Tuesday, December 8, 2020

A New Panel Estimated GFR, Including β2-Microglobulin and β-Trace Protein and Not Including Race, Developed in a Diverse Population

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Assessment of glomerular filtration rate (GFR) is critical for many aspects of medical practice. GFR estimation based on creatinine and cystatin C together (eGFRcr-cys) is more accurate than eGFR based on either creatinine or cystatin C alone, but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. Beta-2-microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine. In a pooled dataset of 7 studies (5017 participants), we developed new estimating equations based on the combinations of these markers, with and without age or sex and race. In a separate pooled dataset of 7 studies (2245 participants) we showed that the equation that used all four markers, age and sex, but not race, was as accurate as eGFRcr-cys. A more accurate race-free eGFR could be an important advance.
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Which Is the Most Appropriate PI3K Inhibitor for Breast Cancer Patients with or without PIK3CA Status Mutant? A Systematic Review and Network Meta-Analysis

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Objective. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a promising treatment target for patients with breast cancer (BC). Our study aimed to evaluate the most effective and safe PI3K inhibitor for patients with BC, especially in PIK3CA mutation. Methods. Electronics databases were systematically searched from their inception to June 2020 for published randomized controlled trials (RCTs) comparing PI3K inhibitor therapy versus non-PI3K inhibitor therapy in patients with BC that mentioned or reported data of PIK3CA-mutated patient subgroups. Eligible RCTs had to report at least one of the following clinical outcomes: objective response rate (ORR), progression-free survival (PFS), or adverse events (AE). Results. Nine eligible RCTs involving 3872 BC patients and four PI3K inhibitor therapy a rms (i.e., alpelisib, buparlisib, pictilisib, and taselisib) were included. In evaluating ORR, beneficial significant results of PI3K inhibitors could be found in the PIK3CA mutated group (1.952, 1.012 to 3.766); analogous results could also be found in 6m-PFS (1.519, 1.144 to 2.018) and PFS from HR data (-0.346, -0.525 to -0.168). From pairwise and network meta-analyses, buparlisib showed the most favorable ORR, as it was significantly different from fulvestrant in the PIK3CA-mutated patient group (2.80, 1.56 to 5.03). Alpelisib ranked first in the assessment of 6m-PFS and was significantly different from fulvestrant in the PIK3CA-mutated group (2.33, 1.45 to 3.44). The above PI3K inhibitors had good safety with few serious AEs. PROSPERO registration CRD42020193932. Conclusion. The PI3K inhibitors alpelisib and buparlisib appear to have superior efficacy and safety therapeutic choices for patients with BC, especially in PIK3CA-mutated patients.
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Relative Telomere Length in Peripheral Blood Cells and Hypertension Risk among Mine Workers: A Case-Control Study in Chinese Coal Miners

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Hypertension is a common chronic disease in middle-aged and elderly people and is an important risk factor for many cardiovascular diseases. Its pathogenesis remains unclear. Epidemiological studies have found that the loss of telomere length in peripheral blood cells can increase the risk of coronary heart disease, myocardial infarction, and other diseases. However, a correlation between loss of telomere length and hypertension has not been established. In this study, we aimed to explore the association between telomere length and the risk of essential hypertension (EH) in Chinese coal miners. A case-control study was performed with 215 EH patients and 222 healthy controls in a large coal mining group located in North China. Face-to-face interviews were conducted by trained staff with the necessary medica l knowledge. Relative telomere length (RTL) was measured by a quantitative real-time PCR assay using DNA extracted from peripheral blood. In the control group, the age-adjusted RTL was statistically significantly lower in miners performing hard physical labour compared with nonphysical labour (). A significantly shorter age-adjusted RTL was found in the control group of participants who consumed alcohol regularly compared with those who do not consume alcohol (). Age-adjusted RTL was negatively correlated with body mass index (BMI) and alcohol consumption. Hypertension was also found to be significantly correlated with factors such as age, BMI, alcohol consumption, smoking, and tea consumption. Our results suggest that RTL is associated with hypertension in coal miners.
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Sex Difference of Ribosome in Stroke-Induced Peripheral Immunosuppression by Integrated Bioinformatics Analysis

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Ischemic stroke (IS) greatly threatens human health resulting in high mortality and substantial loss of function. Recent studies have shown that the outcome of IS has sex specific, but its mechanism is still unclear. This study is aimed at identifying the sexually dimorphic to peripheral immune response in IS progression, predicting potential prognostic biomarkers that can lead to sex-specific outcome, and revealing potential treatment targets. Gene expression dataset GSE37587, including 68 peripheral whole blood samples which were collected within 24 hours from known onset of symptom and again at 24-48 hours after onset (20 women and 14 men), was downloaded from the Gene Expression Omnibus (GEO) datasets. First, using Bioconductor R package, two kinds of differentially expressed genes (DEGs) (nonsex-speci fic- and sex-specific-DEGs) were screened by follow-up (24-48 hours) vs. baseline (24 hours). 30 nonsex-specific DEGs (1 upregulated and 29 downregulated), 79 female-specific DEGs (25 upregulated and 54 downregulated), and none of male-specific DEGs were obtained finally. Second, bioinformatics analysis of female-specific DEGs was performed. Gene Ontology (GO) functional annotation analysis shows that DEGs were mainly enriched in translational initiation, cytosolic ribosome, and structural constituent of ribosome. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis shows that the top 6 enrichment pathways are ribosome, nuclear factor-­kappa B (NF-kappa B) signaling pathway, apoptosis, mineral absorption, nonalcoholic fatty liver disease, and pertussis. Three functional modules were clustered in the protein–protein interaction (PPI) network of DEGs. The top 10 key genes of the PPI network constructed were selected, including RPS14, RPS15A, RPS24, FAU, RPL27, RPL31, RPL34, RPL35A, RSL24D1, and EEF1B2. Sex difference of ribosome in stroke-induced peripheral immunosuppression may be the potential mechanism of sex disparities in outcome after IS, and women are more likely to have stroke-induced immunosuppression. RPS14, RPS15A, RPS24, FAU, RPL27, RPL31, RPL34, RPL35A, RSL24D1, and EEF1B2 may be novel prognostic biomarkers and potential therapeutic targets for IS.
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The Impact of microRNA Regulation on Immune Recovery in HIV-1-Infected Patients Treated during Acute Infection: A Pilot Study

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microRNAs (miRNAs) are small noncoding RNAs involved in a large range of cellular activities and can be used as biomarkers and indicators for diagnosis. We investigated the alterations in miRNA profiles in immune reconstituted vs. nonimmune reconstituted HIV-1-infected individuals to assess the association between miRNAs and the occurrence of immunological nonresponses, with the aim of searching for miRNA-based biomarkers for these HIV-1-infected individuals. Thirteen immunological responders (IRs) and 12 immunological nonresponders (INRs) were recruited, and RNA was collected from the plasma samples of the 25 HIV-1-infected individuals at both baseline and after 24 months of maintaining virological suppression (VS). Next-generation sequencing was used to detect miRNAs and evaluate the expression differenc es in miRNAs between IR and INR patients and between baseline and after 24 months of maintaining VS. Samples from 13 IRs and 11 INRs were successfully sequenced. The horizontal comparison of differentially expressed miRNAs between the groups and the longitudinal comparison of differentially expressed miRNAs between baseline and after 24 months of maintaining VS showed that a large proportion of miRNAs in INRs are downregulated compared to the levels in IRs. We also found that the miRNA let-7d-5p was downregulated in 9 INRs but only in 2 IRs by more than 2-fold. The difference was significant. In summary, these results demonstrate for the first time that a large proportion of miRNAs are downregulated in INRs compared with IRs, and the miRNA let-7d-5p is a potential biomarker for INRs.
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lncRNAs Are Involved in Sevoflurane Anesthesia-Related Brain Function Modulation through Affecting Mitochondrial Function and Aging Process

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Long noncoding RNAs (lncRNAs) play important roles in brain function modulation and neurodegenerative diseases. However, whether lncRNA regulations are involved in the mechanisms of perioperative neurocognitive disorders, especially in anesthesia-related brain dysfunction, remain unknown. Therefore, we explored the expression and regulation pattern profiles of lncRNAs in the hippocampus of aged rats after sevoflurane anesthesia. Three lncRNAs and 772 protein-coding genes were identified by microarray analysis and evidenced by in vitro and in vivo experiments as differentially expressed. Functional annotation and differentially expressed- (DE-) lncRNA-mRNA coexpression networks reveal that DE-lncRNAs are associated with mitochondrial dysfunction and oxidative stress, aging-related metabolism alterations, DN A damage, and apoptosis, as well as neurodegenerative features during sevoflurane anesthesia. These results suggest that lncRNAs play roles in general anesthesia-related brain function modulation during the perioperative context and provide insights into the lncRNA-related modulation mechanisms and targets.
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Different Genotype Distribution of Human Papillomavirus between Cervical and Esophageal Cancers: A Study in Both High-Incidence Areas, Xinjiang, China

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The aim of this study is to reveal the certain human papillomavirus (HPV) genotype distribution between cervical cancer and esophageal cancer in the both high-incidence geographic regions. For this study, we collected and detected the infection of HPV in 120 paraffin-embedded esophageal tissues and 152 paraffin-embedded cervical tissues, respectively. The esophageal tissues include 40 normal epithelium (ENOR), 26 dysplasia (DYS), and 54 invasive squamous cell carcinoma (ESCC). The cervical tissues consisted of 40 normal epithelium (CNOR), 53 intraepithelial neoplasia (CIN), and 59 invasive squamous cell carcinoma (CSCC). Both esophageal and cervical tissues collected in this study came from the same area, in which both the ESCC and CSCC were in high incidence, Xinjiang province, China. HPV GenoArray test kits were served to analyze the HPV infection. The result shows that among the 59 CSCC tissues, the total infection rate of HPV was 98.3% (58/59). The positive rate of HPV-16 i nfection was 63.8% (37/58). It indicated that HPV-16 is the most common infection among all of the high-risk HPV. The multiple infection rate was 19.0% (11/58). Among the 54 ESCC, a total of 7 genotypes were detected. The total infection rate of HPV was 61.1% (33/54). The positive rate of HPV-16 infection was 63.6% (21/33). The multiple infection rate was 6.1% (2/33). Our result shows that high-risk-type HPV-16 was associated with both cervical cancer and esophageal cancer, which play a role in the high-incidence area in Xinjiang. We hope that our results could point out the direction for the treatment strategy of HPV-associated cancer, cervical cancer, and esophageal cancer and for the application of HPV vaccines in the future.
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Sequencing and Characterization of Mitochondrial Protein-Coding Genes for Schizothorax niger (Cypriniformes: Cyprinidae) with Phylogenetic Consideration

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The present study was conducted to get more information about the genome and locate the taxonomic position of Schizothorax niger in Schizothoracinae through mitochondrial 13 protein-coding genes (PCGs). These PCGs for S. niger were found to be 11409 bps in length ranging from 165 (ATPase 8) to 1824 bps (NADH dehydrogenase subunit 5) and encode 3801 amino acids. In these PCGs, 4 genes overlap on the similar strands, while one shown on the opposite one: ATPase 6+8 and NADH dehydrogenase subunit 4+4L overlap by 7 nucleotides. Similarly, ND5-ND6 overlap by 4 nucleotides, while ATP6 and COIII overlap by 1 nucleotide. Similarly, four commonly used amino acids in S. niger were Leu (15.6 %), Ile (10.12 %), Thr (8.12 %), and Ala (8.7 %). The results presented that COII, COIII, NDI, ND4L, and Cytb had substantia l amino acid conservation as compared to the COI gene. Through phylogenetic analysis, it was observed that S. niger is closely linked with S. progastus, S. labiatus, S. plagiostomus, and S. nepalensis with high bootstrap values. The present study provided more genomic data to know the diversity of the mitochondrial genome and its molecular evolution in Schizothoracinae.
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Ultrashort Wave Combined with Human Umbilical Cord Mesenchymal Stem Cell (HUC-MSC) Transplantation Inhibits NLRP3 Inflammasome and Improves Spinal Cord Injury via MK2/TTP Signalling Pathway

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Objective. To investigate the curative effects of HUC-MSCs combined with USW on spinal cord injury (SCI) and the effects on inflammatory microenvironment and to explore the regulatory mechanisms of MK2/TTP signalling pathway and NLRP3 inflammasome. Methods. The SCI rat model was established using the modified Allen method; rats were administered with USW, HUC-MSCs, and combination therapy of USW and HUC-MSCs; the therapeutic efficacies in each group of rats were monitored and represented in BBB score. SCI levels were observed using HE staining and IF. The microglia polarisation state and released contents of inflammatory factors were detected. IF and Western Blotting were performed on to detect the expression levels of MK2/TTP signalling pathway and NLRP3 inflammasome-related proteins. Furthermore, the regulatory mechanisms of MK2/TTP pathway and NLRP3 were explored by performing on the in vitro study. Results. Combination therapy of USW and HUC-MSCs was found of significant ef ficacy on improving motor functions of SCI rats, and it was further proved that this combination therapy can reduce spinal cord injury in SCI rats, of which USW plays a more important role. While transplantation of HUC-MSCs can promote microglial cells developing to SCI repair, and M2 microglial cells were taking advantages gradually. The combination therapy can inhibit the expression of MK2; downregulate NLRP3 inflammasome; suppress the expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18; and simultaneously suppress the release of IL-1β and IL-18, thereby reducing spinal cord neurons apoptosis. It was found that the steady state of microglial polarisation maintained by combined treatment of USW and HUC-MSCs was destroyed with the upregulation of MK2 expression in cells, of which, M1 type microglial cell was dominant and the increased contents of inflammatory factors were detected. However, overexpressed MK2 relieved the inhibition of NLRP3 expression by TTP. Conclusions. Combination therapy of USW and HUC-MSCs can downregulate NLRP3 expression, relieve inflammatory responses, improve immune microenvironment, and rescue spinal cord injury via suppressing phosphorylation level of MK2.
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An Immune-Related Gene Panel for Preoperative Lymph Node Status Evaluation in Advanced Gastric Cancer

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Background and Aim: Gastric cancer (GC) is the common leading cause of cancer-related death worldwide. Immune-related genes (IRGs) may potentially predict lymph node metastasis (LNM). We aimed to develop a preoperative model to predict LNM based on these IRGs. Methods: In this paper, we compared and evaluated three machine learning models to predict LNM based on publicly available gene expression data from TCGA-STAD. The Pearson correlation coefficient (PCC) method was utilized to feature selection according to its relationships with LN status. The performance of the model was assessed using the area under the curve (AUC) and F1 score. Results: The Naive Bayesian model showed better performance and was constructed based on 26 selected gene features, with AUCs of 0.741 in the training set and 0.688 in the test set. The F1 score in the training set and test set was 0.652 and 0.597, respectively. Furthermore, Naive Bayesian model based on 26 IRGs is the first diagnostic tool for t he identification of LNM in advanced GC. Conclusion: These results indicate that our new methods have the value of auxiliary diagnosis with promising clinical potential.
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An AKT2-specific nanobody that targets the hydrophobic motif induces cell cycle arrest, autophagy and loss of focal adhesions in MDA-MB-231 cells

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Publication date: January 2021

Source: Biomedicine & Pharmacotherapy, Volume 133

Author(s): Tijs Merckaert, Olivier Zwaenepoel, Kris Gevaert, Jan Gettemans

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The course of physical capacity in wheelchair users during training for the HandbikeBattle and at one-year follow-up

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Objective (1) to compare physical capacity at one-year follow-up with physical capacity before and after the training period for the HandbikeBattle event; (2) to identify determinants of the course of physical capacity during follow-up. Design Prospective observational study. Former rehabilitation patients (N=33) with health conditions such as spinal cord injury or amputation were included. A handcycling/arm crank graded exercise test was performed before (January, T1) and after the training period (June, T2), and at one-year follow-up (June, T4). Outcomes: Peak power output (POpeak (W)) and peak oxygen uptake (VO2peak (L/min)). Determinants: sex (M/F); age (years); classification; physical capacity, musculoskeletal pain, exercise stage of change, and exercise self-efficacy at T1; and HandbikeBattle participation at T4. Results Multilevel regression analyses showed that POpeak and VO2peak increased during the training period and did not significantly change during follow-up (T1: 112±37W, 1.70±0.48L/min; T2: 130±40W, 2.07±0.59L/min; T4: 126±42W, 2.00±0.57L/min). Participants who competed again in the HandbikeBattle showed slight improvement in physical capacity during follow-up, whereas participants who did not compete again showed a decrease. Conclusion Physical capacity showed an increase during the training period and remained stable after one-year follow-up. Being (repeatedly) committed to a challenge might facilitate long-term exercise maintenance. Corresponding author: Ingrid Kouwijzer, Center for Human Movement Sciences, UMCG, University of Groningen, A. Deusingln 1, Bld 3215, 9713AV Groningen, the Netherlands, phone number: 050-3616015, i.kouwijzer@umcg.nl Author Disclosures: the authors report no conflict of interest. This study was funded by HandicapNL, Stichting Mitialto, Stichting Beatrixoord Noord-Nederland, University Medical Center Groningen, Heliomare Rehabilitation Center and Stichting Handbike Events. There are no financial benefits to the authors. There are no previous presentations, manuscripts or abstracts in any form. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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