bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials
Authors: Tornyos Dániel , Meuer Maximilian , Lukács Réka , El Alaoui El Abdallaoui Oumaima , Kupó Péter , Faludi Réka , Komócsi András 
Published: December 2022

BackgroundGliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results.ObjectivesWe aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes.MethodsSystematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke.ResultsTwenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin.ConclusionOur meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition.Systematic review registration[www.ClinicalTrials.gov], identifier [CRD42022358078].
Prediction model of obstructive sleep apnea–related hypertension: Machine learning–based development and interpretation study
Authors: Shi Yewen , Ma Lina , Chen Xi , Li Wenle , Feng Yani , Zhang Yitong , Cao Zine , Yuan Yuqi , Xie Yushan , Liu Haiqin , Yin Libo , Zhao Changying , Wu Shinan , Ren Xiaoyong 
Published: December 2022

BackgroundObstructive sleep apnea (OSA) is a globally prevalent disease closely associated with hypertension. To date, no predictive model for OSA-related hypertension has been established. We aimed to use machine learning (ML) to construct a model to analyze risk factors and predict OSA-related hypertension.Materials and methodsWe retrospectively collected the clinical data of OSA patients diagnosed by polysomnography from October 2019 to December 2021 and randomly divided them into training and validation sets. A total of 1,493 OSA patients with 27 variables were included. Independent risk factors for the risk of OSA-related hypertension were screened by the multifactorial logistic regression models. Six ML algorithms, including the logistic regression (LR), the gradient boosting machine (GBM), the extreme gradient boosting (XGBoost), adaptive boosting (AdaBoost), bootstrapped aggregating (Bagging), and the multilayer perceptron (MLP), were used to develop the model on the training set. The validation set was used to tune the model hyperparameters to determine the final prediction model. We compared the accuracy and discrimination of the models to identify the best machine learning algorithm for predicting OSA-related hypertension. In addition, a web-based tool was developed to promote its clinical application. We used permutation importance and Shapley additive explanations (SHAP) to determine the importance of the selected features and interpret the ML models.ResultsA total of 18 variables were selected for the models. The GBM model achieved the most extraordinary discriminatory ability (area under the receiver operating characteristic curve = 0.873, accuracy = 0.885, sensitivity = 0.713), and on the basis of this model, an online tool was built to help clinicians optimize OSA-related hypertension patient diagnosis. Finally, age, family history of hypertension, minimum arterial oxygen saturation, body mass index, and percentage of time of SaO2 &lt; 90% were revealed by the SHAP method as the top five critical variables contributing to the diagnosis of OSA-related hypertension.ConclusionWe established a risk prediction model for OSA-related hypertension patients using the ML method and demonstrated that among the six ML models, the gradient boosting machine model performs best. This prediction model could help to identify high-risk OSA-related hypertension patients, provide early and individualized diagnoses and treatment plans, protect patients from the serious consequences of OSA-related hypertension, and minimize the burden on society.
Sustained high glucose intake accelerates type 1 diabetes in NOD mice
Authors: Li Xiangqian , Wang Lina , Meng Gang , Chen Xiaoling , Yang Shushu , Zhang Mengjun , Zheng Zhengni , Zhou Jie , Lan Zhu , Wu Yuzhang , Wang Li 
Published: December 2022

IntroductionEpidemiological studies have suggested that dietary factors, especially high consumption of high glycaemic index carbohydrates and sugars, may trigger or exacerbate the progression of type 1 diabetes. We aimed to provide experimental evidence to confirm this relevance and to explore the underlying mechanisms.MethodsNOD mice were given sustained high-glucose drinking or glucose-free water and observed for the incidence of type 1 diabetes and islet inflammation. RNAseq was performed to detect the transcriptome changes of the NOD islet beta cell line NIT-1 after high glucose treatment, and mass spectrometry was performed to detect the proteome changes of NIT-1-cells-derived sEVs.ResultsSustained high glucose drinking significantly aggravates islet inflammation and accelerates the onset of type 1 diabetes in NOD mice. Mechanistically, high glucose treatment induces aberrant ER stress and up-regulates the expression of autoantigens in islet beta cell. Moreover, high glucose treatment alters the proteome of beta-cells-derived sEVs, and significantly enhances the ability of sEVs to promote DC maturation and stimulate immune inflammatory response.DiscussionThis study provides evidence for negative effect of high glucose intake as a dietary factor on the pathogenesis of type 1 diabetes in genetically predisposed individuals. Therefore, avoiding high sugar intake may be an effective disease prevention strategy for children or adults susceptible to type 1 diabetes.
GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans
Authors: Plomgaard Peter , Hansen Jakob S. , Townsend Logan K. , Gudiksen Anders , Secher Niels H. , Clemmesen Jens O. , Støving Rene K. , Goetze Jens P. , Wright David C. , Pilegaard Henriette 
Published: December 2022

ObjectiveGrowth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known.MethodPlasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).ResultsThe splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P&lt;0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P&lt;0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.ConclusionIn humans, GDF15 is a “hepatokine” which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.
Relationship of the metabolic score for insulin resistance and the risk of stroke in patients with hypertension: A cohort study
Authors: Cai Xintian , Hu Junli , Zhu Qing , Wang Mengru , Liu Shasha , Dang Yujie , Hong Jing , Li Nanfang 
Published: December 2022

BackgroundThe current status of the dose-response relationship between the metabolic score for insulin resistance (METS-IR) and new-onset stroke in hypertensive patients and its subtypes is unclear. This study aimed to determine the association between METS-IR and incident stroke and its subtypes within a cohort of Chinese hypertensive patients.MethodsA total of 14032 hospitalized patients with hypertension from January 1, 2010, to December 31, 2021, were included in this retrospective cohort study. Cox models and restricted cubic splines were applied to determine the association between METS-IR and the risk of stroke.ResultsDuring a median follow-up of 4.80 years, 1067 incident stroke cases occurred. Patients in the highest quartile group of METS-IR levels exhibited a higher risk of stroke (HR, 1.80; 95% CI, 1.50-2.17) and ischemic stroke (HR, 1.96; 95% CI, 1.60–2.42) than those in the lowest quartile group. However, no significant associations were observed between METS-IR and the risk of hemorrhagic stroke. Restricted cubic spline analysis suggested a nearly J-shaped association between METS-IR and risk of stroke and ischemic stroke (P for nonlinearity &lt; 0.001). METS-IR did produce a significant improvement in the C statistic when added to the basic model (from 0.637 to 0.664, P &lt; 0.001). Notably, the addition of METS-IR to the basic model resulted in a significant improvement in predicting incident total stroke and ischemic stroke.ConclusionsThis cohort study suggests a relationship between METS-IR and the risk of stroke and ischemic stroke. Further studies are required to elucidate the underlying mechanisms.
Association between metabolic scores for visceral fat and chronic kidney disease: A cross-sectional study
Authors: Yu Peng , Meng Xiaoyu , Kan Ranran , Wang Zhihan , Yu Xuefeng 
Published: December 2022

IntroductionCentral obesity is closely linked to the risk of chronic kidney disease (CKD). This study aimed to evaluate the association between the novel central obesity index- metabolic score for visceral fat (METS-VF) and the risk of CKD in a Chinese population, and to compare its ability to predict CKD with other central obesity indices including waist circumference (WC), waist-to-height ratio (WHtR), lipid accumulation product (LAP), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), and cardiometabolic index (CMI).MethodsThis cross-sectional study included 8866 individuals from China. Demographic information, lifestyle data, and medical history data were collected, and physical examinations, anthropometric measurements and laboratory tests were performed for each participant. CKD was defined as an estimated GFR&lt; 60 ml/min/1.73m2. Multivariate logistic regression models were used to evaluate the association between the METS-VF and the prevalence of CKD. Receiver operating characteristic (ROC) analyses were performed to assess and compare the predictive abilities of the central obesity indices and determine the optimal cut-off points.ResultsA graded increase in the prevalence of CKD was observed with increasing METS-VF tertiles. Moreover, the METS-VF was independently associated with the risk of CKD after adjustment for current smoking, current drinking, physical activity level, diabetes, hypertension, CVD history and BMI. Compared with participants with a METS-VF in the lowest tertile, the multivariate-adjusted ORs and 95% CIs for participants with a METS-VF in the highest tertile were 3.943 (2.435-6.385) in the overall population, 3.585 (1.585-8.109) for men and 4.627 (2.485-8.616) for women. Significant interactions were found between the METS-VF and the risk of CKD by age (P value for interaction = 0.023). In ROC analysis, the METS-VF had a higher AUC value than other indices for predicting CKD in men and had comparable or higher AUC than other indices for women. For predicting CKD, the optimal cut-off value of the METS-VF was 6.891 for men and 6.744 for women. The METS-VF yielded the greatest Youden index among all indices for both sexes.ConclusionA higher METS-VF was independently associated with a greater risk of CKD. The METS-VF can be a useful clinical indicator for identifying CKD, as it had superior predictive power for CKD when compared with other central obesity indices.
Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma
Authors: Wang Yichen , Zhang Xuyao , Xu Caili , Nan Yanyang , Fan Jiajun , Zeng Xian , Kwon Byoung S. , Ju Dianwen 
Published: December 2022

IntroductionAlthough PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL).MethodsSubcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment.ResultsOur results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy.DiscussionIn summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.
Disparities in inflammation between non-Hispanic black and white individuals with lung cancer in the Greater Chicago Metropolitan area
Authors: Byrne Cecily A. , Gomez Sandra L. , Kim Sage , Oddo Vanessa M. , Koh Timothy J. , Fantuzzi Giamila 
Published: December 2022

BackgroundLung cancer incidence and mortality rates are higher in Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) individuals in the Chicago metropolitan area, which may be related to exposure to chronic stress which may increase inflammation.Specific aimWe investigated disparities in inflammation as measured by neutrophil to lymphocyte ratio (NLR) in individuals with lung cancer by race and by neighborhood concentrated disadvantage index (CDI).MethodsThis retrospective, cross-sectional study included 263 NHB and NHW adults with lung cancer. We analyzed NLR as a continuous and categorical variable to determine degree and prevalence of inflammation. We used Mann Whitney U, t-tests, Chi square tests, linear and logistic regression models as appropriate.ResultsMore than 60% of subjects had inflammation (NLR ≥ 3) at lung cancer diagnosis. The degree of inflammation was significantly lower in NHB (NLR 5.50 +/- 7.45) compared to NHW individuals (NLR 6.53 +/- 6.53; p=0.01) but did not differ by neighborhood CDI. The prevalence of inflammation (NLR ≥ 3) was significantly lower in NHB (55.07%) compared to NHW individuals (71.20%; p&lt;0.01) and in those from the most disadvantaged (54.07%) compared to the least disadvantaged (71.88%; p&lt;0.01) neighborhoods.ConclusionAt lung cancer diagnosis, there is a lower degree and prevalence of inflammation in NHB compared to NHW individuals, and lower prevalence in those residing in the most disadvantaged neighborhoods. Further research is needed to determine mechanisms of inflammation that may be contributing to lung cancer disparities as well as whether NLR is an appropriate biomarker when examining racial differences in inflammation.
A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice
Authors: Ma Qianqian , Hu Xiaozhi , Liu Fangyu , Cao Zhonglian , Han Lei , Zhou Kaicheng , Bai Yu , Zhang Yuting , Nan Yanyang , Lv Qianying , Rao Jia , Wu Tao , Yang Xue , He Haidong , Ju Dianwen , Xu Hong 
Published: December 2022

IntroductionThe pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvβ3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism.MethodsGenes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks.ResultsIn this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN.ConclusionCollectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery.
Analysis of m7G methylation modification patterns and pulmonary vascular immune microenvironment in pulmonary arterial hypertension
Authors: Wang Desheng , Mo Yanfei , Zhang Dongfang , Bai Yang 
Published: December 2022

BackgroundM7G methylation modification plays an important role in cardiovascular disease development. Dysregulation of the immune microenvironment is closely related to the pathogenesis of PAH. However, it is unclear whether m7G methylation is involved in the progress of PAH by affecting the immune microenvironment.MethodsThe gene expression profile of PAH was obtained from the GEO database, and the m7G regulatory factors were analyzed for differences. Machine learning algorithms were used to screen characteristic genes, including the least absolute shrinkage and selection operator, random forest, and support vector machine recursive feature elimination analysis. Constructed a nomogram model, and receiver operating characteristic was used to evaluate the diagnosis of disease characteristic genes value. Next, we used an unsupervised clustering method to perform consistent clustering analysis on m7G differential genes. Used the ssGSEA algorithm to estimate the relationship between the m7G regulator in PAH and immune cell infiltration and analyze the correlation with disease-characteristic genes. Finally, the listed drugs were evaluated through the screened signature genes.ResultsWe identified 15 kinds of m7G differential genes. CYFIP1, EIF4E, and IFIT5 were identified as signature genes by the machine learning algorithm. Meanwhile, two m7G molecular subtypes were identified by consensus clustering (cluster A/B). In addition, immune cell infiltration analysis showed that activated CD4 T cells, regulatory T cells, and type 2 T helper cells were upregulated in m7G cluster B, CD56 dim natural killer cells, MDSC, and monocyte were upregulated in the m7G cluster A. It might be helpful to select Calpain inhibitor I and Everolimus for the treatment of PAH.ConclusionOur study identified CYFIP1, EIF4E, and IFIT5 as novel diagnostic biomarkers in PAH. Furthermore, their association with immune cell infiltration may facilitate the development of immune therapy in PAH.