bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ubiquitin-specific peptidase 5 facilitates cancer stem cell-like properties in lung cancer by deubiquitinating β-catenin
Authors: Tung Chia-Hao , Wu Jia-En , Huang Meng-Fan , Wang Wen-Lung , Wu Yi-Ying , Tsai Yao-Tsung , Hsu Xiu-Rui , Lin Sheng-Hsiang , Chen Yuh-Ling , Hong Tse-Ming 
Published: September 2023

Abstract
Background
Lung cancer has the highest mortality rate in the world, and mounting evidence suggests that cancer stem cells (CSCs) are associated with poor prognosis, recurrence, and metastasis of lung cancer. It is urgent to identify new biomarkers and therapeutic targets for targeting lung CSCs.

Methods
We computed the single-sample gene set enrichment analysis (ssGSEA) of 1554 Reactome gene sets to identify the mRNA expression-based stemness index (mRNAsi)-associated pathways using the genome-wide RNA sequencing data of 509 patients from The Cancer Genome Atlas (TCGA) cohort of lung adenocarcinoma (LUAD). Phenotypic effects of ubiquitin-specific peptidase 5 (USP5) on the CSC-like properties and metastasis were examined by in vitro sphere formation assay, migration assay, invasion assay, and in vivo xenografted animal models. Cycloheximide chase assay, co-immunoprecipitation assay, and deubiquitination assay were performed to confirm the effect of USP5 on the deubiquitination of β-catenin.

Results
We demonstrated that USP5 expression were positively correlated with the stemness-associated signatures and poor outcomes in lung cancer specimens. Silencing of endogenous USP5 reduced CSC-like characteristics, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. Furthermore, USP5 interacted with β-catenin, which resulted in deubiquitination, stabilization of β-catenin, and activation of Wnt/β-catenin pathway. Accordingly, expression of USP5 was positively correlated with the enrichment score of the Wnt/TCF pathway signature in human lung cancer. Silencing of β-catenin expression suppressed USP5-enhancing sphere formation. Targeting USP5 with the small molecule WP1130 promoted the degradation of β-catenin, and showed great inhibitory effects on sphere formation, migration, and invasion. Finally, we identified a poor-prognosis subset of tumors characterized by high levels of USP5, Wnt signaling score, and Stemness score in both TCGA-LUAD and Rousseaux_2013 datasets.

Conclusions
These findings reveal a clinical evidence for USP5-enhanced Wnt/β-catenin signaling in promoting lung cancer stemness and metastasis, implying that targeting USP5 could provide beneficial effects to improve lung cancer therapeutics.
Could vaccinating adults against malaria materially reduce adult mortality in high-transmission areas?
Authors: Gelband Hellen , Carshon-Marsh Ronald , Ansumana Rashid , Swaray Ibrahim Bob , Pandey Arjun , Aimone Ashley , Bogoch Isaac , Eikelboom John , Jha Prabhat 
Published: September 2023

AbstractAfter a period of unprecedented progress against malaria in the 2000s, halving the global disease burden by 2015, gains overall in sub-Saharan Africa have slowed and even reversed in some places, beginning well before the COVID-19 pandemic. The highly effective drugs, treated nets, and diagnostics that fueled the initial progress all face some threats to their effectiveness, and global funding to maintain and increase their use over the long term is not guaranteed. Malaria vaccines are among the most promising new interventions that could accelerate the elimination of malaria. Vaccines are still in early stages of rollout in children, the age group (along with pregnant women) that has been the focus of malaria strategies for a century. At the same time, over the past decade, a case has been made, based largely on evidence from verbal autopsies in at least a few high-transmission areas, that the malaria death rate among adults has been greatly underestimated. Could vaccinating adults help to bring down the adult malaria mortality rate, contribute to reduced transmission, or both? A randomized trial of a malaria vaccine is proposed in Sierra Leone, a highly endemic setting, to shed light on this proposition.
Extracellular matrix-induced signaling pathways in mesenchymal stem/stromal cells
Authors: Novoseletskaya Ekaterina Sergeevna , Evdokimov Pavel Vladimirovich , Efimenko Anastasia Yurievna 
Published: September 2023

AbstractThe extracellular matrix (ECM) is a crucial component of the stem cell microenvironment, or stem-cell niches, and contributes to the regulation of cell behavior and fate. Accumulating evidence indicates that different types of stem cells possess a large variety of molecules responsible for interactions with the ECM, mediating specific epigenetic rearrangements and corresponding changes in transcriptome profile. Signals from the ECM are crucial at all stages of ontogenesis, including embryonic and postnatal development, as well as tissue renewal and repair. The ECM could regulate stem cell transition from a quiescent state to readiness to perceive the signals of differentiation induction (competence) and the transition between different stages of differentiation (commitment). Currently, to unveil the complex networks of cellular signaling from the ECM, multiple approaches including screening methods, the analysis of the cell matrixome, and the creation of predictive networks of protein–protein interactions based on experimental data are used. In this review, we consider the existing evidence regarded the contribution of ECM-induced intracellular signaling pathways into the regulation of stem cell differentiation focusing on mesenchymal stem/stromal cells (MSCs) as well-studied type of postnatal stem cells totally depended on signals from ECM. Furthermore, we propose a system biology-based approach for the prediction of ECM-mediated signal transduction pathways in target cells.
Increased expression of OPN contributes to idiopathic pulmonary fibrosis and indicates a poor prognosis
Authors: Ji Jie , Zheng Shudan , Liu Yuxin , Xie Tian , Zhu Xiaoyu , Nie Yang , Shen Yi , Han Xiaodong 
Published: September 2023

Abstract
Background
Idiopathic pulmonary fibrosis (IPF) is fibrotic lung disease with no effective treatment. It is characterized by destruction of alveolar structure and pulmonary interstitial fibrosis, leading to dyspnea and even asphyxia death of patients. Epithelial-mesenchymal transition (EMT) is considered to be a driving factor in the pathogenesis of IPF. Osteopontin (OPN) is a secreted protein widely present in the extracellular matrix and involved in the occurrence and development of a variety of diseases.

Methods
The original datasets were obtained from NCBI GEO databases analyzed with the online tool GEO2R and EasyGEO. Bleomycin induced mouse pulmonary fibrosis model and OPN/OPN-biotin treated mouse model were established to investigate the role of OPN in mouse pulmonary fibrosis and the target cells of OPN. A549 cells and HBE cells were used to explore the mechanism of OPN-induced epithelial-mesenchymal transition (EMT) in epithelial cells and mass spectrometry was used to detect OPN downstream receptors. Precision-cut lung slices and lentivirus-treated mice with pulmonary fibrosis were used to examine the therapeutic effect of OPN and its downstream pathways on pulmonary fibrosis.

Results
We demonstrate that the content of OPN in IPF bronchoalveolar lavage fluid (BALF) is high compared to the normal groups, and its expression level is correlated with prognosis. At the animal level, OPN was highly expressed at all stages of pulmonary fibrosis in mice, and the bronchoalveolar lavage fluid (BALF) could accurately reflect its expression in the lung. Next, we reveal that OPN was mainly expressed by macrophages and the main target cells of OPN were epithelial cells. Mice developed pulmonary fibrosis accompanied after treating the mice with OPN. Both in vitro and in vivo experiments confirmed that OPN could induce EMT of alveolar epithelial cells. Mechanistically, OPN binding triggered phosphorylation of FAK by CD44, thus activating snail1-mediated profibrotic protein synthesis. Inhibition of FAK phosphorylation and its downstream pathways can effectively alleviate pulmonary fibrosis in precision sections of lung tissue (PCLS) assay. OPN knockdown in bleomycin-induced lung fibrosis mice led to significantly less fibrosis.

Conclusion
Our data suggest that OPN mediates lung fibrosis through EMT, implicating its potential therapeutic target and prognostic indicator role for IPF. OPN may be a target for the diagnosis and treatment of IPF.
The heterogeneity and clonal evolution analysis of the advanced prostate cancer with castration resistance
Authors: Liu Ao , Gao Yi , Wang Qi , Lin Wenhao , Ma Zhiyang , Yang Xiaoqun , Chen Lu , Xu Danfeng 
Published: September 2023

Abstract
Background
Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients.

Methods
In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed.

Results
The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the “Homogeneous origin clonal model” was shorter than the “Heterogeneous origin clonal model”. The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance.

Conclusion
Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.
Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer
Authors: Mogenet Alice , Finetti Pascal , Denicolai Emilie , Greillier Laurent , Boudou-Rouquette Pascaline , Goldwasser François , Lumet Gwenael , Ceccarelli Michele , Birnbaum Daniel , Bedognetti Davide , Mamessier Emilie , Barlesi Fabrice , Bertucci François , Tomasini Pascale 
Published: September 2023

Abstract
Background
Anti-PD1/PDL1 immune checkpoint inhibitors (ICI) transformed the prognosis of patients with advanced non-small cell lung cancer (NSCLC). However, the response rate remains disappointing and toxicity may be life-threatening, making urgent identification of biomarkers predictive for efficacy. Immunologic Constant of Rejection signature (ICR) is a 20-gene expression signature of cytotoxic immune response with prognostic value in some solid cancers. Our objective was to assess its predictive value for benefit from anti-PD1/PDL1 in patients with advanced NSCLC.

Methods
We retrospectively profiled 44 primary tumors derived from NSCLC patients treated with ICI as single-agent in at least the second-line metastatic setting. Transcriptomic analysis was performed using the nCounter® analysis system and the PanCancer Immune Profiling Panel. We then pooled our data with clinico-biological data from four public gene expression data sets, leading to a total of 162 NSCLC patients treated with single-agent anti-PD1/PDL1. ICR was applied to all samples and correlation was searched between ICR classes and the Durable Clinical Benefit (DCB), defined as stable disease or objective response according to RECIST 1.1 for a minimum of 6 months after the start of ICI.

Results
The DCB rate was 29%; 22% of samples were classified as ICR1, 30% ICR2, 22% ICR3, and 26% ICR4. These classes were not associated with the clinico-pathological variables, but showed enrichment from ICR1 to ICR4 in quantitative/qualitative markers of immune response. ICR2-4 class was associated with a 5.65-fold DCB rate when compared with ICR1 class. In multivariate analysis, ICR classification remained associated with DCB, independently from PDL1 expression and other predictive immune signatures. By contrast, it was not associated with disease-free survival in 556 NSCLC TCGA patients untreated with ICI.

Conclusion
The 20-gene ICR signature was independently associated with benefit from anti-PD1/PDL1 ICI in patients with advanced NSCLC. Validation in larger retrospective and prospective series is warranted.
Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis
Authors: Li Shuting , Luo Congwei , Chen Sijia , Zhuang Yiyi , Ji Yue , Zeng Yiqun , Zeng Yao , He Xiaoyang , Xiao Jing , Wang Huizhen , Chen Xiaowen , Long Haibo , Peng Fenfen 
Published: September 2023

Abstract
Background
Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown.

Methods
The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed.

Results
BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway.

Conclusion
Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.
Transcriptome profiling of patient-derived tumor xenografts suggests novel extracellular matrix-related signatures for gastric cancer prognosis prediction
Authors: Deng Ziqian , Guo Ting , Bi Jiwang , Wang Gangjian , Hu Ying , Du Hong , Zhou Yuan , Jia Shuqin , Xing Xiaofang , Ji Jiafu 
Published: September 2023

Abstract
Background
A major obstacle to the development of personalized therapies for gastric cancer (GC) is the prevalent heterogeneity at the intra-tumor, intra-patient, and inter-patient levels. Although the pathological stage and histological subtype diagnosis can approximately predict prognosis, GC heterogeneity is rarely considered. The extracellular matrix (ECM), a major component of the tumor microenvironment (TME), extensively interacts with tumor and immune cells, providing a possible proxy to investigate GC heterogeneity. However, ECM consists of numerous protein components, and there are no suitable models to screen ECM-related genes contributing to tumor growth and prognosis. We constructed patient-derived tumor xenograft (PDTX) models to obtain robust ECM-related transcriptomic signatures to improve GC prognosis prediction and therapy design.

Methods
One hundred twenty two primary GC tumor tissues were collected to construct PDTX models. The tumorigenesis rate and its relationship with GC prognosis were investigated. Transcriptome profiling was performed for PDTX-originating tumors, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to extract prognostic ECM signatures and establish PDTX tumorigenicity-related gene (PTG) scores. The predictive ability of the PTG score was validated using two independent cohorts. Finally, we combined PTG score, age, and pathological stage information to establish a robust nomogram for GC prognosis prediction.

Results
We found that PDTX tumorigenicity indicated a poor prognosis in patients with GC, even at the same pathological stage. Transcriptome profiling of PDTX-originating GC tissues and corresponding normal controls identified 383 differentially expressed genes, with enrichment of ECM-related genes. A robust prognosis prediction model using the PTG score showed robust performance in two validation cohorts. A high PTG score was associated with elevated M2 polarized macrophage and cancer-associated fibroblast infiltration. Finally, combining the PTG score with age and TNM stage resulted in a more effective prognostic model than age or TNM stage alone.

Conclusions
We found that ECM-related signatures may contribute to PDTX tumorigenesis and indicate a poor prognosis in GC. A feasible survival prediction model was built based on the PTG score, which was associated with immune cell infiltration. Together with patient ages and pathological TNM stages, PTG score could be a new approach for GC prognosis prediction.
Effectiveness and safety of outpatient rehabilitation versus home-based rehabilitation after knee arthroplasty: a systematic review and meta-analysis
Authors: Zhao BiXia , Liu Hui , Du Ke , Zhou Wei , Li Ying 
Published: September 2023

Abstract
Background
Rehabilitation post-knee arthroplasty is integral to regaining knee function and ensuring patients’ overall well-being. The debate over the relative effectiveness and safety of outpatient versus home-based rehabilitation persists.

Methods
A thorough literature review was conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines across four databases. Two researchers independently identified eligible studies centering on knee arthroplasty patients undergoing either outpatient or home-based rehabilitation. Study quality was assessed using the Cochrane Collaboration’s risk of bias tool, while continuous outcomes were subject to meta-analyses using Stata 17 software.

Results
Our analysis identified no significant differences in primary outcomes, including Range of Motion, Western Ontario and McMaster Universities Arthritis Index, Knee Injury and Osteoarthritis Outcome Score, Oxford Knee Score, and the Knee Society Score, between home-based and outpatient rehabilitation across different follow-up points. Adverse reactions, readmission rates, the need for manipulation under anesthesia, reoperation rate, and post-surgery complications were also similar between both groups. Home-based rehabilitation demonstrated cost-effectiveness, resulting in substantial annual savings. Furthermore, quality of life and patient satisfaction were found to be comparable in both rehabilitation methods.

Conclusions
Home-based rehabilitation post-knee arthroplasty appears as an effective, safe, and cost-efficient alternative to outpatient rehabilitation. Despite these findings, further multicenter, long-term randomized controlled trials are required to validate these findings and provide robust evidence to inform early rehabilitation choices post-knee arthroplasty.
The role of preoperative glycemic control in decreasing surgical site infections in lower extremity fractures
Authors: Morisaki Shinsuke , Yoshii Kengo , Tsuchida Shinji , Oda Ryo , Fuke Tomoya , Takahashi Kenji 
Published: September 2023

Abstract
Background
Postoperative surgical site infections (SSIs) are an important complication to prevent in surgical treatment. Patients with diabetes mellitus (DM) have a higher risk of SSIs. Preoperative glycemic control is required. For patients with orthopedic trauma, the duration of preoperative glycemic control is limited because delaying operative treatment is difficult. However, whether preoperative glycemic control would decrease the risk of SSIs in diabetic patients with lower extremity fractures is unclear. The first aim of this study was to investigate the rate of SSIs among patients with DM who had undergone preoperative glycemic control, compared with that of patients without DM. As the secondary aim, we sought to demonstrate among patients with DM whether preoperative glycemic control would affect the development of SSIs between patients with controlled DM and patients with poorly controlled DM.

Methods
In this retrospective cohort study, 1510 patients treated surgically for lower extremity fractures were enrolled. Data collected were patient age, sex, body mass index, history of DM, development of SSIs, tobacco use, the presence of an open fracture, the period between the day of injury and the operation, the length of surgery, and blood glucose levels on admission and on the day before surgery.

Results
The rate of total SSIs was 6.0% among patients with DM and 4.4% among patients without DM (p = 0.31). Multivariate logistic regression revealed a significant association between the development of SSIs and the presence of DM (odds ratio, 1.79; 95% confidence interval 1.01–3.19; p = 0.047). The results of the secondary study revealed that the rate of early SSIs was significantly higher in the poorly controlled DM group than in the controlled DM group (5.9% vs. 1.5%; p = 0.032). However, multivariate logistic regression revealed that control levels of DM were not significantly associated with the development of SSIs.

Conclusions
Even though patients with DM had undergone preoperative glycemic control, SSIs were significantly associated with DM, especially when the patients had poorly controlled DM. This finding suggested that continuous glycemic control is important preoperatively and postoperatively to prevent SSIs.