Predicting early gastric cancer risk using machine learning: A population-based retrospective study.

Background: Early detection and treatment are crucial for reducing gastrointestinal tumour-related mortality. The diagnostic efficiency of the most commonly used diagnostic markers for gastric cancer (GC) is not very high. A single laboratory test cannot meet the requirements of early screening, and machine learning methods are needed to aid the early diagnosis of GC by combining multiple indicators. Methods: Based on the XGBoost algorithm, a new model was developed to distinguish between GC and precancerous lesions in newly admitted patients between 2018 and 2023 using multiple laboratory tests. We evaluated the ability of the prediction score derived from this model to predict early GC. In addition, we investigated the efficacy of the model in correctly screening for GC given negative protein tumour marker results. Results: The XHGC20 model constructed using the XGBoost algorithm could distinguish GC from precancerous disease well (area under the receiver operating characteristic curve [AUC] = 0.901), with a sensitivity, specificity and cut-off value of 0.830, 0.806 and 0.265, respectively. The prediction score was very effective in the diagnosis of early GC. When the cut-off value was 0.27, and the AUC was 0.888, the sensitivity and specificity were 0.797 and 0.807, respectively. The model was also effective at evaluating GC given negative conventional markers (AUC = 0.970), with the sensitivity and specificity of 0.941 and 0.906, respectively, which helped to reduce the rate of missed diagnoses. Conclusions: The XHGC20 model established by the XGBoost algorithm integrates information from 20 clinical laboratory tests and can aid in the early screening of GC, providing a useful new method for auxiliary laboratory diagnosis.

LINC00355 promotes gastric carcinogenesis by scaffolding p300 to activate CDC42 transcription and enhancing HNRNPA2B1 to stabilize CDC42 mRNA dependent on m6A.

LINC00355 is involved in the tumorigenesis of several types of cancer. We verified that LINC00355 is upregulated in gastric cancer (GC) and contributes to GC cells' proliferation and metastasis. RNA sequencing (RNA-seq) and rescue assays suggested that LINC00355 controls gastric carcinogenesis by regulating the expression of cell division cycle 42 (CDC42) guanosine triphosphatase (GTPases), thereby activating their downstream pathways. Most previous studies have shown that LINC00355 acts as a ceRNA by sponging miRNAs to modulate downstream gene expression. Our group focus on epigenetic regulatory potential of LINC00355 in gene expression. Mechanistically, LINC00355 binds to p300 histone acetyltransferase, specifying the histone modification pattern on the CDC42 promoter to activate CDC42 transcription, thereby altering GC cell biology. In addition, HNRNPA2B1, which is upregulated by LINC00355, recognizes the N6-methyladenosine (m6A) sites of CDC42 and enhances the stability of CDC42 mRNA transcripts. Therefore, LINC00355 is mechanistically, functionally, and clinically oncogenic in GC cells.

Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway.

PURPOSE: Considerable evidence suggests that tumor cells with stemness features contribute to initiation, progression, recurrence of gastric cancer (GC) and resistance to therapy, but involvement of underlying regulators and mechanisms remain largely unclear. However, the clinical significance and biological function of Notum in GC tumor sphere formation and tumorigenesis remain unclear. METHODS: Bioinformatics analysis, RT-qPCR, western blot and imunohistochemistry staining were applied to characterize Notum expression in GC specimens. The early diagnostic value of Notum was analyzed by logistic regression analysis method. Cancer stemness assays were used in Notum knockdown and overexpressing cells in vitro and in vivo. RNA-seq was employed to reveal the downstream effectors of Notum. RESULTS: Notum is highly expressed in early stage of GC patients and stem-like GC cells. For discriminating the early-stage and advanced GC patients, the joint analysis had a better diagnostic value. Overexpression of Notum markedly increased stemness features of GC cells to promote tumor sphere formation and tumorigenesis. Conversely, Notum knockdown attenuated the stem-like cell properties in vitro and in vivo. Mechanically, Notum upregulates Sox2 through activating the PI3K/AKT signaling pathway. Notum inhibitor Caffeine exhibited a potent inhibitory effect on stemness features by impairing the PI3K/AKT signaling pathway activity and targeting Sox2. CONCLUSION: Our findings confer a comprehensive and mechanistic function of Notum in GC tumor sphere formation and tumorigenesis that may provide a novel and promising target for early diagnosis and clinical therapy of GC.

Urinary exosomal long non-coding RNAs as noninvasive biomarkers for diagnosis of bladder cancer by RNA sequencing.

Introduction: Cystoscopy is the standard methodology for diagnosis of bladder cancer (BC), but it is invasive and relatively expensive. Previous studies have found that urinary exosomal long non-coding RNAs (lncRNAs) may act as potential noninvasive biomarkers for diagnosis. Here we identified urinary exosomal lncRNAs that are differentially expressed between BC and controls, and established a panel for diagnosis of BC. Methods: We performed RNA sequencing in urinary exosomes of 7 controls and 7 patients, subsequently the differentially expressed lncRNAs were detected in training cohort (50 controls and 50 patients) and validation cohort (43 controls and 43 patients). The diagnostic power of lncRNAs for BC was calculated by the area under curve (AUC). The panel for diagnosis of BC was calculated by logistic regression. Results: The results of RNA sequencing in urinary exosomes showed that 240 upregulated lncRNAs and 275 downregulated lncRNAs were differentially expressed. The levels of MKLN1-AS, TALAM1, TTN-AS1 and UCA1 in BC patients were higher than that in controls in the training and validation cohort by real-time PCR. Using logistic regression, with the combination of these four lncRNAs and NMP22, we identified a panel of five parameters capable of classifying BC patients versus controls on the basis of the training cohort (AUC=0.850). Moreover, the performance of the panel exhibited better performance than either single parameter in the validation cohort. Conclusion: Collectively, this study confirmed the diagnostic value of lncRNAs for BC by high-throughout urinary exosomal RNA sequencing.

BACH2 regulates the function of human CD4+ CD45RA- Foxp3l ° cytokine-secreting T cells and promotes B-cell response in systemic lupus erythematosus.

Although CD4+ CD45RA- Foxp3l ° cytokine-secreting T cells (Fr.III cells) have been reported to be increased in systemic lupus erythematosus (SLE), their function and effects on response of B cells are still unclear. Here, we dissect how BACH2 regulates Fr.III cells function and promotes B-cell response in active SLE patients. We measured cytokines and BACH2 expression, and found that Fr.III cells from SLE patients produce much more inflammatory cytokines and were more able to promote B- cell proliferation, IgG, IgA, and TNF-α production than controls in a co-culture system. Fr.III cells expressed high levels of ICOS and CD154, but a low level of Tfr and BACH2, BACH2 expression was negatively correlated with SLE Disease Activity Index. Overexpressed of BACH2 in Fr.III cells, decreased cytokines expression and reduced B-cell response. Furthermore, we identified a reduction of H3K27ac level binding at the BACH2 locus in the SLE Fr.III cells and SLE serum stimulation decreased H3K27ac binding at the BACH2 locus, which could be restored using trichostatin A (TSA). In conclusion, BACH2 was associated with SLE disease activity, regulated the function of Fr.III cells, and promoted B-cells response. Targeting BACH2 may be a new immune intervention therapy of SLE.

Prognostic value of YKL-40 in solid tumors: a meta-analysis of 41 cohort studies.

BACKGROUND: Serum/plasma YKL-40 can be a useful index that is associated with tumor development. However, the prognostic value of serum/plasma YKL-40 in patients with solid tumors is still unclear. We aimed to utilize the existing literature to investigate the prognostic value of serum/plasma YKL-40 in solid tumors. METHODS: An extensive literature search for relevant studies was conducted with the Embase, Medline and Web of Science databases. The effect on survival was measured with the hazard ratio (HR). Then, pooled HRs and 95% confidence intervals (CIs) were calculated using the random and fixed-effects models according to the heterogeneity of the included studies. RESULTS: This meta-analysis was based on 41 publications and comprised a total of 7762 patients with solid tumors. The pooled HR showed that elevated serum/plasma YKL-40 was significantly associated with poor OS (HR, 1.44; 95% CI 1.33-1.56). We also found that elevated serum/plasma YKL-40 had significant prognostic effects on OS in various cancer subgroups such as gastrointestinal tumors (HR, 1.37; 95% CI 1.18-1.58), ovarian cancer (HR, 2.27; 95% CI 1.69-3.06), melanoma (HR, 1.77; 95% CI 1.18-2.67), lung cancer (HR, 1.73; 95% CI 1.35-2.23), urologic neoplasms (HR, 1.61; 95% CI 1.08-2.40) and glioblastoma (HR, 1.23; 95% CI 1.07-1.42); in contrast, the prognostic effect of serum/plasma YKL-40 was not statistically significant in breast cancer (HR, 1.07; 95% CI 0.98-1.17). CONCLUSIONS: The available evidence supports the hypothesis that elevated serum/plasma YKL-40 is associated with poor survival in patients with solid tumors and that serum/plasma YKL-40 may serve as a novel prognostic biomarker.

OGTT 1h serum C-peptide to plasma glucose concentration ratio is more related to beta cell function and diabetes mellitus.

OBJECTIVE: To clarify the association between C-peptide index and pancreatic beta cell function and diabetes. MATERIALS AND METHODS: We carried out a retrospective analysis of 1021 patients aged 27 to 80 without diabetes from January 2012 to January 2016. All subjects underwent a 75-g oral glucose tolerance test. Blood samples were drawn at 0, 30, 60, 120 and 180 min after the glucose load. Plasma glucose concentrations, serum insulin levels, C-peptide levels, hemoglobin A1c (HbA1c), and other biochemical indicators were determined. C-peptide index was calculated as the ratio of C-peptide to plasma glucose. Disposition index was calculated as the result of the insulin sensitivity × insulin secretion. Area under the receiver operating characteristic curve was used to compare the diagnostic ability of C-peptide index for type 2 diabetes. RESULTS: C-peptide index 1h was the most related one to disposition index (r = 647, p<0.001) and C-peptide release (r = 0.879, p<0.001). Both C-peptide index 1h (Exp(ß) = 0.28, p<0.001) and 2h (Exp(ß) = 0.42, p<0.001) were independently associated with disposition index, but the OR of C-peptide index 1h for diabetes was much lower. Area under the receiver operating characteristic curve of both C-peptide index 1h and 2h were all above 0.9, but the area of C-peptide index 1h was the highest one (0.937 vs 0.917). C-peptide index 1h has the highest diagnostic value (sensitivity = 90%, specificy = 85.2% vs sensitivity = 83.5%, specificy = 87.9%). CONCLUSION: C-peptide index after oral glucose ingestion may reflect the maximal ß-cell function and is more related to diabetes. C-peptide index 1h is the most relevant one.

miR-155 Regulates IL-10-Producing CD24hiCD27+ B Cells and Impairs Their Function in Patients with Crohn's Disease.

Regulatory interleukin-10 (IL-10)-producing B cells (B10 cells) play a critical role in preventing and curing autoimmune diseases in experimental mouse models. However, the precise cellular and molecular mechanisms of action of B10 cells in humans, especially in patients with Crohn's disease (CD), remain to be determined. miR-155 regulates many physiological and pathological conditions, including inflammation such as that in CD. In this study, we aimed to explore the effect of miRNA-155 on IL-10 production by B cells in healthy controls (HCs) and CD patients. Interestingly, we found that CD24hiCD27+ B cells express high levels of miRNA-155 and IL-10, which are positively correlated. Additionally, CD24hiCD27+ B cells express higher levels of Toll-like receptor 9 than those found in other B cell subsets. Overexpression of miRNA-155 promotes IL-10 production, while inhibition of miRNA-155 decreases IL-10 production. We determined that miR-155 directly inhibits the expression of Jarid2, which reduces H3K27me3 binding to the IL10 promoter and increases IL-10 gene expression. In coculture systems, the CD24hiCD27+ B cells from HCs suppressed the secretion of TNFα and IFNγ by monocytes and T cells, respectively. However, the number and function of CD24hiCD27+ B cells from CD patients were decreased. Moreover, we found that miR-155 induces CD24hiCD27+ B cells to produce higher levels of TNFα instead of IL-10 in CD patients than in the controls and that the increased number of IL-10+TNFα+ B cells reduces the induction of Foxp3 expression and the inhibition of IFNγ production by CD4+CD25- T cells, as well as TNFα production by monocytes. Our study demonstrates the critical role of miRNA-155 in the regulation of IL-10 production by B cells and reveals the novel molecular mechanism underlying the functional impairment of B10 cells in CD patients. Our study has the potential to drive the development of B10 cell-based strategies to ameliorate disease progression in CD patients.

Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3+ Regulatory T Cells Frequency and Function during the Ulcerative Colitis.

Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFß and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1) expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFα, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC.

Prognostic Value of Circulating Tumor Cells in Ovarian Cancer: A Meta-Analysis.

BACKGROUND: The prognostic value of circulating tumor cells (CTCs) in ovarian cancer has been investigated in previous studies, but the results are controversial. Therefore we performed a meta-analysis to systematically review these data and evaluate the value of CTCs in ovarian cancer. MATERIALS AND METHODS: A literary search for relevant studies was performed on Embase, Medline and Web of Science databases. Then pooled hazard ratios (HRs) for survival with 95% confidence intervals (CIs), subgroup analyses, sensitivity analyses, meta-regression analyses and publication bias were conducted. RESULTS: This meta-analysis is based on 11 publications and comprises a total of 1129 patients. The prognostic value of the CTC status was significant in overall survival (OS) (HR, 1.61;95% CI,1.22-2.13) and progression-free survival (PFS)/disease-free survival (DFS) (HR, 1.44; 95%CI, 1.18-1.75). Furthermore, subgroup analysis revealed that the value of CTC status in OS was significant in "RT-PCR" subgroup (HR, 2.02; 95% CI, 1.34-3.03), whereas it was not significant in "CellSearch" subgroup (HR, 1.15; 95% CI 0.45-2.92) and "other ICC" subgroup (HR, 1.09; 95% CI 0.62-1.90). The presence of CTC was also associated with an increased CA-125 (OR, 4.07; 95%CI, 1.87-8.85). CONCLUSION: Our study demonstrates that CTC status is associated with OS and PFS/DFS in ovarian cancer.