Development and verification of a manganese metabolism- and immune-related genes signature for prediction of prognosis and immune landscape in gastric cancer

BackgroundGastric cancer (GC) poses a global health challenge due to its widespread prevalence and unfavorable prognosis. Although immunotherapy has shown promise in clinical settings, its efficacy remains limited to a minority of GC patients. Manganese, recognized for its role in the body’s anti-tumor immune response, has the potential to enhance the effectiveness of tumor treatment when combined with immune checkpoint inhibitors.MethodsGene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases was utilized to obtain transcriptome information and clinical data for GC. Unsupervised clustering was employed to stratify samples into distinct subtypes. Manganese metabolism- and immune-related genes (MIRGs) were identified in GC by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. We conducted gene set variation analysis, and assessed the immune landscape, drug sensitivity, immunotherapy efficacy, and somatic mutations. The underlying role of NPR3 in GC was further analyzed in the single-cell RNA sequencing data and cellular experiments.ResultsGC patients were classified into four subtypes characterized by significantly different prognoses and tumor microenvironments. Thirteen genes were identified and established as MIRGs, demonstrating exceptional predictive effectiveness in GC patients. Distinct enrichment patterns of molecular functions and pathways were observed among various risk subgroups. Immune infiltration analysis revealed a significantly greater abundance of macrophages and monocytes in the high-risk group. Drug sensitivity analysis identified effective drugs for patients, while patients in the low-risk group could potentially benefit from immunotherapy. NPR3 expression was significantly downregulated in GC tissues. Single-cell RNA sequencing analysis indicated that the expression of NPR3 was distributed in endothelial cells. Cellular experiments demonstrated that NPR3 facilitated the proliferation of GC cells.ConclusionThis is the first study to utilize manganese metabolism- and immune-related genes to identify the prognostic MIRGs for GC. The MIRGs not only reliably predicted the clinical outcome of GC patients but also hold the potential to guide future immunotherapy interventions for these patients

local lemma: a new strategy of pruning in sat solvers

ACM Special Interest Group on Applied Computing (SIGAPP); Hes.so; icare; CUSSTThis paper proposes a search tree pruning strategy for SAT solving. It is called Local Lemma, because it generates lemmas from explored subtrees and these lemmas are valid only in a part of the search tree. The paper explains the basic principle of the strategy, illustrates it with an example, and presents some experimental results. © 2010 ACM

High Neutrophil-to-Lymphocyte Ratio Predicts Cardiovascular Mortality in Chronic Hemodialysis Patients

The neutrophil-to-lymphocyte ratio (NLR) is a novel simple biomarker of inflammation. It has emerged as a predictor of poor prognosis in cancer and cardiovascular disease in general population. But little was known of its prognostic value in chronic hemodialysis (HD) patients. Here we investigated the association between NLR and cardiovascular risk markers, including increased pulse pressure (PP), left ventricular mass index (LVMI) and intima-media thickness (IMT), and mortality in HD patients. Two hundred and sixty-eight HD patients were enrolled in this study and were followed for 36 months. The primary end point was all-cause mortality and cardiovascular mortality. Multivariable Cox regression was used to calculate the adjusted hazard ratios for NLR on all-cause and cardiovascular survival. We pinpointed that higher NLR in HD patients was a predictor of increased PP, LVMI, and IMT; HD patients with higher NLR had a lower survival at the end of the study; furthermore, high NLR was an independent predictor of all-cause and cardiovascular mortality when adjusted for other risk factors. In conclusion, higher NLR in HD patients was associated with cardiovascular risk factors and mortality

High Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Associated with Poor Survival in Patients with Hemodialysis

Background. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers for systemic inflammation condition. Although NLR has emerged as a risk factor for poor survival in end-stage renal disease (ESRD) patients, the relationship between PLR and mortality is still unknown. We aimed to explore the interaction of NLR and PLR in predicting mortality in hemodialysis (HD) patients. Method. We enrolled 360 HD patients for a 71-month follow-up. The endpoint was all-cause and cardiovascular (CV) mortality. Pearson correlation analysis was conducted to evaluate the relationship between factors and NLR or PLR. Kaplan-Meier curves and Cox proportional analysis were used to assess the prognostic value of NLR and PLR. Results. NLR was positively correlated with neutrophil and negatively correlated with lymphocyte, hemoglobin, and serum albumin. PLR was positively correlated with neutrophil and platelet and negatively correlated with lymphocyte and hemoglobin. In multivariate Cox regression, a higher NLR level was independently associated with all-cause mortality (OR 2.011, 95% CI 1.082-3.74, p=0.027), while a higher PLR level might predict CV mortality (OR 2.768, 95% CI 1.147-6.677, p=0.023) in HD patients. Conclusion. NLR and PLR are cheap and reliable biomarkers for all-cause and CV mortality to predict survival in HD patients

High Erythropoiesis Resistance Index Is a Significant Predictor of Cardiovascular and All-Cause Mortality in Chinese Maintenance Hemodialysis Patients

Background. Renal anemia is a common complication of hemodialysis patients. Erythropoietin (EPO) hyporesponsiveness has been recognized as an important factor to poor efficacy of recombinant human erythropoietin in the treatment of renal anemia. More importantly, increased erythropoiesis resistance index (ERI) may be associated with inflammation and increased mortality. Objective. The objective of this research was to investigate correlated factors of EPO responsiveness and to clarify the relationships between EPO hyporesponsiveness and cardiovascular mortality and all-cause mortality among maintenance hemodialysis patients. Methods. This prospective cohort study enrolled 276 maintenance hemodialysis patients for a 55-month follow-up to investigate the factors related to ERI and its relationship to all-cause mortality and cardiovascular mortality. Results. ERI was positively correlated with predialysis serum high-sensitivity C-reactive protein (r=0.234, p11.04 IU/kg/w/g/dL (both p<0.01). The high ERI group was significantly associated with higher risk for all-cause mortality (OR 1.781, 95% CI 1.091 to 2.910, p=0.021) and cardiovascular mortality (OR 1.972, 95% CI 1.139 to 3.417, p=0.015) after adjusting for confounders. Conclusions. Predialysis serum albumin, high-sensitivity C-reactive protein, ferritin, and creatinine were independent correlated factors of EPO responsiveness among maintenance hemodialysis patients. Patients with higher ERI values had a higher all-cause mortality rate and cardiovascular mortality rate

High Neutrophil-to-Lymphocyte Ratio is a Significant Predictor of Cardiovascular and All-Cause Mortality in Patients Undergoing Peritoneal Dialysis

Background/Aims: Chronic inflammation is associated with increased risk of cardiovascular death in patients with end-stage renal disease (ESRD). Although elevated neutrophil-to-lymphocyte ratio (NLR), a novel inflammatory marker, has been shown to predict cardiovascular disease and all-cause mortality in the general population, limited evidence is available for its role in ESRD. Methods: We enrolled 86 patients undergoing peritoneal dialysis (PD) for a 36-month follow-up to investigate the association between the NLR and arterial stiffness markers, namely, carotid-femoral pulse wave velocity (cfPWV) and carotid augmentation index (AIx), and mortality in PD patients. The primary endpoints were cardiovascular mortality and all-cause mortality. Kaplan–Meier curves were used to show the cumulative incidence of cardiovascular mortality and all-cause mortality. Results: High NLR was found to be a predictor of increased cfPWV (β = 1.150; P &#x3c; 0.001) and AIx (β = 3.945; P &#x3c; 0.001) in patients on PD. Patients with higher NLR had lower survival during follow-up. Kaplan–Meier curves showed that the cumulative incidences of both cardiovascular mortality and all-cause mortality were significantly higher in patients with NLR ≥ 4.5 (both P &#x3c; 0.01). Conclusion: Our results suggest that high NLR is independently associated with arterial stiffness and predicts cardiovascular and all-cause mortality in PD patients

Effect of Lanthanum Carbonate on All-Cause Mortality in Patients Receiving Maintenance Hemodialysis: a Meta-Analysis of Randomized Controlled Trials

Background/Aims: Hyperphosphatemia is common in patients on hemodialysis. The efficacy of lanthanum carbonate (LC) in the treatment of hyperphosphatemia in these patients remains controversial. The objective of this meta-analysis was to evaluate the effect of LC on all-cause mortality in patients on maintenance hemodialysis. Methods: We electronically searched the PubMed, EMBASE, and Cochrane Library databases for all randomized controlled trials (RCTs) comparing LC with other phosphate binders used in adult hemodialysis patients, including calcium carbonate, calcium acetate, and sevelamer. Results: Nine RCTs involving 2813 patients were suitable for inclusion. Our results showed that all-cause mortality was significantly lower in patients who received LC than in those who received standard therapy (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.32–0.63, P&#x3c;0.00001). Compared with the controls, patients who received LC had significantly lower serum calcium and higher serum intact parathyroid hormone levels. However, there was no significant difference between the groups in the cardiovascular event rate (OR: 0.58, 95% CI: 0.31–1.06, P=0.07) or in serum phosphorus levels. Conclusion: Compared with standard therapy, LC reduced all-cause mortality in patients on hemodialysis but did not decrease the risk of cardiovascular events. The decrease in serum phosphorus level was similar between LC and the other phosphate binders, but the risk of hypercalcemia was lower in patients who received LC

Association of Circulating Levels of ADMA with Carotid Intima-Media Thickness in Patients with CKD: a Systematic Review and Meta-Analysis

Background/Aims: The incidence of cardiovascular disease in patients with chronic kidney disease (CKD) is significantly higher than that in the general population. Carotid intima-media thickness (CIMT) is considered to be an important predictor of atherosclerosis. Asymmetric dimethylarginine (ADMA) acted as an endogenous nitric oxide synthase inhibitor, which was elevated in patients with CKD, but whether plasma ADMA correlate with the CIMT in CKD patients is still not elucidated. Methods: We searched the PubMed, Cochrane Library and Embase electronic database. A total of 334 related articles were retrieved, after screened by the inclusion and exclusion criterions, 6 articles were selected. Results: After an overall pooled estimate of correlation coefficient (R) within the 6 articles, we found that levels of circulating ADMA were positively related to CIMT in the patients with CKD. Furthermore, the partial correlation coefficient (PR) was used to reduce the interference caused by the hybrid factors. After correction of other risk factors, it also turned out that levels of circulating ADMA were positively related to CIMT. Conclusion: Circulating levels of ADMA in CKD patients were positively related to CIMT, which could be a predictor of early-onset atherosclerosis and atherosclerotic disease in patients with CKD