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Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA–producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties.

BackgroundNo study has shown the oncologic non-inferiority of robotic pancreatoduodenectomy (RPD) versus open pancreatoduodenectomy (OPD) for pancreatic cancer (PC).MethodsThis is a single institution propensity score matched study comparing RPD and ODP for resectable PC, based on factors predictive of R1 resection (≤ 1 mm). Only patients operated on after completion of the learning curve in both procedures and for whom circumferential margins were assessed according to the Leeds pathology protocol were included. The primary study endpoint was the rate of R1 resection. Secondary study endpoints were as follows: number of examined lymph nodes (N), rate of perioperative transfusions, percentage of patients receiving adjuvant therapies, occurrence of local recurrence, overall survival, disease-free survival, and sample size calculation for randomized controlled trials (RCT).ResultsFactors associated with R1 resection were tumor diameter, number of positive N, N ratio, logarithm odds of positive N, and duodenal infiltration. The matching process identified 20 RPDs and 24 OPDs. All RPDs were completed robotically. R1 resection was identified in 11 RPDs (55.0%) and in 10 OPDs (41.7%) (p = 0.38). There was no difference in the rate of R1 at each margin as well as in the proportion of patients with multiple R1 margins. RPD and OPD were also equivalent with respect to all secondary study endpoints, with a trend towards lower rate of blood transfusions in RPD. Based on the figures presented herein, a non-inferiority RCT comparing RPD and OPD having the rate of R1 resection as the primary study endpoint requires 3355 pairs.ConclusionsRPD and OPD achieved the same rate of R1 resections in resectable PC. RPD was also non-inferior to OPD with respect to all secondary study endpoints. Because of the high number of patients required to run a RCT, further assessment of RPD for PC would require the implementation of an international registry.

Background As literature largely focuses on long-term outcomes, this study aimed at elucidating the perioperative outcomes of liver transplant patients receiving a graft from two groups of unconventional expanded criteria donors: brain dead aged > 80 years and cardiac dead. Methods Data of 247 cirrhotic patients transplanted at two high volume liver transplant centers were analysed. Confounders were balanced using a stabilized inverse probability therapy weighting and a propensity score for each patient on the original population was generated. The score was created using a multivariate logistic regression model considering a Comprehensive Complication Index ≥ 42 (no versus yes) as the dependent variable and 11 possible clinically relevant confounders as covariate. Results Forty-four patients received the graft from a cardiac-dead donor and 203 from a brain-dead donor aged > 80 years. Intraoperatively, cardiac-dead donors liver transplant cases required more fresh frozen plasma units ( P  < 0.0001) with similar reduced need of fibrinogen to old brain-dead donors cases. The incidence of reperfusion syndrome was similar ( P  = 0.80). In the Intensive Care Unit, both the groups presented a comparable low need for blood transfusions, renal replacement therapy and inotropes. Cardiac-dead donors liver transplantations required more time to tracheal extubation ( P  < 0.0001) and scored higher Comprehensive Complication Index ( P  < 0.0001) however the incidence of a severe complication status (Comprehensive Complication Index  ≥ 42) was similar ( P  = 0.52). ICU stay ( P  = 0.97), total hospital stay ( P  = 0.57), in hospital ( P  = 1.00) and 6 months ( P  = 1.00) death were similar. Conclusion Selected octogenarian and cardiac-dead donors can be used safely for liver transplantation.