Causal relationship, shared genes between rheumatoid arthritis and pulp and periapical disease: evidence from GWAS and transcriptome data.

Objective: Patients with rheumatoid arthritis (RA) have an increased risk of developing pulp and periapical disease (PAP), but the causal relationship and shared genetic factors between these conditions have not been explored. This study aimed to investigate the bidirectional causal relationship between RA and PAP and to analyze shared genes and pathogenic pathways. Methods: We utilized GWAS data from the IEU Open GWAS Project and employed five Mendelian randomization methods (MR Egger, weighted median, inverse variance weighted, simple mode, and weighted mode) to investigate the bidirectional causal relationship between RA and PAP. Transcriptome data for RA and irreversible pulpitis (IRP) were obtained from the GEO database. Hub genes were identified through differential analysis, CytoHubba, machine learning (ML), and other methods. The immune infiltration of both diseases was analyzed using the ssGSEA method. Finally, we constructed a regulatory network for miRNAs, transcription factors, chemicals, diseases, and RNA-binding proteins based on the identified hub genes. Results: RA was significantly associated with an increased risk of PAP (OR = 1.1284, 95% CI 1.0674-1.1929, p < 0.001). However, there was insufficient evidence to support the hypothesis that PAP increased the risk of RA. Integrating datasets and differential analysis identified 84 shared genes primarily involved in immune and inflammatory pathways, including the IL-17 signaling pathway, Th17 cell differentiation, and TNF signaling pathway. Using CytoHubba and three ML methods, we identified three hub genes (HLA-DRA, ITGAX, and PTPRC) that are significantly correlated and valuable for diagnosing RA and IRP. We then constructed a comprehensive regulatory network using the miRDB, miRWalk, ChipBase, hTFtarget, CTD, MalaCards, DisGeNET, and ENCORI databases. Conclusion: RA may increase the risk of PAP. The three key genes, HLA-DRA, ITGAX, and PTPRC, have significant diagnostic value for both RA and IRP.

Polymorphisms in miR-17-92 cluster promoter region is associated with risk and prognosis of endometrial cancer.

Accumulating researches have reported that miR-17-92 cluster expression has strong association with tumorigenesis. In this study, we investigated the effects of 2 genetic polymorphisms in the promoter region of the miR-17-92 cluster and the risk and prognosis of endometrial cancer in northern Chinese women. Two polymorphisms (rs9588884 and rs982873) in the promoter of miR-17-92 cluster were genotyped by polymerase chain reaction and ligase detection reaction (PCR-LDR) in398 EC patients and 420 controls. The levels of miR-17-92 mRNA were investigated in 65EC tissues by real-time quantitative polymerase chain reaction (RT-qPCR). The impact of genetic features on the risk and clinical outcomes of EC was analyzed. The prognostic value of hsa-miR-17 and hsa-miR-20a in EC patients was assessed using the Kaplan-Meier plotter database. The results showed that a significant decrease in risk of EC with rs9588884 (GG vs CC: OR = 0.49, 95% CI = 0.32-0.78, P = .002; G vs C: OR = 0.75, 95% CI = 0.62-0.91, P = .005, respectively). Similarly, association was found between rs982873 and a decreased risk of EC (CC vs TT: OR = 0.53, 95% CI = 0.34-0.82, P = .004; C vs T: OR = 0.77, 95% CI = 0.63-0.94, P = .010, respectively). Moreover, survival analysis showed that the CG or GG genotype of rs9588884 may significantly increase overall survival (OS) compared with the CC genotype in the 5-year follow-up (HR = 0.49, 95% CI = 0.29-0.82 and HR = 0.36, 95% CI = 0.16-0.83, respectively). RT-qPCR results showed that the expression level of miR-17-92 mRNA in EC tissues with the rs9588884 GG genotype was significantly lower than those with the GC + CC genotype (P = .030). However, there was no significant difference in the prognosis and expression level of miR-17-92mRNA in tissues of EC patients with different genotypes of rs982873 (P = .343). In addition, analysis using Kaplan-Meier plotter database showed that high hsa-miR-20a expression was significantly correlated with poor OS in EC patients (HR = 1.63, 95% CI = 1.02-2.61, P = .039). The genetic polymorphisms rs9588884 and rs982873 in the promoter of miR-17-92 cluster decreased EC risk. Both rs9588884 and the expression level of hsa-miR-20a mRNA may be associated with its clinical outcome in EC patients.

Associations between novel anthropometric indices and the prevalence of gallstones among 6,848 adults: a cross-sectional study.

Background: Traditional anthropometric measures, including body mass index (BMI), are insufficient for evaluating gallstone risk. This study investigated the association between novel anthropometric indices and gallstone risk among 6,848 participants from the National Health and Nutrition Examination Survey in the United States. Methods: Measures calculated included weight (WT), BMI, waist circumference (WC), waist-to-height ratio (WtHR), conicity index (CI), A Body Shape Index (ABSI), Body Roundness Index (BRI), Abdominal Volume Index (AVI), and Weight-adjusted Waist Index (WWI). Logistic regression and smooth curve fitting assessed the relationships between these indices and gallstones, complemented by receiver operating characteristic (ROC) curve analysis to evaluate their discriminative power. Results: The results indicated significant differences between study groups, with a positive and independent correlation identified between gallstones and all measures except ABSI. Specifically, per 1 SD increase in WC, WT, BMI, WtHR, and AVI was associated with a 57%, 59%, 52%, 53%, and 53% increased risk of gallstones, respectively. Dose-response analysis confirmed a positive correlation between these indices and gallstone risk. ROC analysis highlighted WtHR and BRI as having superior discriminative abilities (AUC = 0.6703). Further, among participants with a BMI < 30 kg/m2, elevated levels of WT, WtHR, CI, BRI, and WWI significantly increased the risk of gallstones (P < 0.001). Likewise, elevated BMI heightened the risk at low levels of WT, WC, WtHR, BRI, AVI, and CI (P < 0.001). Conclusion: This study supports the positive association between various anthropometric indicators and gallstones, recommending that newer anthropometric indices be considered more extensively to enhance gallstone prevention and treatment strategies.

An artificial intelligence grading system of apical periodontitis in cone-beam computed tomography data.

OBJECTIVES: In order to assist junior doctors in better diagnosing apical periodontitis (AP), an artificial intelligence AP grading system was developed based on deep learning (DL) and its reliability and accuracy were evaluated. METHODS: One hundred and twenty cone-beam computed tomography (CBCT) images were selected to construct a classification dataset with four categories, which were divided by CBCT periapical index (CBCTPAI), including normal periapical tissue, CBCTPAI 1-2, CBCTPAI 3-5, and young permanent teeth. Three classic algorithms (ResNet50/101/152) as well as one self-invented algorithm (PAINet) were compared with each other. PAINet were also compared with two recent Transformer-based models and three attention models. Their performance was evaluated by accuracy, precision, recall, balanced F score (F1-score), and the area under the macro-average receiver operating curve (AUC). Reliability was evaluated by Cohen's kappa to compare the consistency of model predicted labels with expert opinions. RESULTS: PAINet performed best among the four algorithms. The accuracy, precision, recall, F1-score, and AUC on the test set were 0.9333, 0.9415, 0.9333, 0.9336, and 0.9972, respectively. Cohen's kappa was 0.911, which represented almost perfect consistency. CONCLUSIONS: PAINet can accurately distinguish between normal periapical tissues, CBCTPAI 1-2, CBCTPAI 3-5, and young permanent teeth. Its results were highly consistent with expert opinions. It can help junior doctors diagnose and score AP, reducing the burden. It can also be promoted in areas where experts are lacking to provide professional diagnostic opinions.

Traditional Use, Phytochemistry, Pharmacology, Toxicology and Clinical Applications of Persicae Semen: A Review.

Persicae Semen (Taoren), the seed of mature peaches consumed as both food and medicine, is native to the temperate regions of China, distributed in the provinces of North and East China, and currently cultivated worldwide. The primary components of Persicae Semen include volatile oil, protein, amino acids, amygdalin, and prunasin, all of which have pharmacological properties, such as anti-inflammatory, antioxidant, and immune regulatory effects, and are clinically used in the treatment of gynecological, cardiovascular, cerebrovascular, orthopedic, and digestive system diseases. This review provides a comprehensive perspective on the resource status, ethnopharmacology, phytochemistry, pharmacology, and toxicology, as well as the trend of Persicae Semen patent, global distribution, and clinical applications. This review will help facilitate the development and utilization of Persicae Semen in clinical settings.

Effect of Rab18 on liver injury and lipid accumulation by regulating perilipin 2 and peroxisome proliferator-activated receptor gamma in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common chronic liver diseases worldwide, characterized by the presence of lipid droplets. Rab18 is an important lipid droplet protein; however, its effects and mechanisms of action on NAFLD remain unclear. METHODS: Free fatty acid-stimulated AML-12 cells and high-fat diet (HFD)-fed mice were used as NAFLD models. Lentiviruses overexpressing Rab18 (Rab18-OE) or knockdown (Rab18-KD) were used to generate stable cell lines for genetic analysis. Blood serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glucose, and leptin were measured using a biochemical autoanalyzer. Hematoxylin and eosin staining was performed to detect pathological damage to the liver. Lipid accumulation in the cells was assessed by Oil Red O staining. Target expression was measured using qPCR, western blotting, and immunocytochemistry. RESULTS: Rab18 mRNA and protein expression levels increased in free fatty acid-stimulated AML-12 cells and the livers of HFD-fed mice. Rab18-OE increased lipid accumulation in vitro, which was attenuated by Rab18-KD. In vivo, Rab18-OE augmented liver pathological damage, serum alanine aminotransferase/aspartate aminotransferase activity, and triglyceride, total cholesterol, and low-density lipoprotein levels, whereas Rab18-KD decreased these indicators. Rab18-KD also downregulated blood glucose levels in HFD-fed mice. Mechanistically, Rab18-OE and Rab18-KD regulated the mRNA and protein expression levels of perilipin 2 (PLIN2) and peroxisome proliferator-activated receptor gamma (PPARγ) in vitro and in vivo, respectively. Immunocytochemistry revealed that Rab18 colocalized with PLIN2 and PPARγ in AML-12 cells. CONCLUSION: Rab18 expression was elevated in vitro and in vivo in the NAFLD mouse model. Rab18 regulates PLIN2 and PPARγ expression to exaggerate liver injury and lipid accumulation in patients with NAFLD. Thus, Rab18 may be a crucial protein in this disease and a potential therapeutic target.

Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Associations of life's essential 8 with MAFLD and liver fibrosis among US adults: a nationwide cross-section study.

Background: Life's essential' 8 (LE8) is a newly updated cardiovascular health (CVH) metrics from the American Heart Association, with close relevance to metabolism. Our objective is to explore the association between LE8 scores and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced liver fibrosis in American adults. Methods: This population-based cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2018, encompassing adults aged 20 years or older. Validated non-invasive scoring systems were employed to define liver steatosis and advanced liver fibrosis. Multivariable logistic regression and smooth curve fitting techniques were applied to evaluate the associations. All analyses were adjusted for the survey' complex design parameters and accounted for sample weights. Results: A total of 11,820 participants were included. A higher LE8 score was found to be inversely associated with the incidence of MAFLD and advanced liver fibrosis, with odds ratios (OR) of 0.64 (95% CI: 0.57-0.71) for MAFLD and 0.75 (95% CI: 0.61-0.92) for advanced liver fibrosis per 1 standard deviation (SD) increase in LE8 score. Similar patterns were found in the relationship between health behaviors/factors score and incidence of MAFLD and advanced liver fibrosis. In subgroup analyses, the interaction test showed that age, education level, marital status, CVD, hypertension and diabetes had a significant impact on the association between LE8 score and MAFLD (all P for interaction < 0.05). Among male, elderly, wealthy, other race, CVD, diabetes and depression participants, the correlation between LE8 score and advanced liver fibrosis was not statistically significant (P > 0.05). Younger participants exhibited a more pronounced negative association between the CVH metric and both MAFLD and advanced life fibrosis. Conclusion: LE8 and its subscales score were inversely associated with the presence of MAFLD and advanced liver fibrosis in non-linear patterns. Optimal LE8 score may significantly reduce the risk of liver steatosis and fibrosis.

Development and validation of a novel therapeutic drug monitoring-based nomogram for prediction of primary endoscopic response to anti-TNF therapy in active Crohn's disease.

Background: Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. Objectives: To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Design: Cross-sectional study. Methods: The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. Results: The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 µg/mL) and ADA (8.80 µg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. Conclusion: This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.

Therapeutic drug monitoring-based nomogram predicts primary endoscopic response in Crohn's disease The present study established a therapeutic drug monitoring-based nomogram, which exhibits an exceptional predictive value, remarkable accuracy, and discrimination. This algorithmic nomogram holds the potential to enhance clinicians' comprehension of the underlying mechanisms contributing to individual patients' failure in achieving expected efficacy. Such approach is crucial for optimizing therapy options and facilitating biologic switching in refractory Crohn's disease.

Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China.

BACKGROUND: Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients. METHODS: We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People's Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs . persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. RESULTS: We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1 , X 2 , and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P  <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P  <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. CONCLUSIONS: ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC. REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer.

Advanced colorectal cancer (CRC) is characterized by a high recurrence and metastasis rate, which is the primary cause of patient mortality. Unfortunately, effective anti-cancer drugs for CRC are still lacking in clinical practice. We screened FDA-approved drugs by utilizing targeted organoid sequencing data and found that the antifungal drug itraconazole had a potential therapeutic effect on CRC tumors. However, the effect and mechanism of itraconazole on CRC tumors have not been investigated. A cell line-derived xenograft model in tumor-bearing mice was established and single-cell RNA sequencing was performed on tumor samples from four mice with or without itraconazole treatment. The proportion of cell populations and gene expression profiles was significantly different between the two groups. We found that itraconazole could inhibit tumor growth and glycolysis. We revealed that CEBPB was a new target for itraconazole, and that silencing CEBPB could repress CRC glycolysis and tumor growth by inhibiting ENO1 expression. Clinical analysis showed that CEBPB expression was obviously elevated in CRC patients, and was associated with poor survival. In summary, itraconazole treatment remodeled cell composition and gene expression profiles. Itraconazole inhibited cell glycolysis and tumor growth via the CEBPB-ENO1 axis. In this study, we illustrate a new energy metabolism mechanism for itraconazole on tumor growth in CRC that will provide a theoretical basis for CRC targeting/combination therapy.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Comprehensive pan-cancer analysis reveals CCDC58 as a carcinogenic factor related to immune infiltration.

CCDC58, a member of the CCDC protein family, has been primarily associated with the malignant progression of hepatocellular carcinoma (HCC) and breast cancer, with limited research conducted on its involvement in other tumor types. We aimed to assess the significance of CCDC58 in pan-cancer. We utilized the TCGA, GTEx, and UALCAN databases to perform the differential expression of CCDC58 at both mRNA and protein levels. Prognostic value was evaluated through univariate Cox regression and Kaplan-Meier methods. Mutation and methylation analyses were conducted using the cBioPortal and SMART databases. We identified genes interacting with and correlated to CCDC58 through STRING and GEPIA2, respectively. Subsequently, we performed GO and KEGG enrichment analyses. To gain insights into the functional status of CCDC58 at the single-cell level, we utilized CancerSEA. We explored the correlation between CCDC58 and immune infiltration as well as immunotherapy using the ESTIMATE package, TIMER2.0, TISIDB, TIDE, TIMSO, and TCIA. We examined the relationship between CCDC58 and tumor heterogeneity, stemness, DNA methyltransferases, and MMR genes. Lastly, we constructed a nomogram based on CCDC58 in HCC and investigated its association with drug sensitivity. CCDC58 expression was significantly upregulated and correlated with poor prognosis across various tumor types. The mutation frequency of CCDC58 was found to be increased in 25 tumors. We observed a negative correlation between CCDC58 expression and the methylation sites in the majority of tumors. CCDC58 showed negative correlations with immune and stromal scores, as well as with NK T cells, Tregs, CAFs, endothelial cells, and immunomodulators. Its value in immunotherapy was comparable to that of tumor mutational burden. CCDC58 exhibited positive correlations with tumor heterogeneity, stemness, DNA methyltransferase genes, and MMR genes. In HCC, CCDC58 was identified as an independent risk factor and demonstrated potential associations with multiple drugs. CCDC58 demonstrates significant clinical value as a prognostic marker and indicator of immune response across various tumor types. Its comprehensive analysis provides insights into its potential implications in pan-cancer research.

Global status of research on gastrointestinal cancer patients' quality of life: A bibliometric and visual analysis from 2003 to 2023.

Objective: To analyze the current research status, hotspots, and frontiers in the field of Gastrointestinal (GI) cancer and quality of life (QoL) through the bibliometrics method, and to provide references and guidance for future research. Methods: Literature related to GI cancer and QoL from April 1, 2003 to March 31, 2023 was retrieved from the Web of Science Core Collection database. CiteSpace 6.2.R1 was performed for collaboration analysis, keyword co-occurrence analysis, and document co-citation analysis. Results: A total of 1224 publications were included in this study. There has been a significant increase in the number of publications in this field over the past two decades. The United States, the Karolinska Institute and the University of Amsterdam, and Pernilla Lagergren are the most prolific country, institution, and author, respectively. The links between most of the research constituents were relatively thin (centrality <0.1). The keyword analysis indicates that the benefits of physical activity on QoL, the levels of psychological distress and its relationship with QoL, as well as the development and validation of QoL measurement tools have been the research hotspots. Open-label/double-blind trials exploring therapeutic interventions and more targeted new drugs or more effective drug combinations, and longitudinal studies determining the direction of the association between psychological distress and QoL at different time points, may be emerging trends in this field. Conclusion: The cooperation among countries, institutions, and authors in this field should be strengthened. In addition, the health benefits of light physical activity, interventions for QoL, trajectory and direction of the relationship between psychological distress and QoL may be the focus of future research.

Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease.

Intestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment of a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated mice with IEC-specific deletion of Gpr65 (Gpr65ΔIEC) and investigated the role of epithelial GPR65 using DSS- and C. rodentium-induced murine colitis models. RNA sequencing analysis was conducted on colonic IECs from Gpr65fl/fl and Gpr65ΔIEC mice, and colonoids and colonic epithelial cell lines were used to evaluate the pH-sensing effect of GPR65. The expression of GPR65 was determined in IECs from patients with inflammatory bowel disease (IBD) and DSS colitis mice by qRT-PCR, Western blot, and immunohistochemistry, respectively. We observed that the absence of GPR65 in IECs abrogated homeostatic antimicrobial programs, including the production of antimicrobial peptides (AMPs) and defense response-associated proteins. Gpr65ΔIEC mice displayed dysbiosis of the gut microbiota and were prone to DSS- and C. rodentium-induced colitis, as characterized by significantly disrupted epithelial antimicrobial responses, pathogen invasion, and increased inflammatory infiltrates in the inflamed colon. RNA sequencing analysis revealed that deletion of GPR65 in IECs provoked dramatic transcriptome changes with respect to the downregulation of immune and defense responses to bacteria. Forced AMP induction assays conducted in vivo or in ex vivo colonoids revealed that IEC-intrinsic GPR65 signaling drove antimicrobial defense. Mechanistically, GPR65 signaling promoted STAT3 phosphorylation to optimize mucosal defense responses. Epithelial cell line and colonoid assays further confirmed that epithelial GPR65 sensing pH synergized with IL-22 to facilitate antimicrobial responses. Finally, the expression of GPR65 was markedly decreased in the inflamed epithelia of IBD patients and DSS colitis mice. Our findings define an important role of epithelial GPR65 in regulating intestinal homeostasis and mucosal inflammation and point toward a potential therapeutic approach by targeting GPR65 in the treatment of IBD.

Characterization of stem cell subtypes and prognostic signature in hepatocellular carcinoma.

BACKGROUND: Cancer stem cells (CSCs) were linked to cancer aggressiveness and poor prognosis in patients with hepatocellular carcinoma (HCC). METHODS: We integrated two external HCC cohorts to develop the stem cell subtypes according to unsupervised clustering with 26 stem cell gene sets. Between the subtypes, differences in prognosis, clinical characteristics, recognized HCC subtypes, metabolic profile, immune-related features, somatic mutation, and drug sensitivity were examined. The prognostic signature was created, and validated by numerous cohorts, and used to assess the efficacy of immunotherapy and transcatheter arterial chemoembolization (TACE) treatment. The nomogram was developed based on the signature and clinical features. We further examined the function of KIF20A in HCC and proved that KIF20A had the potential to regulate the stemness of HCC cells through western blot. RESULTS: Low stem cell patterns, a good prognosis, positive clinical features, specific molecular subtypes, low metastatic characteristics, and an abundance of metabolic and immunological aspects were associated with Cluster 1, whereas Cluster 2 was the reverse. Chemotherapy and immunotherapy were more effective in Cluster 1. Cluster 1 and CTNNB1 and ALB mutation were more closely. Additionally, the prognosis, immunotherapeutic, and TACE therapy responses were all worse in the high-risk group. The nomogram could predict the survival probability of HCC patients. KIF20A was discovered to be overexpressed in HCC and was revealed to be connected to the stemness of the HepG2 cell line. CONCLUSIONS: Two stem cell subgroups with different prognoses, metabolic, and immunological characteristics in HCC patients were identified. We also created a 7-gene prognostic signature and a nomogram to estimate the survival probability. The function of KIF20A in HCC stemness was initially examined.

Quantitative evaluation of artifact expression in conebeam computed tomography of mesoporous calcium silicate nanoparticles as a promising root canal sealer.

OBJECTIVES: We aimed to quantitatively compare the area and volume of artifacts in cone beam computed tomography produced by mesoporous calcium silicate nanoparticles (MCSNs), AH Plus sealer, and iRoot SP sealer when used as root canal sealers. METHODS: We prepared 40 single-rooted mandibular premolars and divided them into an MCSN sealer group, an AH Plus sealer group, an iRoot SP sealer group, and a no-sealer (control) group. We filled the canals with gutta-percha using the single-cone method and subjected them to conebeam computed tomography before and after the placement of root fillings using the same exposure parameters. We evaluated the images to quantify the areas of hyperdense and hypodense artifacts and non-affected teeth and reconstructed 3-dimensional image models of the materials to study volume distortion artifacts. RESULTS: The MCSN sealer group produced a significantly smaller hyperdense and volume distortion artifacts than the AH Plus and iRoot SP groups (P < .01), but the area and volume of hypodense artifacts did not differ significantly among the groups (P > .05). CONCLUSIONS: When used as a root canal sealer, MCSNs generate a significantly smaller area and volume of hyperdense artifacts than AH Plus and iRoot SP sealers. By significantly reducing the generation of high-density artifacts, MCSNs may facilitate the evaluation of root canal filling quality and the diagnosis of root canal abnormalities.

Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker.

Lipoylated dihydrolipoamide S-acetyltransferase (DLAT), the component E2 of the multi-enzyme pyruvate dehydrogenase complex, is one of the key molecules of cuproptosis. However, the prognostic value and immunological role of DLAT in pan-cancer are still unclear. Using a series of bioinformatics approaches, we studied combined data from different databases, including the Cancer Genome Atlas, Genotype Tissue-Expression, the Cancer Cell Line Encyclopedia, Human Protein Atlas, and cBioPortal to investigate the role of DLAT expression in prognosis and tumor immunity response. We also reveal the potential correlations between DLAT expression and gene alterations, DNA methylation, copy number variation (CNV), tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune infiltration levels, and various immune-related genes across different cancers. The results show that DLAT displays abnormal expression within most malignant tumors. Through gene set enrichment analysis (GSEA), we found that DLAT was significantly associated with immune-related pathways. Further, the expression of DLAT was also confirmed to be correlated with the tumor microenvironment and diverse infiltration of immune cells, especially tumor-associated macrophages (TAMs). In addition, we found that DLAT is co-expressed with genes encoding major histocompatibility complex (MHC), immunostimulators, immune inhibitors, chemokines, and chemokine receptors. Meanwhile, we demonstrate that DLAT expression is correlated with TMB in 10 cancers and MSI in 11 cancers. Our study reveals that DLAT plays an essential role in tumorigenesis and cancer immunity, which may be used to function as a prognostic biomarker and potential target for cancer immunotherapy.

Improving bowel preparation for colonoscopy with a smartphone application driven by artificial intelligence.

Optimal bowel preparation is a prerequisite for a successful colonoscopy; however, the rate of inadequate bowel preparation remains relatively high. In this study, we establish a smartphone app that assesses patient bowel preparation using an artificial intelligence (AI)-based prediction system trained on labeled photographs of feces in the toilet and evaluate its impact on bowel preparation quality in colonoscopy outpatients. We conduct a prospective, single-masked, multicenter randomized clinical trial, enrolling outpatients who own a smartphone and are scheduled for a colonoscopy. We screen 578 eligible patients and randomize 524 in a 1:1 ratio to the control or AI-driven app group for bowel preparation. The study endpoints are the percentage of patients with adequate bowel preparation and the total BBPS score, compliance with dietary restrictions and purgative instructions, polyp detection rate, and adenoma detection rate (secondary). The prediction system has an accuracy of 95.15%, a specificity of 97.25%, and an area under the curve of 0.98 in the test dataset. In the full analysis set (n = 500), adequate preparation is significantly higher in the AI-driven app group (88.54 vs. 65.59%; P < 0.001). The mean BBPS score is 6.74 ± 1.25 in the AI-driven app group and 5.97 ± 1.81 in the control group (P < 0.001). The rates of compliance with dietary restrictions (93.68 vs. 83.81%, P = 0.001) and purgative instructions (96.05 vs. 84.62%, P < 0.001) are significantly higher in the AI-driven app group, as is the rate of additional purgative intake (26.88 vs. 17.41%, P = 0.011). Thus, our AI-driven smartphone app significantly improves the quality of bowel preparation and patient compliance.

Plantations thinning: A meta-analysis of consequences for soil properties and microbial functions.

Thinning is a widely-used management practice to reduce tree competition and improve wood production and quality in forest plantations. Thinning affects the soil ecosystem by changing the microclimate and plant growth, as well as litter inputs above and belowground, with all the resulting consequences for microbial communities and functions. Although many case studies have been carried out, a comprehensive understanding of the thinning effects on soil properties and microbial communities and functions in plantations remains to be explored. In this study, a meta-analysis was performed on 533 paired observations based on 90 peer-reviewed articles to evaluate the general responses of soil (mainly 0-20 cm depth) physicochemical properties, microbial biomass and community structure, and enzyme activities to thinning. Results showed that thinning increased soil temperature (13 %), moisture (8.0 %), electric conductivity (13 %), and the contents of total nitrogen (TN, 4.1 %), dissolved organic carbon (DOC, 9.7 %), nitrate N (NO3--N, 27 %) and available phosphorous (22 %). For microbial properties, thinning decreased the fungi to bacteria ratio (F:B, -28 %) and the gram-positive bacteria to gram-negative bacteria ratio (G+:G-, -12 %), while increased microbial biomass C (7.1 %), microbial respiration (13 %), and nutrient-cycle related enzyme activities, including phenol oxidase (14 %), cellobiohydrolase (21 %), urease (10 %), and acid phosphatase (9 %). In particular, moderate thinning (30-60 % intensity) has higher conservation benefits for soil C and nutrients than light and heavy intensity, thus being recommended as the optimal thinning activity. This meta-analysis suggests that thinning consistently altered soil properties, shifted microbial community compositions from K- to-r strategist dominance, and stimulated microbial activities. These results are essential for optimizing plantation thinning management and provide evidence for applying the macro-ecology theory to ecosystem disturbance in soil microbial ecology.