Mechanisms of primary resistance to immune checkpoint inhibitors in NSCLC.

Immune checkpoint inhibitors (ICIs) redefined the therapeutics of non-small cell lung cancer (NSCLC), leading to significant survival benefits and unprecedented durable responses. However, the majority of the patients develop resistance to ICIs, either primary or acquired. Establishing a definition of primary resistance to ICIs in different clinical scenarios is challenging and remains a work in progress due to the changing landscape of ICI-based regimens, mainly in the setting of early-stage NSCLC. The mechanisms of primary resistance to ICIs in patients with NSCLC include a plethora of pathways involving a cross-talk of the tumor cells, the tumor microenvironment and the host, leading to the development of an immunosuppressive phenotype. The optimal management of patients with NSCLC following primary resistance to ICIs represents a significant challenge in current thoracic oncology. Research in this field includes exploring other immunotherapeutic approaches, such as cancer vaccines, and investigating novel antibody-drug conjugates in patients with NSCLC.

Low temperature exerts protective effects by inhibiting mitochondria-mediated apoptosis pathway following pressure injury to rat muscle.

OBJECTIVE: We aimed to determine the effect of different low-temperature range interventions at different time-points in a rat model of pressure injury (PI) produced by Ischemia/Reperfusion (I/R) injury. METHODS: Sprague-Dawley rats were randomly assigned to blank control, injury control, and temperature intervention groups. Rats in the injury control and temperature intervention groups (involving exposure to different temperature range at different time-points) were subjected to three cycles of I/R injury with 2-h ischemia and 0.5-h reperfusion to induce PI. RESULTS: The muscle tissues exhibited degenerative changes after compression. Low temperature intervention of 16-18°C in the ischemia period resulted in the lowest degree of tissue damage and significantly decreased levels of Bcl-2-associated X protein (Bax), caspase-9, and caspase-3. Moreover, it resulted in the highest expression level of B-cell lymphoma 2 (Bcl-2) and lowest expression levels of Bax, caspase-9, and caspase-3 in muscle tissues among all intervention groups. CONCLUSION: Low-temperature intervention at 16-18°C during the ischemia period showed optimal effects on the expressions of apoptotic factors during the development of PI with I/R-induced tissue damage.

Low temperature exerts protective effects by inhibiting mitochondria-mediated apoptosis pathway following pressure injury to rat muscle / A baixa temperatura exerce efeitos protetores ao inibir a via de apoptose mediada por mitocôndrias após lesão por pressão no músculo de rato / La baja temperatura ejerce efectos protectores al inhibir la vía de apoptosis mediada por mitocondrias después de una lesión por presión en el músculo de la rata

ABSTRACT Objective: We aimed to determine the effect of different low-temperature range interventions at different time-points in a rat model of pressure injury (PI) produced by Ischemia/Reperfusion (I/R) injury. Methods: Sprague-Dawley rats were randomly assigned to blank control, injury control, and temperature intervention groups. Rats in the injury control and temperature intervention groups (involving exposure to different temperature range at different time-points) were subjected to three cycles of I/R injury with 2-h ischemia and 0.5-h reperfusion to induce PI. Results: The muscle tissues exhibited degenerative changes after compression. Low temperature intervention of 16-18°C in the ischemia period resulted in the lowest degree of tissue damage and significantly decreased levels of Bcl-2-associated X protein (Bax), caspase-9, and caspase-3. Moreover, it resulted in the highest expression level of B-cell lymphoma 2 (Bcl-2) and lowest expression levels of Bax, caspase-9, and caspase-3 in muscle tissues among all intervention groups. Conclusion: Low-temperature intervention at 16-18°C during the ischemia period showed optimal effects on the expressions of apoptotic factors during the development of PI with I/R-induced tissue damage.

RESUMO Objetivo: Nosso objetivo foi determinar o efeito de diferentes intervenções na faixa de baixa temperatura em diferentes pontos do tempo em um modelo de lesão por pressão (IP) de rato produzida por lesão de isquemia/reperfusão (I/R). Métodos: Ratos Sprague-Dawley foram aleatoriamente designados para grupos de controle em branco, controle de lesão e intervenção por temperatura. Ratos nos grupos de controle de lesão e intervenção de temperatura (envolvendo exposição a diferentes faixas de temperatura em diferentes momentos) foram submetidos a três ciclos de lesão de I/R com isquemia de 2 h e reperfusão de 0,5 h para induzir IP. Resultados: Os tecidos musculares exibiram alterações degenerativas após a compressão. A intervenção em baixa temperatura de 16-18°C no período de isquemia resultou no menor grau de dano ao tecido e diminuiu significativamente os níveis de proteína X associada a Bcl-2 (Bax), caspase-9 e caspase-3. Além disso, resultou no nível de expressão mais alto de linfoma de células B 2 (Bcl-2) e níveis de expressão mais baixos de Bax, caspase-9 e caspase-3 em tecidos musculares entre todos os grupos de intervenção. Conclusão: A intervenção em baixa temperatura de 16-18°C durante o período de isquemia mostrou efeitos ótimos nas expressões de fatores apoptóticos durante o desenvolvimento de IP com dano tecidual induzido por I/R.

RESUMEN Objetivo: Nuestro objetivo fue determinar el efecto de diferentes intervenciones de rango de temperatura baja en diferentes puntos de tiempo en un modelo de rata de lesión por presión (IP) producida por lesión por isquemia/reperfusión (I/R). Métodos: Se asignaron aleatoriamente ratas Sprague-Dawley a grupos de control en blanco, control de lesiones e intervención de temperatura. Las ratas en los grupos de control de lesiones e intervención de temperatura (que implican exposición a diferentes rangos de temperatura en diferentes puntos de tiempo) se sometieron a tres ciclos de lesión I/R con isquemia de 2 h y reperfusión de 0,5 h para inducir IP. Resultados: Los tejidos musculares presentaron cambios degenerativos después de la compresión. La intervención a baja temperatura de 16-18°C en el período de isquemia resultó en el grado más bajo de daño tisular y niveles significativamente reducidos de proteína X asociada a Bcl-2 (Bax), caspasa-9 y caspasa-3. Además, dio como resultado el nivel de expresión más alto de linfoma de células B 2 (Bcl-2) y los niveles de expresión más bajos de Bax, caspasa-9 y caspasa-3 en los tejidos musculares entre todos los grupos de intervención. Conclusión: La intervención a baja temperatura a 16-18°C durante el período de isquemia mostró efectos óptimos sobre la expresión de factores apoptóticos durante el desarrollo de IP con daño tisular inducido por I/R.