The metabolic microenvironment of melanomas: prognostic value of MCT1 and MCT4

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.This work was supported by FAPESP grant to VLV (2012/04194-1) and CP (2015/25351-6). VMG received a doctoral fellowship (SFRH/BD/51997/2012) from Fundacao para a Ciencia e a Tecnologia (FCT) and ON. 2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000017) co-funded by Programa Operacional Regional do Norte (ON.2- O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN), through Fundo Europeu de Desenvolvimento Regional (FEDER).info:eu-repo/semantics/publishedVersio

Cerebellar Afferents from neurons in the extraocular motor nuclei: a fluorescent retrograde double-labeling study in the sheep

The fluorescent retrograde double labeling technique has been used to identify within the extraocular motor nuclei of the sheep the neurons projecting to the cerebellum and to provide evidence whether they are motor neurons sending collaterals to the cerebellum or a separate population of neurons. The study was performed on eight sheep. The fluorescent tracers used were Fast Blue and the diamidino yellow dihydrochloride. In one and the same animal a fluorescent tracer was injected into the extraocular muscles (EOMs) and the other into bilateral points of the vermal folia II-V and paramedian lobule, or into the vermal folia VI, VIIA and VIIB, or into the underlying fastigial nuclei. Within the oculomotor, trochlear, and abducens nuclei, almost all of the motor neurons were labeled by the tracer injected into the EOMs and only a few cells were fluorescent for the tracer infiltrated into the cerebellum. These latter labelings were present bilaterally, and their number and distribution did not show apparent differences after injecting the paramedian lobule and the vermal folia or the fastigial nucleus. Along the rostrocaudal extent of the oculomotor and trochlear nuclei, the neurons projecting to the cerebellum were intermingled with the motor neurons located in the nuclear area facing the medial longitudinal fasciculus. In the abducens nucleus they were restricted to the caudal pole of the nucleus, which is located ventrolaterally to the genu of the facial nerve. Double-labeled neurons were never found. The absence of double-labeled cells, in spite of the efficiency of the tracer infiltration into the EOMs and into the cerebellum, demonstrates that the cerebellar projections from the extraocular motor nuclei are not collaterals of the motor neurons, but axons of a separate population of neurons. [...

A comparative prospective study of two available solutions for kidney and liver preservation

Abstract: Background. Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. Patients and Methods. From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. Results. Perfusate volume used was significantly lower in the UW group, being 4,732+/-796 mL versus 5,826+834 mL in the CEL group (P<0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 mumol/L, respectively) as compared with CEL (51.3 and 63.4 mumol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P=NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P=NS) and 89.9% versus 90.6% (P=NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P=NS), respectively; PNF rates were 1.9% and 1.7% (P=NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P=NS) and 99.4% versus 97.7% (P=NS). Conclusions. CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting

A comparative prospective study of two available solutions for kidney and liver preservation

Abstract: Background. Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. Patients and Methods. From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. Results. Perfusate volume used was significantly lower in the UW group, being 4,732+/-796 mL versus 5,826+834 mL in the CEL group (P<0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 mumol/L, respectively) as compared with CEL (51.3 and 63.4 mumol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P=NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P=NS) and 89.9% versus 90.6% (P=NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P=NS), respectively; PNF rates were 1.9% and 1.7% (P=NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P=NS) and 99.4% versus 97.7% (P=NS). Conclusions. CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting

A COMPARATIVE PROSPECTIVE STUDY OF TWO AVAILABLE SOLUTIONS FOR KIDNEY AND LIVER PRESERVATION

BACKGROUND: Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. PATIENTS AND METHODS: From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. RESULTS: Perfusate volume used was significantly lower in the UW group, being 4,732 +/- 796 mL versus 5,826 + 834 mL in the CEL group (P &lt; 0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 micromol/L, respectively) as compared with CEL (51.3 and 63.4 micromol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P = NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P = NS) and 89.9% versus 90.6% (P = NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P = NS), respectively; PNF rates were 1.9% and 1.7% (P = NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P = NS) and 99.4% versus 97.7% (P = NS). CONCLUSIONS: CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting

A comparative prospective study of two available solutions for kidney and liver preservation.

BACKGROUND: Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. PATIENTS AND METHODS: From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. RESULTS: Perfusate volume used was significantly lower in the UW group, being 4,732 +/- 796 mL versus 5,826 + 834 mL in the CEL group (P < 0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 micromol/L, respectively) as compared with CEL (51.3 and 63.4 micromol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P = NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P = NS) and 89.9% versus 90.6% (P = NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P = NS), respectively; PNF rates were 1.9% and 1.7% (P = NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P = NS) and 99.4% versus 97.7% (P = NS). CONCLUSIONS: CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvestin

Mutational profle of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.This work was supported by the Barretos Cancer Hospital; FINEP (MCTI/FINEP/MS/SCTIE/DECIT-CT-INFRA grant number 02/2010); Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer); and National Council for Scientifc and Technological Development (CNPq, Brazil)