bluuebunny/crossref_metadata_2025_split huggingface dataset:
Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study
Authors: Chen Songzan , Yang Fangkun , Xu Tian , Wang Yao , Zhang Kaijie , Fu Guosheng , Zhang Wenbin 
Published: May 2021

BackgroundAlthough several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.MethodsA two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p &lt; 5 × 10–8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.ResultsIn total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.
Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer
Authors: Zhang Facai , Wang Xiaoming , Bai Yunjin , Hu Huan , Yang Yubo , Wang Jiahao , Tang Yin , Ma Honggui , Feng Dechao , Li Dengxiong , Han Ping 
Published: May 2021

ObjectivesThis study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer.MethodsWe downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer.ResultsEight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets.ConclusionWe successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients’ prognosis.
The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease
Authors: Zheng Hengqi B. , de la Morena M. Teresa , Suskind David L. 
Published: May 2021

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) represents a cohort of inflammatory bowel disease (IBD) patients diagnosed before 6 years of age. Unlike IBD diagnosed at older ages, VEO-IBD can be associated with underlying primary immunodeficiencies. VEO-IBD has been linked to monogenic variations in over 70 genes involved in multiple pathways of immunity. As sequencing technologies and platforms evolve and become readily available, an increasing number of genes linked to VEO-IBD have emerged. Although monogenic defects are rare in VEO-IBD, diagnosis of these variants can often dictate specific treatment. In this mini-review, we set out to describe monogenic variants previously characterized in multiple patients in the literature that contribute to VEO-IBD, diagnostic tools, unique treatment modalities for specific genetic diagnoses, and future directions in the field of VEO-IBD. Although this mini-review is by no means comprehensive of all the novel monogenic variants linked to VEO-IBD, we hope to provide relevant information that is readily accessible to clinicians and educators.
Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach
Authors: Granata Simona , Bruschi Maurizio , Deiana Michela , Petretto Andrea , Lombardi Gianmarco , Verlato Alberto , Elia Rossella , Candiano Giovanni , Malerba Giovanni , Gambaro Giovanni , Zaza Gianluigi 
Published: May 2021

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: −1.8, p &lt; 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p &lt; 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.
Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma
Authors: Xu Qianhui , Hu Yuanbo , Chen Shaohuai , Zhu Yulun , Li Siwei , Shen Feng , Guo Yifan , Sun Tao , Chen Xiaoyu , Jiang Jinpeng , Huang Wen 
Published: May 2021

Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer.Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan–Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the “maftools” package to delineate the tumor mutation burden (TMB).Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5′-cytosine-phosphate-guanine-3′ (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)–related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status.Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.
Repetitive Transcranial Magnetic Stimulation at Different Sites for Dysphagia After Stroke: A Randomized, Observer-Blind Clinical Trial
Authors: Zhong Lida , Rao Jinzhu , Wang Jing , Li Fang , Peng Yang , Liu Huiyu , Zhang Yan , Wang Pu 
Published: May 2021

Background: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) protocols on patients with poststroke dysphagia is still unclear.Objective: This trial aimed to explore and analyze the effectiveness of 5 Hz rTMS on the unaffected hemisphere, affected hemisphere, and cerebellum in stroke patients with dysphagia.Methods: This observer-blind and randomized controlled trial included a total of 147 patients with stroke. Patients were divided into four treatment groups: the unaffected hemispheric group, the affected hemispheric group, the cerebellum group and the control group. Each group received traditional dysphagia treatment 5 days a week for 2 weeks. All recruited patients except for those in the control group underwent 10 consecutive rTMS sessions for 2 weeks. For the affected hemispheric group and unaffected hemispheric group, 5 Hz rTMS was applied to the affected mylohyoid cortical region or to the unaffected mylohyoid cortical region. For the cerebellum group, 5 Hz rTMS was applied to the mylohyoid cortical representation of the cerebellum (4.3 cm lateral and 2.4 cm below the inion). The Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS), Penetration/Aspiration Scale (PAS), Gugging Swallowing Screen (GUSS), and Standardized Swallowing Assessment (SSA) were used to evaluate clinical swallowing function before the intervention (baseline), immediately after the intervention and 2 weeks after the intervention.Results: There were significant time and intervention interaction effects on the FEDSS, PAS, SSA, and GUSS scores (p &lt; 0.05). In a direct comparison of the swallowing parameters of the four groups, the changes in FEDSS, PAS, SSA, and GUSS scores showed a significantly greater improvement in the unaffected hemispheric group, the affected hemispheric group and cerebellum group than in the control group (p &lt; 0.05).Conclusions: Whether stimulating the unaffected hemisphere or the affected hemisphere, 5 Hz high-frequency rTMS on mylohyoid cortical tissue might have a positive effect on poststroke patients with dysphagia. In addition, cerebellar rTMS is a safe method that represents a potential treatment for poststroke dysphagia, and more clinical trials are needed to develop this technique further.Clinical Trial Registration:chictr.org.cn, identifier: ChiCTR2000032255.
Case Report: Deep Brain Stimulation of the Nucleus Basalis of Meynert for Advanced Alzheimer's Disease
Authors: Zhang Wei , Liu Wei , Patel Bhavana , Chen Yingchuan , Wang Kailiang , Yang Anchao , Meng Fangang , Wagle Shukla Aparna , Cen Shanshan , Yu John , Ramirez-Zamora Adolfo , Zhang Jianguo 
Published: May 2021

Patients with advanced Alzheimer's disease (AD) experience cognitive impairment and physical disabilities in daily life. Currently, there are no treatments available to slow down the course of the disease, and limited treatments exist only to treat symptoms. However, deep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) has been reported to improve cognitive function in individuals with AD. Here, we report the effects of NBM-DBS on cognitive function in a subject with severe AD. An 80-year-old male with severe AD (Clinical Dementia Rating scale: 3.0 points) underwent surgery for bilateral NBM-DBS electrode placement. After 10 weeks of stimulation, Mini-Mental State Examination (MMSE) assessment improved from a score of 5 to 9 points, and assessment using the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-cog) showed a marked reduction in total score from 43 to 33 points, suggesting cognitive benefits from NBM-DBS. The patient's postoperative course was complicated by a subdural effusion that occurred several days after surgery, with complete recovery. Interestingly, the subject also displayed abnormal thermoregulation with stimulation initiation and stimulation parameter modifications. NBM-DBS may serve as a potential therapy for severe AD patients.Clinical Trial Registration: ChiCTR1900022324.
Prognostic Significance of Systemic Immune-Inflammation Index in Patients With Diffuse Large B-Cell Lymphoma
Authors: Wang Zanzan , Zhang Jiawei , Luo Shuna , Zhao Xiaoying 
Published: May 2021

ObjectiveThe systemic immune-inflammation index (SII) based on neutrophil, platelet and lymphocyte counts, is a prognostic biomarker in some solid cancers. However, the prognostic value of SII has not yet been validated. This study was to evaluate the role of SII in predicting survival for patients with diffuse large B cell lymphoma (DLBCL).MethodsWe retrospectively investigated 224 patients with DLBCL between August 2005 and October 2018. Kaplan–Meier analysis and Cox proportional hazard models were used to assess the prognostic value of SII.ResultsIn the ROC curve analysis, SII had the highest AUC and was more accurate as a prognostic factor. Patients with higher SII tended to have higher level of LDH, more advanced stage, poor PS, and high IPI score compared with low SII group. In univariate analyses, SII, PLR and NLR were all prognostic for progression-free survival and overall survival. Moreover, only SII, older age, HBSAg-positive and IPI were the independent prognostic factors for patients in multivariate analysis. The nomogram based on SII, older age, HBSAg status and IPI showed accurate prognostic ability for predicting 3-years and 5-years survival rates (c-index, 0.791) compared to the IPI alone (c-index, 0.716).ConclusionSII was a powerful tool for predicting outcome in patients with DLBCL. It might assist the separation of high-risk patients among patients with the same IPI.
Preoperative Prediction of Meningioma Consistency via Machine Learning-Based Radiomics
Authors: Zhai Yixuan , Song Dixiang , Yang Fengdong , Wang Yiming , Jia Xin , Wei Shuxin , Mao Wenbin , Xue Yake , Wei Xinting 
Published: May 2021

ObjectivesThe aim of this study was to establish and validate a radiomics nomogram for predicting meningiomas consistency, which could facilitate individualized operation schemes-making.MethodsA total of 172 patients was enrolled in the study (train cohort: 120 cases, test cohort: 52 cases). Tumor consistency was classified as soft or firm according to Zada’s consistency grading system. Radiomics features were extracted from multiparametric MRI. Variance selection and LASSO regression were used for feature selection. Then, radiomics models were constructed by five classifiers, and the area under curve (AUC) was used to evaluate the performance of each classifiers. A radiomics nomogram was developed using the best classifier. The performance of this nomogram was assessed by AUC, calibration and discrimination.ResultsA total of 3840 radiomics features were extracted from each patient, of which 3719 radiomics features were stable features. 28 features were selected to construct the radiomics nomogram. Logistic regression classifier had the highest prediction efficacy. Radiomics nomogram was constructed using logistic regression in the train cohort. The nomogram showed a good sensitivity and specificity with AUCs of 0.861 and 0.960 in train and test cohorts, respectively. Moreover, the calibration graph of the nomogram showed a favorable calibration in both train and test cohorts.ConclusionsThe presented radiomics nomogram, as a non-invasive prediction tool, could predict meningiomas consistency preoperatively with favorable accuracy, and facilitated the determination of individualized operation schemes.
Bioinformatics, Molecular Docking and Experiments In Vitro Analyze the Prognostic Value of CXC Chemokines in Breast Cancer
Authors: Wang Fei , Yuan Chong , Wu He-Zhen , Liu Bo , Yang Yan-Fang 
Published: May 2021

The increasing incidence and mortality rate of Breast cancer (BC) make it a major public health problem around the world. CXC chemokines can mediate the migration of immune cells and regulate apoptosis in tumor. However, the expression and prognostic value of them in BC and their targeted drugs have not been clarified. Therefore, in this study, ONCOMINE, GEPIA2.0, UALCAN, Venny2.1.0, cBioPortal, STRING, Gene MANIA, Pathway Commons, DAVID6.8, Omicshare, Cytoscape3.6.1, TIMER2.0, Drug Bank, TCMSP, RSCBPDB, PubChem, pkCSM, Chem Draw, AutoDockTools-1.5.6 and PyMOL were utilized for analysis. The expression of CXCL1-3, CXCL9-13 between BC and normal tissues was significantly different in all the three databases. And the expression of CXCL1-2, CXCL12-13 was correlated with the stages of BC. But only CXCL1-3 were prone to mutation, and negatively correlated with survival and prognosis of BC patients. Taken together, CXCL1-2 might be therapeutic targets and biomarkers for BC patients. In addition, both of them were associated with immune infiltration. The results of molecular docking showed that Quercetin was most likely to be developed as drugs that interacted directly with CXCL1-2. And GLU29 of CXCL1, ASP-1, PRO-96, TRP-47 and LEU-45 of CXCL2 were the most potential sites, which provided valuable reference for further study of pharmacodynamics and mechanism. In addition, the inhibitory effect of Quercetin on proliferation and promoting apoptosis of BC related cell lines were confirmed in vitro. Western blot and Real-Time PCR confirmed that it increased the expression of CXCL1-2 in MDA-MB-231 and MCF-7 cells.
Prognostic Value of Tumor-Stroma Ratio in Rectal Cancer: A Systematic Review and Meta-analysis
Authors: Zhu Yuzhou , Jin Zechuan , Qian Yuran , Shen Yu , Wang Ziqiang 
Published: May 2021

BackgroundTumor-stroma ratio (TSR) is a promising new prognostic predictor for patients with rectal cancer (RC). Although several studies focused on this pathologic feature, results from those studies were still inconsistent.MethodsThis research aimed to estimate the prognostic values of TSR for RC. A search of PubMed, EMBASE, and Web of Science was carried out. A meta-analysis was performed on disease-free survival, cancer-specific survival, and overall survival in patients with RC.ResultsThe literature search generated 1,072 possible studies, of which a total of 15 studies, involving a total of 5,408 patients, were eventually included in the meta-analysis. Thirteen of the 15 articles set the cutoff for the ratio of stroma at 50%, dividing patients into low-stroma and high-stroma groups. Low TSR (rich-stroma) was significantly associated with poorer survival outcome. (DFS: HR 1.54, 95% CI 1.32–1.79; OS: HR 1.52 95% CI 1.34–1.73; CSS: HR 2.05 95% CI 1.52–2.77).ConclusionPresent data support TSR to be a risk predictor for poor prognosis in RC patients.
Identification of Immunosuppressive Medication Nonadherence Factors Through a Combined Theory Model in Renal Transplant Recipients
Authors: Zhang Pengpeng , Zhu Xiao , Yan Jin , Liu Jia 
Published: May 2021

Background: Immunosuppressive medication (IM) nonadherence is associated with poor transplant outcomes. Therefore, it is of great importance to identify predictive factors with IM nonadherence. We aimed to improve the predicted capacity of the theory of planned behavior (TPB) by adding health belief model’s (HBM) variables in renal transplant patients (RTPs).Methods: This cross-sectional study distributed questionnaires to patients who had undergone renal transplant and follow-up regularly in the transplant center of Third Xiangya Hospital in China. The self-developed questionnaire collected data in three aspects: general data questionnaire, TPB, HBM-specific questionnaire, and Basel Assessment of Adherence to Immunosuppressive Medications scale.Results: A total of 1,357 of 1,480 patients completed the survey, with a participation rate of 91.69% and IM nonadherence rate of 33.53%. The marital status, household income, preoperative drinking history, the time after transplantation, and religion showed independent predictive factors with IM nonadherence (p &lt; 0.05). Strikingly, adding HBM variables to the TPB theory model significantly increased its prediction ability to IM nonadherence (52%). Also, HBM manifested the highest coefficient of effect (−0.620). Particularly, perceived barriers and perceived seriousness, the variables of the HBM model, played a vital influence on medication nonadherence (−0.284 and 0.256).Conclusion: Our study here reveals the first investigation of the combined effects of the TPB and HBM model on IM nonadherence in Chinese RTPs, which could significantly improve the predictive ability of any single model. Meanwhile, future interventions should be conducted to both increase perceived seriousness and reduce perceived barriers for taking IM, which will effectively decrease IM nonadherence rates and improve transplant outcomes.