Laursengarza5620

AIMS Malignant pleural mesothelioma (MPM) is a rare malignancy with dismal prognosis. While the epithelioid type is associated with more favorable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. METHODS AND RESULTS Tumor specimens of 192 patients with epithelioid MPM from five European centers were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival. Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histologic subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer overall survival than the solid/trabecular group (732 vs. 397 days, p=0.0013). Pleomorphic tumors had the shortest overall survival (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumors showed a greater improvement in overall survival after receiving multimodal therapy than those with solid or trabecular tumors. CONCLUSIONS Histologic subtypes of epithelioid MPM have a prognostic impact and might help to select patients for intensive multimodal treatment approaches. This article is protected by copyright. All rights reserved.Melanogenesis, migration, and proliferation of melanocytes are important factors that determine the hair colors of mammals. MicroRNAs (miRNAs) have been shown to be closely relation to these processes. In melanocytes of alpacas, insulin-like growth factor 1 (IGF1) has been shown to improve melanogenesis through the cyclic AMP (cAMP) pathway. miR-379 was predicted to target insulin-like growth factor (IGF) receptor 1 (IGF1R), which binds to IGF1. Therefore, we hypothesized that miR-379 could mediate melanogenesis, migration, and proliferation of melanocytes. Here, we report that miR-379 was highly expressed in alpaca melanocytes. Subsequent overexpression of miR-379 in alpaca melanocytes led to the generation of the phenotype of melanogenesis, proliferation and migration. In addition, the expression of genes related to these phenotypes in melanocytes were detected. Our results showed that miR-379 targets IGF1R in melanocytes. The overexpression of miR-379 stimulated dendrite extension or elongation and limited the perinuclear distribution of melanin, but inhibited melanogenesis via cAMP response element (CRE) binding protein (CREB) /microphthalmia-associated transcription factor (MITF) pathway. miR-379 attenuated melanocyte migration by downregulating the focal adhesion kinase (FAK), and enhanced melanocyte proliferation by upregulating protein kinase B (AKT). These observations suggest the involvement of miR-379 in the physiological regulation of melanocytes, mediated by targeting IGF1R on insulin receptor (IR) compensation and subsequent crosstalk. This article is protected by copyright. All rights reserved.Integral membrane proteins (IMPs) control countless fundamental biological processes and constitute the majority of drug targets. For this reason, uncovering their molecular mechanism of action has long been an intense field of research. They are, however, notoriously difficult to work with, mainly due to their localization within the heterogeneous of environment of the biological membrane and the instability once extracted from the lipid bilayer. High-resolution structures have unveiled many mechanistic aspects of IMPs but also revealed that the elucidation of static pictures has limitations. Hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) has recently emerged as a powerful biophysical tool for interrogating the conformational dynamics of proteins and their interactions with ligands. Its versatility has proven particularly useful to reveal mechanistic aspects of challenging classes of proteins such as IMPs. This review recapitulates the accomplishments of HDX-MS as it has matured into an essential tool for membrane protein structural biologists. © 2020 The Authors. Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society.BACKGROUND Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post- zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Beckernevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. METHODS Direct sequencing of ACTB gene in affected and unaffected tissue isolated from 1 case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. RESULTS In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. CONCLUSIONS CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related and expand the phenotypic spectrum of ACTB mutations. This article is protected by copyright. Brincidofovir research buy All rights reserved. This article is protected by copyright. All rights reserved.BACKGROUND Aberrant miRNAs expression regulates the occurrence and progression of a variety of cancers, including oral squamous cell carcinoma (OSCC). This study aims to illustrate the potential effects of miR-454/nuclear receptor subfamily 3 group C member 2 (NR3C2) on the biological behaviors of OSCC cells. METHODS GEO database was applied to detect and analyze the expression of miR-545 and NR3C2 in OSCC tissues. Two OSCC cell lines including CAL27 and Tca-83 were utilized to determine the function of miR-454/NR3C2 on OSCC cells biological behaviors. miR-454 and NR3C2 expressions were regulated by miR-454 mimic/inhibitor and pcDNA3.1-NR3C2/si-NR3C2, respectively. Cells biological behaviors were evaluated by cell proliferation, colony formation, and transwell assays. RESULTS The data collected from GEO database indicated that miR-454 expression was upregulated in OSCC tissues; however, the expression of NR3C2 assumed a downward trend. In vitro experiments, the expression trend of miR-454 in OSCC cell lines was consistent with that of the trend in tissues, and the OSCC cells growth and movement abilities significantly decreased after miR-454 depletion.