bluuebunny/crossref_metadata_2025_split huggingface dataset:
Luteinizing hormone-based modified GnRH antagonist protocol in normal responders undergoing in vitro fertilization treatment: A multi-center randomized controlled trial
Authors: Liu Shan , Lv Yasu , Liu Minghui , Han Shuo , Liu Xiaoqun , Zhao Zhiming , Cui Wei , Yang Aijun , Li Yuan 
Published: August 2022

ObjectiveTo study the clinical efficacy and cost-effectiveness of a modified gonadotrophin-releasing hormone (GnRH) antagonist protocol based on luteinizing hormone (LH) levels through one complete assisted reproductive technology (ART) cycle in normal responders.DesignNon-inferiority, multicenter randomized controlled trial.SettingUniversity-based hospitals and an academic medical center.PatientsA total of 372 patients fulfilled the inclusion criteria and were eligible to participate.Intervention(s)Participants were randomized at a 1:1 ratio and stimulated with the conventional flexible GnRH antagonist protocol (control group) or LH-based modified GnRH antagonist protocol (study group).Main Outcome MeasuresThe primary outcome was the cumulative ongoing pregnancy rate per aspiration. The secondary outcomes were number of oocytes retrieved, number of good quality embryos, cumulative positive βhCG rate, cumulative clinical pregnancy rate, pregnancy loss rate, moderate and severe ovarian hyperstimulation syndrome (OHSS), and financial expenditure.ResultsThe cumulative ongoing pregnancy rate was 65.1% in the study group and 70.1% in the control group (odds ratio, 0.79; 95% confidence interval, 0.50–1.26; P = 0.33). The multivariate regression analyses results showed that the number of retrieved oocytes was positively associated with the odds for a higher cumulative ongoing pregnancy rate (adjusted odds ratio, 1.11, 95% confidence interval, 1.06–1.17, P &lt; 0.001). The treatment protocol, female age, and body mass index were not independent predictors. The incremental cost-effectiveness ratio for luteinizing hormone-based gonadotrophin releasing hormone antagonist protocol versus the conventional flexible gonadotrophin releasing hormone antagonist protocol was estimated at 3568.6 USD for each additional ongoing pregnancy.ConclusionThe luteinizing hormone-based gonadotrophin releasing hormone antagonist protocol had clinical efficacy similar to the conventional flexible gonadotrophin releasing hormone antagonist protocol in normal responders undergoing in vitro fertilization treatment but was more cost-effective considering the cumulative ongoing pregnancy rate in the entire assisted reproductive technology cycle.Clinical Trial Registrationwww.chictr.org.cn, identifier: ChiCTR1800018077URL of the registration sitehttp://www.chictr.org.cn/edit.aspx?pid=27389&amp;htm=4.Trial registration date29 August 2018.Date of first patient enrollment1 September 2018.
ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition
Authors: Tang Jian , Ma Shinan , Gao Yujiu , Zeng Fan , Feng Ying , Guo Chong , Hu Lin , Yang Lingling , Chen Yanghui , Zhang Qiufang , Yuan Yahong , Guo Xingrong 
Published: August 2022

BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.
Targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization for non-islet cell tumor hypoglycemia secondary to a liver metastatic solitary fibrous tumor: A case report and literature review
Authors: Jin Kai , Zhong Shan , Lin Liya , Wu Jianjun , Wang Yuqi , Cui Weijuan , Gu Wei , Chao Ming , Song Xiaoxiao 
Published: August 2022

Doege–Potter syndrome is a rare paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. Doege–Potter syndrome always presents with recurrent fasting hypoglycemia, which can occasionally be life-threatening. The best choice of treatment for Doege–Potter syndrome and solitary fibrous tumor is complete resection. However, when it is unfeasible, local-regional treatment can be used as a palliative therapy. Herein, we report a case of a 46-year-old man with Doege–Potter syndrome that occurred secondary to the liver and pancreatic metastatic solitary fibrous tumors. After he received six rounds of targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization (TILA-TACE) treatment in our hospital, his hypoglycemia was clinically cured, and the liver metastatic tumor was well controlled. We suggest that TILA-TACE can be considered when curative resection is unfeasible for metastatic liver solitary fibrous tumors to help a patient obtain further surgery opportunities.
Association of long-term visit-to-visit variability of HbA1c and fasting glycemia with hypoglycemia in type 2 diabetes mellitus
Authors: Long Chen , Tang Yaling , Huang Jiangsheng , Liu Suo , Xing Zhenhua 
Published: August 2022

BackgroundSelf-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM.MethodsIn this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell’s C method.ResultsAfter adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03–1.16; P &lt; 0.01) and HMA events (HR: 1.11; 95% CI: 1.03–1.20; P &lt; 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31–1.49; P &lt; 0.01) and HMA events (HR: 1.46; 95% CI: 1.35–1.57; P &lt; 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P &lt; 0.01).ConclusionsIncreased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability.Trial registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT00000620.
Research progress on the pharmacological effects of berberine targeting mitochondria
Authors: Fang Xinyi , Wu Haoran , Wei Jiahua , Miao Runyu , Zhang Yanjiao , Tian Jiaxing 
Published: August 2022

Berberine is a natural active ingredient extracted from the rhizome of Rhizoma Coptidis, which interacts with multiple intracellular targets and exhibits a wide range of pharmacological activities. Previous studies have preliminarily confirmed that the regulation of mitochondrial activity is related to various pharmacological actions of berberine, such as regulating blood sugar and lipid and inhibiting tumor progression. However, the mechanism of berberine’s regulation of mitochondrial activity remains to be further studied. This paper summarizes the molecular mechanism of the mitochondrial quality control system and briefly reviews the targets of berberine in regulating mitochondrial activity. It is proposed that berberine mainly regulates glycolipid metabolism by regulating mitochondrial respiratory chain function, promotes tumor cell apoptosis by regulating mitochondrial apoptosis pathway, and protects cardiac function by promoting mitophagy to alleviate mitochondrial dysfunction. It reveals the mechanism of berberine’s pharmacological effects from the perspective of mitochondria and provides a scientific basis for the application of berberine in the clinical treatment of diseases.
In Silico Characterization of Uncharacterized Proteins From Multiple Strains of Clostridium Difficile
Authors: Abbasi Bilal Ahmed , Dharan Aishwarya , Mishra Astha , Saraf Devansh , Ahamad Irsad , Suravajhala Prashanth , Valadi Jayaraman 
Published: August 2022

Clostridium difficile (C. difficile) is a multi-strain, spore-forming, Gram-positive, opportunistic enteropathogen bacteria, majorly associated with nosocomial infections, resulting in severe diarrhoea and colon inflammation. Several antibiotics including penicillin, tetracycline, and clindamycin have been employed to control C. difficile infection, but studies have suggested that injudicious use of antibiotics has led to the development of resistance in C. difficile strains. However, many proteins from its genome are still considered uncharacterized proteins that might serve crucial functions and assist in the biological understanding of the organism. In this study, we aimed to annotate and characterise the 6 C. difficile strains using in silico approaches. We first analysed the complete genome of 6 C. difficile strains using standardised approaches and analysed hypothetical proteins (HPs) employing various bioinformatics approaches coalescing, including identifying contigs, coding sequences, phage sequences, CRISPR-Cas9 systems, antimicrobial resistance determination, membrane helices, instability index, secretory nature, conserved domain, and vaccine target properties like comparative homology analysis, allergenicity, antigenicity determination along with structure prediction and binding-site analysis. This study provides crucial supporting information about the functional characterization of the HPs involved in the pathophysiology of the disease. Moreover, this information also aims to assist in mechanisms associated with bacterial pathogenesis and further design candidate inhibitors and bona fide pharmaceutical targets.
Environmental scan of family chart linking for genetic cascade screening in a U.S. integrated health system
Authors: Haas Cameron B. , Ralston James , Fullerton Stephanie M. , Scrol Aaron , Henrikson Nora B. 
Published: August 2022

Background: An alternative to population-based genetic testing, automated cascade genetic testing facilitated by sharing of family health history, has been conceptualized as a more efficient and cost-effective approach to identify hereditary genetic conditions. However, existing software and applications programming interfaces (API) for the practical implementation of this approach in health care settings have not been described.Methods: We reviewed API available for facilitating cascade genetic testing in electronic health records (EHRs). We emphasize any information regarding informed consent as provided for each tool. Using semi-structured key informant interviews, we investigated uptake of and barriers to integrating automated family cascade genetic testing into the EHR.Results: We summarized the functionalities of six tools related to utilizing family health history to facilitate cascade genetic testing. No tools were explicitly capable of facilitating family cascade genetic testing, but few enterprise EHRs supported family health history linkage. We conducted five key informant interviews with four main considerations that emerged including: 1) incentives for interoperability, 2) HIPAA and regulations, 3) mobile-app and alternatives to EHR deployment, 4) fundamental changes to conceptualizing EHRs.Discussion: Despite the capabilities of existing technology, limited bioinformatic support has been developed to automate processes needed for family cascade genetic testing and the main barriers for implementation are nontechnical, including an understanding of regulations, consent, and workflow. As the trade-off between cost and efficiency for population-based and family cascade genetic testing shifts, the additional tools necessary for their implementation should be considered.
Identification of m6A- and ferroptosis-related lncRNA signature for predicting immune efficacy in hepatocellular carcinoma
Authors: Xie Hongjun , Shi Muqi , Liu Yifei , Cheng Changhong , Song Lining , Ding Zihan , Jin Huanzhi , Cui Xiaohong , Wang Yan , Yao Dengfu , Wang Peng , Yao Min , Zhang Haijian 
Published: August 2022

BackgroundN6-methyladenosine (m6A) methylation and ferroptosis assist long noncoding RNAs (lncRNAs) in promoting immune escape in hepatocellular carcinoma (HCC). However, the predictive value of m6A- and ferroptosis-related lncRNAs (mfrlncRNAs) in terms of immune efficacy remains unknown.MethodA total of 365 HCC patients with complete data from The Cancer Genome Atlas (TCGA) database were used as the training cohort, and half of them were randomly selected as the validation cohort. A total of 161 HCC patients from the International Cancer Genome Consortium (ICGC) database were used as external validation (ICGC cohort).ResultsWe first identified a group of specific lncRNAs associated with both m6A regulators and ferroptosis-related genes and then constructed prognosis-related mfrlncRNA pairs. Based on this, the mfrlncRNA signature was constructed using the least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Notably, the risk score of patients was proven to be an independent prognostic factor and was better than the TNM stage and tumor grade. Moreover, patients with high-risk scores had lower survival rates, higher infiltration of immunosuppressive cells (macrophages and Tregs), lower infiltration of cytotoxic immune cells (natural killer cells), poorer immune efficacy (both immunophenoscore and score of tumor immune dysfunction and exclusion), higher IC50, and enrichment of the induced Treg pathway, which confirmed that the mfrlncRNA signature contributed to survival prediction and risk stratification of patients with HCC.ConclusionsThe mfrlncRNA signature, which has great prognostic value, provides new clues for identifying “cold” and “hot” tumors and might have crucial implications for individualized therapy to improve the survival rate of patients with HCC.
Crosstalk of three novel types of programmed cell death defines distinct microenvironment characterization and pharmacogenomic landscape in breast cancer
Authors: Xu Lijun 
Published: August 2022

BackgroundPrior studies have highlighted that novel programmed cell death (PCD) modalities, including ferroptosis, pyroptosis, and necroptosis, are correlated with tumor progression and antitumor immunity. Nonetheless, comprehensive analysis of tumor microenvironment (TME) profiles mediated by the crosstalk of distinct PCD forms has not been conducted in breast cancer (BC).MethodsHere, we curated 34 identified PCD-associated genes (PCDAGs) and applied the consensus clustering algorithm to establish PCD-mediated tumor patterns in BC. Subsequently, based on prognostic differentially expressed genes extracted from distinct PCD-mediated patterns, we applied the LASSO algorithm to construct CD_Score. Furthermore, the correlation analysis between CD_Score and TME features, molecular subtypes, clinicopathological characteristics, drug response, and immunotherapeutic efficacy was performed.ResultsThree distinct PCD-clusters were determined among 2,038 BC samples, which did not only display different clinical outcomes but highly correlated to the established immunological tumor phenotypes: “desert,” “excluded,” and “inflamed” immune profiles. Based on the CD_Score derived from the PCD-related gene signature, BC patients could be stratified into CD_Score-low and -high group, of which the former displayed satisfactory survival outcome and enhanced immune infiltration. Further exploration identified that the CD_Score-high group significantly correlated with elevated neoantigen load and higher mutation frequency in SMGs (e.g., TP53 and MAP3K1) and reduced expression of immune checkpoint proteins.ConclusionsThis research is the first to emphasize the close relationship between distinct cell death modalities and the diversity and complexity of immune infiltration in TME. We established the CD_Score, which could help enhance our cognition of TME features and facilitate the clinical application of immunotherapy.
Contribution of pathogenic T helper 1 and 17 cells to bursitis and tenosynovitis in polymyalgia rheumatica
Authors: Reitsema Rosanne D. , Jiemy William F. , Wekema Lieske , Boots Annemieke M. H. , Heeringa Peter , Huitema Minke G. , Abdulahad Wayel H. , van Sleen Yannick , Sandovici Maria , Roozendaal Caroline , Diepstra Arjan , Kwee Thomas , Dasgupta Bhaskar , Brouwer Elisabeth , van der Geest Kornelis S. M. 
Published: August 2022

BackgroundAlthough polymyalgia rheumatica (PMR) is a very common rheumatic inflammatory disease, current insight into the pathobiology of PMR is limited and largely based on studies in blood. We investigated T helper 1 (TH1) and T helper 17 (TH17) cell responses in blood, synovial fluid and bursa tissue of patients with PMR.Materials and methodsBlood samples were collected from 18 patients with new-onset PMR and 32 healthy controls. Synovial fluid was aspirated from the inflamed shoulder bursae or biceps tendon sheath of 13 patients. Ultrasound-guided biopsies of the subacromial-subdeltoid (SASD) bursa were obtained from 11 patients. T cells were examined by flow cytometry, immunohistochemistry and immunofluorescence staining.ResultsBesides an increase of TH17 (CD4+IL-17+IFN-γ-) cells and T cytotoxic 17 (TC17; CD8+IL-17+IFN-γ-) cells, no other major changes were noted in the circulating T cell compartment of patients with PMR. Absolute numbers of CD4+ and CD8+ T cells were similar in blood and synovial fluid of patients with PMR. Synovial fluid T cells showed an effector-memory (CD45RO+CCR7-) phenotype. Percentages of TH1 (CD4+IFN-γ+IL-17-) cells and TH1/TH17 (CD4+IFN-γ+IL-17+) cells, but not TH17 or TC17 cells, were increased in the synovial fluid. Bursa tissue biopsies contained a small number of T cells, which were mostly CD8 negative. The majority of bursa tissue T cells produced IFN-γ but not IL-17. For comparison, B cells were scarcely detected in the bursa tissue.ConclusionAlthough the circulating TH17 cell pool is expanded in patients with PMR, our findings indicate that TH1 cells are involved in the inflammation of bursae and tendon sheaths in this condition. Our study points towards the TH1 cell pathway as a potential target for therapy in PMR.
Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients
Authors: Giannella Alessandra , Riccetti Silvia , Sinigaglia Alessandro , Piubelli Chiara , Razzaboni Elisa , Di Battista Piero , Agostini Matteo , Dal Molin Emanuela , Manganelli Riccardo , Gobbi Federico , Ceolotto Giulio , Barzon Luisa 
Published: August 2022

BackgroundSARS-CoV-2 induces a spectrum of clinical conditions ranging from asymptomatic infection to life threatening severe disease. Host microRNAs have been involved in the cytokine storm driven by SARS-CoV-2 infection and proposed as candidate biomarkers for COVID-19.MethodsTo discover signatures of circulating miRNAs associated with COVID-19, disease severity and mortality, small RNA-sequencing was performed on serum samples collected from 89 COVID-19 patients (34 severe, 29 moderate, 26 mild) at hospital admission and from 45 healthy controls (HC). To search for possible sources of miRNAs, investigation of differentially expressed (DE) miRNAs in relevant human cell types in vitro.ResultsCOVID-19 patients showed upregulation of miRNAs associated with lung disease, vascular damage and inflammation and downregulation of miRNAs that inhibit pro-inflammatory cytokines and chemokines, angiogenesis, and stress response. Compared with mild/moderate disease, patients with severe COVID-19 had a miRNA signature indicating a profound impairment of innate and adaptive immune responses, inflammation, lung fibrosis and heart failure. A subset of the DE miRNAs predicted mortality. In particular, a combination of high serum miR-22-3p and miR-21-5p, which target antiviral response genes, and low miR-224-5p and miR-155-5p, targeting pro-inflammatory factors, discriminated severe from mild/moderate COVID-19 (AUROC 0.88, 95% CI 0.80-0.95, p&lt;0.0001), while high leukocyte count and low levels of miR-1-3p, miR-23b-3p, miR-141-3p, miR-155-5p and miR-4433b-5p predicted mortality with high sensitivity and specificity (AUROC 0.95, 95% CI 0.89-1.00, p&lt;0.0001). In vitro experiments showed that some of the DE miRNAs were modulated directly by SARS-CoV-2 infection in permissive lung epithelial cells.ConclusionsWe discovered circulating miRNAs associated with COVID-19 severity and mortality. The identified DE miRNAs provided clues on COVID-19 pathogenesis, highlighting signatures of impaired interferon and antiviral responses, inflammation, organ damage and cardiovascular failure as associated with severe disease and death.