PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas

PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5′UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology. © Copyright 2015, Mary Ann Liebert, Inc. 2015

Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism

Background & aims: β-hydroxy-β-methylbutyrate (HMB) is purported as a key nutritional supplement for the preservation of muscle mass in health, disease and as an ergogenic aid in exercise. Of the two available forms of HMB (calcium (Ca-HMB) salt or free acid (FA-HMB)) – differences in plasma bioavailability have been reported. We previously reported that ∼3 g oral FA-HMB increased muscle protein synthesis (MPS) and reduced muscle protein breakdown (MPB). The objective of the present study was to quantify muscle protein metabolism responses to oral Ca-HMB. Methods: Eight healthy young males received a primed constant infusion of 1,2 13C2 leucine and 2H5 phenylalanine to assess MPS (by tracer incorporation in myofibrils) and MPB (via arterio-venous (A-V) dilution) at baseline and following provision of ∼3 g of Ca-HMB; muscle anabolic (MPS) and catabolic (MPB) signalling was assessed via immunoblotting. Results: Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 μM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < 0001) and suppressions in MPB (PA: 7.6 ± 1.2 μmol Phe per leg min−1, Ca-HMB: 5.2 ± 0.8 μmol Phe per leg min−1, p < 0.01). Increases in the phosphorylation of mTORc1 substrates i.e. p70S6K1 and RPS6 were also observed, with no changes detected in the MPB targets measured. Conclusions: These findings support the pro-anabolic properties of HMB via mTORc1, and show that despite proposed differences in bioavailability, Ca-HMB provides a comparable stimulation to MPS and suppression of MPB, to FA-HMB, further supporting its use as a pharmaconutrient in the modulation of muscle mass

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway

Background There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation. Methods We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls. Results The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465). Conclusions The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise

T-cell regulation in Erythema Nodosum Leprosum.

Leprosy is a disease caused by Mycobacterium leprae where the clinical spectrum correlates with the patient immune response. Erythema Nodosum Leprosum (ENL) is an immune-mediated inflammatory complication, which causes significant morbidity in affected leprosy patients. The underlying cause of ENL is not conclusively known. However, immune-complexes and cell-mediated immunity have been suggested in the pathogenesis of ENL. The aim of this study was to investigate the regulatory T-cells in patients with ENL. Forty-six untreated patients with ENL and 31 non-reactional lepromatous leprosy (LL) patient controls visiting ALERT Hospital, Ethiopia were enrolled to the study. Blood samples were obtained before, during and after prednisolone treatment of ENL cases. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of regulatory T-cells by flow cytometry. Five markers: CD3, CD4 or CD8, CD25, CD27 and FoxP3 were used to define CD4+ and CD8+ regulatory T-cells. Clinical and histopathological data were obtained as supplementary information. All patients had been followed for 28 weeks. Patients with ENL reactions had a lower percentage of CD4+ regulatory T-cells (1.7%) than LL patient controls (3.8%) at diagnosis of ENL before treatment. After treatment, the percentage of CD4+regulatory T-cells was not significantly different between the two groups. The percentage of CD8+ regulatory T-cells was not significantly different in ENL and LL controls before and after treatment. Furthermore, patients with ENL had higher percentage of CD4+ T-ells and CD4+/CD8+ T-cells ratio than LL patient controls before treatment. The expression of CD25 on CD4+ and CD8+ T-cells was not significantly different in ENL and LL controls suggesting that CD25 expression is not associated with ENL reactions while FoxP3 expression on CD4+ T-cells was significantly lower in patients with ENL than in LL controls. We also found that prednisolone treatment of patients with ENL reactions suppresses CD4+ T-cell but not CD8+ T-cell frequencies. Hence, ENL is associated with lower levels of T regulatory cells and higher CD4+/CD8+ T-cell ratio. We suggest that this loss of regulation is one of the causes of ENL

Modelling the potential impacts of climate change on the hydrology of the Aipe river basin in Huila, Colombia

[EN] The dynamics of a global world, and humans performing as a new geological force, require that an effort is undertaken to make robust decisions in order to devise strategies for the management and adaptation to climate change. This study aims to investigate the potential impact of climate change on the hydrology of the Aipe river basin in Huila, Colombia. The abcd Thomas model (four parameters) was calibrated and validated for the stream flows of the Aipe catchment (1992¿2012). The sensitivity and identifiability of the parameters were evaluated using the Monte Carlo Analysis Toolbox (MCAT). The results show the ability of the model to simulate the monthly stream flow (Nash¿Sutcliffe efficiency coefficient of 0,89). The most influential parameters are: a (water storage in the soil) and c (contribution to the aquifer). From the simulated scenarios, the baseline (1992¿2012) was estimated to be an average flow of 15,44 m3s¿1; the trend extrapolation scenario estimated a rate 13,79 m3s¿1 (¿10,64%); while for the multi-model assembly scenario it was 9,34 m3s¿1 (¿39,47%) and for the A2 scenario it was 5,74 m3s¿1 (¿62,60%). Lastly, we propose a set of strategies for adaptation to climate change that are committed to the integral management of water resources.[ES] La dinámica de un mundo global y el hombre como nueva fuerza geológica plantean la necesidad de tomar decisiones robustas, diseñar estrategias de manejo y de adaptarse al cambio climático. Este estudio investiga la respuesta hidrológica de la cuenca hidrográfica del río Aipe (688.9 km2 ), en Huila, Colombia, en acorde con los escenarios de cambio climático desde 2011 a 2040. El modelo hidrológico abcd de Thomas (4 parámetros) fue calibrado y validado comparando el caudal simulado y lo observado en el punto de cierre de la cuenca (en la estación Puente Carretera), usando series históricas mensuales (1992¿2012). Realizamos la evaluación de la sensibilidad e identificabilidad de los parámetros con la herramienta `Monte Carlo Analysis Toolbox¿ (MCAT). Los resultados muestran que el modelo es capaz de representar adecuadamente los caudales mensuales observados en el punto de desagüe de la cuenca, al encontrarse un índice de eficiencia de Nash¿Sutcliffe (NSE) de 0,89. Los parámetros más influyentes son a (almacenamiento del agua en el suelo) y c (aporte al acuífero). Con respecto a la simulación de los escenarios, la línea base (1992¿2012) estimó un caudal medio de 15,44 m3 s ¿1 ; el escenario de extrapolación de tendencias estimó un caudal de 13,79 m3 s ¿1 (¿10,64%); el escenario de ensamble multi-modelo de 9,34 m3 s ¿1 (¿39,47%) y el escenario A2 de 5,74 m3 s ¿1 (¿62,60%). Proponemos una batería de medidas de adaptación al cambio climático que buscan la gestión integral del recurso hídrico.Romero-Cuellar, J.; Buitrago-Vargas, A.; Quintero-Ruiz, T.; Francés, F. (2018). Simulación hidrológica de los impactos potenciales del cambio climático en la cuenca hidrográfica del río Aipe, en Huila, Colombia. RIBAGUA - Revista Iberoamericana del Agua. 5(1):63-78. https://doi.org/10.1080/23863781.2018.1454574S63785

Identification of Gliadin Bands 42 and 45 in <i>Triticum durum</i> Def.

Se evaluaron por electroforesis en gel de poliacrilamida variedades y líneas de mejoramiento de trigo candeal, estableciendo la presencia o ausencia de las bandas 45 y 42, relacionadas con la fuerza del gluten. Para ello se utilizó la técnica de electroforesis en gel de poliacrilamida a pH 3,1. Las variedades Marquis, Wascana y los biotipos A y B de Duramba se utilizaron como referencia para el estudio de la Movilidad Relativa de las bandas. Todas las variedades presentaron la banda 45, con excepción de Thomas Ventanía, que presentó la 42.El objetivo del trabajo fue evaluar dicha técnica y su utilidad en la selección de cultivares sobre la base de su calidad industrial.Lines and varieties of durum wheat were evaluated in order to determine the presence or absence of 45 and 42 bands which are related with gluten strength. For this purpose polyacrylamide gel electrophoresis at pH 3,1 was used. Varieties Marquis, Wascana and biotypes A and B of Duramba were used as references for the study of relative bands mobility. All varieties presented band 45, excepting Thomas Ventanía which presented band 42. The aim of this work was to evaluate this technique to verify if it is useful as a selection criteria in breeding for industrial quality.Facultad de Ciencias Agrarias y Forestale

Identification of Gliadin Bands 42 and 45 in <i>Triticum durum</i> Def.

Se evaluaron por electroforesis en gel de poliacrilamida variedades y líneas de mejoramiento de trigo candeal, estableciendo la presencia o ausencia de las bandas 45 y 42, relacionadas con la fuerza del gluten. Para ello se utilizó la técnica de electroforesis en gel de poliacrilamida a pH 3,1. Las variedades Marquis, Wascana y los biotipos A y B de Duramba se utilizaron como referencia para el estudio de la Movilidad Relativa de las bandas. Todas las variedades presentaron la banda 45, con excepción de Thomas Ventanía, que presentó la 42.El objetivo del trabajo fue evaluar dicha técnica y su utilidad en la selección de cultivares sobre la base de su calidad industrial.Lines and varieties of durum wheat were evaluated in order to determine the presence or absence of 45 and 42 bands which are related with gluten strength. For this purpose polyacrylamide gel electrophoresis at pH 3,1 was used. Varieties Marquis, Wascana and biotypes A and B of Duramba were used as references for the study of relative bands mobility. All varieties presented band 45, excepting Thomas Ventanía which presented band 42. The aim of this work was to evaluate this technique to verify if it is useful as a selection criteria in breeding for industrial quality.Facultad de Ciencias Agrarias y Forestale