Molecular characterization and clinical relevance of metabolic signature subtypes in gastric cancer.

Metabolic reprogramming dictates tumor molecular attributes and therapeutic potentials. However, the comprehensive metabolic characteristics in gastric cancer (GC) remain obscure. Here, metabolic signature-based clustering analysis identifies three subtypes with distinct molecular and clinical features: MSC1 showed better prognosis and upregulation of the tricarboxylic acid (TCA) cycle and lipid metabolism, combined with frequent TP53 and RHOA mutation; MSC2 had moderate prognosis and elevated nucleotide and amino acid metabolism, enriched by intestinal histology and mismatch repair deficient (dMMR); and MSC3 exhibited poor prognosis and enhanced glycan and energy metabolism, accompanied by diffuse histology and frequent CDH1 mutation. The Shandong Provincial Hospital (SDPH) in-house dataset with matched transcriptomic, metabolomic, and spatial-metabolomic analysis also validated these findings. Further, we constructed the metabolic subtype-related prognosis gene (MSPG) scoring model to quantify the activity of individual tumors and found a positive correlation with cuproptosis signaling. In conclusion, comprehensive recognition of the metabolite signature can enhance the understanding of diversity and heterogeneity in GC.

Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway.

Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms.

Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer.

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin ß1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

Resting heart rate control and prognosis in coronary artery disease patients with hypertension previously treated with bisoprolol: a sub-group analysis of the BISO-CAD study.

BACKGROUND: Resting heart rate (RHR) is considered as a strong predictor of total mortality and hospitalization due to heart failure in hypertension patients. Bisoprolol fumarate, a second-generation beta-adrenoreceptor blockers (ß-blocker) is commonly prescribed drug to manage hypertension. The present study was to retrospectively evaluate changes in the average RHR and its association with cardiovascular outcomes in bisoprolol-treated coronary artery disease (CAD) patients from the CAD treated with bisoprolol (BISO-CAD) study who had comorbid hypertension. METHODS: We performed ad-hoc analysis for hypertension sub-group of the BISO-CAD study (n = 866), which was a phase IV, multination, multi-center, single-arm, observational study carried out from October 2011 to July 2015 across China, South Korea, and Vietnam. Multivariate regression analysis was used to identify factors associated with incidence of composite cardiac clinical outcome (CCCO), the results were presented as adjusted odds ratio (OR) along with 95% confidence interval (CI) and adjusted P value. RESULTS: A total of 681 patients (mean age: 64.77 ± 10.33 years) with hypertension from BISO-CAD study were included in the analysis. Bisoprolol improved CCCOs in CAD patients with comorbid hypertension, with RHR <65 and <70 beats/min compared with RHR ≥65 and ≥75 beats/min, respectively, in the efficacy analysis (EA) set. In addition, it lowered RHR in both intent-to-treat (ITT) and EA groups after 6, 12, and 18 months of treatment. Further, RHR 70 to 74 beats/min resulted in significantly higher risk of CCCOs EA set of patients (adjusted OR: 4.34; 95% CI: 1.19-15.89; P = 0.03). Also, events of hospitalization due to acute coronary syndrome were higher when RHR 69 to 74 beats/min compared to RHR <69 beats/min in ITT patients. CONCLUSION: Bisoprolol can effectively reduce RHR in Asian CAD patients with comorbid hypertension and hence, improve CCCO without affecting their blood pressure.

Hand Grip Strength And Peak Expiratory Flow Among Individuals With Diabetes: Findings From the China Health and Retirement Longitudinal Study Baseline Survey.

The manifestation of muscle dysfunction associated with diabetes is commonly observed in skeletal muscles. The negative effect of hyperglycemia on muscle function is systemic and it may extend to abdominal muscles. Hence, the purpose of this study was to determine whether hand grip strength (HGS), an indicator of peripheral muscle strength, correlates with peak expiratory flow (PEF), which reflects the strength of abdominal muscles, among middle-aged and older Chinese individuals with diabetes. After controlling for all variables except for physical activity, 10 L/min increase in PEF was associated with 0.2 kg increase in HGS (ß = .02, p < .0001). In the model additionally controlling for physical activity, the effect size of PEF on HGS did not change (ß = .02, p < .0001). Our results suggest that among individuals with diabetes, PEF is positively related to HGS. The relationship may suggest a decline in PEF and a weakness of abdominal muscles.

Occurrence of composite cardiac endpoints with change in resting heart rate among Chinese patients with coronary artery disease: Chinese cohort from the real-world BISO-CAD study.

OBJECTIVE: We evaluated change in resting heart rate (RHR) and its impact on prognosis in Chinese coronary artery disease (CAD) patients treated with bisoprolol, and also assessed drug safety and tolerability. METHODS: This phase IV, single arm observational study was a sub-study of the BISO-CAD study conducted across 20 hospitals in China between October 2011 and July 2015 with follow-up at 6, 12 and 18 months after baseline. The primary endpoint was occurrence of composite cardiac events. RESULTS: A total of 663 CAD patients (baseline RHR 75.47 ± 6.62 bpm) were enrolled in the intent-to-treat (ITT) set, and 513 patients were included in the efficacy analysis (EA) set. In the ITT set, the risk and the number of composite cardiac events in patients with mean RHR 69-74 bpm were significantly higher than in the <65 bpm group (ITT: estimate 1.03 ± 0.47, p = .029). The incidence of the composite cardiac endpoint was not affected by continuous mean RHR (p = .5070). RHR significantly decreased from baseline to 18 months, most obviously in the first 6 months (p < .0001). Ejection fraction and fractional shortening significantly improved in both the ITT and EA sets. An average RHR of 69-74 bpm had a significant effect on admission to hospital for acute coronary syndrome in the ITT (estimate 1.10, HR 3.004, p = .0196) and EA (estimate 1.26, HR 3.526, p = .0132) groups. Seven (1.1%) patients reported drug related adverse events. CONCLUSION: Reduction in RHR with bisoprolol lowered the incidence of composite cardiac events along with an acceptable safety and tolerability profile.

Heart rate control is associated with reduced cardiovascular events in Asian patients with coronary artery disease treated with bisoprolol (BISO-CAD): results from a multi-national, real-world experience.

OBJECTIVE: To evaluate the association between decrease in resting heart rate (RHR) and occurrence of composite cardiac clinical outcomes in coronary artery disease (CAD) patients after bisoprolol treatment. METHODS: This phase IV, multi-national, single-arm, open-label, non-randomized, observational trial was conducted between October 2011 and July 2015 across 42 hospitals from China, South Korea and Vietnam. RESULTS: Analysis of 866 patients (mean age 63.85 ± 10.35; mean RHR at baseline 75.71 ± 6.87 bpm in intent-to-treat [ITT]; 75.56 ± 6.73 in efficacy analysis [EA] sets) was performed. Patients with lower mean RHR had fewer composite cardiac events and patients with RHR of 69-74 bpm reported significantly higher outcomes than patients with RHR <65 bpm (p = .0449). A significant association with occurrence of the composite cardiac outcome and hospital admission for unstable angina or revascularization was reported in the EA set (regression estimate: 0.03, 95% CI 0.00-0.07, p = .0412) and not in the ITT set for bisoprolol treated CAD patients. Composite cardiac outcomes significantly increased in patients with mean RHR ≥70 bpm compared to patients with mean RHR <70 bpm (p = .0328). Adverse events (AEs) were reported in 206 (23.8%) patients, of whom 102 (11.8%) patients had serious adverse event (SAEs). Among the patients with SAEs, 11 (1.3%) patients died. Treatment related adverse events were only 12 (1.4%). No treatment related SAE happened. CONCLUSION: The findings showed bisoprolol to be efficacious, in terms of lowering RHR and causing a significant decrease in the occurrence of the composite cardiac outcome, as well as safe in Asian patients with CAD.

Comparative effectiveness of metformin monotherapy in extended release and immediate release formulations for the treatment of type 2 diabetes in treatment-naïve Chinese patients: Analysis of results from the CONSENT trial.

AIMS: Metformin treatment for type 2 diabetes mellitus (T2DM) can be limited by gastrointestinal (GI) adverse events (AEs), resulting in treatment discontinuation. We investigated whether once-daily metformin extended release (XR) is superior in terms of GI tolerability, with non-inferior efficacy, compared with thrice-daily metformin immediate release (IR) in treatment-naïve Chinese patients with T2DM. MATERIALS AND METHODS: This prospective, open-label, randomized, multicentre, phase IV interventional study enrolled Chinese T2DM patients to receive either metformin XR or metformin IR with a 2-week screening period, a 16-week treatment period and a 2-week follow-up period without treatment. Co-primary endpoints were a non-inferiority assessment of metformin XR vs metformin IR in glycated haemoglobin (HbA1c) least squares mean (LSM) change from baseline to week 16 and the superiority of GI tolerability for metformin XR vs metformin IR. RESULTS: Overall, 532 patients were randomized to metformin IR (n = 267) or metformin XR (n = 265). The HbA1c LSM change was -1.61% and -1.58% in each group, respectively (LSM difference, 0.03; 95% confidence interval [CI], -0.10, 0.17). Incidences of drug-related AEs were 26.5% (n = 66) in the metformin IR-only group and 32.2% (n = 85) in the metformin XR-only group, and GI AEs were 23.8% and 22.3% in each group, respectively (difference, -1.52; 95% CI, -8.60, 5.56). The treatment difference met the predefined non-inferiority upper CI margin of 0.4% in HbA1c. CONCLUSIONS: Metformin XR was non-inferior to metformin IR for the LSM change in HbA1c from baseline to week 16 and not superior to metformin IR for overall GI AE incidence during treatment of Chinese T2DM patients.

Comparison of bisoprolol to a metoprolol CR/ZOK tablet for control of heart rate and blood pressure in mild-to-moderate hypertensive patients: the CREATIVE study.

This open-label study investigated the long action of bisoprolol compared with metoprolol CR/ZOK for controlling the mean dynamic heart rate (HR) and blood pressure (BP) in patients with mild-to-moderate primary hypertension. Patients from seven centers in China were treated with either bisoprolol 5 mg or metoprolol CR/ZOK 47.5 mg once daily for 12 weeks. The primary end points were the mean dynamic HR reduction and the mean dynamic diastolic BP (DBP) control in the last 4 h of the treatment period. Secondary end points included ambulatory monitoring of the BP and HR, safety and compliance. A total of 186 patients, with 93 patients in each group, were enrolled and analyzed. In the last 4 h of the treatment period, patients receiving bisoprolol demonstrated a significantly greater reduction in the mean dynamic HR compared with patients receiving metoprolol CR/ZOK (least squares means (LSmeans) of difference: -3.79 b.p.m.; 97.5% confidence interval (CI): -7.45, -0.14; P=0.0202). Furthermore, in the last 4 h of the treatment period, bisoprolol demonstrated non-inferiority vs. metoprolol CR/ZOK in lowering the mean dynamic DBP (LSmeans of difference: -1.00; 97.5% CI: -4.79, 2.78; P=0.5495). Bisoprolol further significantly lowered the 24-h mean ambulatory, mean daytime and mean nighttime HR. The overall adverse event rate was similar between the two groups. Noncompliance was reported in 3 (3.53%) and 6 (7.32%) patients in the bisoprolol and metoprolol CR/ZOK groups, respectively. In conclusion, bisoprolol provided superior dynamic HR reduction and non-inferior dynamic BP reduction vs. metoprolol CR/ZOK in patients with mild-to-moderate hypertension. No new safety concerns were found.

Oral nicorandil reduces ischemic attacks in patients with stable angina: A prospective, multicenter, open-label, randomized, controlled study.

OBJECTIVE: To evaluate the efficacy and safety of oral nicorandil in coronary heart disease (CHD) patients with stable angina. METHOD: Eligible patients were randomized 1:1 to the nicorandil or control group. Current standard antianginal treatment was continued in both groups, while the patients in the nicorandil group received an additional 12-week treatment of nicorandil (5mg thrice daily). Primary endpoint was the number of myocardial ischemia measured by 24h Holter after 12-week treatment. Secondary endpoints included various 24h Holter indicators, angina occurrence, 6-min walking test (6MWT), ECG QT dispersion (QTd), safety and compliance. CLINICAL TRIAL REGISTRATION: NCT01396395. RESULTS: A total of 402 adult patients with stable angina were enrolled. Two hundred patients were randomized to standard therapy plus nicorandil and 202 patients to standard therapy only. The baseline characteristics of the two groups were comparable. The number of myocardial ischemia attacks after treatment was significantly lower in the nicorandil group (LSMEANS 0.896) than the control group (LSMEANS 1.782), with an adjusted ratio of 0.503 (95% CI: 0.301, 0.840; P=0.0086). No significant differences in total myocardial ischemic burden, maximum ST-depression, longest duration of ST-depression, 6MWT, or heart rate variability were noted between the two groups. Twenty three (11.7%) of nicorandil group and 13 (6.3%) patients of control group reported at least one treatment emergent adverse event, respectively. CONCLUSION: Nicorandil significantly reduced the number of ischemic attacks when added to standard antianginal treatment in CHD patients with stable angina. It was well tolerated with no new safety signal identified.