bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol consumption and colorectal cancer risk: A mendelian randomization study
Authors: Li Yuwei , Ye Ding , Zhou Wenkai , Liu Bin , Mao Yingying , Sun Xiaohui 
Published: September 2022

Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis.Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption.Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05–1.12, p = 1.51 × 10–5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27–1.52, p = 5.29 × 10–13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99–1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98–1.05, p = 0.545 by IVW).Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.
Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics
Authors: Bizjak Daniel Alexander , Stangl Manfred , Börner Nikolaus , Bösch Florian , Durner Joachim , Drunin Gergana , Buhl Jasmine-Leonike , Abendroth Dietmar 
Published: September 2022

IntroductionIn patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples.Material and methodsThe study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms &gt;20 weeks with still significant elevated Kyn-levels.ResultsMean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values &lt; 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values &lt;0.001) and CRP (r=0.488, p-values&lt;0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range.ConclusionSerum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.
Membrane attack complexes, endothelial cell activation, and direct allorecognition
Authors: Song Guiyu , Wang Shaoxun , Barkestani Mahsa Nouri , Mullan Clancy , Fan Matthew , Jiang Bo , Jiang Quan , Li Xue , Jane-wit Dan 
Published: September 2022

Endothelial cells (ECs) form a critical immune interface regulating both the activation and trafficking of alloreactive T cells. In the setting of solid organ transplantation, donor-derived ECs represent sites where alloreactive T cells encounter major and minor tissue-derived alloantigens. During this initial encounter, ECs may formatively modulate effector responses of these T cells through expression of inflammatory mediators. Direct allorecognition is a process whereby recipient T cells recognize alloantigen in the context of donor EC-derived HLA molecules. Direct alloresponses are strongly modulated by human ECs and are galvanized by EC-derived inflammatory mediators.Complement are immune proteins that mark damaged or foreign surfaces for immune cell activation. Following labeling by natural IgM during ischemia reperfusion injury (IRI) or IgG during antibody-mediated rejection (ABMR), the complement cascade is terminally activated in the vicinity of donor-derived ECs to locally generate the solid-phase inflammatory mediator, the membrane attack complex (MAC). Via upregulation of leukocyte adhesion molecules, costimulatory molecules, and cytokine trans-presentation, MAC strengthen EC:T cell direct alloresponses and qualitatively shape the alloimmune T cell response. These processes together promote T cell-mediated inflammation during solid organ transplant rejection.In this review we describe molecular pathways downstream of IgM- and IgG-mediated MAC assembly on ECs in the setting of IRI and ABMR of tissue allografts, respectively. We describe work demonstrating that MAC deposition on ECs generates ‘signaling endosomes’ that sequester and post-translationally enhance the stability of inflammatory signaling molecules to promote EC activation, a process potentiating EC-mediated direct allorecognition. Additionally, with consideration to first-in-human xenotransplantation procedures, we describe clinical therapeutics based on inhibition of the complement pathway. The complement cascade critically mediates EC activation and improved understanding of relevant effector pathways will uncover druggable targets to obviate dysregulated alloimmune T cell infiltration into tissue allografts.
Identification of immune cell infiltration and diagnostic biomarkers in unstable atherosclerotic plaques by integrated bioinformatics analysis and machine learning
Authors: Wang Jing , Kang Zijian , Liu Yandong , Li Zifu , Liu Yang , Liu Jianmin 
Published: September 2022

ObjectiveThe decreased stability of atherosclerotic plaques increases the risk of ischemic stroke. However, the specific characteristics of dysregulated immune cells and effective diagnostic biomarkers associated with stability in atherosclerotic plaques are poorly characterized. This research aims to investigate the role of immune cells and explore diagnostic biomarkers in the formation of unstable plaques for the sake of gaining new insights into the underlying molecular mechanisms and providing new perspectives for disease detection and therapy.MethodUsing the CIBERSORT method, 22 types of immune cells between stable and unstable carotid atherosclerotic plaques from RNA-sequencing and microarray data in the public GEO database were quantitated. Differentially expressed genes (DEGs) were further calculated and were analyzed for enrichment of GO Biological Process and KEGG pathways. Important cell types and hub genes were screened using machine learning methods including least absolute shrinkage and selection operator (LASSO) regression and random forest. Single-cell RNA sequencing and clinical samples were further used to validate critical cell types and hub genes. Finally, the DGIdb database of gene–drug interaction data was utilized to find possible therapeutic medicines and show how pharmaceuticals, genes, and immune cells interacted.ResultsA significant difference in immune cell infiltration was observed between unstable and stable plaques. The proportions of M0, M1, and M2 macrophages were significantly higher and that of CD8+ T cells and NK cells were significantly lower in unstable plaques than that in stable plaques. With respect to DEGs, antigen presentation genes (CD74, B2M, and HLA-DRA), inflammation-related genes (MMP9, CTSL, and IFI30), and fatty acid-binding proteins (CD36 and APOE) were elevated in unstable plaques, while the expression of smooth muscle contraction genes (TAGLN, ACAT2, MYH10, and MYH11) was decreased in unstable plaques. M1 macrophages had the highest instability score and contributed to atherosclerotic plaque instability. CD68, PAM, and IGFBP6 genes were identified as the effective diagnostic markers of unstable plaques, which were validated by validation datasets and clinical samples. In addition, insulin, nivolumab, indomethacin, and α-mangostin were predicted to be potential therapeutic agents for unstable plaques.ConclusionM1 macrophages is an important cause of unstable plaque formation, and CD68, PAM, and IGFBP6 could be used as diagnostic markers to identify unstable plaques effectively.
PD-1 inhibitors plus anti-angiogenic therapy with or without intensity-modulated radiotherapy for advanced hepatocellular carcinoma: A propensity score matching study
Authors: Su Ke , Guo Lu , Ma Wenqiong , Wang Jing , Xie Yunchuan , Rao Mingyue , Zhang Jianwen , Li Xueting , Wen Lianbin , Li Bo , Yang Xiaoli , Song Yanqiong , Huang Weihong , Chi Hao , Gu Tao , Xu Ke , Liu Yanlin , Chen Jiali , Wu Zhenying , Jiang Yi , Li Han , Zeng Hao , Wang Pan , Feng Xunjie , Chen Siyu , Yang Binbin , Jin Hongping , He Kun , Han Yunwei 
Published: September 2022

BackgroundWhether intensity-modulated radiotherapy (IMRT) can enhance the efficacy of the programmed death (PD)-1 inhibitors combined with anti-angiogenic therapy for hepatocellular carcinoma (HCC) is unclear. Therefore, we conducted this multicenter retrospective study to investigate the efficacy of the combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT.MethodsFrom April 2019 to March 2022, a total of 197 patients with HCC [combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT (triple therapy group), 54; PD-1 inhibitors plus anti-angiogenic therapy (control group), 143] were included in our study. Propensity score matching (PSM) was applied to identify two groups with similar baselines. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) of the two groups were compared before and after matching.ResultsPrior to PSM, the triple therapy group had higher ORR (42.6% vs 24.5%, P = 0.013) and more superior median OS (mOS) (20.1 vs 13.3 months, P = 0.009) and median PFS (mPFS) (8.7 vs 5.4 months, P = 0.001) than the control group. Following PSM, the triple therapy group still exhibited better mPFS (8.7 vs 5.4 months, P = 0.013) and mOS (18.5 vs 12.6 months, P = 0.043) than the control group. However, the ORR of the two groups was similar (40% vs 25%, P = 0.152). No significant difference was observed in the treatment-related adverse events between the two groups (P &lt; 0.05 for all). ConclusionsThe combination of PD-1 inhibitors with anti-angiogenic therapy and IMRT for HCC is a promising regimen.
The relationship between physical activity and trait anxiety in college students: The mediating role of executive function
Authors: Dong Zhiwei , Wang Peng , Xin Xin , Li Shufan , Wang Jing , Zhao Jinlei , Wang Xing 
Published: September 2022

ObjectivesAimed to analyze the mediating effect of executive function between physical activity level and trait anxiety in college students.MethodsThe International Physical Activity Questionnaire, State-Trait Anxiety Inventory, Stroop task, 1-back task, and More-odd shifting task were used to analyze 248 college students.ResultsTrait anxiety were significantly correlated with shifting function (r = 0.182, P = 0.004) and inhibition function (r = 0.163, P = 0.010) and not with working memory (r = 0.056, P = 0.385). Vigorous physical activity (VPA) was most highly correlated with inhibition function (Beta = −0.144, P = 0.024) and working memory (Beta = −0.208, P = 0.001), and light physical activity (LPA) was most highly correlated with shifting function (Beta = −0.211, P = 0.001). Physical activity had a 72.31% association with trait anxiety (B = −0.195), with 11.79% mediated by inhibition function (B = −0.023) and 15.90% by shifting function (B = −0.031).ConclusionCollege students' physical activity promotes both inhibition and shifting functions, which in turn affect trait anxiety. VPA had a direct effect, while the effect of moderate physical activity (MPA) and LPA was completely mediated exclusively through executive functions, and the mediating effect of shifting function was the highest. It is recommended that college workers should motivate students with high trait anxiety to engage in more VPA and pay attention to changes in their inhibition and shifting functions.
MRI radiomics-based machine learning model integrated with clinic-radiological features for preoperative differentiation of sinonasal inverted papilloma and malignant sinonasal tumors
Authors: Gu Jinming , Yu Qiang , Li Quanjiang , Peng Juan , Lv Fajin , Gong Beibei , Zhang Xiaodi 
Published: September 2022

ObjectiveTo explore the best MRI radiomics-based machine learning model for differentiation of sinonasal inverted papilloma (SNIP) and malignant sinonasal tumor (MST), and investigate whether the combination of radiomics features and clinic–radiological features can produce a superior diagnostic performance.MethodsThe database of 247 patients with SNIP (n=106) or MST (n=141) were analyzed. Dataset from scanner A were randomly divided into training set (n=135) and test set 1 (n=58) in a ratio of 7:3, and dataset from scanner B and C were used as an additional independent test set 2 (n=54). Fourteen clinic-radiological features were analyzed by using univariate analysis, and those with significant differences were applied to construct clinical model. Based on the radiomics features extracted from single sequence (T2WI or CE-T1WI) and combined sequence, four commonly used classifiers (logistic regression (LR), support vector machine (SVM), decision tree (DT) and k-nearest neighbor (KNN)) were employed to constitute twelve different machine learning models, and the best-performing one was confirmed as the optimal radiomics model. Furthermore, a combined model incorporated best radiomics feature subsets and clinic-radiological features was developed. The diagnostic performances of these models were assessed by the area under the receiver operating characteristic (ROC) curve (AUC) and the calibration curves.ResultsFive clinic-radiological features (age, convoluted cerebriform pattern sign, heterogeneity, adjacent bone involvement and infiltration of surrounding tissue) were considered to be significantly different between the tumor groups (P &lt; 0.05). Among the twelve machine learning models, the T2WI-SVM model exhibited optimal predictive efficacy for classification tasks on the two test sets, with the AUC of 0.878 and 0.914, respectively. For three types of diagnostic models, the combined model achieved highest AUC of 0.912 (95%CI: 0.807-0.970) and 0.927 (95%CI: 0.823-0.980) for differentiation of SNIP and MST in test 1 and test 2 sets, which performed prominently better than clinical model (P=0.011, 0.005), but not significantly different from the optimal radiomics model (P=0.100, 0.452).ConclusionThe machine learning model based on T2WI sequence and SVM classifier achieved best performance in differentiation of SNIP and MST, and the combination of radiomics features and clinic-radiological features significantly improved the diagnostic capability of the model.
Prognostic value of receptor tyrosine kinases in malignant melanoma patients: A systematic review and meta-analysis of immunohistochemistry
Authors: Lei Xuan , Zhang Yiming , Mao Lianghao , Jiang Pan , Huang Yumeng , Gu Jia , Tai Ningzheng 
Published: September 2022

BackgroundSubstantial evidence suggests that receptor tyrosine kinases (RTKs) are overexpressed in tumors; however, few studies have focused on the prognostic value of RTKs in melanoma.ObjectivesThe objective of this study is to evaluate the association between overexpression of RTKs and survival in melanoma patients based on immunohistochemistry (IHC) analysis.MethodsOur review is registered on PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42021261460. Seven databases were searched, and data were extracted. We used IHC to measure the association between overexpression of RTKs and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and clinicopathology in melanoma patients. Pooled analysis was conducted to assess the differences between Hazard Ratios along with 95% confidence intervals.ResultsOf 5,508 publications examined following the database search, 23 publications were included in this study, which included data from a total of 2,072 patients. Vascular endothelial growth factor receptor 2 (VEGF-R2) overexpression was associated with worse OS and DFS in melanoma. Furthermore, there was an association between OS and the expression of several RTKs, including epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition factor (MET), vascular endothelial growth factor receptor 1 (VEGF-R1), and insulin-like growth factor 1 receptor (IGF-1R). There were no significant correlations between EGFR overexpression and worse DFS or PFS. EGFR overexpression was associated with worse OS cutaneous and nasal melanoma, but not uveal melanoma. However, MET overexpression was related to worse OS in both cutaneous and uveal melanoma. Furthermore, EGFR overexpression was associated with a worse OS in Europe compared to other geographic areas. Moreover, EGFR and MET overexpression showed significant prognostic value in patients with the cut-off “≥10% staining”.ConclusionsOur findings build concrete evidence that overexpression of RTKs is associated with poor prognosis and clinicopathology in melanoma, highlighting RTK expression has the potential to inform individualized combination therapies and accurate prognostic evaluation.
The Prognostic Value of Pretherapy Peripheral Blood Inflammatory Indices in Myelodysplastic Syndromes
Authors: Shi Cong , Gong Shengping , Niu Tingting , Li Tongyu , Wu An , Zheng Xiaojiao , Yang Shujun , Ouyang Guifang , Mu Qitian 
Published: September 2022

BackgroundInflammation appears to have a critical role in carcinogenesis tumor growth according to emerging research. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and plasma C-reactive protein (CRP) are considered to reflect the systemic inflammatory response and clinical prognosis. The prognostic value of inflammatory indices in myelodysplastic syndrome (MDS) patients remains unclear.MethodsA total of 213 MDS patients were enrolled for the study. Univariate and multivariate analyses were performed to determine the prognostic significance of various indicators, including PLR, NLR, and CRP.ResultsMDS patients with higher PLR, NLR, and CRP levels had significantly shorter overall survival (OS). Based on univariate analysis, age (≥60 years), gender (men), lower hemoglobin level (&lt;10 g/dl), higher bone marrow blast percentage (&gt;5%), poorer karyotype, and higher Revised International Prognostic Scoring System (IPSS-R) score were significantly associated with shorter OS. Patients with higher CRP levels had shorter leukemia-free survival (LFS,P= 0.041). However, higher PLR and NLR had no significant influence on LFS (P&gt; 0.05). Multivariate Cox proportional hazards regression analysis indicated that high PLR and CRP were also independent adverse prognostic factors for OS in MDS.ConclusionsElevated PLR and CRP predict poor prognosis independent of the IPSS-R and provide a novel evaluation factor for MDS patients.
Wenzi Jiedu Recipe ameliorates colorectal cancer by remodeling the gut microbiota and tumor microenvironment
Authors: Qiu Wenli , Sang Tianqing , Chen Haibin , Zhou Hongli , Wang Zhongqiu , Zhou Hongguang 
Published: September 2022

IntroductionWenzi Jiedu Recipe (WJR), traditional Chinese medicine (TCM) formula, has been proven to be clinically useful in the treatment of colorectal cancer (CRC). However, its underlying mechanisms are still elusive, which limits its wider application. Thus, we aimed to evaluate the effect of WJR on CRC and elucidate mechanisms underlying its action.MethodsNetwork pharmacology was employed to clarify the “herb-active ingredient-target” network of WJR. The 16S rDNA sequencing method was used to analyze the changes of gut microbes mediated by WJR in tumor-bearing mice with CRC. The proportions of CD4+ T cell and CD8+ T cell were measured by flow cytometry. Levels of the cytokines interleukin (IL)-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA).ResultsWJR showed significant anti-CRC effects both in vitro and in vivo. Network pharmacology revealed that WJR exerts anti-CRC therapeutic effect on multiple targets and signaling pathways. Gut microbiota analysis revealed that WJR therapy significantly enriched for Oscillibacter and Bacteroides_acidifacien. In particular, we found that WJR significantly increased the proportion of CD8+ T cells and the expression of immune-associated cytokines IL-10, IFN-γ, and TNF-α.ConclusionThe regulation of gut microbiota by WJR may be the breakthrough point to clarify its mechanism of action in the treatment of CRC, and it has a good prospect of clinical application.
Efficacy of erlotinib in NSCLC harboring rare EGFR extracellular domain mutation (T263P) and common mutations: Case report and literature review
Authors: Wang Qian , Wang Yong , Zhang Xinwei , Fang Chen , Qian Xiaoying , Li Yong 
Published: September 2022

The epidermal growth factor receptor (EGFR) typically contains an extracellular domain (ECD), a transmembrane (TM) domain, and an intracellular kinase (KD) domain. ECD mutations of EGFR in NSCLC may affect its normal function and intrinsic resistance to tyrosine kinase inhibitors (TKIs) and the effectiveness of drugs for these patients is unsatisfactory. Recently, we found an EGFR T263P mutation located at the ECD, which has never been reported in Chinese non-small cell lung cancer (NSCLC). Hence, we reported that a patient with advanced lung adenocarcinoma harboring the EGFR T263P mutation, L858R mutation and MET amplification was resistant to osimertinib but significantly benefited from erlotinib and capmatinib treatment. This patient achieved a partial response and had progression-free survival (PFS) for more than 19 months. In summary, we are the first researchers to report in detail on a Chinese patient carrying the T263P mutation and summarize all the ECD mutations in NSCLC. We believe this finding will enlighten us to treat patients with EGFR ECD mutations and more patients deserve further study.