Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells

Background/Aims: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. Methods: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. Results: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15 P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172 P-Cdk4/ Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR- 720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. Conclusion: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cellsEspaña Ministry of Economy and Competitiveness (MINECO) cofinanced by the ERDF (BFU2016-75352-P AEI/FEDER, EU

An actionable guide to creating Educational Escape Rooms: handbook

Sem resumo disponível.publishe

En praktisk guide til brugen af didaktiske gåderum undervisning: håndbog

No abstract available.publishe

Papillary thyroid cancer 2020: do you have to be a conservative to be a progressivist?

Resumen En los últimos años, se han publicado diversas guías y documentos de consenso por parte de diferentes sociedades y organismos oficiales, que han cambiado de manera sustancial el enfoque en el abordaje terapéutico de buena parte de los carcinomas papilares de tiroides, los catalogados como de menor riesgo, grupo que, a su vez, ha ido recibiendo una redefinición por parte de estos mismos documentos que hace que constituyan un subgrupo cada vez más numeroso. Estas tendencias, relativas tanto al tratamiento quirúrgico respecto a sus indicaciones y a la extensión idónea de la cirugía, como a las indicaciones de los tratamientos complementarios, radioiodo y supresión de TSH fundamentalmente, no han estado exentas de controversia e incluso polémica. En este trabajo se hace una revisión pormenorizada de los cambios más importantes que se han ido proponiendo en el abordaje del carcinoma papilar de tiroides en la bibliografía reciente y de sus aspectos más controvertidos.</p

Retroperitoneoscopy in acute pancreatitis.

Resumen La pancreatitis aguda es un proceso inflamatorio donde el tratamiento médico precoz y una secuencia de abordaje escalonada (step-up approach) reduce, significativamente, la morbilidad y mortalidad. El desarrollo de la laparoscopia ha permitido disponer de abordajes mínimamente invasivos como la retroperitoneoscopia (VARD). La VARD es una técnica poco invasiva que minimiza la respuesta sistémica al estrés quirúrgico. Ofrece la ventaja de una mejor visualización de las estructuras vasculares pancreáticas y minimiza la lesión de éstas. Permite realizar nuevos lavados y drenajes por vía retroperitoneal, evitando la altísima morbi-mortalidad asociada a una laparotomía. La VARD es una técnica quirúrgica alternativa, válida y reproducible en el tratamiento de la PAN, que ofrece resultados comparables e incluso superiores, en algunas series, a los de la cirugía abierta, con resultados satisfactorios en cuanto a morbilidad y mortalidad postoperatoria.</p

Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis

Hepatic steatosis is a risk factor for the progression of non-alcoholic fatty liver disease. The role of pro-inflammatory interleukin (IL)-6 in hepatic steatosis etiology is controversial. We investigated in vivo and in primary hepatocyte cultures whether IL-6 has a modulator role in liver and mitochondria lipid composition and cell death in a choline-deficient (CD) diet rat model of hepatic steatosis. Dietary choline deficiency increased triglycerides and cholesterol, and reduced phosphatidylcholine (PC), phosphatidylethanolamine (PE) and the membrane integrity marker PC:PE ratio in liver. Choline-deficient diet enhanced systemic IL-6, and IL-6 receptor expression and cell death vulnerability in hepatocytes. Derangement of the mitochondrial electron transport chain and of its phospholipid environment was found in CD rat liver mitochondria, which exhibited elevated concentrations of triglycerides, cardiolipin and PC and elevated PC:PE ratio. The cell treatment with IL-6, but not PC, eliminated much of the CD-promoted lipid imbalance in mitochondria but not tumor-necrosis factor (TNF)-α-induced cell death. However, PC supplementation prevented the TNF-α-induced DNA fragmentation, cytochrome-c release and caspase-3 activity in control and CD hepatocytes. In conclusion, IL-6 ameliorated the mitochondria lipid disturbance in hepatocytes isolated from steatotic animals. Furthermore, PC is identified as a new survival agent that reverses several TNFα-inducible responses that are likely to promote steatosis and necrosis. </jats:p