bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of hub genes and pathophysiological mechanism related to acute unilateral vestibulopathy by integrated bioinformatics analysis
Authors: Cheng Yajing , Zheng Jianrong , Zhan Ying , Liu Cong , Lu Bihua , Hu Jun 
Published: September 2022

BackgroundAlthough many pathological mechanisms and etiological hypotheses of acute unilateral vestibulopathy (AUVP) have been reported, but the actual etiology remains to be elucidated.ObjectiveThis study was based on comprehensive bioinformatics to identify the critical genes of AUVP and explore its pathological mechanism.MethodsGene expression profiles of AUVP and normal samples were collected from GSE146230 datasets of the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was constructed, and the WGCNA R-package extracted significant modules. The limma R-package was applied to identify differentially expressed genes (DEGs). The common genes of practical modules and DEGs were screened for GO and KEGG pathways analysis. The protein–protein interaction (PPI) layout and hub genes validation was created by Cytoscape software using the link from the STRING database. The functions of hub genes were predicted through the CTD (comparative genetics database).ResultsA total of 332 common genes were screened from practical modules and DEGs. Functional enrichment analysis revealed that these genes were predominantly associated with inflammation and infection. After construction of PPI, expressions of hub genes, and drawing ROC curves, LILRB2, FPR1, AQP9, and LILRA1 are highly expressed in AUVP (p &lt; 0.05) and have a certain diagnostic efficacy for AUVP (AUC &gt; 0.7), so they were selected as hub genes. The functions of hub genes suggested that the occurrence of AUVP may be related to inflammation, necrosis, hepatomegaly, and other conditions in CTD.ConclusionLILRB2, FPR1, AQP9, and LILRA1 may play essential roles in developing AUVP, providing new ideas for diagnosing and treating AUVP.
Evaluation of the clinical practice guidelines and consensuses on calcium and vitamin D supplementation in healthy children using the Appraisal of Guidelines for Research and Evaluation II instrument and Reporting Items for Practice Guidelines in Healthcare statement
Authors: He Lanzhi , Zhou Pengxiang , Zhou Xin , Tian Shuxia , Han Jing , Zhai Suodi 
Published: September 2022

BackgroundThis study aimed to assess the methodological and reporting quality of the guidelines and consensus on calcium and vitamin D supplementation in healthy children, and the consistency of these recommendations.MethodsA systematic search of relevant guideline websites and databases, including PubMed, Embase, CNKI, WangFang, and SinoMed, was undertaken from inception to April 7, 2021, by two independent reviewers who assessed the eligible guidelines using the validated Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) tools. Overall, the between-reviewer agreement was evaluated using an intra-class correlation coefficient.ResultsA total of 24 guidelines and consensuses from 2002 to 2022 were identified from China, the United States, Canada, France, Australia, New Zealand, Europe, and other countries and regions. These were of mixed quality, and scored poorly in the rigor of development, editorial independence, and applicability of the domains of AGREE II. Among the seven domains of the RIGHT checklist, domain one (basic information) had the highest reporting rate (69.3%), whereas domain five (review and quality assurance) had the lowest reporting rate (11.5%). The overall quality of the included guidelines and consensuses was low. Only 12 guidelines were recommended, with modifications. The recommended calcium intake for children of different ages varies greatly (400–1,150 mg/day). Among the included guidelines and consensuses, a vitamin D (VD) prevention dose of 400 IU/day in infants was generally considered safe, and 25-hydroxyvitamin-D [25(OH)D] levels of &lt;20 ng/mL (50 nmol/L) or 20–30 ng/mL (50–75 nmol/L) indicated VD deficiency or insufficiency. However, the recommended amount of VD for children of different age groups and risk strata differed considerably (400–4,000 IU/day or 10–100 μg/day). The choice of VD2 or VD3 supplements and sunlight exposure also differed across the guidelines and consensuses.ConclusionThere is considerable variability in calcium and VD guidelines and consensus development methods in calcium and VD supplementation for healthy children. Therefore, efforts are necessary to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin recommendations.
Clinicopathological characteristics and outcome of primary sarcomatoid carcinoma of the gallbladder
Authors: Zou Rui-Qi , Hu Hai-Jie , Lv Tian-Run , Liu Fei , Ma Wen-Jie , Wang Jun-Ke , Dai Yu-Shi , Yang Si-Qi , Hu Ya-Fei , Li Fu-Yu 
Published: September 2022

PurposeOur study aims to examine the clinicopathological features, disease progression, management, and outcomes of gallbladder sarcomatoid carcinoma (GBSC) patients.MethodsBetween January 2000 and December 2020, 50 gallbladder cancer (GBC) patients who received surgical treatment and were pathologically verified as GBSC at our institution were enrolled. The clinical and pathological features and survival of these patients were retrospectively reviewed.ResultsThe median overall survival (OS) of GBSC patients was 14.5 months, and the 1-, 2- and 3-year OS rates were 68.0%, 32.0%, and 10.0%, respectively. The median progression-free survival (PFS) was 10.0 months, and the 1-, 2-, and 3-year PFS rates were 42.0%, 16.0%, and 2.0%, respectively. Patients who received radical resection had obviously better OS (18.0 vs. 7.0 months, P&lt;0.001) and PFS (12.0 vs. 5.0 months, P&lt;0.001) than those who underwent palliative resection. Multivariate analysis revealed that vascular invasion (P=0.033), curative operation (P&lt;0.001) and postoperative chemotherapy (P=0.033) were independent risk factors for PFS. We further identified postoperative chemotherapy (P=0.010) and curative operation (P&lt;0.001) as independent prognostic factors affecting the OS of GBSC patients. After curative surgery, patients who underwent S-1-based chemotherapy showed significantly longer recurrence-free survival (RFS) than those who underwent other chemotherapy regimens (20.0 vs 11.0 months, P=0.028).ConclusionGBSC patients always have aggressive biological behaviors and remarkably poor prognoses. Most GBSC patients are diagnosed in advanced stages, and timely radical operation together with postoperative chemotherapy is important. S-1-based chemotherapy may be a selectively efficient regimen to prolong the survival of GBSC patients.
Hepcidin is upregulated and is a potential therapeutic target associated with immunity in glioma
Authors: Dong Tianyu , Zhang Bo , Zhang Runjiao , Wang Chang , Liu Xiaopeng , Wang Fei , Hao Nana , Tan Ke , Chang Yan-Zhong 
Published: September 2022

BackgroundGlioma is the most common primary malignant brain tumor with high mortality and poor prognosis. Hepcidin is a fascinating iron metabolism regulator. However, the prognostic value of hepcidin HAMP in gliomas and its correlation with immune cell infiltration remain unclear. Here, we comprehensively elucidate the prognostic value and potential role of hepcidin in gliomas.MethodsHepcidin gene expression and clinical characteristics in glioma were analyzed using the CGGA, TCGA, Rembrandt and Gravendeel glioma databases. A survival analysis was conducted using Kaplan–Meier and Cox regression analyses. A gene set enrichment analysis (GSEA) was conducted to select the pathways significantly enriched for hepcidin associations. The correlations between hepcidin and immune cell infiltration and immunotherapy were analyzed using network platforms such as CIBERSORT and TIMER.ResultsIn glioma tissues, the expression of hepcidin was significantly increased. High hepcidin expression is related to grade, age, PRS type, IDH mutation, chemotherapy status and 1p19q codeletion status, which significantly indicates the poor prognosis of glioma patients. Hepcidin can be used as an independent prognostic factor for glioma through the multivariate COX regression analysis. The results of Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG) and gene set enrichment analysis (GSEA) indicated that hepcidin was involved in the immune response. In addition, hepcidin expression was positively correlated with the degree of immune cell infiltration, the expression of various immune cell markers and the efficacy of immunotherapy.ConclusionOur results indicate that hepcidin can be used as a candidate biomarker to judge the prognosis and immune cell invasion of gliomas.
Clinical implications of the tumor microenvironment using multiplexed immunohistochemistry in patients with advanced or metastatic renal cell carcinoma treated with nivolumab plus ipilimumab
Authors: Kim Jwa Hoon , Kim Gi Hwan , Ryu Yeon-Mi , Kim Sang-Yeob , Kim Hyung-Don , Yoon Shin Kyo , Cho Yong Mee , Lee Jae Lyun 
Published: September 2022

PurposeImmune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown.MethodsTwenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells.ResultsThe median age of the study patients was 61 years (range, 39–80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016).ConclusionThe properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets.
Adaptive dose painting for prostate cancer
Authors: Fredén Emil , Tilly David , Ahnesjö Anders 
Published: September 2022

PurposeDose painting (DP) is a radiation therapy (RT) strategy for patients with heterogeneous tumors delivering higher dose to radiation resistant regions and less to sensitive ones, thus aiming to maximize tumor control with limited side effects. The success of DP treatments is influenced by the spatial accuracy in dose delivery. Adaptive RT (ART) workflows can reduce the overall geometric dose delivery uncertainty. The purpose of this study is to dosimetrically compare ART and non-adaptive conventional RT workflows for delivery of DP prescriptions in the treatment of prostate cancer (PCa).Materials and methodsWe performed a planning and treatment simulation study of four study arms. Adaptive and conventional workflows were tested in combination with DP and Homogeneous dose. We used image data from 5 PCa patients that had been treated on the Elekta Unity MR linac; the patients had been imaged in treatment position before each treatment fraction (7 in total). The local radiation sensitivity from apparent diffusion coefficient maps of 15 high-risk PCa patients was modelled in a previous study. these maps were used as input for optimization of DP plans aiming for maximization of tumor control probability (TCP) under rectum dose constraints. A range of prostate doses were planned for the homogeneous arms. Adaptive plans were replanned based on the anatomy-of-the-day, whereas conventional plans were planned using a pre-treatment image and subsequently recalculated on the anatomy-of-the-day. The dose from 7 fractions was accumulated using dose mapping. The endpoints studied were the TCP and dose-volume histogram metrics for organs at risk.ResultsAccumulated DP doses (adaptive and conventional) resulted in high TCP, between 96-99%. The largest difference between adaptive and conventional DP was 2.6 percentage points (in favor of adaptive DP). An analysis of the dose per fraction revealed substantial target misses for one patient in the conventional workflow that—if systematic—could jeopardize the TCP. Compared to homogeneous prescriptions with equal mean prostate dose, DP resulted in slightly higher TCP.ConclusionCompared to homogeneous dose, DP maintains or marginally increases the TCP. Adaptive DP workflows could avoid target misses compared to conventional workflows.
Histone lysine methylation patterns in prostate cancer microenvironment infiltration: Integrated bioinformatic analysis and histological validation
Authors: Quan Yongjun , Zhang Xiaodong , Wang Mingdong , Ping Hao 
Published: September 2022

BackgroundEpigenetic reprogramming through dysregulated histone lysine methylation (HLM) plays a crucial role in prostate cancer (PCa) progression. This study aimed to comprehensively evaluate HLM modification patterns in PCa microenvironment infiltration.Materials and methodsNinety-one HLM regulators in The Cancer Genome Atlas (TCGA) dataset were analyzed using bioinformatics. Differentially expressed genes (DEGs) and survival analyses were performed using TCGA-PRAD clinicopathologic and follow-up information. Consensus clustering analysis divided patients into subgroups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Tumor mutation burden (TMB) and tumor microenvironment (TME) cell infiltration were evaluated in different HLM clusters. Quantitative real-time PCR (qPCR) analysis assessed HLM regulators in clinical PCa tissues.ResultsThe tumor vs. normal (TN), Gleason score (GS) &gt; 7 vs. GS &lt; 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS &gt; 7, pT3, HR &gt; 1, and TP53 mutation) (P &lt; 0.05) and verified in clinical PCa tissues. Consensus clustering analysis revealed three distinct HLM modification patterns (HLMclusters). However, no significant differences in recurrence-free survival (RFS) rates were found among the groups (P &gt; 0.05). We screened 189 HLM phenotype-related genes that overlapped in the pairwise comparisons of HLMclusters and P &lt; 0.01 in the Cox regression analysis. Three distinct subgroups (geneClusters) were revealed based on the 189 genes, in which cluster A involved the most advanced PCa (PSA &gt; 10, T3-4, GS8-10, and biochemical recurrence) and the poorest RFS. The HLM score (HLMscore) was calculated by principal component analysis (PCA) of HLM phenotype-related genes that have positive predictive value for RFS (P &lt; 0.001) and immune therapy responses (in the CTLA4-positive and -negative responses accompanied by a PD1-negative response).ConclusionWe comprehensively evaluated HLM regulators in the PCa microenvironment using TCGA-PRAD, revealing a nonnegligible role of HLM patterns in PCa complexity and heterogeneity. Elucidating the effects of HLM regulators in PCa may enhance prognostics, aggressiveness assessments, and immunotherapy strategies.
Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination
Authors: Yang Kaidi , Yang Tongxin , Yang Tao , Yuan Ye , Li Fang 
Published: September 2022

BackgroundMalignant pleural mesothelioma (MPM) is a rare and intractable disease exhibiting a remarkable intratumoral heterogeneity and dismal prognosis. Although immunotherapy has reshaped the therapeutic strategies for MPM, patients react with discrepant responsiveness.MethodsHerein, we recruited 333 MPM patients from 5 various cohorts and developed an in-silico classification system using unsupervised Non-negative Matrix Factorization and Nearest Template Prediction algorithms. The genomic alterations, immune signatures, and patient outcomes were systemically analyzed across the external TCGA-MESO samples. Machine learning-based integrated methodology was applied to identify a gene classifier for clinical application.ResultsThe gene expression profiling-based classification algorithm identified immune-related subtypes for MPMs. In comparison with the non-immune subtype, we validated the existence of abundant immunocytes in the immune subtype. Immune-suppressed MPMs were enriched with stroma fraction, myeloid components, and immunosuppressive tumor-associated macrophages (TAMs) as well exhibited increased TGF-β signature that informs worse clinical outcomes and reduced efficacy of anti-PD-1 treatment. The immune-activated MPMs harbored the highest lymphocyte infiltration, growing TCR and BCR diversity, and presented the pan-cancer immune phenotype of IFN-γ dominant, which confers these tumors with better drug response when undergoing immune checkpoint inhibitor (ICI) treatment. Genetically, BAP1 mutation was most commonly found in patients of immune-activated MPMs and was associated with a favorable outcome in a subtype-specific pattern. Finally, a robust 12-gene classifier was generated to classify MPMs with high accuracy, holding promise value in predicting patient survival.ConclusionsWe demonstrate that the novel classification system can be exploited to guide the identification of diverse immune subtypes, providing critical biological insights into the mechanisms driving tumor heterogeneity and responsible for cancer-related patient prognoses.
Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and β-catenin pathway in vitro
Authors: Chang Chin-Kuo , Chu Shu-Chen , Huang Jing-Yang , Chen Pei-Ni , Hsieh Yih-Shou 
Published: September 2022

Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified.Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin.Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin.Conclusion:Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/β-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.
Pyrroloquinoline quinone modulates YAP-related anti-ferroptotic activity to protect against myocardial hypertrophy
Authors: Zhou Jiabin , Yu Tao , Wu Gujie , Xu Peng , Wang Chen , Su Yiling , Wang Li , Lu Qi 
Published: September 2022

Background: Pyrroloquinoline quinone (PQQ) has been reported to exhibit cardioprotective and antioxidant activities. Accordingly, this study was developed to explore the effects of PQQ treatment on myocardial hypertrophy and the underlying mechanism of action governing any observed beneficial effects.Methods: A transverse aortic constriction (TAC) model of myocardial hypertrophy was established in vivo using C57BL/6 mice, while neonatal murine cardiomyocytes were stimulated with phenylephrine (PE) as an in vitro validation model system.Results: Treatment of TAC model mice with PQQ significantly suppressed myocardial hypertrophy and fibrosis, in addition to inhibiting the ferroptotic death of hypertrophic myocardial cells in vivo. Subsequent in vitro analyses revealed that treatment with PQQ was sufficient to significantly alleviate PE-induced hypertrophic activity and to prevent ferroptotic induction in these primary murine cardiomyocytes. At the mechanistic level, PQQ was found to promote the upregulation of Yes-associated Protein (YAP), to suppress YAP phosphorylation, and to drive the nuclear translocation of YAP within hypertrophic cardiomyocytes. The use of a specific siRNA construct to knock down YAP expression in vitro further confirmed the ability of PQQ to protect against myocardial hypertrophy at least in part through anti-ferroptotic mechanisms.Conclusion: PQQ can regulate the pathogenesis of myocardial hypertrophy through the induction of YAP-related anti-ferroptotic activity, highlighting the potential value of PQQ as a novel therapeutic agent capable of slowing or preventing the progression of myocardial hypertrophy and thus delaying the onset of heart failure.