Bryanramos1021

Copyright © 2020 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.BACKGROUND We investigated whether a heterozygous mutation that we newly identified in HTRA1 (high-temperature requirement serine protease A1 gene) in a pedigree with autosomal dominant hereditary cerebral small vessel disease (SVD) reduces the function of HTRA1 and affects the transforming growth factor-β1 (TGF-β1)/Smad signaling. METHODS Whole-exome sequence from the proband and her two sisters was examined using whole-exome enrichment and sequencing. Expression of HTRA1 and TGF-β1/Smad and HTRA1 activity were assayed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting analyses after transfecting wild-type and mutant HTRA1 genes into HEK293 cells. RESULTS A new heterozygous mutation (c.614C>Gp.Ser205Cys) in HTRA1 was identified in the sequence encoding the trypsin-like serine protease domain. The mutation was predicted to be deleterious by in silico tools. Moreover, in vitro activity and protein analyses revealed a loss-of-function effect of the mutation the proteolytic activity of mutant HTRA1 was decreased, and, notably, this was accompanied by an increase in TGF-β1/Smad protein levels. CONCLUSIONS The heterozygous mutation HTRA1 S205C causing diminished protease activity is associated with-and could represent a cause of-autosomal dominant hereditary cerebral SVD. Our results also indicate a relationship between HTRA1 and TGF-β1/Smad signaling. © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.AIMS The aim of this study is to evaluate the contemporary use of a pulmonary artery catheter (PAC) in acute myocardial infarction-cardiogenic shock (AMI-CS). METHODS AND RESULTS A retrospective cohort of AMI-CS admissions using the National Inpatient Sample (2000-2014) was identified. Admissions with concomitant cardiac surgery or non-AMI aetiology for cardiogenic shock were excluded. The outcomes of interest were in-hospital mortality, resource utilization, and temporal trends in cohorts with and without PAC use. In the non-PAC cohort, the use and outcomes of right heart catheterization was evaluated. Multivariable regression and propensity matching was used to adjust for confounding. During 2000-2014, 364 001 admissions with AMI-CS were included. PAC was used in 8.1% with a 75% decrease during over the study period (13.9% to 5.4%). Greater proportion of admissions to urban teaching hospitals received PACs (9.5%) compared with urban non-teaching (7.1%) and rural hospitals (5.4%); P less then 0.001. Youngen behalf of European Society of Cardiology.AIMS Identification of patients with type 2 diabetes (T2D) at increased risk of incident heart failure (HF) beyond traditional risk factors such as prior myocardial infarction (MI) might allow selection of patients who would benefit from preventative treatment. Microvascular disease (MiVD) is thought to play a pathophysiological role in the development of HF in T2D; however, its association with new-onset HF with reduced or preserved ejection fraction has not been specifically defined. METHODS AND RESULTS Patients in the Genetics of Diabetes Audit and Research Tayside Scotland study were linked to echocardiography, prescriptions, and clinical outcomes. In total, 9141 patients with T2D were identified for analysis. Clinical variables and the presence of retinopathy, nephropathy, and neuropathy were assessed. Cumulative incidence was calculated for the association of both individual and the total number of MiVD states and incident HF. Median follow-up was 9.3 years. In total, there were 900 HF events. The presence of any MiVD was independently associated with both HF with reduced ejection fraction (hazard ratio 1.40; 95% confidence interval 1.11-1.76, P = 0.004) and HF with preserved ejection fraction (hazard ratio 1.38; 95% confidence interval 1.10-1.72, P = 0.005), with a stepwise association between the number of MiVD states and risk of incident HF (P for trend less then 0.001). Similar associations were found in sensitivity analyses limited to patients without a prior MI, and using competing risks analysis. CONCLUSIONS Individuals with T2D and with MiVD are at risk of incident HF independent of a history of prior HF or MI. Patients with MiVD could benefit from screening for HF and individualized therapy with treatments that lower HF risk. © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.BACKGROUND Non-small cell lung cancer (NSCLC) occupies the majority of lung cancer cases and is notorious for the awful prognosis. LIM domains-containing 1 (LIMD1) is suggested as a tumor suppressor in lung cancer, but its mechanism in NSCLC remains elusive. Present study aimed to uncover the mechanism of LIMD1 in NSCLC. METHODS qRT-PCR was performed to analyze the level of LIMD1. The functions of LIMD1 in NSCLC cells were evaluated by CCK-8, EdU, and caspase-3 activity assays. RIP and pull-down assays were applied to determine the interaction of LIMD1 with heterogeneous nuclear ribonucleoprotein U (hnRNP U) and LIMD1-AS1. RESULTS LIMD1 was downregulated in NSCLC samples and cells. Functionally, LIMD1 hindered proliferation and drove apoptosis in NSCLC cells. VE-821 Moreover, long noncoding RNA (lncRNA) LIMD1 antisense RNA 1 (LIMD1-AS1) was downregulated in NSCLC samples and cell lines. LIMD1-AS1 knockdown abrogated NSCLC cell growth in vitro and in vivo. Mechanistically, LIMD1-AS1 stabilized LIMD1 mRNA through interacting with hnRNP U. Rescue experiments suggested that LIMD1-AS1 repressed NSCLC progression through LIMD1. CONCLUSIONS LIMD1-AS1 suppressed NSCLC progression through stabilizing LIMD1 mRNA via hnRNP U, providing new thoughts for the improvement of molecular-targeted therapy for NSCLC. © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.Due to high rates of proliferation and DNA synthesis, neoplastic cells have higher requirements of iron than normal cells. For that reason, neoplastic cells have remodelled iron metabolism pathways, over-expressing genes encoding for iron uptake proteins, among which Transferrin Receptor-1 (TFR-1). Accumulating evidence has proven that overexpression of TFR-1 and high Iron concentration, are both widespread condition of cancer cells, both essential to tumour onset and progression. We studied TFR-1 and PCNA immunohistochemical expression in fifteen (15) Canine osteoblastic osteosarcomas (COS). After immunohistochemical staining, counting of TFR-1 positive cells by two independent observers showed that 85%-95% of neoplastic cells were strongly labelled at cytoplasmic level by anti-TFR-1 antibody in all examined COS. Furthermore, 70%-80% of neoplastic cells were positively labelled at the nuclear level by PCNA. Surprisingly, about 100% of intratumour vascular endothelial cells were also positive, whereas extratumour vascular endothelial cells were negative.