Prognostic relevance of ventricular arrhythmias in surgical patients with gastrointestinal tumors.

BACKGROUND: Individuals diagnosed with gastrointestinal tumors are at an increased risk of developing cardiovascular diseases. Among which, ventricular arrhythmia is a prevalent clinical concern. This suggests that ventricular arrhythmias may have predictive value in the prognosis of patients with gastrointestinal tumors. AIM: To explore the prognostic value of ventricular arrhythmias in patients with gastrointestinal tumors receiving surgery. METHODS: We retrospectively analyzed data from 130 patients undergoing gastrointestinal tumor resection. These patients were evaluated by a 24-h ambulatory electrocardiogram (ECG) at the Sixth Affiliated Hospital of Sun Yat-sen University from January 2018 to June 2020. Additionally, 41 general healthy age-matched and sex-matched controls were included. Patients were categorized into survival and non-survival groups. The primary endpoint was all-cause mortality, and secondary endpoints included major adverse cardiovascular events (MACEs). RESULTS: Colorectal tumors comprised 90% of cases. Preoperative ambulatory ECG monitoring revealed that among the 130 patients with gastrointestinal tumors, 100 (76.92%) exhibited varying degrees of premature ventricular contractions (PVCs). Ten patients (7.69%) manifested non-sustained ventricular tachycardia (NSVT). The patients with gastrointestinal tumors exhibited higher PVCs compared to the healthy controls on both conventional ECG [27 (21.3) vs 1 (2.5), P = 0.012] and 24-h ambulatory ECG [14 (1.0, 405) vs 1 (0, 6.5), P < 0.001]. Non-survivors had a higher PVC count than survivors [150.50 (7.25, 1690.50) vs 9 (0, 229.25), P = 0.020]. During the follow-up period, 24 patients died and 11 patients experienced MACEs. Univariate analysis linked PVC > 35/24 h to all-cause mortality, and NSVT was associated with MACE. However, neither PVC burden nor NSVT independently predicted outcomes according to multivariate analysis. CONCLUSION: Patients with gastrointestinal tumors exhibited elevated PVCs. PVCs > 35/24 h and NSVT detected by 24-h ambulatory ECG were prognostically significant but were not found to be independent predictors.

Single-cell profiling reveals kidney CD163+ dendritic cell participation in human lupus nephritis.

OBJECTIVES: The current work aimed to provide a comprehensive single-cell landscape of lupus nephritis (LN) kidneys, including immune and non-immune cells, identify disease-associated cell populations and unravel their participation within the kidney microenvironment. METHODS: Single-cell RNA and T cell receptor sequencing were performed on renal biopsy tissues from 40 patients with LN and 6 healthy donors as controls. Matched peripheral blood samples from seven LN patients were also sequenced. Multiplex immunohistochemical analysis was performed on an independent cohort of 60 patients and validated using flow cytometric characterisation of human kidney tissues and in vitro assays. RESULTS: We uncovered a notable enrichment of CD163+ dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. In contrast to their counterparts in blood, DC3s in LN kidney displayed activated and highly proinflammatory phenotype. DC3s showed strong interactions with CD4+ T cells, contributing to intrarenal T cell clonal expansion, activation of CD4+ effector T cell and polarisation towards Th1/Th17. Injured proximal tubular epithelial cells (iPTECs) may orchestrate DC3 activation, adhesion and recruitment within the LN kidneys. In cultures, blood DC3s treated with iPTECs acquired distinct capabilities to polarise Th1/Th17 cells. Remarkably, the enumeration of kidney DC3s might be a potential biomarker for induction treatment response in LN patients. CONCLUSION: The intricate interplay involving DC3s, T cells and tubular epithelial cells within kidneys may substantially contribute to LN pathogenesis. The enumeration of renal DC3 holds potential as a valuable stratification feature for guiding LN patient treatment decisions in clinical practice.

Group 3 Innate Lymphoid Cells Exacerbate Lupus Nephritis by Promoting B Cell Activation in Kidney Ectopic Lymphoid Structures.

Group 3 innate lymphoid cells (ILC3s) represent a new population in immune regulation, yet their role in lupus nephritis (LN) remains elusive. In the present work, systemic increases in ILC3s, particularly in the kidney, are observed to correlate strongly with disease severity in both human and murine LN. Using MRL/lpr lupus mice and a nephrotoxic serum-induced LN model, this study demonstrates that ILC3s accumulated in the kidney migrate predominantly from the intestine. Furthermore, intestinal ILC3s accelerate LN progression, manifested by exacerbated autoimmunity and kidney injuries. In LN kidneys, ILC3s are located adjacent to B cells within ectopic lymphoid structures (ELS), directly activating B cell differentiation into plasma cells and antibody production in a Delta-like1 (DLL1)/Notch-dependent manner. Blocking DLL1 attenuates ILC3s' effects and protects against LN. Altogether, these findings reveal a novel pathogenic role of ILC3s in B cell activation, renal ELS formation and autoimmune injuries during LN, shedding light on the therapeutic value of targeting ILC3s for LN.

The association of preoperative high-sensitivity cardiac troponin i and long-term outcomes in colorectal cancer patients received tumor resection surgery.

BACKGROUND: This study aimed to evaluate the association between preoperative hs-cTnI and long-term mortality and major adverse cardiovascular events (MACE) in colorectal cancer patients. METHODS: This single-center retrospective cohort study included 1105 consecutive colorectal cancer patients who received tumor resection surgery between January 2018 and June 2020. Inclusion criteria were an age ≥ 18 years and had been tested for hs-cTnI on admission within 7 days prior to tumor resection surgery. Exclusion criteria were emergent surgery, failure to received tumor resection surgery, hospital death, there was clinical evidence of unstable coronary artery disease or pulmonary embolism occurred before operation according to medical record. The primary endpoint was all-cause death. Secondary endpoint was major adverse cardiovascular events (MACE). RESULTS: A total of 1105 patients were enrolled: 1032 with normal hs-cTnI and 73 with elevated hs-cTnI. The mean follow-up was 24.4 ± 10.8 months, 176 patients died and 39 patients met MACE. In the elevated troponin group, 50%, 32.1% and 17.9% died from cancer, cardiovascular and other causes, while those in the normal troponin group were 75.7%, 2% and 22.3%, there was statistical difference between 2 groups (P < 0.001). Patients with elevated preoperative hs-cTnI had significantly higher mortality (P < 0.001) and more MACE (P < 0.001) compared with those with normal hs-cTnI. A propensity-matching analysis were performed, resulting in 151 patients with normal hs-cTnI and 60 patients with elevated hs-cTnI. The matched population had the similar results for all-cause death (P = 0.009) and MACE (P = 0.001). The results were consistent after further excluding 147 patients who had received chemoradiotherapy prior to surgery in subgroup analysis. The results of multivariate Cox regression analysis shown that hs-cTnI was one of the best predictors for all-cause death (hazard ratio [HR] 2.278; 95% confidence interval [CI] 1.19-4.361) and MACE (HR, 3.523; 95%CI, 1.477-8.403) in total populations, similar results were found in subgroup analysis. CONCLUSIONS: Colorectal cancer patients without myocardial ischemia manifestation but with elevated hs-cTnI prior to tumor resection surgery were at increased risk for long-term all-cause death and MACE, irrespective of whether they have received chemoradiotherapy prior to surgery.

Risk factors of preoperative myocardial injury in patients with gastrointestinal tumors.

BACKGROUND: Recent studies indicated that the prognosis of patients with gastrointestinal tumors is frequently influenced by its complications, notably myocardial injury. The main object is to investigate the occurrence and risk factors of myocardial injury in patients with gastrointestinal tumor. METHODS: 1126 patients who received gastrointestinal tumor related surgery from May 2018 to June 2020 in the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively collected and divided into the non-myocardial injury group and the myocardial injury group (high-sensitive cardiac troponin I (hs-cTnI) ≥ 0.028 ng/ml). The occurrence and risk factors of myocardial injury in patients with gastrointestinal tumor are analyzed. The influence of myocardial injury on the ICU detention time in gastrointestinal tumor patients is also studied. RESULTS: In total, 78 (6.93%) patients developed myocardial injuries. Compared with patients in the non-myocardial injury group, patients in the myocardial injury group have a higher prevalence of cardiovascular risk factors (including advanced age and higher smoking ratio), a higher prevalence of comorbidities (such as previous coronary artery disease, hypertension, atrium fibrillation and diabetes), and a higher rate of premedication (such as anticoagulation, ß-blocker, Angiotensin-converting enzyme inhibitor/Angiotensin II receptor blocker, and diuretic) (all with P-value < 0.05). In addition, patients in the myocardial injury group also presented with a higher revised cardiac risk index (Lee index), higher neutrophil granulocyte ratio, lower hemoglobin, and higher likelihood of impaired cardiac structure and function (all with P-value < 0.05). There was a trend of statistical significance in the ICU detention time between the myocardial injury group and the non-myocardial injury group (1[1,3] vs. 2[1,10], P = 0.064). In this study, there were 7 patients presented with clinical symptoms in the myocardial injury group (chest discomfort in 4 cases, non-compressive precordial chest pain in 1 case, dyspnea in 2 cases). In the multivariate analysis, advanced age, increased Lee index score, increased neutrophil granulocyte ratio, decreased left ventricular ejection fraction (LVEF), increased interventricular septum were independent risk factors for myocardial injury. CONCLUSION: In conclusion, advanced age, increased Lee index, increased neutrophil granulocyte ratio, decreased left ventricular ejection fraction, and increased ventricular septum were independent risk factors for preoperative myocardial injury in patients with gastrointestinal tumors. The proportion of clinical symptoms in gastrointestinal tumor patients with myocardial injury was low, indicating the necessity to closely monitor the cardiac status of individuals with gastrointestinal tumors.

Identification of novel key genes and potential candidate small molecule drugs in diabetic kidney disease using comprehensive bioinformatics analysis.

Objective: The currently established diagnostic and prognostic tools for diabetic kidney disease (DKD) have limitations, which demands the necessity to find new genes and pathways associated with diagnosis and treatment. Our study aims to reveal the gene expression alteration and discover critical genes involved in the development of DKD, thus providing novel diagnostic molecular markers and therapeutic targets. Materials and methods: The differences of infiltrating immune cells within kidney were compared between healthy living donors and DKD patients. Besides, differentially expressed genes (DEGs) within kidney from healthy living donor, early stage DKD and advanced stage DKD samples were detected. Furthermore, the weighted co-expressed network (WGCNA) and protein-protein interaction (PPI) network were constructed, followed by recognition of core hub genes and module analysis. Receiver operating characteristic (ROC) curve analysis was implemented to determine the diagnostic value of hub genes, correlation analysis was employed to explore the association between hub genes and infiltrating immune cells, and certain hub genes was validated by quantitative real-time PCR and immunohistochemistry staining in cultured tubule cells and diabetic mice kidney. Finally, the candidate small molecules as potential drugs to treat DKD were anticipated through utilizing virtual screening and molecular docking investigation. Results: Our study revealed significantly higher proportion of infiltrating immune cells within kidney from DKD patients via probing the immune landscape by single-cell transcriptomics. Besides, 126 commonly shared DEGs identified among three group samples were enriched in immune biological process. In addition, the ROC curve analysis demonstrated the strong diagnostic accuracy of recognized hub genes (NFKB1, DYRK2, ATAD2, YAP1, and CHD3) from PPI network. Correlation analysis further confirmed the positive association between these hub genes with infiltrating natural killer cells. More importantly, the mRNA transcripts and protein abundance of YAP1 were significantly higher in high glucose-treated renal tubule cells and diabetic mice kidney, and the small molecules exhibiting the best binding affinities with YAP1 were predicted and acquired. Conclusion: Our findings for the first time indicate that NFKB1, DYRK2, ATAD2, YAP1, and CHD3 might be potential novel biomarkers and therapeutic targets for DKD, providing insights into the molecular mechanisms underlying the pathogenesis of DKD.

Computational Analysis Reveals the Characteristics of Immune Cells in Glomerular and Tubulointerstitial Compartments in IgA Nephropathy Patients.

Objective: The commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments of IgA nephropathy (IgAN) remains largely undetermined. We aim to perform bioinformatic analysis for providing a comprehensive insight into the characteristics of immune cells and associated molecular mechanisms in IgAN. Materials and Methods: We performed integrated bioinformatic analyses by using IgAN-related datasets from the Gene Expression Omnibus database. First, the differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, CIBERSORT was employed to determine the landscape of infiltrating immune cells in both glomerular and tubulointerstitial compartments of IgAN patients, followed by Pearson's correlation analysis and principal component analysis (PCA). Finally, commonly shared DEGs between glomerular and tubulointerstitial entities were recognized, followed by correlation analyses to identify the dominant commonly shared DEGs associated with immune cell infiltration in IgAN. Results: GO and KEGG enrichment analyses showed apparently distinct biological processes in the glomerular and tubulointerstitial compartments of IgAN. In addition, CIBERSORT analyses revealed a clear trend of increasing proportions of M1 macrophage and M2 macrophage in the glomerular compartment while noticeably higher proportions of resting CD4+ memory T cells and M2 macrophages in the tubulointerstitial compartments. The PCA analyses showed that the varying composition of immune cells in both glomerular and tubulointerstitial entities was compelling to distinguish IgAN patients from healthy living controls. In addition, 21 commonly shared DEGs between glomerular and tubulointerstitial entities were recognized as key regulators in the pathogenesis of IgAN, among which the enhanced hemoglobin subunit beta (HBB) gene expression was found to be positively associated with M2 macrophage in the glomerular compartment and resting CD4+ memory T cells in the tubulointerstitial compartment. Most importantly, FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene deficiency was recognized as the dominant alteration in promoting M2 macrophage infiltration in the glomerular compartment of IgAN. Conclusion: The findings from our current study for the first time reveal commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments, as well as decode the essential role of M2 macrophages and associated molecular patterns within the microenvironments of IgAN.

The therapeutic effect and mechanism of Rapamycin combined with HO-3867 on monocrotaline-induced pulmonary hypertension in rats.

This study test was designed to investigate the possible modulatory effect of rapamycin combined with HO-3867 in monocrotaline(MCT)-induced pulmonary arterial hypertension in rats. We hypothesized that combined treatment with rapamycin and HO-3867 is superior to either alone in attenuating MCT-induced rat pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). 2 weeks later, rapamycin (2 mg/kg i.p.) and HO3867 (10 mg/kg i.h.) were administered daily, alone and in combination, for 2 weeks. Right ventricular systolic pressure, echocardiography were recorded and then rats were sacrificed. Histological analysis of pulmonary arteries medial wall thickness, right ventricular hypertrophy index (RVHI), the ratio of right ventricular to body weight, and collagen volume fraction (CVF) of right ventricular were performed. Moreover, the expression of t-STAT3, p-STAT3, t-Akt, p-Akt in lung and t-STAT3, p-STAT3, t-S6, p-S6 in right ventricular were examined. The result showed that combined treatment provided a considerable improvement toward maintaining hemodynamic changes, lung vascular remodeling as well as amending RV remodeling and function. Furthermore, Combined treatment can normalize the protein levels of two signal pathways in lung and heart tissue, where p-S6 or p-Akt significantly decreased compared to HO-3867 alone, or p-STAT3 significantly reduced compared to rapamycin alone. In conclusion, combined treatment with rapamycin and HO-3867 is superior to either alone in attenuating MCT-induced PAH in rats.

Dapagliflozin has No Protective Effect on Experimental Pulmonary Arterial Hypertension and Pulmonary Trunk Banding Rat Models.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel class of hypoglycemic drugs, show excellent cardiovascular benefits, and have further improved heart failure outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status. However, the efficacy of SGLT2 inhibitors in pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction remains unknown. This study aimed to evaluate the effects of dapagliflozin in rats with PAH and RV dysfunction. PAH was induced in rats by monocrotaline (MCT) subcutaneous injection (60 mg/kg). Isolated RV dysfunction was induced in another group of rats by pulmonary trunk banding (PTB). Dapagliflozin (1.5 mg/kg) was administered daily via oral gavage one day (prevention groups) or two weeks (reversal groups) after modeling. Echocardiography and hemodynamic assessments were used to observe pulmonary vascular resistance and RV function. Histological staining was used to observe pulmonary vascular and RV remodeling. As compared with MCT group, dapagliflozin treatment did not significantly improve the survival of rats. Pulmonary arterial media wall thickness in MCT group was significantly increased, but dapagliflozin did not significantly improved vascular remodeling both in the prevention group and reversal group. In MCT group, RV hypertrophy index, RV area, the fibrosis of RV increased significantly, and RV function decreased significantly. Consistently, dapagliflozin did not show protective effect on the RV remodeling and function. In the PTB model, we also did not find the direct effect of dapagliflozin on the RV. This is a negative therapeutic experiment, suggesting human trials with dapagliflozin for PAH or RV failure should be cautious.