The Characteristics of Transcription Factors Regulating T Cell Exhaustion Were Analyzed to Predict the Prognosis and Therapeutic Effect in Patients with HCC.

Purpose: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths, posing a significant threat to people in diverse regions. T-cell exhaustion (Tex) can hinder the efficacy of immunotherapy in patients with HCC, and the transcription factors that regulate Tex in HCC have not yet been fully elucidated. Patients and Methods: We used the single sample gene set enrichment analysis (ssGSEA) method to define the transcription factor pathway that regulates Tex and employed LASSO regression analysis to establish Tex related genes (TEXRS). To predict differences in immunotherapy efficacy between the two groups, we used the immunophenotype score and submap algorithm. RT-qPCR was used to detect the expression levels of the model genes in 21 pairs of HCC tissues. Finally, we assessed the cell communication strength and identified ligand receptors using the "CellChat" R package. Results: Nine Tex transcription factors were identified as regulators of the HCC immune microenvironment, with Tex scores affecting patient survival. Patients with a high Tex Risk Score (TEXRS) had significantly worse overall survival compared to patients with low TEXRS. After adjusting for confounding factors, TEXRS remained an independent prognostic factor. Importantly, TEXRS performed well in multiple independent external validation cohorts. Various algorithms have shown that patients in the low-TEXRS group might benefit more from immunotherapy. Finally, RT-qPCR analysis of 21 HCC samples showed that C7, CD5L, and SDS were significantly downregulated in HCC tissues, consistent with the bioinformatics analysis results. Conclusion: TEXRS proved to be a valuable predictor of immunotherapy and transcatheter arterial chemoembolization efficacy in patients with HCC. This holds promise for enhancing the prognosis and treatment outcomes of patients with HCC.

Features and development trends of primary care research conducted by practice-based research networks from 1991 to 2023: a scoping review protocol.

BACKGROUND: Practice-based research networks (PBRNs) have been recognized as essential laboratories and mechanisms for developing primary care research. This scoping review aims to examine and map the features and development trends of productivity, research categories, and methods in original primary care research conducted by global PBRNs between 1991 and 2023. METHODS: We have assembled an interdisciplinary team that will undertake this scoping review, following the framework developed by Arksey and O'Malley. Targeted literature includes original primary care research conducted by PBRNs, published from January 1, 1991, to December 31, 2023. An integrated search strategy will gather publications from 3 electronic databases (PubMed, Web of Science, and Embase), 16 major primary health care journals, and 364 relevant organizations. Two experienced researchers will independently screen the titles, keywords, and abstracts of all references and extract data regarding eight key elements. Disagreements between the reviewers will be resolved through group discussions, moderated by a third reviewer. Articles to be included will (1) be conducted in the primary care context, (2) be led by PBRNs, (3) provide a full report of original research, and (4) be published in a peer-reviewed journal between the aforementioned dates in any language. Exclusions encompass reviews, letters, commentaries, case reports, and conference papers. Final data will be displayed using tables and charts according to different conceptual categories. DISCUSSION: This scoping review is one of the initial attempts to delineate the development trends and features of primary care research conducted by PBRNs. This study will provide reference information for researchers in countries/regions that are building their research infrastructure and capacity in general practice, family medicine, and primary care. SYSTEMATIC REVIEW REGISTRATION: Registered in OSF on July 25, 2022 ( https://osf.io/zgv9c ).

Bioinformatic Analysis of the Mechanism of Action of COL3A1 in Pan-Cancer and Design of Specific Inhibitors for Its Conformation.

In this study, we investigated the mechanism of action of COL3A1 in various types of cancers by bioinformatics analysis and designed some specific inhibitors aimed at the treatment of this gene. We found that COL3A1 was highly expressed in several cancer types and correlated with tumor progression and prognosis. Through systems biology analysis, we identified a central role for COL3A1 in cancer development, including cell proliferation, metastasis and invasion. We also used molecular dynamics simulations and drug screening techniques to design anticancer drugs with potential COL3A1 inhibitory functions. These results provide a strong rationale for the development and use of COL3A1 as a therapeutic target.

Comprehensive Analysis of m7G-Related Genes and Chronic Hepatitis B: Diagnostic Markers, Immune Microenvironment Regulation, Disease Progression.

Chronic hepatitis B (CHB) is a major public health problem in the world. It is the main cause of liver cirrhosis and liver cancer. Although many important roles of RNA modification in stem cells or tumor diseases have been identified, the role of N7-methylguanosine (m7G) modification in the process of chronic HBV infection has not been clearly defined. Therefore, we conducted a systematic analysis on the process of chronic HBV infection. We found that a total of 18 m7G-related genes were altered in chronic HBV infection, and then we screened out CHB potential diagnostic biomarkers using machine learning and random forest methods. RT-qPCR was performed on the samples of healthy people and CHB, which further verified the possibility of being a diagnostic marker. Then, we typed CHB patients based on these 18 genes. We found that the immune microenvironment of different subtypes was different. Among them, patients with subtype-Ⅰ had severe immune response, that is, relatively serious immune cell infiltration, rich immune pathways, relatively many HLA genes, and immune checkpoints. Finally, we conducted an in-depth discussion on our m7G-related genes, and found that m7G gene related to immune cell infiltration may be involved in the disease progression of CHB patients, which was also confirmed in the GSE84044 dataset. In conclusion, m7G-related genes can not only serve as diagnostic markers of CHB, but also participate in the regulation of immune microenvironment and play an important role in the progression of CHB.

The necroptosis related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC.

The number of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection remains large, despite the remarkable effectiveness of antiviral drugs and vaccines for HBV in preventing and treating HBV infection. Necroptosis is closely related to the occurrence of inflammation, clearance of viral infection, and tumor progression. Presently, little is known about the changes in necroptosis-related genes in the progression from chronic HBV infection (CHI) to HBV-related hepatic fibrosis (HBV-HF) and HBV-related hepatocellular carcinoma (HBV-HCC). In this study, Cox regression analysis was performed using GSE14520 chip data and a necroptosis-related genes survival prognosis score (NRGPS) was established for HBV-HCC patients. NRGPS was constructed using three model genes (G6PD, PINK1 and LGALS3), and verified by data sequencing in the TCGA database. The HBV-HCC cell model was established by transfection of pAAV/HBV1.2C2, constructed by homologous recombination, into HUH7 and HEPG2 cells. The expression levels of G6PD, PINK1, and LGALS3 were detected using RT-qPCR. We further analyzed the expression of the model genes in GSE83148, GSE84044, and GSE14520 and found that LGALS3 was consistently highly expressed in CHI, high fibrosis score and high NRGPS. In addition, immune microenvironment analysis showed that LGALS3 was not only associated with the infiltration of regulatory T cells in the immune microenvironment but also with expression of CCL20 and CCR6. The expression levels of model genes, FOXP3 and CCR6, were analyzed using RT-qPCR in peripheral blood mononuclear cells of 31 hepatitis B surface antibody positive patients, 30 CHI, 21 HBV-HF, and 20 HBV-HCC. In further cell-model experiments, we analyzed the expression of CCL20 by RT-qPCR and the changes in cell proliferation and migration by CCK8 and transwell assays, respectively, in HBV-HCC cell models after LGALS3 knockdown. The findings of this study suggest that LGALS3 could be a biomarker for adverse progression following chronic HBV infection and may also be involved in the regulation of the immune microenvironment, making it a potential therapeutic target.

Paradoxical autosomal recessive bestrophinopathy-like phenotypes shown in an autosomal dominant pedigree.

PURPOSE: This study aimed to evaluate the clinical and genetic characteristics of eight members from a Chinese Han family who displayed autosomal recessive bestrophinopathy (ARB)-like retinal changes in autosomal dominant (AD) inheritance pattern. METHODS: Clinical investigations included slit-lamp, tonometry, fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, electrooculography, and ultrasound biomicroscopy. Ocular axial length measurements were collected retrospectively. The targeted exome sequencing (TES) was applied for the genetic analysis of the proband. PCR-based Sanger sequencing was performed on the family for validation and co-segregation analysis. RESULTS: Eight members in the three-generation pedigree complained about vision loss and seven of them had detailed clinical assessments, demonstrating ocular phenotypes including extramacular and vascular arcades subretinal deposits and Arden ratio decline on electrooculography that resembled ARB. Bilateral anterior chamber structure abnormalities were observed in seven cases and three patients were diagnosed with angle-closure glaucoma. Despite clinical phenotypes supporting ARB, there was only a single heterozygous mutation of c.227T > C (p.Ile76Thr) in the BEST1 gene detected in all eight patients, which showcased AD inheritance. CONCLUSIONS: An ARB-like phenotype could be caused by a heterozygous mutation of the BEST1 gene and inherited in an AD fashion.

Dysregulated Circulating Apoptosis- and Autophagy-Related lncRNAs as Diagnostic Markers in Coronary Artery Disease.

OBJECTIVE: Increasing evidence emphasizes the implications of dysregulated apoptosis and autophagy cellular processes in coronary artery disease (CAD). Herein, we aimed to explore apoptosis- and autophagy-related long noncoding RNAs (lncRNAs) in peripheral blood of CAD patients. METHODS: The mRNA and lncRNA expression profiles were retrieved from the Gene Expression Omnibus (GEO) database. With ∣fold change | >1.5 and adjusted p value < 0.05, differentially expressed apoptosis- and autophagy-related mRNAs were screened between CAD and healthy blood samples. Also, differentially expressed lncRNAs were identified for CAD. Using the psych package, apoptosis- and autophagy-related lncRNAs were defined with Spearson's correlation analysis. Receiver operating characteristic (ROC) curves were conducted for the assessment of the diagnosed efficacy of these apoptosis- and autophagy-related lncRNAs. RESULTS: Our results showed that 24 apoptosis- and autophagy-related mRNAs were abnormally expressed in CAD than normal controls. 12 circulating upregulated and 1 downregulated apoptosis- and autophagy-related lncRNAs were identified for CAD. The ROCs confirmed that AC004485.3 (AUC = 0.899), AC004920.3 (AUC = 0.93), AJ006998.2 (AUC = 0.776), H19 (AUC = 0.943), RP5-902P8.10 (AUC = 0.956), RP5-1114G22.2 (AUC = 0.883), RP11-247A12.1 (AUC = 0.885), RP11-288L9.4 (AUC = 0.928), RP11-344B5.2 (AUC = 0.858), RP11-452C8.1 (AUC = 0.929), RP11-565A3.1 (AUC = 0.893), and XXbac-B33L19.4 (AUC = 0.932) exhibited good performance in differentiating CAD from healthy controls. CONCLUSION: Collectively, our findings proposed that circulating apoptosis- and autophagy-related lncRNAs could become underlying diagnostic markers for CAD in clinical practice.