Independent prognostic implications of RRM2 in lung adenocarcinoma.

Background: Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2. Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have symptoms and signs of HF with normal or near-normal left ventricular ejection fraction (LVEF ≥50%). Roughly half of all patients with HF worldwide have an LVEF ≥50% and nearly half have an LVEF <50%. Thanks to the increased scientific attention about the condition and improved characterization and diagnostic tools, the incidence of HF with reduced ejection fraction (HFrEF) dropped while that of HFpEF has increased by 45%. HFpEF has no single guideline for diagnosis or treatment, the patient population is heterogeneously and inconsistently described, and longitudinal studies are lacking. To better understand and overcome the disease, in this review, we updated the latest knowledge of HFpEF pathophysiology, introduced the existing promising diagnostic methods and treatments, and summarized its prognosis by reviewing the most recent cohort studies.

Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have symptoms and signs of HF with normal or near-normal left ventricular ejection fraction (LVEF ≥50%). Roughly half of all patients with HF worldwide have an LVEF ≥50% and nearly half have an LVEF <50%. Thanks to the increased scientific attention about the condition and improved characterization and diagnostic tools, the incidence of HF with reduced ejection fraction (HFrEF) dropped while that of HFpEF has increased by 45%. HFpEF has no single guideline for diagnosis or treatment, the patient population is heterogeneously and inconsistently described, and longitudinal studies are lacking. To better understand and overcome the disease, in this review, we updated the latest knowledge of HFpEF pathophysiology, introduced the existing promising diagnostic methods and treatments, and summarized its prognosis by reviewing the most recent cohort studies.

Puerarin pre-conditioning on the expression levels of CK-MB, cTnI and inflammatory factors in patients undergoing cardiac valve replacement.

Effect of puerarin preconditioning on the expression levels of nuclear factor κB (NF-κB), interleukin 6 (IL-6), interleukin 8 (IL-8), troponin I (cTnI), and creatine kinase isoenzyme MB (CK-MB) in the neutrophils of patients undergoing cardiac valve replacement under cardiopulmonary bypass (CPB) was evaluated. We enrolled 50 patients scheduled for cardiac valve replacement and assigned them randomly divided into either a puerarin or a control group. Puerarin was dissolved in 10 ml normal saline before CPB, and administered by intravenous infusion to patients in the puerarin group. The control group was administered an equivalent amount of saline. We used flow cytometry to determine the expression levels of NF-κB, IL-6 and IL-8 in neutrophils and an auto chemistry analyzer to determine the serum levels of cTnI and CK-MB before anesthesia induction (T0), 30 min after aortic declamping (T1), 4 h after aortic declamping (T2), and 8 h after aortic declamping (T3). We found the mean serum cTnI and CK-MB levels of the puerarin group tended to decrease with time. The positive rates of NF-κB, IL-6 and IL-8 at different time-points were lower in patients of the puerarin group than in those of the control group (and the differences at T3 were statistically significant). The clinical manifestations of patients in the puerarin group after operation were better than those in the control group (P<0.05). We found that the expression levels of NF-κB, IL-6 and IL-8 were positively correlated with the levels of CK-MB and cTnI (P<0.05). Puerarin preconditioning can reduce the NF-κB activation and the overexpression of IL-6 and IL-8 in neutrophils, and it inhibits the release of myocardial enzyme cTnI and CK-MB reflecting myocardial cell protection. Puerarin seems to improve safety and efficacy of valvular replacement operations.

Histamine H1 type receptor antagonist loratadine ameliorates oxidized LDL induced endothelial dysfunction.

Oxidized LDL (ox-LDL) is one of the major risk factors of atherosclerosis. Endothelial dysfunction caused by ox-LDL is an early event in the pathogenesis of cardiovascular diseases. Preclinical studies have been performed to explore efficient means of preventing endothelial abnormalities. In this study, we revealed that loratadine, a histamine H1 type receptor specific antagonist, possesses a protective effect by relieving ox-LDL-induced endothelial inflammation. Treatment of endothelial cells with ox-LDL induces expression of the H1 receptor. The presence of loratadine in endothelial culture efficiently suppressed ox-LDL-induced attachment of monocytes to endothelial cells, production of ROS and vascular adhesion molecules, and induction cytokines including VCAM-1, E-selectin, TNF-α, IL-6 and IL-8. Mechanistically, we show that loratadine potently blocks ox-LDL-induced JNK activation as well as the AP-1 and NF-κB signaling pathways. Collectively, our data disclose a new role for loratadine in endothelial protection.