bluuebunny/crossref_metadata_2025_split huggingface dataset:
High glucose induced HIF-1α/TREK1 expression and myometrium relaxation during pregnancy
Authors: Li Tengteng , Fei Jiajia , Yu Huihui , Wang Xingxing , Bai Jingjing , Chen Fucai , Li Dan , Yin Zongzhi 
Published: February 2023

BackgroundThe incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM patients have a significantly higher rate of cesarean section and postpartum hemorrhage, suggesting changes in uterine contractility. TWIK-1-related potassium channel (TREK1) expressed in the pregnant uterus and its role in uterine contraction. In this study, we examined the expression of HIF-1α and TREK1 proteins in GDM uterine and investigated whether high glucose levels are involved in the regulation of human uterine smooth muscle cells (HUSMCs) contraction through TREK1, and verified the role of HIF-1α in this process.MethodsCompared the uterine contractility between GDM and normal patients undergoing elective lower segment cesarean section. The HUSMCs were divided into normal glucose group, high glucose group, normal glucose with CoCl2 group, CoCl2 with echinomycin/L-Methionine group, and high glucose with echinomycin/L-Methionine group; Compare the cell contractility of each group. Compared the expression of hypoxia-inducible factor-1α (HIF-1α) and TREK1 protein in each group.ResultsThe contractility of human uterine strips induced by both KCl and oxytocin was significantly lower in patients with GDM compared with that in normal individuals, with increased TREK1 and HIF-1α protein expression. The contractility of cultured HUSMCs was significantly decreased under high glucose levels, which was consistent with increased expression of HIF-1α and TREK1 proteins. The contractility of HUSMCs was decreased when hypoxia was induced by CoCl2 and increased when hypoxia was inhibited by echinomycin. The TREK1 inhibitor L-methionine also recovered the decreased contractility of HUSMCs under high glucose levels or hypoxia.DiscussionThe high glucose levels decreased the contractility of the myometrium, and increased expression of HIF-1a and TREK1 proteins play a role in changes in uterus contractility.
The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes
Authors: Dixon Sydney A. , Mishra Sidharth , Dietsche Katrina B. , Jain Shalini , Mabundo Lilian , Stagliano Michael , Krenek Andrea , Courville Amber , Yang Shanna , Turner Sara A. , Meyers Abby G. , Estrada Doris E. , Yadav Hariom , Chung Stephanie T. 
Published: February 2023

Disclosure summaryDr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose.BackgroundMetformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin’s side effects by shifting microbiota composition and activity.ObjectiveThe aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity.MethodsIn a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase.ResultsSix Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month.ConclusionAdministration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT04209075.
Visceral fat correlates with insulin secretion and sensitivity independent of BMI and subcutaneous fat in Chinese with type 2 diabetes
Authors: Huang Haishan , Zheng Xiaobin , Wen Xiaoming , Zhong Jingyi , Zhou Yanting , Xu Lingling 
Published: February 2023

AimClinical heterogeneity exists in overall obesity and abdominal obesity in terms of insulin secretion and sensitivity. Further, the impact of visceral fat (VF) on the first- and second-phase insulin secretion (FPIS and SPIS) is controversial. We aim to investigate insulin secretion and sensitivity in Chinese patients with T2DM according to different BMI and VF levels.MethodsThis study enrolled 300 participants. A dual bioelectrical impedance analyzer was used to assess the visceral and subcutaneous fat area (VFA and SFA). VF levels were categorized as normal or high, with the cutoff value of 100 cm2. FPIS and SPIS were evaluated by arginine stimulation test and standardized steamed bread meal tolerance test, respectively. β-cell function (HOMA2-β), insulin resistance (HOMA2-IR), and Gutt’s insulin sensitivity index (Gutt-ISI) were also calculated. Spearman’s correlation analysis and multivariate linear regression analysis were adopted for statistical analysis.ResultsParticipants were categorized into four groups: normal weight-normal VF, normal weight-high VF, overweight/obese-normal VF and overweight/obese-high VF. Multivariate linear regression showed that both VFA and SFA were correlated with FPIS, HOMA2-IR and Gutt-ISI after controlling for gender and diabetes duration. After further adjustment for BMI and VFA, some associations of SFA with insulin secretion and sensitivity disappeared. After adjustment for gender, diabetes duration, BMI and SFA, VFA was positively correlated with FPIS, SPIS and HOMA2-IR. Subjects with overweight/obese-high VF were more likely to have higher FPIS, HOMA2-IR and lower Gutt-ISI (all p &lt; 0.05).ConclusionVF affects both FPIS and SPIS, and worsens insulin sensitivity independent of BMI and subcutaneous fat in Chinese patients with T2DM.Clinical trial registrationhttp://www.chictr.org.cn, identifier ChiCTR2200062884.
Exploration of prognostic genes and risk signature in breast cancer patients based on RNA binding proteins associated with ferroptosis
Authors: Chen Xiang , Yang Changcheng , Wang Wei , He Xionghui , Sun Hening , Lyu Wenzhi , Zou Kejian , Fang Shuo , Dai Zhijun , Dong Huaying 
Published: February 2023

Background: Breast cancer (BRCA) is a life-threatening malignancy in women with an unsatisfactory prognosis. The purpose of this study was to explore the prognostic biomarkers and a risk signature based on ferroptosis-related RNA-binding proteins (FR-RBPs).Methods: FR-RBPs were identified using Spearman correlation analysis. Differentially expressed genes (DEGs) were identified by the “limma” R package. The univariate Cox and multivariate Cox analyses were executed to determine the prognostic genes. The risk signature was constructed and verified with the training set, testing set, and validation set. Mutation analysis, immune checkpoint expression analysis in high- and low-risk groups, and correlation between risk signature and chemotherapeutic agents were conducted using the “maftools” package, “ggplot2” package, and the CellMiner database respectively. The Human Protein Atlas (HPA) database was employed to confirm protein expression trends of prognostic genes in BRCA and normal tissues. The expression of prognostic genes in cell lines was verified by Real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-meier (KM) plotter database analysis was applied to predict the correlation between the expression levels of signature genes and survival statuses.Results: Five prognostic genes (GSPT2, RNASE1, TIPARP, TSEN54, and SAMD4A) to construct an FR-RBPs-related risk signature were identified and the risk signature was validated by the International Cancer Genome Consortium (ICGC) cohort. Univariate and multivariate Cox regression analysis demonstrated the risk score was a robust independent prognostic factor in overall survival prediction. The Tumor Mutational Burden (TMB) analysis implied that the high- and low-risk groups responded differently to immunotherapy. Drug sensitivity analysis suggested that the risk signature may serve as a chemosensitivity predictor. The results of GSEA suggested that five prognostic genes might be related to DNA replication and the immune-related pathways. RT-qPCR results demonstrated that the expression trends of prognostic genes in cell lines were consistent with the results from public databases. KM plotter database analysis suggested that high expression levels of GSPT2, RNASE1, and SAMD4A contributed to poor prognoses.Conclusion: In conclusion, this study identified the FR-RBPs-related prognostic genes and developed an FR-RBPs-related risk signature for the prognosis of BRCA, which will be of great significance in developing new therapeutic targets and prognostic molecular biomarkers for BRCA.
Genome-wide association study and identification of systemic comorbidities in development of age-related macular degeneration in a hospital-based cohort of Han Chinese
Authors: Shih Chien-Hung , Chuang Hao-Kai , Hsiao Tzu-Hung , Yang Yi-Ping , Gao Chong-En , Chiou Shih-Hwa , Hsu Chih-Chien , Hwang De-Kuang 
Published: February 2023

Background: Age-related macular degeneration (AMD) is the main cause of severe vision loss in elderly populations of the developed world with limited therapeutic medications available. It is a multifactorial disease with a strong genetic susceptibility which exhibits the differential genetic landscapes among different ethnic groups.Methods: To investigate the Han Chinese-specific genetic variants for AMD development and progression, we have presented a genome-wide association study (GWAS) on 339 AMD cases and 3,390 controls of a Han Chinese population recruited from the Taiwan Precision Medicine Initiative (TPMI).Results: In this study, we have identified several single nucleotide polymorphisms (SNPs) significantly associated with AMD, including rs10490924, rs3750848, and rs3750846 in the ARMS2 gene, and rs3793917, rs11200638, and rs2284665 in the HTRA1 gene, in which rs10490924 was highly linked to the other variants based upon linkage disequilibrium analysis. Moreover, certain systemic comorbidities, including chronic respiratory diseases and cerebrovascular diseases, were also confirmed to be independently associated with AMD. Stratified analysis revealed that both non-exudative and exudative AMD were significantly correlated with these risk factors. We also found that homozygous alternate alleles of rs10490924 could lead to an increased risk of AMD incidence compared to homozygous references or heterozygous alleles in the cohorts of chronic respiratory disease, cerebrovascular disease, hypertension, and hyperlipidemia. Ultimately, we established the SNP models for AMD risk prediction and found that rs10490924 combined with the other AMD-associated SNPs identified from GWAS improved the prediction model performance.Conclusion: These results suggest that genetic variants combined with the comorbidities could effectively identify any potential individuals at a high risk of AMD, thus allowing for both early prevention and treatment.
Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune microenvironment
Authors: Liu Qing , Bao Hongbo , Zhang Sibin , Song Tianjun , Li Chenlong , Sun Guiyin , Sun Xiaoyang , Fu Tianjiao , Wang Yujie , Liang Peng 
Published: February 2023

Background: Gliomas are brain tumors that arise from glial cells, and they are the most common primary intracranial tumors with a poor prognosis. Cellular senescence plays a critical role in cancer, especially in glioma. In this study, we constructed a senescence-related lncRNA (SRlncRNA) signature to assess the prognosis of glioma.Methods: The Cancer Genome Atlas was used to collect SRlncRNA transcriptome profiles and clinical data about glioma. Patients were randomized to training, testing, and whole cohorts. LASSO and Cox regression analyses were employed to construct the SRlncRNA signature, and Kaplan–Meier (K-M) analysis was performed to determine each cohort’s survival. Receiver operating characteristic (ROC) curves were applied to verify the accuracy of this signature. Gene set enrichment analysis was used to visualize functional enrichment (GSEA). The CIBERSORT algorithm, ESTIMATE and TIMER databases were utilized to evaluate the differences in the infiltration of 22 types of immune cells and their association with the signature. RT–qPCR and IHC were used to identify the consistency of the signature in tumor tissue.Results: An SRlncRNA signature consisting of six long non-coding RNAs (lncRNAs) was constructed, and patients were divided into high-risk and low-risk groups by the median of their riskscore. The KM analysis showed that the high-risk group had worse overall survival, and the ROC curve confirmed that the riskscore had more accurate predictive power. A multivariate Cox analysis and its scatter plot with clinical characteristics confirmed the riskscore as an independent risk factor for overall survival. GSEA showed that the GO and KEGG pathways were mainly enriched in the immune response to tumor cells, p53 signaling pathway, mTOR signaling pathway, and Wnt signaling pathway. Further validation also yielded significant differences in the risk signature in terms of immune cell infiltration, which may be closely related to prognostic differences, and qRT–PCR and IHC confirmed the consistency of the expression differences in the major lncRNAs with those in the prediction model.Conclusion Our findings indicated that the SRlncRNA signature might be used as a predictive biomarker and that there is a link between it and immune infiltration. This discovery is consistent with the present categorization system and may open new avenues for research and personalized therapy.
Gene profiling reveals the role of inflammation, abnormal uterine muscle contraction and vascularity in recurrent implantation failure
Authors: Dong Xinyi , Zhou Mi , Li Xinyu , Huang Huijing , Sun Yun 
Published: February 2023

Objective: Recurrent implantation failure (RIF) is now disturbing numerous infertile couples accepting assisted reproductive technology (ART). And the endometrial factors are crucial causes of recurrent implantation failure. However, its mechanism is still unclear. Thus, the aim of this study is to identify altered biologic processes in endometrium that may contribute to recurrent implantation failure.Methods: We recruited two microarray datasets (GSE103465, GSE111974) from Gene Expression Omnibus database (GEO), which contain endometrium from RIF and normal women during implantation period. Using the online tools GEO2R and Venny, we identified Differentially Expressed Genes (DEGs) of selected datasets, and obtained common DEGs. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) and BioCatar pathway enrichment were conducted with Enrichr platform, “ssgsea” and “ggplot2” package of RStudio. PPI networks and hub gene related TF-gene interaction and TF-miRNA co-regulation networks were built via online tools STRING and NetworkAnalyst. Immune infiltration analysis was performed by CIBERSORT platform. Recurrent implantation failure subgroup identification was achieved through “ConsensusClusterPlus,” “tsne,” “ssgsea”, and “ggpubr” package in RStudio. Diagnostic characteristic ROC curves were constructed via “pROC” and “ggplot2” package of RStudio. Enrichr platform was utilized to find drugs targeting hub genes.Results: 26 common DEGs were confirmed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes/BioCarta analysis determined common DEGs were mainly enriched in inflammation associated pathways including TNF, NF-κB, IL-4, IL-10, IL-6, and TGF-β signaling pathways. Five hub genes (PTGS2, VCAM1, EDNRB, ACTA2, and LIF) and related TF-gene and TF-miRNA interactions were identified. Immune infiltration analysis indicated the importance of macrophage M2 in recurrent implantation failure patients. Importantly, subgroup identification analysis highlighted that recurrent implantation failure patients can be divided into two subgroups with different phenotypes. Moreover, the ROC curves and drugs may provide new diagnostic and therapeutic thought for recurrent implantation failure.
The 4G/5G polymorphism of plasminogen activator inhibitor type 1 is a predictor of allergic cough
Authors: Tang Rui , Lyu Xiaohong , Li Hong , Sun Jinlyu 
Published: February 2023

Background: It has been suggested that genetic factors may be substantially linked to allergy disorders. This study aims to investigate the relationship between the genetic susceptibility of Chinese patients with allergy disorders and the polymorphisms of plasminogen activator inhibitor 1 gene (PAI-1) rs1799762, cysteinyl leukotriene receptor 1 gene (CYSLTR1) rs320995, gasdermin B gene (GSDMB) rs7216389, glycoprotein IIIa gene (GPIIIa) rs5918, glycoprotein Ib alpha gene (GP1BA) rs6065, platelet endothelial aggregation receptor 1 gene (PEAR1) rs12041331, and tumor necrosis factor alpha gene (TNF-α) rs1800629.Methods: From the Peking Union Medical College Hospital, this study enrolled 60 healthy participants and 286 participants with allergic diseases. TaqMan-minor groove binder (MGB) quantitative polymerase chain reaction (qPCR) was used to examine the gene polymorphisms in each group.Results: The TaqMan-MGB qPCR results were completely consistent with the DNA sequencing results, according to other studies in this medical center (Kappa = 1, p &lt; .001). Only the distribution of PAI-1 rs1799762 was different between patients with allergic cough and healthy people (χ2 = 7.48, p = .0238). With regard to cough patients, the 4G4G and 5G5G genotypes were more frequent (allergic cough vs. healthy individuals: 4G4G 57.9% vs. 26.7%; 5G5G 20.0% vs. 13.3%), but the 4G5G genotype was more frequent in healthy people (allergic cough vs. healthy individuals: 45.7% vs. 60.0%). The CYSLTR1 rs320995, GSDMB rs7216389, GPIIIa rs5918, GP1BA rs6065, PEAR1 rs12041331, and TNF-α rs1800629 polymorphisms, however, did not show any of such relationships.Conclusion: The PAI-1 rs1799762 polymorphisms may be associated with the genetic susceptibility of Chinese allergic disease patients with cough performance.
Identification of tumor mutation burden-associated molecular and clinical features in cancer by analyzing multi-omics data
Authors: Li Mengyuan , Gao Xuejiao , Wang Xiaosheng 
Published: February 2023

BackgroundTumor mutation burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in cancer. Systematic identification of molecular features correlated with TMB is significant, although such investigation remains insufficient.MethodsWe analyzed associations of somatic mutations, pathways, protein expression, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), competing endogenous RNA (ceRNA) antitumor immune signatures, and clinical features with TMB in various cancers using multi-omics datasets from The Cancer Genome Atlas (TCGA) program and datasets for cancer cohorts receiving the immune checkpoint blockade therapy.ResultsAmong the 32 TCGA cancer types, melanoma harbored the highest percentage of high-TMB (≥ 10/Mb) cancers (49.4%), followed by lung adenocarcinoma (36.9%) and lung squamous cell carcinoma (28.1%). Three hundred seventy-six genes had significant correlations of their mutations with increased TMB in various cancers, including 11 genes (ARID1A, ARID1B, BRIP1, NOTCH2, NOTCH4, EPHA5, ROS1, FAT1, SPEN, NSD1,and PTPRT) with the characteristic of their mutations associated with a favorable response to immunotherapy. Based on the mutation profiles in three genes (ROS1, SPEN, and PTPRT), we defined the TMB prognostic score that could predict cancer survival prognosis in the immunotherapy setting but not in the non-immunotherapy setting. It suggests that the TMB prognostic score’s ability to predict cancer prognosis is associated with the positive correlation between immunotherapy response and TMB. Nine cancer-associated pathways correlated positively with TMB in various cancers, including nucleotide excision repair, DNA replication, homologous recombination, base excision repair, mismatch repair, cell cycle, spliceosome, proteasome, and RNA degradation. In contrast, seven pathways correlated inversely with TMB in multiple cancers, including Wnt, Hedgehog, PI3K-AKT, MAPK, neurotrophin, axon guidance, and pathways in cancer. High-TMB cancers displayed higher levels of antitumor immune signatures and PD-L1 expression than low-TMB cancers in diverse cancers. The association between TMB and survival prognosis was positive in bladder, gastric, and endometrial cancers and negative in liver and head and neck cancers. TMB also showed significant associations with age, gender, height, weight, smoking, and race in certain cohorts.ConclusionsThe molecular and clinical features significantly associated with TMB could be valuable predictors for TMB and immunotherapy response and therefore have potential clinical values for cancer management.