings from a mouse gastroduodenal reflux model. <em>Esophagus<\/em>. 2019;16(3):264-271. doi:10.1007\/s10388-019-00660-5\"},{\"id\":\"eb4dddb0-2df2-4376-8359-4cf6fdf8e502\",\"content\":\"He J, Fang Y, Chen X. Surgical models of gastroesophageal reflux with mice. <em>J Vis Exp<\/em>. 2015;(102):e53012. doi:10.3791\/53012\"},{\"id\":\"efc86773-d02d-4337-a80f-6d06cde91197\",\"content\":\"Akhtar AZ, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: a review.\u00a0<em>Rev\u00a0Neurosci<\/em>. 2008;19(1):47-60. doi:10.1515\/REVNEURO.2008.19.1.47\"},{\"id\":\"be726af9-0da0-47f9-a010-d1ac77843d1a\",\"content\":\"Angius\u00a0D, Wang H, Spinner RJ, Gutierrez-Cotto Y,\u00a0Yaszemski\u00a0MJ, Windebank AJ. A systematic review of animal models used to study nerve regeneration in tissue-engineered scaffolds.\u00a0<em>Biomaterials<\/em>. 2012;33(32):8034-8039.\u00a0doi:10.1016\/j.biomaterials.2012.07.056\"},{\"id\":\"1605ad63-928f-4b4a-8a0c-c569f1083844\",\"content\":\"Akhtar AZ, Pippin JJ, Sandusky CB. Animal studies in spinal cord injury: a systematic review of methylprednisolone.\u00a0<em>Altern Lab Anim<\/em>. 2009;37(1):43-62. doi:10.1177\/026119290903700108\"},{\"id\":\"da6fa10f-b3b0-4a9a-9d5f-fdb695ac74de\",\"content\":\"Kaplan HM, Mishra P, Kohn J. The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans.\u00a0<em>J Mater Sci: Mater Med<\/em>. 2015;26(8):226. doi:10.1007\/s10856-015-5558-4\"},{\"id\":\"c132c9d7-6067-45ab-be00-8fde1d671af4\",\"content\":\"Gliksten\u00a0L, Yip PK. Current spinal cord injury animal models are too simplistic for clinical translation.\u00a0<em>J\u00a0Exp\u00a0Neurol<\/em>.\u00a02023;4(1):6-10.\u00a0doi:10.33696\/Neurol.4.068\"},{\"id\":\"7ad6b49c-da20-4530-9577-47928b199909\",\"content\":\"Kaplan HM, et al. (2015). Rat models may limit human nerve conduit design. <em>J Mater Sci Mater Med,<\/em> 26(8), 226.\"},{\"id\":\"5237fd46-854a-41a8-b5aa-44ad772b1fae\",\"content\":\"Cheriyan\u00a0T, Ryan DJ,\u00a0Weinreb\u00a0JH, et al.\u00a0Spinal cord injury models: a review.\u00a0<em>Spinal Cord<\/em>. 2014;52(8):588-595. doi:10.1038\/sc.2014.91\"},{\"id\":\"d22b862d-a56b-41d0-8cd7-ffe63a301648\",\"content\":\"Cheriyan T, et al. (2014). Spinal cord injury models. <em>Spinal Cord,<\/em> 52(8), 588\u2013595.\"},{\"id\":\"544d66a2-622b-40c6-95e3-e53bc3b44279\",\"content\":\"Mobini\u00a0S, Song YH, McCrary MW, Schmidt CE. Advances in ex vivo models and lab-on-a-chip devices for neural tissue engineering.\u00a0<em>Biomaterials<\/em>.\u00a02019;198:146-166.\u00a0doi:10.1016\/J.BIOMATERIALS.2018.05.012\"},{\"id\":\"328d07cb-d0e7-45f7-9a24-7aea35715d34\",\"content\":\"Mobini S, et al. (2019). Ex vivo models and lab-on-a-chip for neural tissue engineering. <em>Biomaterials,<\/em> 198, 146\u2013166.\"},{\"id\":\"a5dc6b9d-7af7-4290-94e3-de4a81215f6a\",\"content\":\"Zhuang P, Sun AX,\u00a0An\u00a0J, Chua CK, Chew SY. 3D neural tissue models: from spheroids to bioprinting.\u00a0<em>Biomaterials<\/em>.\u00a02018;154:113-133.\u00a0doi:10.1016\/J.BIOMATERIALS.2017.10.002\"},{\"id\":\"e9c5f67b-bcbc-4ac5-8e83-776367874baa\",\"content\":\"Angius D, et al. (2012). Animal models for nerve regeneration in tissue-engineered scaffolds. <em>Biomaterials,<\/em> 33(32), 8034\u20138039.\"},{\"id\":\"c85d3c45-a0be-481e-9789-1ee224b265a5\",\"content\":\"Beltr\u00e1n SM, Bobo J, Habib A, et al. Characterization of neural\u00a0mechanotransduction\u00a0response in human traumatic brain injury organoid model.\u00a0<em>Sci Rep<\/em>. 2023;13(1):13536. doi:10.1038\/s41598-023-40431-y\"},{\"id\":\"afa9e3ab-8b66-436e-8bf5-4d25a1903ebd\",\"content\":\"Xue W, Li B, Liu H, et al. Generation of dorsoventral human spinal cord organoids via functionalizing composite scaffold for drug testing.\u00a0<em>iScience<\/em>. 2023;26(1):105898.\u00a0doi:10.1016\/j.isci.2022.105898\"},{\"id\":\"e827147a-3b4f-4c97-a902-a70ce9541ba5\",\"content\":\"Shrirao\u00a0AB, Kung FH, Omelchenko A, et al. Microfluidic platforms for the study of neuronal injury in vitro.\u00a0<em>Biotechnol\u00a0Bioeng<\/em>. 2018;115(4):830. doi:10.1002\/BIT.26519\"},{\"id\":\"e0c3e4c2-7d04-4e9d-ab3c-a18053304776\",\"content\":\"Amirifar\u00a0L, Shamloo A, Nasiri R, et al. Brain-on-a-chip: recent advances in design and techniques for microfluidic models of the brain in health and disease.\u00a0<em>Biomaterials<\/em>.\u00a02022;285:121531.\u00a0doi:10.1016\/j.biomaterials.2022.121531\"},{\"id\":\"794dc1ae-894a-40c7-a53e-8172f45c8508\",\"content\":\"Pan X, Li J, Li W, et al. Axons-on-a-chip for mimicking non-disruptive diffuse axonal injury underlying traumatic brain injury.\u00a0<em>Lab Chip<\/em>. 2022;22(23):4541-4555. doi:10.1039\/D2LC00730D\"},{\"id\":\"c162ec0f-5ec1-460b-b69d-601bebdda678\",\"content\":\"Mobini S, et al. (2019). Ex vivo models and lab-on-a-chip for neural tissue engineering. <em>Biomaterials,<\/em> 198, 146\u2013166.\"},{\"id\":\"873c1ae5-9632-4afa-9b1f-a4ed00d3a2a2\",\"content\":\"Potashkin\u00a0JA, Blume SR, Runkle NK. Limitations of animal models of Parkinson\u2032s disease.\u00a0<em>Parkinsons Dis<\/em>. 2011;2011(1):658083. doi:10.4061\/2011\/658083\"},{\"id\":\"8d0db68d-494d-426c-bafb-4462c61c8fa9\",\"content\":\"Cummings JL,\u00a0Morstorf\u00a0T, Zhong K. Alzheimer\u2019s disease drug-development pipeline: few candidates, frequent failures.\u00a0<em>Alzheimers\u00a0Res Ther<\/em>. 2014;6(4):37. doi:10.1186\/alzrt269\"},{\"id\":\"01aa3885-6f22-4e4d-9242-74e389eef972\",\"content\":\"Mullane K, Williams M. Preclinical models of Alzheimer\u2019s disease: relevance and translational validity.\u00a0<em>Curr\u00a0Protoc\u00a0Pharmacol<\/em>. 2019;84(1):e57. doi:10.1002\/cpph.57\"},{\"id\":\"ef4cc749-ce97-44df-809f-e4d92142b681\",\"content\":\"Burke JF, Kerber KA, Langa KM, Albin RL,\u00a0Kotagal\u00a0V.\u00a0Lecanemab: looking before we leap.\u00a0<em>Neurology<\/em>. 2023;101(15):661-665. doi:10.1212\/WNL.0000000000207505\"},{\"id\":\"fa6531b8-bdce-4349-8b91-a601f9ddc566\",\"content\":\"H\u00f8ilund-Carlsen PF, Alavi A, Barrio JR, et al. Donanemab, another anti-Alzheimer\u2019s drug with risk and uncertain benefit.\u00a0<em>Ageing Res Rev<\/em>.\u00a02024;99:102348.\u00a0doi:10.1016\/j.arr.2024.102348\"},{\"id\":\"e76e47f9-8ebf-4c6c-bec5-a8d70c2157aa\",\"content\":\"Burns TC, Li MD, Mehta S, Awad AJ, Morgan AA. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: a systematic bioinformatics-based critique of preclinical models.\u00a0<em>Eur\u00a0J\u00a0Pharmacol<\/em>.\u00a02015;759:101-117.\u00a0doi:10.1016\/j.ejphar.2015.03.021\"},{\"id\":\"50be7246-a3b2-4332-a69d-c850094ed9cf\",\"content\":\"Lane E, Dunnett S. Animal models of Parkinson\u2019s disease and L-dopa induced dyskinesia: how close are we to the clinic?\u00a0<em>Psychopharmacology\u00a0(Berl)<\/em>.\u00a02008;199(3):303-312.\u00a0doi:10.1007\/s00213-007-0931-8\"},{\"id\":\"4a890ad8-7cd4-49ef-8b5a-92ce5eff3b4d\",\"content\":\"Granzotto\u00a0A,\u00a0Vissel\u00a0B,\u00a0Sensi\u00a0SL.\u00a0Lost in translation: inconvenient truths on the utility of mouse models in Alzheimer\u2019s disease research. Behrens TE, ed.\u00a0<em>eLife<\/em>. 2024;13:e90633. doi:10.7554\/eLife.90633\"},{\"id\":\"75e7b8bd-fd91-4959-98f0-03ac53c32781\",\"content\":\"Ehrnhoefer\u00a0DE, Butland SL,\u00a0Pouladi\u00a0MA, Hayden MR. Mouse models of Huntington disease: variations on a theme.\u00a0<em>Dis Model Mech<\/em>. 2009;2(3-4):123-129. doi:10.1242\/dmm.002451\"},{\"id\":\"18c0e15a-3d08-4195-a498-6d3c582b1afb\",\"content\":\"Aghaizu\u00a0ND, Jolly S, Samra SK, et al. Microglial expression of the\u00a0Wnt\u00a0signaling modulator DKK2 differs between human Alzheimer\u2019s disease brains and mouse neurodegeneration models.\u00a0<em>eNeuro<\/em>. 2023;10(1). doi:10.1523\/ENEURO.0306-22.2022\"},{\"id\":\"81b4d110-03b6-450e-a0c0-d55e188a391f\",\"content\":\"Menache\u00a0A, Beuter A. Lessons from the analysis of non-human primates for understanding human aging and neurodegenerative diseases.\u00a0<em>Front Hum\u00a0Neurosci<\/em>. 2016;10. doi:10.3389\/fnhum.2016.00033\"},{\"id\":\"ae257fdb-8274-4389-aa88-91390084c54f\",\"content\":\"\u00a0Olsson IAS, Hansen AK, Sand\u00f8e P. Animal welfare and the refinement of neuroscience research methods\u2014a case study of Huntington\u2019s disease models.\u00a0<em>Lab Anim<\/em>. 2008;42(3):277-283. doi:10.1258\/la.2008.007147\"},{\"id\":\"1e763afc-bab0-4d38-93d0-3137846469dc\",\"content\":\"Pistollato\u00a0F, Ohayon EL, Lam A, et al. Alzheimer disease research in the 21<sup>st<\/sup>\u00a0century: past and current failures, new\u00a0perspectives\u00a0and funding priorities.\u00a0<em>Oncotarget<\/em>. 2016;7(26):38999-39016. doi:10.18632\/oncotarget.9175\"},{\"id\":\"1eb3a4e0-8cb3-4530-af51-be7f6183eaac\",\"content\":\"Shrirao AB, Kung FH, Omelchenko A, et al. Microfluidic platforms for the study of neuronal injury in vitro. <em>Biotechnol Bioeng<\/em>. 2018;115(4):830. doi:10.1002\/BIT.26519\"},{\"id\":\"0b986690-ffac-45d4-82d3-660badf2ce23\",\"content\":\"Amirifar L, et al. (2022). Brain-on-a-chip advances for microfluidic brain models. <em>Biomaterials,<\/em> 285, 121531.\"},{\"id\":\"ff9ccac2-2850-434a-b2c7-139a8eeb0f98\",\"content\":\"Amirifar L, Shamloo A, Nasiri R, et al. Brain-on-a-chip: recent advances in design and techniques for microfluidic models of the brain in health and disease. <em>Biomaterials<\/em>. 2022;285:121531. doi:10.1016\/j.biomaterials.2022.121531\"},{\"id\":\"cec7dce4-7bcf-4c87-87bc-501ca3f2f565\",\"content\":\"Pan X, Li J, Li W, et al. Axons-on-a-chip for mimicking non-disruptive diffuse axonal injury underlying traumatic brain injury. <em>Lab Chip<\/em>. 2022;22(23):4541-4555. doi:10.1039\/D2LC00730D\"},{\"id\":\"61053cdb-d3e1-49e0-93d3-338c3f79c215\",\"content\":\"Lam I, Ndayisaba A, Lewis AJ, et al. Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of \u03b1-synuclein inclusions. <em>Neuron<\/em>. 2024;112(17):2886-2909.e16. doi:10.1016\/j.neuron.2024.06.002\"},{\"id\":\"32013bed-278a-45ce-abec-6bd25e3aaa24\",\"content\":\"Sun Z, Kwon JS, Ren Y, et al. Modeling late-onset Alzheimer\u2019s disease neuropathology via direct neuronal reprogramming. <em>Science<\/em>. 2024;385(6708):adl2992. doi:10.1126\/science.adl2992\"},{\"id\":\"6b631497-7d4a-4306-99cd-6999f25b3b6e\",\"content\":\"Shen Y, Timsina J, Heo G, et al. CSF proteomics identifies early changes in autosomal dominant Alzheimer\u2019s disease. <em>Cell<\/em>. 2024;187(22):6309-6326.e15. doi:10.1016\/j.cell.2024.08.049\"},{\"id\":\"fbdab90e-1fa8-4ee4-9e3b-04368b8eb397\",\"content\":\"Palma-Florez S, L\u00f3pez-Canosa A, Moralez-Zavala F, et al. BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer\u2019s disease. <em>J Nanobiotechnology<\/em>. 2023;21:115. doi:10.1186\/s12951-023-01798-2\"},{\"id\":\"f43fdfcb-49bf-4b80-86e5-3f049aa8ce59\",\"content\":\"Reumann D, Krauditsch C, Novatchkova M, et al. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain\u2013striatum\u2013cortex assembloids. <em>Nat Methods<\/em>. 2023;20(12):2034-2047. doi:10.1038\/s41592-023-02080-x\"},{\"id\":\"507b2c90-f1ed-4995-b00c-ea58a2759f7f\",\"content\":\"Rosety I, Zagare A, Saraiva C, et al. Impaired neuron differentiation in GBA-associated Parkinson\u2019s disease is linked to cell cycle defects in organoids. <em>NPJ Parkinsons Dis<\/em>. 2023;9(1):1-16. doi:10.1038\/s41531-023-00616-8\u00a0\"},{\"id\":\"55b207c4-27c2-4ef5-b1d0-36758b72c1c1\",\"content\":\"Barmpa K, Saraiva C, Lopez-Pigozzi D, et al. Modeling early phenotypes of Parkinson\u2019s disease by age-induced midbrain-striatum assembloids. <em>Commun Biol<\/em>. 2024;7(1):1-19. doi:10.1038\/s42003-024-07273-4\"},{\"id\":\"18463416-0bda-47d8-aae6-d0f9c5bf3a87\",\"content\":\"Pediaditakis I, Kodella KR, Manatakis DV, et al. Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption. <em>Nat Commun<\/em>. 2021;12(1):5907. doi:10.1038\/s41467-021-26066-5\"},{\"id\":\"4ce00b5c-3e8d-4f8a-95ba-9f243d9446b7\",\"content\":\"Lisowski P, Lickfett S, Rybak-Wolf A, et al. Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure. <em>Nat Commun<\/em>. 2024;15(1):7027. doi:10.1038\/s41467-024-51216-w\"},{\"id\":\"ee570513-5ef3-4945-9b8f-ed59f2e72a54\",\"content\":\"Badu-Mensah A, Guo X, Mendez R, Parsaud H, Hickman JJ. The effect of skeletal muscle-specific creatine treatment on ALS NMJ integrity and function. <em>Int J Mol Sci<\/em>. 2023;24(17):13519. doi:10.3390\/ijms241713519\"},{\"id\":\"fcf754ae-f526-4abd-b088-8533715b34b6\",\"content\":\"van der Geest AT, Jakobs CE, Ljubikj T, et al. Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS\/FTD cerebral organoids. <em>Acta Neuropathol Commun<\/em>. 2024;12(1):152. doi:10.1186\/s40478-024-01857-1\"},{\"id\":\"53b3febe-7a31-444c-900d-e1b1de9a4329\",\"content\":\"Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. <em>Nat Neurosci<\/em>. 2010;13(10):1161-1169. doi:10.1038\/nn.2647\"},{\"id\":\"15bcc946-dbc4-4285-b449-0a1e3ed20de1\",\"content\":\"Molendijk ML, de Kloet ER. Immobility in the forced swim test is adaptive and does not reflect depression. <em>Psychoneuroendocrinology<\/em>. 2015;62:389-391. doi:10.1016\/j.psyneuen.2015.08.028\"},{\"id\":\"ec47efa9-5e69-4f9b-ad87-966051395383\",\"content\":\"De Pablo JM, Parra A, Segovia S, Guillam\u00f3n A. Learned immobility explains the behavior of rats in the forced swimming test. <em>Physiol Behav<\/em>. 1989;46(2):229-237. doi:10.1016\/0031-9384(89)90261-8\"},{\"id\":\"48383639-ef56-4724-b89f-5402cee096f4\",\"content\":\"Jefferys D, Funder J. The effect of water temperature on immobility in the forced swimming test in rats. <em>Eur J Pharmacol<\/em>. 1994;253(1-2):91-94. doi:10.1016\/0014-2999(94)90761-7\"},{\"id\":\"f300d69f-1114-4fe9-b89b-10e73b590a95\",\"content\":\"Lucki I, Dalvi A, Mayorga AJ. Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. <em>Psychopharmacology (Berl)<\/em>. 2001;155(3):315-322. doi:10.1007\/s002130100694\"},{\"id\":\"3af7fa0f-c28a-4f4d-b696-8b7806493522\",\"content\":\"Rosas-S\u00e1nchez GU, German-Ponciano LJ, Rodr\u00edguez-Landa JF. Considerations of pool dimensions in the forced swim test in predicting the potential antidepressant activity of drugs. <em>Front Behav Neurosci<\/em>. 2022;15:757348. doi:10.3389\/fnbeh.2021.757348\"},{\"id\":\"a1c96c7c-308b-44c2-9d9c-a94f356c01cd\",\"content\":\"Trunnell ER, Carvalho C. The forced swim test has poor accuracy for identifying novel antidepressants. <em>Drug Discov Today<\/em>. 2021;26(12):2898-2904. doi:10.1016\/j.drudis.2021.08.003\"},{\"id\":\"8baafa78-0984-4108-afe4-8ff9cd7de325\",\"content\":\"Trunnell ER, Baines J, Farghali S, et al. The need for guidance in antidepressant drug development: revisiting the role of the forced swim test and tail suspension test. <em>Regul Toxicol Pharmacol<\/em>. 2024;151:105666. doi:10.1016\/j.yrtph.2024.105666\"},{\"id\":\"105f4c65-2212-4260-a890-1bc13b938a42\",\"content\":\"Berrio JP, Hestehave S, Kalliokoski O. Reliability of sucrose preference testing following short or no food and water deprivation\u2014a systematic review and meta-analysis of rat models of chronic unpredictable stress. <em>Transl Psychiatry<\/em>. 2024;14(1):1-10. doi:10.1038\/s41398-024-02742-0\"},{\"id\":\"dfd3ec4d-2db6-46f5-a353-1843757c62c2\",\"content\":\"Scheggi S. Still controversial issues on assessing anhedonia in experimental modeling of depression. <em>Transl Psychiatry<\/em>. 2024;14(1):1-2. doi:10.1038\/s41398-024-03057-w\"},{\"id\":\"7f85a86e-aab3-4876-ad19-d4f43354a2c5\",\"content\":\"Verharen JPH, de Jong JW, Zhu Y, Lammel S. A computational analysis of mouse behavior in the sucrose preference test. <em>Nat Commun<\/em>. 2023;14(1):2419. doi:10.1038\/s41467-023-38028-0\"},{\"id\":\"9d722a92-a161-4ccf-a8bf-8ec463094268\",\"content\":\"V\u00f5ikar V, Stanford SC. The open field test. In: Harro J, ed. <em>Psychiatric Vulnerability, Mood, and Anxiety Disorders: Tests and Models in Mice and Rats<\/em>. Springer US; 2023:9-29. doi:10.1007\/978-1-0716-2748-8_2\"},{\"id\":\"bd273750-7c2d-41a3-b1b2-799ae3f50da5\",\"content\":\"Rosso M, Wirz R, Loretan AV, et al. Reliability of common mouse behavioural tests of anxiety: a systematic review and meta-analysis on the effects of anxiolytics. <em>Neurosci Biobehav Rev<\/em>. 2022;143:104928. doi:10.1016\/j.neubiorev.2022.104928\"},{\"id\":\"7114cae6-10c1-4c92-b0e9-6c525c15b1b6\",\"content\":\"Dixit PV, Sahu R, Mishra DK. Marble-burying behavior test as a murine model of compulsive-like behavior. <em>J Pharmacol Toxicol Methods<\/em>. 2020;102:106676. doi:10.1016\/j.vascn.2020.106676\"},{\"id\":\"cbbb1555-7416-4d5e-8cf5-545ca8e5ace7\",\"content\":\"Markov DD, Novosadova EV. Chronic unpredictable mild stress model of depression: possible sources of poor reproducibility and latent variables. <em>Biology (Basel)<\/em>. 2022;11(11):1621. doi:10.3390\/biology11111621\"},{\"id\":\"73c43d59-914d-45af-9856-e8e3fb27b829\",\"content\":\"Silverman JL. Animal models for psychiatric research: novel directions for behavioral neuroscience in translation. <em>Neurosci Biobehav Rev<\/em>. 2023;152:105309. doi:10.1016\/j.neubiorev.2023.105309\"},{\"id\":\"2cbc6467-404a-40a5-a811-4cafa6e7323c\",\"content\":\"Carvalho C, Varela SAM, Marques TA, Knight A, Vicente L. Are in vitro and in silico approaches used appropriately for animal-based major depressive disorder research? <em>PLoS One<\/em>. 2020;15(6):e0233954. doi:10.1371\/journal.pone.0233954\"},{\"id\":\"19c00b04-2260-4382-b5c4-0ec626ca2cf0\",\"content\":\"Carvalho C, Peste F, Marques TA, Knight A, Vicente LM. The contribution of rat studies to current knowledge of major depressive disorder: results from citation analysis. <em>Front Psychol<\/em>. 2020;11:1486. doi:10.3389\/fpsyg.2020.01486\"},{\"id\":\"a3d63714-be52-43f5-b22f-067ac761d110\",\"content\":\"Carvalho C, Herrmann K, Marques TA, Knight A. Time to abolish the forced swim test in rats for depression research? <em>JAAE<\/em>. 2021;4(2):170-178. doi:10.1163\/25889567-BJA10026\"},{\"id\":\"f7b711be-9c6e-473b-8f65-f1ffaa1a52df\",\"content\":\"Kato T, Kasahara T, Kubota-Sakashita M, Kato TM, Nakajima K. Animal models of recurrent or bipolar depression. <em>Neuroscience<\/em>. 2016;321:189-196. doi:10.1016\/j.neuroscience.2015.08.016\"},{\"id\":\"10cd95b2-cd00-4032-9a50-00a8e4ac720b\",\"content\":\"Garner JP. The significance of meaning: why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? <em>ILAR J<\/em>. 2014;55(3):438-456. doi:10.1093\/ilar\/ilu047\"},{\"id\":\"461ca1ab-6fb9-4155-b15b-a75736395edc\",\"content\":\"Molendijk ML, de Kloet ER. Forced swim stressor: trends in usage and mechanistic consideration. <em>Eur J Neurosci<\/em>. 2022;55(9-10):2813-2831. doi:10.1111\/EJN.15139\"},{\"id\":\"ffb83547-3d7b-46ac-8ff0-4c6a15a9993c\",\"content\":\"Trunnell et al., 2024\"},{\"id\":\"66d85322-bc6a-4931-9993-e0e3fb65598c\",\"content\":\"Jin H, Romano G, Marshall C, Donaldson AE, Suon S, Iacovitti L. Tyrosine hydroxylase gene regulation in human neuronal progenitor cells does not depend on Nurr1 as in the murine and rat systems. <em>J Cell Physiol<\/em>. 2006;207(1):49-57. doi:10.1002\/jcp.20534\"},{\"id\":\"e2e0f43d-54d5-44a7-823e-2828119473d8\",\"content\":\"Hodge RD, Bakken TE, Miller JA, et al. Conserved cell types with divergent features in human versus mouse cortex. <em>Nature<\/em>. 2019;573(7772):61-68. doi:10.1038\/s41586-019-1506-7\"},{\"id\":\"ad0c603b-47da-4e3b-8c00-382ab2cc7884\",\"content\":\"Dixon TA, Muotri AR. Advancing preclinical models of psychiatric disorders with human brain organoid cultures. <em>Mol Psychiatry<\/em>. 2023;28(1):83-95. doi:10.1038\/s41380-022-01708-2\"},{\"id\":\"56c06caf-27d2-45d6-bd6f-96d9c7e23157\",\"content\":\"Figdor C. Animal models in neuropsychiatry: do the benefits outweigh the moral costs? <em>Camb Q Healthc Ethics<\/em>. 2022;31(4):530-535. doi:10.1017\/S0963180122000147\"},{\"id\":\"cf80c8c8-283b-4b42-b9c1-83914b277c9e\",\"content\":\"Dixon &amp; Muotri, 2023\"},{\"id\":\"cfaa5c04-0e1d-49c9-ab46-3478a46d5055\",\"content\":\"Urenda JP, Dosso AD, Birtele M, Quadrato G. Present and future modeling of human psychiatric connectopathies with brain organoids. <em>Biol Psychiatry<\/em>. 2023;93(7):606-615. doi:10.1016\/j.biopsych.2022.12.017\"},{\"id\":\"40f25b41-71f5-487c-8a09-557d3a7239bf\",\"content\":\"Levy RJ, Pa\u015fca SP. What have organoids and assembloids taught us about the pathophysiology of neuropsychiatric disorders? <em>Biol Psychiatry<\/em>. 2023;93(7):632-641. doi:10.1016\/j.biopsych.2022.11.01\"},{\"id\":\"62aaba4c-f8dd-4c16-a08d-a9291860872b\",\"content\":\"Li C, Fleck JS, Martins-Costa C, et al. Single-cell brain organoid screening identifies developmental defects in autism. <em>Nature<\/em>. 2023;621(7978):373-380. doi:10.1038\/s41586-023-06473-y\"},{\"id\":\"04c6d376-007b-4984-a980-ea0c394298ef\",\"content\":\"Onesto MM, Kim JI, Pasca SP. Assembloid models of cell-cell interaction to study tissue and disease biology. <em>Cell Stem Cell<\/em>. 2024;31(11):1563-1573. doi:10.1016\/j.stem.2024.09.017\"},{\"id\":\"49701689-071a-469a-8f89-96348f80a41a\",\"content\":\"Levy &amp; Pa\u015fca, 2023\"},{\"id\":\"eff889ea-73f1-4833-b314-b41ce2e4872b\",\"content\":\"Miura Y, Kim JI, Jurju\u021b O, et al. Assembloid model to study loop circuits of the human nervous system. <em>bioRxiv. <\/em>Preprint posted online October 14, 2024\"},{\"id\":\"645fe329-137e-4c03-93a9-57491fdef324\",\"content\":\"Kim JI, Miura Y, Li MY, et al. Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. <em>Neuron<\/em>. 2024;0(0). doi:10.1016\/j.neuron.2024.09.020\"},{\"id\":\"9f130a40-a0ec-4328-81ed-3b0324dffba4\",\"content\":\"Courchesne E, Taluja V, Nazari S, et al. Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms. <em>Mol Autism<\/em>. 2024;15(1):22. doi:10.1186\/s13229-024-00602-8\"},{\"id\":\"72ee992e-0472-41b7-ae34-82d3a862dc9a\",\"content\":\"Papes F, Camargo AP, de Souza JS, et al. Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content. <em>Nat Commun<\/em>. 2022;13(1):2387. doi:10.1038\/s41467-022-29942-w\"},{\"id\":\"3910c00c-f1db-422f-a179-6bfd160a9cee\",\"content\":\"Sebastian R, Jin K, Pavon N, et al. Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids. <em>Nat Commun<\/em>. 2023;14(1):3770. doi:10.1038\/s41467-023-39420-6\"},{\"id\":\"75310f32-3c8b-493a-8f8f-e724cbd50d97\",\"content\":\"Science. PsychENCODE2. AAAS. 2024. Accessed December 2, 2024. https:\/\/www.science.org\/collections\/psychencode2\"},{\"id\":\"b5a77dda-c499-4768-9dd3-9444735b707a\",\"content\":\"Lynall ME, Soskic B, Hayhurst J, et al. Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells. <em>Nat Commun<\/em>. 2022;13(1):6102. doi:10.1038\/s41467-022-33885-7\"},{\"id\":\"e95708ec-9c5c-499a-af7d-d97da684ee59\",\"content\":\"Kundu S, Sair H, Sherr EH, Mukherjee P, Rohde GK. Discovering the gene-brain-behavior link in autism via generative machine learning. <em>Sci Adv<\/em>. 2024;10(24):eadl5307. doi:10.1126\/sciadv.adl5307\"},{\"id\":\"52842d9d-5897-4519-8652-6238040bd79c\",\"content\":\"Gaudfernau F, Lefebvre A, Engemann DA, et al. Cortico-cerebellar neurodynamics during social interaction in autism spectrum disorders. <em>NeuroImage Clin<\/em>. 2023;39:103465. doi:10.1016\/j.nicl.2023.103465\"},{\"id\":\"a62f2103-16d6-4119-bf8c-6ef909497ce4\",\"content\":\"Wang M, Barker PB, Cascella NG, et al. Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study. <em>Mol Psychiatry<\/em>. 2023;28(5):2018-2029. doi:10.1038\/s41380-023-01969-5\"},{\"id\":\"fb25b73c-00f8-4933-8aa3-fea428d33690\",\"content\":\"Nour MM, McNamee DC, Liu Y, Dolan RJ. Trajectories through semantic spaces in schizophrenia and the relationship to ripple bursts. <em>Proc Natl Acad Sci U S A<\/em>. 2023;120(42):e2305290120. doi:10.1073\/pnas.2305290120\"},{\"id\":\"3d0b3e37-06b7-409d-bbb1-1edad662cca2\",\"content\":\"Tozzi L, Zhang X, Pines A, et al. Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. <em>Nat Med<\/em>. 2024;30(7):2076-2087. doi:10.1038\/s41591-024-03057-9\"},{\"id\":\"f755388f-8bb7-4686-8c1a-010a06c3b97a\",\"content\":\"Arnold C. Discovering how environment affects autism. <em>Hopkins Bloomberg Public Health<\/em>. November 3, 2023. Accessed December 2, 2024. <a href=\\\"https:\/\/magazine.publichealth.jhu.edu\/2023\/discovering-how-environment-affects-autism\\\">https:\/\/magazine.publichealth.jhu.edu\/2023\/discovering-how-environment-affects-autism<\/a>\"},{\"id\":\"9b6f7cbc-b839-4867-b28c-37af2caa2714\",\"content\":\"Ahrens AP, Hy\u00f6tyl\u00e4inen T, Petrone JR, et al. Infant microbes and metabolites point to childhood neurodevelopmental disorders. <em>Cell<\/em>. 2024;187(8):1853-1873.e15. doi:10.1016\/j.cell.2024.02.035\"},{\"id\":\"44c88bc5-46b1-41b6-8636-2d25573e24e1\",\"content\":\"Guti\u00e9rrez-Casares JR, Quintero J, Seg\u00fa-Verg\u00e9s C, et al. In silico clinical trial evaluating lisdexamfetamine\u2019s and methylphenidate\u2019s mechanism of action computational models in an attention-deficit\/hyperactivity disorder virtual patients\u2019 population. <em>Front Psychiatry<\/em>. 2023;14:939650. doi:10.3389\/fpsyt.2023.939650\"},{\"id\":\"635c7069-655c-4a7a-b847-a653310086b0\",\"content\":\"Siekmeier PJ. An in silico, biomarker-based method for the evaluation of virtual neuropsychiatric drug effects. <em>Neural Comput<\/em>. 2017;29(4):1021-1052. doi:10.1162\/NECO_a_00944\"},{\"id\":\"631ed052-332a-4871-a503-304085e05104\",\"content\":\"Boodman E. Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals. STAT. March 11, 2020. Accessed December 3, 2024. <a href=\\\"https:\/\/www.statnews.com\/2020\/03\/11\/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing\/\\\">https:\/\/www.statnews.com\/2020\/03\/11\/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing\/<\/a>\"},{\"id\":\"bb996f9c-ea71-434b-afd1-4dfad51260c3\",\"content\":\"Zimmer C. Prototype vaccine protects monkeys from coronavirus. <em>The New York Times<\/em>. May 20, 2020. Accessed December 3, 2024.\u00a0<br><a href=\\\"https:\/\/www.nytimes.com\/2020\/05\/20\/health\/coronavirus-vaccine-harvard.html.\\\">https:\/\/www.nytimes.com\/2020\/05\/20\/health\/coronavirus-vaccine-harvard.html<\/a>.\"},{\"id\":\"144630d0-7843-4f94-8ad5-fefb0694d349\",\"content\":\"Zimmer C. (2020). Prototype vaccine protects monkeys. <em>The New York Times.<\/em> Retrieved December 3, 2024.\"},{\"id\":\"9d652e52-1ad6-4e0b-8357-2cf52c9512c7\",\"content\":\"Hwang KS, Seo EU, Choi N, Kim J, Kim HN. 3D engineered tissue models for studying human-specific infectious viral diseases. <em>Bioact Mater<\/em>. 2023;21:576-594. doi:10.1016\/j.bioactmat.2022.09.010\"},{\"id\":\"373448ee-683a-4b04-9597-572c1b5a7de2\",\"content\":\"Hwang et al., 2023\"},{\"id\":\"e6dea537-908f-4b0c-9480-14f5795949b1\",\"content\":\"Alonso-Roman R, Mosig AS, Figge MT, et al. Organ-on-chip models for infectious disease research. <em>Nat Microbiol<\/em>. 2024;9(4):891-904. doi:10.1038\/s41564-024-01645-6\"},{\"id\":\"8ff615ed-1d18-4610-a1c2-42ad26a70a9f\",\"content\":\"Hwang KS, Seo EU, Choi N, Kim J, Kim HN. 3D engineered tissue models for studying human-specific infectious viral diseases. <em>Bioact Mater<\/em>. 2023;21:576-594. doi:10.1016\/j.bioactmat.2022.09.010\"},{\"id\":\"64e35358-f1e7-4f80-af2e-272dfc96e0e4\",\"content\":\"Morrocchi E, Haren S van, Palma P, Levy O. Modeling human immune responses to vaccination in vitro. <em>Trends Immunol<\/em>. 2024;45(1):32-47. doi:10.1016\/j.it.2023.11.002\"},{\"id\":\"9beaf43b-f224-4306-80f6-cd7c8bf4e721\",\"content\":\"Flagg M, de Wit E. Advancing zoonotic respiratory virus research through the use of organoids. <em>Curr Opin Virol<\/em>. 2024;68-69:101435. doi:10.1016\/j.coviro.2024.101435\"},{\"id\":\"ed152674-6dd3-453c-adfb-bd758ba65b96\",\"content\":\"Gebert JT, Scribano F, Engevik KA, Perry JL, Hyser JM. Gastrointestinal organoids in the study of viral infections. <em>Am J Physiol Gastrointest Liver Physiol<\/em>. 2023;324(1):G51-G59. doi:10.1152\/ajpgi.00152.2022\u00a0\"},{\"id\":\"ff49183b-ccbc-41df-a8bf-d41dfe7273b6\",\"content\":\"Tang X, Xue D, Zhang T, et al. A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection. <em>Nat Cell Biol<\/em>. 2023;25(3):381-389. doi:10.1038\/s41556-023-01095-y\"},{\"id\":\"2df06206-65b6-4a16-b541-341b1b1c7b36\",\"content\":\"Leibel SL, McVicar RN, Murad R, et al. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response. <em>Proc Natl Acad Sci U S A<\/em>. 2024;121(30):e2408109121. doi:10.1073\/pnas.2408109121\"},{\"id\":\"6c9ebdf4-5dba-40a3-b243-7d7fd4339558\",\"content\":\"Ng JH, Sun A, Je HS, Tan EK. Unravelling pathophysiology of neurological and psychiatric complications of COVID-19 using brain organoids. <em>Neuroscientist<\/em>. 2023;29(1):30-40. doi:10.1177\/10738584211015136\"},{\"id\":\"755591bc-12f5-47c4-9707-611b12bbd782\",\"content\":\"Shaker MR, Slonchak A, Al-mhanawi B, et al. Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2. <em>Sci Adv<\/em>. 2024;10(23):eadj4735. doi:10.1126\/sciadv.adj4735\"},{\"id\":\"c39857f0-1282-4745-9fe0-6d880890f7f5\",\"content\":\"Mesci P, Souza JS de, Martin-Sancho L, et al. SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir. <em>PLoS Biol<\/em>. 2022;20(11):e3001845. doi:10.1371\/journal.pbio.3001845\"},{\"id\":\"10ff12ed-0301-4ed7-b0b0-ece1deaf5a60\",\"content\":\"Deguchi S, Kosugi K, Hashimoto R, et al. Elucidation of the liver pathophysiology of COVID-19 patients using liver-on-a-chips. <em>PNAS Nexus<\/em>. 2023;2(3):pgad029. doi:10.1093\/pnasnexus\/pgad029\"},{\"id\":\"3fea169c-56bc-47ad-8a48-9565778ab980\",\"content\":\"Flagg M, Williamson BN, Ortiz-Morales JA, Lutterman TR, de Wit E. Comparison of contemporary and historic highly pathogenic avian influenza A(H5N1) virus replication in human lung organoids. <em>Emerg Infect Dis<\/em>. 2025;31(2):318-322. doi:10.3201\/eid3102.241147\"},{\"id\":\"d224f830-fdf4-4e89-93ec-d969dd1aae7d\",\"content\":\"Widerspick L, Steffen JF, Tappe D, Mu\u00f1oz-Fontela C. Animal model alternatives in filovirus and bornavirus research. <em>Viruses<\/em>. 2023;15(1):158. doi:10.3390\/v15010158\"},{\"id\":\"fa3da7c4-1f25-4fca-9f2f-ef2e38f63491\",\"content\":\"Widerspick L, et al. (2023). Animal model alternatives in filovirus and bornavirus research. <em>Viruses,<\/em> 15(1), 158.\"},{\"id\":\"c7492489-64fb-4dc4-a070-e35a44606b5d\",\"content\":\"Altman MC, Reeves SR, Parker AR, et al. Interferon response to respiratory syncytial virus by bronchial epithelium from children with asthma is inversely correlated with pulmonary function. <em>J Allergy Clin Immunol<\/em>. 2018;142(2):451-459. doi:10.1016\/j.jaci.2017.10.004\"},{\"id\":\"c1d71a5d-5536-406e-b897-30f225b653cb\",\"content\":\"van Dijk LLA, Rijsbergen LC, Rubio BT, et al. Virus neutralization assays for human respiratory syncytial virus using airway organoids. <em>Cell Mol Life Sci<\/em>. 2024;81(1):267. doi:10.1007\/s00018-024-05307-y\"},{\"id\":\"4551c279-9048-4cb0-84c2-f08a1b31b2d8\",\"content\":\"Walitt B, Singh K, LaMunion SR, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis\/chronic fatigue syndrome. <em>Nat Commun<\/em>. 2024;15(1):907. doi:10.1038\/s41467-024-45107-3\"},{\"id\":\"96a33d3b-142e-4b89-a4d4-914cd3024804\",\"content\":\"Maria NI, Rapicavoli RV, Alaimo S, et al. Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing. <em>Heliyon<\/em>. 2023;9(3). doi:10.1016\/j.heliyon.2023.e14115\"},{\"id\":\"bd4db79e-2652-4294-aa48-4c8e226cc8f4\",\"content\":\"Borsky S, Hennighausen H, Leiter A, Williges K. CITES and the zoonotic disease content in international wildlife trade. <em>Environ Resource Econ (Dordr)<\/em>. 2020;76(4):1001-1017. doi:10.1007\/s10640-020-00456-7\u00a0\"},{\"id\":\"f57a02e5-7129-49a1-8601-4be949222377\",\"content\":\"Johnson CK, Hitchens PL, Pandit PS, et al. Global shifts in mammalian population trends reveal key predictors of virus spillover risk. <em>Proc Biol Sci<\/em>. 2020;287(1924):20192736. doi:10.1098\/rspb.2019.2736\"},{\"id\":\"e403585c-97ae-48cb-84ad-f55190da4c36\",\"content\":\"United States Department of Justice Southern District of Florida. Cambodian officials and six coconspirators indicted for taking part in primate smuggling scheme. Justice.gov. November 16, 2022. Accessed December 3, 2024. <a href=\\\"https:\/\/www.justice.gov\/usao-sdfl\/pr\/cambodian-officials-and-six-co-conspirators-indicted-taking-part-primate-smuggling-0\\\">https:\/\/www.justice.gov\/usao-sdfl\/pr\/cambodian-officials-and-six-co-conspirators-indicted-taking-part-primate-smuggling-0<\/a>\"},{\"id\":\"3bfc99c5-89e1-4a25-986a-a53a30bdae5f\",\"content\":\"Taetzsch SJ, Swaney EM, Gee JE, et al. Melioidosis in cynomolgus macaques (Macaca fascicularis) imported to the United States from Cambodia. <em>Comp Med<\/em>. 2022;72(6):394-402. doi:10.30802\/AALAS-CM-22-000024\"},{\"content\":\"Swisher SD, Taetzsch SJ, Laughlin ME, et al. Outbreak of Mycobacterium orygis in a shipment of cynomolgus macaques imported from Southeast Asia\u2013<a href=\\\"#_msocom_1\\\">[ET1]<\/a>\u00a0United States, February-May 2023. <em>MMWR Morb Mortal Wkly Rep<\/em>. 2024;73(7):145-148. doi:10.15585\/mmwr.mm7307a2\",\"id\":\"a6777a7b-9c4f-47f0-bafb-4f077ce56f56\"},{\"id\":\"ff8ab1a3-ff0f-41d5-b214-db885d564bfe\",\"content\":\"Weber K, Mayoral FJ, Vallejo C, et al. Natural outbreak of Mycobacterium caprae infection in imported laboratory cynomolgus macaques (Macaca fascicularis): diagnostic pitfalls and management of safety precautions. <em>J Toxicol Pathol<\/em>. 2024;37(4):197-206. doi:10.1293\/tox.2024-0048\"},{\"id\":\"f993a22d-b249-40ac-8f79-5fa6805de934\",\"content\":\"National Center for Emerging and Zoonotic Infectious Diseases. Tuberculosis and nonhuman primates. Published online July 2023.\"},{\"content\":\"Organizaci\u00f3n Panamericana de la Salud. La carga de enfermedades cardiovasculares. Accessed June 2025. https:\/\/www.paho.org\/es\/enlace\/carga-enfermedades-cardiovasculares\",\"id\":\"0a2f23b5-c867-495b-a162-e9c14045b93e\"},{\"id\":\"2d0f7a5d-a3d3-4e54-b29c-ca5388087736\",\"content\":\"Ruscu M, Glavan D, Surugiu R, et al. Pharmacological and stem cell therapy of stroke in animal models: do they accurately reflect the response of humans? <em>Exp Neurol<\/em>. 2024;376:114753. doi:10.1016\/j.expneurol.2024.114753\"},{\"id\":\"eaeb746d-c222-44f6-b0d4-f4e74075388b\",\"content\":\"Crilly S, Zille M, Kasher PR, Modo M. Editorial: Innovative models of stroke pathology. <em>Front Neurol<\/em>. 2023;14. doi:10.3389\/fneur.2023.1266075\"},{\"id\":\"eb60afbf-5adb-4991-b61e-9cc44e9cb661\",\"content\":\"Van Breedam E, Ponsaerts P. Promising strategies for the development of advanced in vitro models with high predictive power in ischaemic stroke research. <em>Int J Mol Sci<\/em>. 2022;23(13):7140. doi:10.3390\/ijms23137140\"},{\"id\":\"5f1a8344-e9fc-4d16-a763-acc54b7f036b\",\"content\":\"Ruscu et al., 2024\"},{\"id\":\"edfdae4a-5ee1-41a1-9330-74975e1d31a5\",\"content\":\"Van Breedam &amp; Ponsaerts, 2022\"},{\"id\":\"5da4d2a4-b809-4100-bad0-5b91ab5214ee\",\"content\":\"Nikolakopoulou P, Rauti R, Voulgaris D, Shlomy I, Maoz BM, Herland A. Recent progress in translational engineered in vitro models of the central nervous system. <em>Brain<\/em>. 2020;143(11):3181-3213. doi:10.1093\/brain\/awaa268\"},{\"id\":\"34edb820-89da-48a7-bf8c-5e0031661029\",\"content\":\"Sommer CJ. Ischemic stroke: experimental models and reality. <em>Acta Neuropathol<\/em>. 2017;133(2):245-261. doi:10.1007\/s00401-017-1667-0\"},{\"id\":\"f8092f5e-63fa-44c9-98e1-04e8c02f0acd\",\"content\":\"Krafft PR, Bailey EL, Lekic T, et al. Etiology of stroke and choice of models. <em>Int J Stroke<\/em>. 2012;7(5):398-406. doi:10.1111\/j.1747-4949.2012.00838.x\"},{\"id\":\"e1bacd73-eaf2-4aee-8b27-2218c3de4262\",\"content\":\"Chen ZQ, Mou R, Feng D, Wang Z, Chen G. The role of nitric oxide in stroke. <em>Med Gas Res<\/em>. 2017;7(3):194-203. doi:10.4103\/2045-9912.215750\"},{\"id\":\"da0d54b4-afcf-441d-a62b-38be76628208\",\"content\":\"Syv\u00e4nen S, Lindhe O, Palner M, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. <em>Drug Metab Dispos<\/em>. 2009;37(3):635-643. doi:10.1124\/dmd.108.024745\"},{\"id\":\"76b8b5a8-c7c3-4d91-a334-be8b8ebf756d\",\"content\":\"Lin S, Lin Y, Nery JR, et al. Comparison of the transcriptional landscapes between human and mouse tissues. <em>Proc Natl Acad Sci U S A<\/em>. 2014;111(48):17224-17229. doi:10.1073\/pnas.1413624111\"},{\"id\":\"0eadcbaf-9db9-4784-b39e-268bd7e45112\",\"content\":\"Johnson S, Dwivedi A, Mirza M, McCarthy R, Gilvarry M. A review of the advancements in the in-vitro modelling of acute ischemic stroke and its treatment. <em>Front Med Technol<\/em>. 2022;4. doi:10.3389\/fmedt.2022.879074\"},{\"id\":\"4f3be857-ebad-40e2-a0fa-68d6c55c170b\",\"content\":\"Roth S, Liesz A. Stroke research at the crossroads\u2014 where are we heading? <em>Swiss Med Wkly<\/em>. 2016;146:w14329. doi:10.4414\/smw.2016.14329\"},{\"id\":\"cdc2b0c8-f4af-4dc5-997a-51dc6c661f5d\",\"content\":\"Sena ES, Bart van der Worp H, Bath PMW, Howells DW, Macleod MR. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. <em>PLoS Biol<\/em>. 2010;8(3):e1000344. doi:10.1371\/JOURNAL.PBIO.1000344\"},{\"id\":\"47246d3c-73ca-421f-894a-c2d8eea14a42\",\"content\":\"Konduri PR, Marquering HA, van Bavel EE, Hoekstra A, Majoie CBLM, The INSIST Investigators. In-silico trials for treatment of acute ischemic stroke. <em>Front Neurol<\/em>. 2020;11. doi:10.3389\/fneur.2020.558125\"},{\"id\":\"dc7f62f1-8e40-4f0d-80e9-2458d3bcb870\",\"content\":\"Konduri PR, et al. (2020). In-silico trials for acute ischemic stroke treatment. <em>Frontiers in Neurology,<\/em> 11, 558125.\"},{\"id\":\"67b971cc-070b-4611-9bdf-c25b9af6a212\",\"content\":\"Sarrami-Foroushani A, Lassila T, MacRaild M, et al. In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials. <em>Nat Commun<\/em>. 2021;12(1):3861. doi:10.1038\/s41467-021-23998-w\"},{\"id\":\"987c44a0-91a1-4d26-b38c-1c064c57b25d\",\"content\":\"KPMG. In silicoregulatory evidence utilisation within the life science sector. InSilicoUK Pro-Innovation Regulations Network; 2024. doi:10.5281\/zenodo.12735158\"},{\"id\":\"a8eea9c0-848b-4cc4-a46f-e4edb52bfb80\",\"content\":\"Nikolakopoulou et al., 2020\"},{\"id\":\"40b042b5-436a-48b6-8849-12d4892046b9\",\"content\":\"Ruscu et al., 2024\"},{\"id\":\"9588dbd0-4cab-4b03-ae82-7d53c390f868\",\"content\":\"He JQ, Sussman ES, Steinberg GK. Revisiting stem cell-based clinical trials for ischemic stroke. <em>Front Aging Neurosci<\/em>. 2020;12. doi:10.3389\/fnagi.2020.575990\"},{\"id\":\"be6adede-e5bd-40c6-ba43-8b7ce3c7b774\",\"content\":\"Laskowitz DT, Bennett ER, Durham RJ, et al. Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase I safety study. <em>Stem Cells Transl Med<\/em>. 2018;7(7):521-529. doi:10.1002\/sctm.18-0008\"},{\"id\":\"7778f291-1832-432e-af97-ef5fd26513a2\",\"content\":\"Boncoraglio GB, Ranieri M, Bersano A, Parati EA, Giovane CD. Stem cell transplantation for ischemic stroke. <em>Cochrane Database Syst Rev<\/em>. 2019;2019(5):CD007231\"},{\"id\":\"01d5c1f8-bd1a-4a87-99ef-5443d725d910\",\"content\":\"Van Breedam &amp; Ponsaerts, 2022\"},{\"id\":\"22a9b601-88ca-4b7f-96f9-5eb244a7f379\",\"content\":\"Giorgi C, Castelli V, d\u2019Angelo M, Cimini A. Organoids modeling stroke in a petri dish. <em>Biomedicines<\/em>. 2024;12(4):877. doi:10.3390\/biomedicines12040877\"},{\"id\":\"73ad396d-6e18-4f1d-ad65-3022472d9492\",\"content\":\"Shakeri A, Wang Y, Zhao Y, et al. Engineering organ-on-a-chip systems for vascular diseases. <em>Arterioscler Thromb Vasc Biol<\/em>. 2023;43(12):2241-2255. doi:10.1161\/ATVBAHA.123.318233\"},{\"id\":\"d3c0265e-e376-4e92-a35f-c440a168ac95\",\"content\":\"Kofman S, Mohan N, Sun X, Ibric L, Piermarini E, Qiang L. Human mini brains and spinal cords in a dish: modeling strategies, current challenges, and prospective advances. <em>J Tissue Eng<\/em>. 2022;13:20417314221113391. doi:10.1177\/20417314221113391\"},{\"id\":\"435807fc-b9b6-404c-92d9-34cbbe802784\",\"content\":\"Jochumsen M, Janjua TAM, Arceo JC, Lauber J, Buessinger ES, K\u00e6seler RL. Induction of neural plasticity using a low-cost open source brain-computer interface and a 3D-printed wrist exoskeleton. <em>Sensors (Basel)<\/em>. 2021;21(2):572. doi:10.3390\/s21020572\"},{\"id\":\"b8d85711-7480-4aaa-9a8f-6031e19eac86\",\"content\":\"Kook MG, Lee SE, Shin N, et al. Generation of cortical brain organoid with vascularization by assembling with vascular spheroid. <em>Int J Stem Cells<\/em>. 2022;15(1):85-94\"},{\"id\":\"fb143e7f-f8f9-4475-a1dd-b6f0bd9754ee\",\"content\":\"Xu R, Boreland AJ, Li X, et al. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. <em>Stem Cell Rep<\/em>. 2021;16(8):1923-1937. doi:10.1016\/j.stemcr.2021.06.011\"},{\"id\":\"f15c3464-da52-4c68-84cb-66b0383cec7f\",\"content\":\"National Centre for the Replacement, Refinement and Reduction of Animals in Research. Research round-up: replacing animals in stroke research. www.nc3rs.org.uk. August 14, 2023. Accessed October 14, 2024. https:\/\/nc3rs.org.uk\/news\/research-round-replacing-animals-stroke-research\"},{\"id\":\"731a0be8-829f-4336-8472-6c2684b488f0\",\"content\":\"Syv\u00e4nen et al., 2009\"},{\"id\":\"478686f0-319a-44fe-bd19-0829119c4017\",\"content\":\"Tzschentke TM. Where do we stand in the field of anti-abuse drug discovery? <em>Expert Opin Drug Discov<\/em>. 2014;9(11):1255-1258. doi:10.1517\/17460441.2014.948415\"},{\"id\":\"4ffd49eb-cd83-4da1-99d2-77724138687b\",\"content\":\"Stephens DN, Crombag HS, Duka T. The challenge of studying parallel behaviors in humans and animal models. In: Sommer WH, Spanagel R, eds. <em>Behavioral Neurobiology of Alcohol Addiction<\/em>. Springer; 2013:611-645. doi:10.1007\/978-3-642-28720-6_133\"},{\"id\":\"a874773c-626e-4576-bb3c-925a46ff2b18\",\"content\":\"Li K, Gu L, Cai H, Lu HC, Mackie K, Guo F. Human brain organoids for understanding substance use disorders. <em>Drug Metab Pharmacokinet<\/em>. 2024;58:101036. doi:10.1016\/j.dmpk.2024.101036\"},{\"id\":\"b9a896ec-9700-4f0b-bb7e-638cc9246093\",\"content\":\"Field M, Kersbergen I. Are animal models of addiction useful? <em>Addiction<\/em>. 2020;115(1):6-12. doi:10.1111\/add.14764\"},{\"id\":\"b6b0acbe-0757-4016-b380-d819e2b85bfb\",\"content\":\"Green AR, King MV, Shortall SE, Fone KCF. Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans. <em>Br J Pharmacol<\/em>. 2012;166(5):1523-1536. doi:10.1111\/j.1476-5381.2011.01819.x\"},{\"id\":\"a694aa88-dc92-4fec-b9a8-66d976b91025\",\"content\":\"Green AR, et al. (2012). MDMA preclinical studies and limits in predicting human adverse events. <em>Br J Pharmacol,<\/em> 166(5), 1523\u20131536.\"},{\"id\":\"b496e41f-7fcc-495e-af35-a45e56e7832d\",\"content\":\"Ahmed SH. Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. <em>Neurosci Biobehav Rev<\/em>. 2010;35(2):172-184. doi:10.1016\/j.neubiorev.2010.04.005\"},{\"id\":\"348c6826-d221-4ec6-9129-4c289fd386b9\",\"content\":\"Ramsden E. Making animals alcoholic: shifting laboratory models of addiction. <em>J Hist Behav Sci<\/em>. 2015;51(2):164-194. doi:10.1002\/jhbs.21715\u00a0\"},{\"id\":\"15626447-9ea8-43ed-8451-a26a46b599c5\",\"content\":\"Ahmed, 2010\"},{\"id\":\"ada753d0-5ec6-43ee-a4cc-09214894de11\",\"content\":\"Ahmed, 2010\"},{\"id\":\"3e6ce804-260d-40c5-b2a8-07978bef88f8\",\"content\":\"Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. <em>Nat Rev Neurosci<\/em>. 2001;2(10):695-703. doi:10.1038\/35094560\u00a0\"},{\"id\":\"e9519310-ad76-4394-89e6-6f8b3fe3cb62\",\"content\":\"Whitten A. Developing new drugs to treat addiction. <em>Drug Discovery News<\/em>. September 3, 2024. Accessed December 3, 2024. https:\/\/www.drugdiscoverynews.com\/developing-new-drugs-to-treat-addiction-16033\"},{\"id\":\"92f3ac1c-ed7c-4559-b0a3-acaa0fd6b886\",\"content\":\"Whitten, 2024\"},{\"id\":\"b16b4a49-22b5-47f0-bdad-df89d194f80a\",\"content\":\"Montoya ID, Volkow ND. IUPHAR Review: New strategies for medications to treat substance use disorders. <em>Pharmacol Res<\/em>. 2024;200:107078. doi:10.1016\/j.phrs.2024.107078\"},{\"id\":\"c057a541-01c5-4388-a74b-5f415c0d56a0\",\"content\":\"Montoya &amp; Volkow, 2024\"},{\"id\":\"049c4d00-2dc8-4a1d-97bc-90abb269f266\",\"content\":\"Field &amp; Kersbergen, 2020<br>\"},{\"id\":\"b636d063-90cb-4b41-9c7d-e6cc3773b0a9\",\"content\":\"Field &amp; Kersbergen, 2020\"},{\"id\":\"d19aef1c-4c2d-40f3-a1e9-01d2a1cfe924\",\"content\":\"Scarnati MS, Halikere A, Pang ZP. Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: current status and outlook. <em>Alcohol<\/em>. 2019;74:83-93. doi:10.1016\/j.alcohol.2018.03.008\"},{\"id\":\"3619417a-a9a2-4678-964e-0bed40a474ad\",\"content\":\"Mendez EF, Grimm SL, Stertz L, et al. A human stem cell-derived neuronal model of morphine exposure reflects brain dysregulation in opioid use disorder: transcriptomic and epigenetic characterization of postmortem-derived iPSC neurons. <em>Front Psychiatry<\/em>. 2023;14. doi:10.3389\/fpsyt.2023.1070556\"},{\"id\":\"55e77e85-7a3c-4aee-abfc-c5dda37b02fb\",\"content\":\"Poisel E, Zillich L, Streit F, et al. DNA methylation in cocaine use disorder\u2014 an epigenome-wide approach in the human prefrontal cortex. <em>Front Psychiatry<\/em>. 2023;14. doi:10.3389\/fpsyt.2023.1075250\"},{\"id\":\"ff31f347-198f-4b87-8ea0-d1aa38bcfa2d\",\"content\":\"Trang KB, Chesi A, Toikumo S, et al. Shared and unique 3D genomic features of substance use disorders across multiple cell types. <em>medRxiv. <\/em>Preprint posted online July 19, 2024. \u00a0doi:10.1101\/2024.07.18.24310649\"},{\"id\":\"74984579-39c9-4770-8f80-96c7e8f1058a\",\"content\":\"Sullivan KA, Kainer D, Lane M, et al. Multi-omic network analysis identifies dysregulated neurobiological pathways in opioid addiction. <em>Biol Psychiatry<\/em>. 2024;(24). doi:10.1016\/j.biopsych.2024.11.013\"},{\"id\":\"bc8e76f4-47f4-4f53-99d9-7ceffada9f1a\",\"content\":\"Guo X, Akanda N, Fiorino G, et al. Human iPSC-derived PreB\u00f6tC-like neurons and development of an opiate overdose and recovery model. <em>Adv Biol (Weinh)<\/em>. 2024;8(8):2300276. doi:10.1002\/adbi.202300276\"},{\"id\":\"8e44778e-a05c-4d35-bf0a-dc1cf14c8039\",\"content\":\"Rudibaugh TP, Tam RW, Estridge RC, Stuppy SR, Keung AJ. Single-cell assessment of human stem cell-derived mesolimbic models and their responses to substances of abuse. <em>Organoids<\/em>. 2024;3(2):126-147. doi:10.3390\/organoids3020009\"},{\"id\":\"cfe0c7ff-0eed-44e7-a53a-d199a69aaf36\",\"content\":\"Li et al., 2024\"},{\"id\":\"1085d05a-5a4b-41c0-84f4-3791acea7fea\",\"content\":\"McMillan H, Lundy FT, Dunne OM, et al. Endogenous Mas-related G-protein-coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves. <em>FASEB J<\/em>. 2021;35(5):e21492. doi:10.1096\/fj.202001667RR\"},{\"id\":\"52e58bd8-78a7-43d7-bec6-0839b991631a\",\"content\":\"Mayo Clinic Staff. Women\u2019s health. Mayo Clinic. September 28, 2022. Accessed October 9, 2024. https:\/\/www.mayoclinic.org\/healthy-lifestyle\/womens-health\/basics\/womens-health\/hlv-20049411\"},{\"id\":\"008ae57d-3281-44aa-9f56-8e2b0a010a6b\",\"content\":\"Carneiro MM. Women\u2019s health in 2024: change now for tomorrow will be too late. <em>Women &amp; Health<\/em>. 2024;64(1):1-4. doi:10.1080\/03630242.2024.2292320\"},{\"id\":\"d07792ce-cc80-4944-9047-f781eb61f185\",\"content\":\"Cunha GR, Sinclair A, Ricke WA, Robboy SJ, Cao M, Baskin LS. Reproductive tract biology: of mice and men. <em>Differentiation<\/em>. 2019;110:49-63. doi:10.1016\/j.diff.2019.07.004\"},{\"id\":\"77860b87-2d02-45fe-950e-542b7e6976a7\",\"content\":\"Vercellini P, Vigan\u00f2 P, Bandini V, Buggio L, Berlanda N, Somigliana E. Association of endometriosis and adenomyosis with pregnancy and infertility. <em>Fertil Steril<\/em>. 2023;119(5):727-740. doi:10.1016\/j.fertnstert.2023.03.018\"},{\"id\":\"da13c77a-4b50-4bf0-b3f8-e180d46a9840\",\"content\":\"Smolarz B, Szy\u0142\u0142o K, Romanowicz H. Endometriosis: epidemiology, classification, pathogenesis, treatment and genetics (review of literature). <em>Int J Mol Sci<\/em>. 2021;22(19):10554. doi:10.3390\/ijms221910554\"},{\"id\":\"3d3f09e2-4005-4573-8327-ae4fb8e0d5b0\",\"content\":\"World Health Organization. Endometriosis. WHO.int. March 24, 2023. Accessed October 9, 2024. <a href=\\\"https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/endometriosis\\\">https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/endometriosis<\/a>\"},{\"id\":\"ba7f916f-c723-4b8f-9f5b-f94de2826acc\",\"content\":\"Burns KA, Pearson AM, Slack JL, et al. Endometriosis in the mouse: challenges and progress toward a \u2018best fit\u2019 murine model. <em>Front Physiol<\/em>. 2022;12. Accessed January 17, 2024. <a href=\\\"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.806574\\\">https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.806574<\/a>\"},{\"id\":\"25de1692-e53d-4387-8e61-f145903815de\",\"content\":\"Burns et al., 2022\"},{\"id\":\"e12f1113-f9da-4f8a-b4a3-8c68a10c8349\",\"content\":\"Zhao Y, Wang Y, Gu P, Tuo L, Wang L, Jiang SW. Transgenic mice applications in the study of endometriosis pathogenesis. <em>Front Cell Dev Biol<\/em>. 2024;12. doi:10.3389\/fcell.2024.1376414\"},{\"id\":\"9a8c9ed3-7146-4ecd-95ed-70e070a8d6c5\",\"content\":\"Feng D, Menger MD, Wang H, Laschke MW. Luminal epithelium in endometrial fragments affects their vascularization, growth and morphological development into endometriosis-like lesions in mice. <em>Dis Model Mech<\/em>. 2014;7(2):225-232. doi:10.1242\/dmm.013664\"},{\"id\":\"2116da25-12d5-4ac8-951e-3cfb07207cd5\",\"content\":\"Chalouhi S. Menopause: a complex and controversial journey. <em>Post Reprod Health<\/em>. 2017;23(3):128-131. doi:10.1177\/2053369117711346\"},{\"id\":\"b7598a6e-7206-440d-94d6-81c3f0c87b5f\",\"content\":\"Bansal R, Aggarwal N. Menopausal hot flashes: a concise review. <em>J Midlife Health<\/em>. 2019;10(1):6. doi:10.4103\/jmh.JMH_7_19\"},{\"id\":\"306ddc8b-9d81-48e0-9ec6-abc2fd3c6bd3\",\"content\":\"Todorova L, Bonassi R, Guerrero Carre\u00f1o FJ, et al. Prevalence and impact of vasomotor symptoms due to menopause among women in Brazil, Canada, Mexico, and Nordic Europe: a cross-sectional survey. <em>Menopause<\/em>. 2023;30(12):1179. doi:10.1097\/GME.0000000000002265\"},{\"id\":\"74d4082d-5d79-40d4-b9b2-04f408b595e6\",\"content\":\"Chalouhi, 2017\"},{\"id\":\"df41a430-4222-46ba-acaa-532e73e42f07\",\"content\":\"Acevedo-Rodriguez A, Kauffman AS, Cherrington BD, Borges CS, Roepke TA, Laconi M. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. <em>J Neuroendocrinol<\/em>. 2018;30(10):e12590. doi:10.1111\/jne.12590\"},{\"id\":\"7f530923-1be6-4ece-a394-6f8a02b86347\",\"content\":\"Zhang Z, He C, Gao Y, et al. \u03b1-ketoglutarate delays age-related fertility decline in mammals. <em>Aging Cell<\/em>. 2021;20(2):e13291. doi:10.1111\/acel.13291\"},{\"id\":\"bef7c181-da06-4a89-921e-1159e270c101\",\"content\":\"Acevedo-Rodriguez et al., 2018\"},{\"id\":\"18f8583d-1ac0-47b5-bf8d-872ce931be9d\",\"content\":\"Koebele SV, Bimonte-Nelson HA. Modeling menopause: the utility of rodents in translational behavioral endocrinology research. <em>Maturitas<\/em>. 2016;87:5-17. doi:10.1016\/j.maturitas.2016.01.015\"},{\"id\":\"68a87a23-d33b-48c1-8eef-23fcc019713b\",\"content\":\"Wood BM, Negrey JD, Brown JL, et al. Demographic and hormonal evidence for menopause in wild chimpanzees. <em>Science<\/em>. 2023;382(6669):eadd5473. doi:10.1126\/science.add5473\"},{\"id\":\"a70feddf-308f-4f52-bd2c-88b8a1e51226\",\"content\":\"Whitton K, Baber R. Androgen-based therapies in women. <em>Best Pract Res Clin Endocrinol Metab<\/em>. 2024;38(1):101783. doi:10.1016\/j.beem.2023.101783\"},{\"id\":\"f0c17532-4f7f-48eb-bf59-5507961be65c\",\"content\":\"Cao LB, Leung CK, Law PWN, et al. Systemic changes in a mouse model of VCD-induced premature ovarian failure. <em>Life Sci<\/em>. 2020;262:118543. doi:10.1016\/j.lfs.2020.118543\"},{\"id\":\"692759fe-bf78-4d6c-8afb-fc82a1983401\",\"content\":\"Lee EH, Han SE, Park MJ, et al. Establishment of effective mouse model of premature ovarian failure considering treatment duration of anticancer drugs and natural recovery time. <em>J Menopausal Med<\/em>. 2018;24(3):196-203. doi:10.6118\/jmm.2018.24.3.196\"},{\"id\":\"0b117682-b74c-4890-8a67-cef1c7188451\",\"content\":\"Russell JK, Jones CK, Newhouse PA. The role of estrogen in brain and cognitive aging. <em>Neurotherapeutics<\/em>. 2019;16(3):649-665. doi:10.1007\/s13311-019-00766-9\"},{\"id\":\"f6f5695b-decf-4141-803d-54b98353b7b2\",\"content\":\"Col\u00f3n-Caraballo M, Garc\u00eda M, Mendoza A, Flores I. Human endometriosis tissue microarray reveals site-specific expression of estrogen receptors, progesterone receptor, and Ki67. <em>Appl Immunohistochem Mol Morphol<\/em>. 2019;27(7):491-500. doi:10.1097\/PAI.0000000000000663\"},{\"id\":\"68b16e78-1156-465c-9698-bae606256f30\",\"content\":\"Becker CM, Laufer MR, Stratton P, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. <em>Fertil Steril<\/em>. 2014;102(5). doi:10.1016\/j.fertnstert.2014.07.709\"},{\"id\":\"a58cf240-c68a-4985-b771-49f190bbf448\",\"content\":\"Blass I, Sahar T, Shraibman A, Ofer D, Rappoport N, Linial M. Revisiting the risk factors for endometriosis: a machine learning approach. <em>J Pers Med<\/em>. 2022;12(7):1114. doi:10.3390\/jpm12071114\"},{\"id\":\"ce046412-734c-43f7-8bf9-8dfc15360fd3\",\"content\":\"Deng ZM, Dai FF, Wang RQ, et al. Organ-on-a-chip: future of female reproductive pathophysiological models. <em>J Nanobiotechnology<\/em>. 2024;22(1):455. doi:10.1186\/s12951-024-02651-w\"},{\"id\":\"df47c072-46b9-4a8c-a46a-4e053ef93d3f\",\"content\":\"Blundell C, Tess ER, Schanzer ASR, et al. A microphysiological model of the human placental barrier. <em>Lab Chip<\/em>. 2016;16(16):3065-3073. doi:10.1039\/c6lc00259e\"},{\"id\":\"fe49c1a2-7341-4e03-a039-f0c55ce96227\",\"content\":\"Ghorbanpour SM, Richards C, Pienaar D, et al. A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia. <em>Cell Mol Life Sci<\/em>. 2023;80(2):44. doi:10.1007\/s00018-022-04648-w\"},{\"id\":\"bacbf547-9a95-4acb-92a5-1c2d41604472\",\"content\":\"Lee JS, Romero R, Han YM, et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. <em>J Matern Fetal Neonatal Med<\/em>. 2016;29(7):1046-1054. doi:10.3109\/14767058.2015.1038518\"},{\"id\":\"07c8f50a-88e4-47bd-ae95-61244dcca480\",\"content\":\". Lermant A, Rabussier G, Davidson L, Lanz HL, Murdoch CE. Protocol for a placenta-on-a-chip model using trophoblasts differentiated from human induced pluripotent stem cells. <em>STAR Protoc<\/em>. 2024;5(1):102879. doi:10.1016\/j.xpro.2024.102879\u00a0\"},{\"id\":\"055c3df9-2fab-4c7e-b7aa-87ff95070a09\",\"content\":\"Ahn J, Yoon MJ, Hong SH, et al. Three-dimensional microengineered vascularised endometrium-on-a-chip. <em>Hum Reprod<\/em>. 2021;36(10):2720-2731. doi:10.1093\/humrep\/deab186\"},{\"id\":\"3d2e7353-3e96-4adc-b3a9-c937bf39b9be\",\"content\":\"Wang L, Chen XJ, Liang JH, Zhang ZK, Cao TS, Zhang L. Preliminary application of three-dimensional printing in congenital uterine anomalies based on three-dimensional transvaginal ultrasonographic data. <em>BMC Women\u2019s Health<\/em>. 2022;22(1):290. doi:10.1186\/s12905-022-01873-0\"},{\"id\":\"fe92fc63-2954-4c0e-aa35-a3963d989f88\",\"content\":\"Mare\u010dkov\u00e1 M, Garcia-Alonso L, Moullet M, et al. An integrated single-cell reference atlas of the human endometrium. <em>Nat Genet<\/em>. 2024;56(9):1925-1937. doi:10.1038\/s41588-024-01873-w\"},{\"id\":\"b84aeb83-a894-4425-a40f-aeda76725731\",\"content\":\"Lukac S, Hancke K, Janni W, et al. Three-dimensional model for improvement of endometriosis care (3D-E). <em>Int J Gynaecol Obstet<\/em>. 2024;165(2):416-423. doi:10.1002\/ijgo.15165\"},{\"content\":\"United Network for Organ Sharing. Data and trends. October 15, 2024. Accessed June 26, 2025. <a href=\\\"https:\/\/unos.org\/data\/\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/unos.org\/data\/<\/a>\",\"id\":\"27183fb0-b6df-4e54-bc41-626d7ef77b7c\"},{\"content\":\"Gobierno de M\u00e9xico. Estado actual de receptores, donaci\u00f3n y trasplantes en M\u00e9xico 2024. Accessed June 26, 2025. <a href=\\\"https:\/\/www.gob.mx\/cms\/uploads\/attachment\/file\/967152\/ESTADISTICAS_ANUAL_2024.pdf\\\">https:\/\/www.gob.mx\/cms\/uploads\/attachment\/file\/967152\/ESTADISTICAS_ANUAL_2024.pdf<\/a>\",\"id\":\"df06caa6-0e33-4ad0-adab-3e840e52e528\"},{\"content\":\"Ministerio de Salud y Protecci\u00f3n Social. MinSalud e INS conmemoran el D\u00eda Mundial del Donante de \u00d3rganos y Tejidos. Accessed June 26, 2025. <a href=\\\"https:\/\/www.minsalud.gov.co\/Paginas\/minsalud-e-ins-conmemoran-el-dia-mundial-del-donante-de-organos-y-tejidos.aspx\\\">https:\/\/www.minsalud.gov.co\/Paginas\/minsalud-e-ins-conmemoran-el-dia-mundial-del-donante-de-organos-y-tejidos.aspx<\/a>\",\"id\":\"88446638-ca05-441f-a811-4ced4aec01e4\"},{\"id\":\"fbceca82-c6dc-4dab-94f9-1cfdb7eb736d\",\"content\":\"United States Senate Committee on Finance. A system in need of repair: addressing organizational failures of the U.S.\u2019s Organ Procurement and Transplantation Network. August 3, 2022. Accessed October 15, 2024. <a href=\\\"https:\/\/www.finance.senate.gov\/hearings\/a-system-in-need-of-repair-addressing-organizational-failures-of-the-uss-organ-procurement-and-transplantation-network\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.finance.senate.gov\/hearings\/a-system-in-need-of-repair-addressing-organizational-failures-of-the-uss-organ-procurement-and-transplantation-network<\/a>\"},{\"id\":\"212e2190-692b-4520-b625-c07ff4cdd228\",\"content\":\"Kizer KW, English RA, Hackmann M, eds. <em>Realizing the Promise of Equity in the Organ Transplantation System<\/em>. National Academies Press; 2022.\"},{\"id\":\"1754ebd7-0154-42f9-9cac-f63d7bdab721\",\"content\":\"In America, lots of usable organs go unrecovered or get binned. <em>The Economist<\/em>. September 16, 2023. Accessed October 15, 2024. <a href=\\\"https:\/\/www.economist.com\/united-states\/2023\/09\/16\/in-america-lots-of-usable-organs-go-unrecovered-or-get-binned\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.economist.com\/united-states\/2023\/09\/16\/in-america-lots-of-usable-organs-go-unrecovered-or-get-binned<\/a>\"},{\"id\":\"aee49ab5-5f5e-4f3b-aeca-e6d2de2575e8\",\"content\":\"Mohan S, Chiles MC, Patzer RE, et al. Factors leading to the discard of deceased donor kidneys in the United States.\u202f<em>Kidney Int<\/em>. 2018;94(1):187-198.\"},{\"id\":\"3b8b518a-bf17-42ee-b8d0-a8fb1c6997ae\",\"content\":\"Jena B. Why do so many donated kidneys end up in the trash? <em>Freakonomics<\/em>. November 11, 2021. Accessed October 24, 2024. <a href=\\\"https:\/\/freakonomics.com\/podcast\/why-do-so-many-donated-kidneys-end-up-in-the-trash\/\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/freakonomics.com\/podcast\/why-do-so-many-donated-kidneys-end-up-in-the-trash\/<\/a>\"},{\"id\":\"873d9338-5037-4160-8adf-dc9f53a2fc52\",\"content\":\"Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024.\"},{\"id\":\"4dcee4ec-65c8-425c-84d8-fc37baa923f0\",\"content\":\"Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024.\"},{\"id\":\"050927b4-6a8f-4ef0-86e5-eea3ce9c49d0\",\"content\":\"Jena B. (2021). Why do so many donated kidneys end up in the trash? <em>Freakonomics.<\/em> Retrieved October 24, 2024.\"},{\"id\":\"dde7c07f-5389-4951-ad34-7d58940c62b3\",\"content\":\"Health Resource and Services Administration. Organ Procurement and Transplantation Network (OPTN) modernization initiative. Updated November 2024. Accessed December 6, 2024. <a href=\\\"https:\/\/www.hrsa.gov\/optn-modernization\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.hrsa.gov\/optn-modernization<\/a>\"},{\"id\":\"8dabffcc-0193-4ebe-ac3a-8e5b93828ae3\",\"content\":\"HRSA. (2024). OPTN modernization initiative. Retrieved December 6, 2024.\"},{\"id\":\"44331a34-2ab3-481c-bd67-490e385fd02f\",\"content\":\"U.S. Department of Health and Human Services. In historic step, HRSA makes first ever multi-vendor awards to modernize the nation\u2019s organ transplant system and end the current contract monopoly. September 19, 2024. Accessed October 15, 2024. <a href=\\\"https:\/\/www.hhs.gov\/about\/news\/2024\/09\/19\/hrsa-makes-first-ever-multi-vendor-awards-to-modernize-the-nations-organ-transplant-system.html\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.hhs.gov\/about\/news\/2024\/09\/19\/hrsa-makes-first-ever-multi-vendor-awards-to-modernize-the-nations-organ-transplant-system.html<\/a>\"},{\"id\":\"d96e5f24-7d5c-4391-ba1c-f3cdffaffd47\",\"content\":\"FDA Center for Biologics Evaluation and Research. Source animal, product, preclinical, and clinical issues concerning the use of xenotransplantation products in humans. December 2016. Accessed October 15, 2024. <a href=\\\"https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/source-animal-product-preclinical-and-clinical-issues-concerning-use-xenotransplantation-products\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/source-animal-product-preclinical-and-clinical-issues-concerning-use-xenotransplantation-products<\/a>\"},{\"id\":\"92ef33d3-34b5-4d4c-83d9-e534c52863f9\",\"content\":\"Hawthorne WJ. Ethical and legislative advances in xenotransplantation for clinical translation: focusing on cardiac, kidney and islet cell xenotransplantation.<em> Front Immunol. <\/em>2024;15:1355609\"},{\"id\":\"a1a9b500-2c79-4576-ac13-dd869b9cba47\",\"content\":\"Regalado A. The xenotransplant patient who died received a heart infected with a pig virus. <em>MIT Technology Review<\/em>. May 4, 2022. Accessed October 15, 2024. <a href=\\\"https:\/\/www.technologyreview.com\/2022\/05\/04\/1051725\/xenotransplant-patient-died-received-heart-infected-with-pig-virus\/\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.technologyreview.com\/2022\/05\/04\/1051725\/xenotransplant-patient-died-received-heart-infected-with-pig-virus\/<\/a>\"},{\"id\":\"8b838035-0ed2-44fe-8c5d-a5ba6cf41b76\",\"content\":\"Regalado A. (2022). Xenotransplant patient received heart infected with pig virus. <em>MIT Technology Review.<\/em> Retrieved October 15, 2024.\"},{\"id\":\"727a251d-c956-4310-a9b1-7b744bbc155c\",\"content\":\"Bobier C, Hurst DJ, Rodger D. Should Xenotransplantation Surgeries Be Authorized Under the Food and Drug Administration's Expanded Access\u00a0Pathway?.\u00a0<em>AMA J Ethics<\/em>. 2025;27(3):E197-E200.\u00a0doi:10.1001\/amajethics.2025.197\"},{\"id\":\"e7b6b9bb-960f-4f8e-9633-a208b336ecc0\",\"content\":\"Healey\u00a0N. World-first pig kidney trials mark turning point for xenotransplantation.\u00a0<em>Nat Med<\/em>. 2025. doi:10.1038\/d41591-025-00020-0\"},{\"id\":\"5c485b5d-b65d-4fef-a7a3-2338e570fa69\",\"content\":\"Health Resources &amp; Services Administration. HRSA directive for OPTN donation after circulatory death policy development.\u00a0HRSA.gov. May 28, 2025. Accessed February 6, 2026.\u00a0<a href=\\\"https:\/\/www.hrsa.gov\/optn\/policies-bylaws\/public-comment\/hrsa-directive-optn-donation-after-circulatory-death-policy-\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/www.hrsa.gov\/optn\/policies-bylaws\/public-comment\/hrsa-directive-optn-donation-after-circulatory-death-policy-<\/a>development\"},{\"id\":\"44444a99-e1a7-408d-a9a7-9af3ad4ea167\",\"content\":\"Advanced Research Projects Agency for Health. ARPA-H awards teams set to\u00a0bioprint\u00a0universally matched organs on demand.\u00a0ARPA-H.gov. January 12, 2026. Accessed February 6, 2026.\u00a0<a href=\\\"https:\/\/arpa-h.gov\/news-and-events\/arpa-h-awards-teams-set-bioprint-universally-matched-organs-demand\\\" target=\\\"_blank\\\" rel=\\\"noreferrer noopener\\\">https:\/\/arpa-h.gov\/news-and-events\/arpa-h-awards-teams-set-bioprint-universally-matched-organs-demand<\/a>\"},{\"content\":\"DeRoos LJ, Marrero WJ, Tapper EB, et al. Estimated association between organ availability and presumed consent in solid organ transplant. <em>JAMA Netw Open<\/em>. 2019;2(10):e1912431\",\"id\":\"5efee13d-1326-4987-b97c-067db919a717\"},{\"content\":\"Ministerio de Salud. INCUCAI. Accessed June 26, 2025.\u00a0 <a href=\\\"https:\/\/www.argentina.gob.ar\/salud\/donarorganos\\\">https:\/\/www.argentina.gob.ar\/salud\/donarorganos<\/a>\",\"id\":\"c8ae5797-2caa-4f71-891a-d929ddbf7a34\"},{\"content\":\"Ministerio de Salud y Protecci\u00f3n Social. Enlace Minsalud, 16 de febrero de 2017. Accessed July 2, 2026. https:\/\/www.minsalud.gov.co\/sites\/rid\/Lists\/BibliotecaDigital\/RIDE\/DE\/COM\/enlace-minsalud-92-donacion.pdf\",\"id\":\"96e80953-165b-49c4-8687-722f3d804a91\"},{\"content\":\"Instituto de Salud P\u00fablica. Lo que tienes que saber sobre la donaci\u00f3n de \u00f3rganos en Chile. Accessed June 26, 2025. <a href=\\\"https:\/\/www.ispch.gob.cl\/noticia\/lo-que-tienes-que-saber-sobre-la-donacion-de-organos-en-chile\/\\\">https:\/\/www.ispch.gob.cl\/noticia\/lo-que-tienes-que-saber-sobre-la-donacion-de-organos-en-chile\/<\/a>\",\"id\":\"c421c8d5-b39c-459c-b739-75d1a67aaf35\"},{\"content\":\"Gobierno de Per\u00fa. Donaci\u00f3n de \u00f3rganos y tejidos: preguntas frecuentes. Accessed November 14, 2025. <a href=\\\"https:\/\/www.gob.pe\/100384-donacion-de-organos-y-tejidos-preguntas-frecuentes\\\">https:\/\/www.gob.pe\/100384-donacion-de-organos-y-tejidos-preguntas-frecuentes<\/a>\",\"id\":\"ac49ad9e-9993-4907-8c29-ece6de164c79\"},{\"content\":\"Gobierno de Uruguay. Expresi\u00f3n de voluntad de donaci\u00f3n (positiva o negativa). Accessed June 26, 2025. <a href=\\\"https:\/\/www.gub.uy\/tramites\/expresion-voluntad-donacion-positiva-negativa\\\">https:\/\/www.gub.uy\/tramites\/expresion-voluntad-donacion-positiva-negativa<\/a>\",\"id\":\"b30d9ed2-4716-4e24-bb4c-6a9c9b65e34c\"},{\"id\":\"09deb376-7863-4fe7-bd62-3a07bdae478c\",\"content\":\"Streit S, Johnston-Webber C, Mah J, et al. Ten lessons from the Spanish model of organ donation and transplantation. <em>Transpl Int.<\/em> 2023;36:11009\"},{\"content\":\"Streit S, et al. (2023). Ten lessons from the Spanish model of organ donation and transplantation. <em>Transpl Int,<\/em> 36, 11009.\",\"id\":\"457e59c2-127e-4a61-96aa-ff1a293836d4\"}]"},"secton":[18],"class_list":["post-1348","page","type-page","status-publish","hentry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA<\/title>\n<meta name=\"description\" content=\"PETA Scientists&#039; comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/science.peta.org\/es\/investigacion-biomedica\/\" \/>\n<meta property=\"og:locale\" content=\"es_ES\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA\" \/>\n<meta property=\"og:description\" content=\"PETA Scientists&#039; comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/science.peta.org\/es\/investigacion-biomedica\/\" \/>\n<meta property=\"og:site_name\" content=\"Modernicemos la Investigaci\u00f3n YA\" \/>\n<meta property=\"article:modified_time\" content=\"2026-07-02T18:42:43+00:00\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"77 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/science.peta.org\\\/es\\\/investigacion-biomedica\\\/\",\"url\":\"https:\\\/\\\/science.peta.org\\\/es\\\/investigacion-biomedica\\\/\",\"name\":\"Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/science.peta.org\\\/es\\\/#website\"},\"datePublished\":\"2026-01-29T22:30:23+00:00\",\"dateModified\":\"2026-07-02T18:42:43+00:00\",\"description\":\"PETA Scientists' comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.\",\"breadcrumb\":{\"@id\":\"https:\\\/\\\/science.peta.org\\\/es\\\/investigacion-biomedica\\\/#breadcrumb\"},\"inLanguage\":\"es-ES\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\\\/\\\/science.peta.org\\\/es\\\/investigacion-biomedica\\\/\"]}]},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\\\/\\\/science.peta.org\\\/es\\\/investigacion-biomedica\\\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"name\":\"Home\",\"item\":\"https:\\\/\\\/science.peta.org\\\/es\\\/\"},{\"@type\":\"ListItem\",\"position\":2,\"name\":\"Investigaci\u00f3n biom\u00e9dica\"}]},{\"@type\":\"WebSite\",\"@id\":\"https:\\\/\\\/science.peta.org\\\/es\\\/#website\",\"url\":\"https:\\\/\\\/science.peta.org\\\/es\\\/\",\"name\":\"Modernicemos la Investigaci\u00f3n YA\",\"description\":\"\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":{\"@type\":\"EntryPoint\",\"urlTemplate\":\"https:\\\/\\\/science.peta.org\\\/es\\\/?s={search_term_string}\"},\"query-input\":{\"@type\":\"PropertyValueSpecification\",\"valueRequired\":true,\"valueName\":\"search_term_string\"}}],\"inLanguage\":\"es-ES\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA","description":"PETA Scientists' comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/","og_locale":"es_ES","og_type":"article","og_title":"Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA","og_description":"PETA Scientists' comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.","og_url":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/","og_site_name":"Modernicemos la Investigaci\u00f3n YA","article_modified_time":"2026-07-02T18:42:43+00:00","twitter_card":"summary_large_image","twitter_misc":{"Est. reading time":"77 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"WebPage","@id":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/","url":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/","name":"Investigaci\u00f3n biom\u00e9dica - Modernicemos la Investigaci\u00f3n YA","isPartOf":{"@id":"https:\/\/science.peta.org\/es\/#website"},"datePublished":"2026-01-29T22:30:23+00:00","dateModified":"2026-07-02T18:42:43+00:00","description":"PETA Scientists' comprehensive report on the use of animals in experimentation, testing, and education, and common-sense strategy for revitalizing the U.S. scientific enterprise to protect human health and the environment.","breadcrumb":{"@id":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/#breadcrumb"},"inLanguage":"es-ES","potentialAction":[{"@type":"ReadAction","target":["https:\/\/science.peta.org\/es\/investigacion-biomedica\/"]}]},{"@type":"BreadcrumbList","@id":"https:\/\/science.peta.org\/es\/investigacion-biomedica\/#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/science.peta.org\/es\/"},{"@type":"ListItem","position":2,"name":"Investigaci\u00f3n biom\u00e9dica"}]},{"@type":"WebSite","@id":"https:\/\/science.peta.org\/es\/#website","url":"https:\/\/science.peta.org\/es\/","name":"Modernicemos la Investigaci\u00f3n YA","description":"","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/science.peta.org\/es\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"es-ES"}]}},"_links":{"self":[{"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/pages\/1348","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/comments?post=1348"}],"version-history":[{"count":45,"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/pages\/1348\/revisions"}],"predecessor-version":[{"id":1453,"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/pages\/1348\/revisions\/1453"}],"wp:attachment":[{"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/media?parent=1348"}],"wp:term":[{"taxonomy":"secton","embeddable":true,"href":"https:\/\/science.peta.org\/es\/wp-json\/wp\/v2\/secton?post=1348"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}