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Effective classifiers for the prediction of individual adjuvant chemotherapy (AC) benefits are scarce.This study aimed to construct a useful classifier to predict the AC benefit and recurrence hazard based on preoperative hematological indices through a multicenter database.Multivariate analysis revealing GCRF (comprehensive deep learning classifier) as an independent prognostic factor associated with overall survival (OS) and disease-free survival (DFS). Locally advanced gastric cancer (LAGC) patients are categorized into the high-risk group (HRG) and low-risk group (LRG). In HRG, OS and DFS of the AC group are significantly higher than those of the non-AC group (all p˂0.05), whereas in LRG, OS and DFS of the AC group are comparable to those of the non-AC group (all p gt; 0.05). Furthermore, combined GCRF with 8th AJCC TNM staging system, only 650 (51.1%) patients can benefit most from AC among 1273 patients with pStage II-III. From the perspective of recurrence pattern, the recurrence rate of HRG is significantly higher than that of LRG in any recurrence type, including local recurrence, peritoneal recurrence, and distant recurrence (all p˂0.05). Furthermore, the mean time to peritoneal recurrence and lung metastasis in HRG is earlier than that in the LRG (p = 0.028 and 0.011, respectively).In summary, our novel classifier based on deep learning preoperative hematological indices can predict not only the AC benefit of LAGC patients, but also the recurrence hazard after surgery. This classifier is expected to be an effective supplement to the 8th AJCC TNM staging system for the prediction of AC benefits and is helpful for clinical decision in AC individual administration. Further large-scale western studies are warranted.

Background. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer (LC) and one of the leading causes of cancer-related death worldwide. LUAD has a low survival rate owing to tumour invasion and metastasis. Circulating tumour cells (CTCs) are precursors of distant metastasis, which are considered to adopt the characteristics of cancer stem cells (CSCs). Therefore, analysing the risk factors of LUAD from the perspective of CTCs may provide novel insights into the metastatic mechanisms and may help to develop diagnostic and therapeutic strategies. Methods. A total of 447 patients from TCGA dataset were included in the training cohort, and 460 patients from the GEO dataset were included in the validation cohort. A CTC-related-gene risk model was constructed using LASSO penalty–Cox analysis, and its predictive value was further verified. Functional enrichment analysis was performed on differentially expressed genes (DEGs), followed by immune correlation analysis based on the results. In addition, western blot, CCK-8 and colony formation assays were used to validate the biological function of RAB26 in LUAD. Results. A novel in-silico CTC-related-gene risk model, named the CTCR model, was constructed, which successfully divided patients into the high- and low-risk groups. The prognosis of the high-risk group was worse than that of the low-risk group. ROC analysis revealed that the risk model outperformed traditional clinical markers in predicting the prognosis of patients with LUAD. Further study demonstrated that the identified DEGs were significantly enriched in immune-related pathways. The immune score of the low-risk group was higher than that of the high-risk group. In addition, RAB26 was found to promote the proliferation of LUAD. Conclusion. A prognostic risk model based on CTC-related genes was successfully constructed, and the relationship between DEGs and tumour immunity was analysed. In addition, RAB26 was found to promote the proliferation of LUAD cells.

Background Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF). Objective Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies. Methods We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial. Results NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE. Conclusion We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death. Trial registration number PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658. Graphics abstract

BackgroundBreast cancer is becoming a tumor with the highest morbidity rate, and inflammation-induced cell death namely pyroptosis reportedly plays dual roles in cancers. However, the specific mechanism between pyroptosis and the clinical prognosis of breast cancer patients is indistinct. Hence, novel pyroptosis-related biomarkers and their contributing factors deserve further exploration to predict the prognosis in breast cancer.MethodsPearson’s correlation analysis, and univariate and multivariate Cox regression analysis were utilized to obtain six optimal pyroptosis-related gene prognostic signatures (Pyro-GPS). The risk score of each breast cancer patient was calculated. Next, a Pyro-GPS risk model was constructed and verified in TCGA cohort (n=1,089) and GSE20711 cohort (n=88). Then analyses of immune microenvironment, genomic variation, functional enrichment, drug response and clinicopathologic feature stratification associated with the risk score of Pyro-GPS were performed. Subsequently, a nomogram based on the risk score and several significant clinicopathologic features was established. Ultimately, we further investigated the role of CCL5 in the biological behavior of MDA-MB-231 cell line.ResultsThe low-risk breast cancer patients have better survival outcomes than the high-risk patients. The low-risk patients also show higher immune cell infiltration levels and immune-oncology target expression levels. There is no significant difference in genetic variation between the two risk groups, but the frequency of gene mutations varies. Functional enrichment analysis shows that the low-risk patients are prominently correlated with immune-related pathways, whereas the high-risk patients are enriched in cell cycle, ubiquitination, mismatch repair, homologous recombination and biosynthesis-related pathways. Pyro-GPS is positively correlated with the IC50 of anti-tumor drugs. Furthermore, comprehensive analyses based on risk score and clinicopathological features were performed to predict the prognosis of breast cancer patients. Additionally, in vitro experiments confirmed that breast cancer cells with high expression of CCL5 had weaker proliferation, invasion and metastasis abilities as well as stronger apoptosis and cell cycle arrest abilities.ConclusionsThe risk score of Pyro-GPS can serve as a promising hallmark to predict the prognosis of BRCA patients. Risk score evaluation may assist to acquire relevant information of tumor immune microenvironment, genomic mutation status, functional pathways and drug sensitivity, and thus provide more effective personalized strategies.

OBJECTIVE: To study the prognostic value of measurable residual disease (MRD) for childhood acute myeloid leukemia (AML) by analyzing MRD-guided risk stratification therapy. METHODS: A total of 93 children with AML were prospectively enrolled in this study. Chemotherapy with the 2015-AML-03 regimen was completed according to the risk stratification determined by genetic abnormality at initial diagnosis and MRD and bone marrow cytology after induction therapy I. Multiparameter flow cytometry was used to dynamically monitor MRD and analyze the prognostic effect of MRD on 3-year cumulative incidence of recurrence (CIR) rate, event-free survival (EFS) rate, and overall survival (OS) rate. RESULTS: The 93 children with AML had a 3-year CIR rate of 48%±6%, a median time to recurrence of 11 months (range 2-32 months), a 3-year OS rate of 65%±6%, and a 3-year EFS rate of 50%±5%. After induction therapy I and intensive therapy I, the MRD-positive children had a significantly higher 3-year CIR rate and significantly lower 3-year EFS and OS rates than the MRD-negative children (P0.05). The multivariate analysis showed that positive MRD after intensive treatment I was a risk factor for 3-year OS rate in children with AML (P

Background:\ud Although heart failure with preserved ejection fraction (HFpEF) is considered a disease of the elderly, younger patients are not spared from this syndrome.\ud \ud Objectives:\ud This study therefore investigated the associations among age, clinical characteristics, and outcomes in patients with HFpEF.\ud \ud Methods:\ud Using data on patients with left ventricular ejection fraction ≥45% from 3 large HFpEF trials (TOPCAT [Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function], I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], and CHARM Preserved [Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity]), patients were categorized according to age: ≤55 years (n = 522), 56 to 64 years (n = 1,679), 65 to 74 years (n = 3,405), 75 to 84 years (n = 2,464), and ≥85 years (n = 398). This study compared clinical and echocardiographic characteristics, as well as mortality and hospitalization rates, mode of death, and quality of life across age categories.\ud \ud Results:\ud Younger patients (age ≤55 years) with HFpEF were more often obese, nonwhite men, whereas older patients with HFpEF were more often white women with a higher prevalence of atrial fibrillation, hypertension, and chronic kidney disease (eGFR

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

OBJECTIVE: To study the clinical features and prognosis of children with acute leukemias of ambiguous lineage (ALAL) under different diagnostic criteria. METHODS: A retrospective analysis was performed on the medical data of 39 children with ALAL who were diagnosed and treated from December 2015 to December 2019. Among the 39 children, 34 received treatment. According to the diagnostic criteria for ALAL by World Health Organization and European Group for the Immunological Characterization of Leukemias, the 39 children were divided into two groups: ALAL group (n=28) and myeloid expression group (n=11). The clinical features, treatment, and prognosis were compared between the two groups. RESULTS: The 34 children receiving treatment had a 3-year event-free survival (EFS) rate of 75%±9% and an overall survival rate of 88%±6%. The children treated with acute myeloid leukemia (AML) protocol had a 3-year EFS rate of 33%±27%, those treated with acute lymphoblastic leukemia (ALL) protocol had a 3-year EFS rate of 78%±10%, and those who had no remission after induction with AML protocol and then received ALL protocol had a 3-year EFS rate of 100%±0% (P0.05). CONCLUSIONS: ALL protocol has a better clinical effect than AML protocol in children with ALAL, and positive MRD after induction therapy suggests poor prognosis. Hyperleukocytosis and adverse genetic changes are not observed in children with myeloid expression, and such children tend to have a good prognosis, suggesting that we should be cautious to take it as ALAL in diagnosis and treatment.

Breast cancer (BRCA) has become the highest incidence of cancer due to its heterogeneity. To predict the prognosis of BRCA patients, sensitive biomarkers deserve intensive investigation. Herein, we explored the role of N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) as prognostic biomarkers in BRCA patients acquired from The Cancer Genome Atlas (TCGA; n = 1,089) dataset and RNA sequencing (RNA-seq) data (n = 196). Pearson’s correlation analysis, and univariate and multivariate Cox regression were performed to select m6A-related lncRNAs associated with prognosis. Twelve lncRNAs were identified to construct an m6A-related lncRNA prognostic signature (m6A-LPS) in TCGA training (n = 545) and validation (n = 544) cohorts. Based on the 12 lncRNAs, risk scores were calculated. Then, patients were classified into low- and high-risk groups according to the median value of risk scores. Distinct immune cell infiltration was observed between the two groups. Patients with low-risk score had higher immune score and upregulated expressions of four immune-oncology targets (CTLA4, PDCD1, CD274, and CD19) than patients with high-risk score. On the contrary, the high-risk group was more correlated with overall gene mutations, Wnt/β-catenin signaling, and JAK-STAT signaling pathways. In addition, the stratification analysis verified the ability of m6A-LPS to predict prognosis. Moreover, a nomogram (based on risk score, age, gender, stage, PAM50, T, M, and N stage) was established to evaluate the overall survival (OS) of BRCA patients. Thus, m6A-LPS could serve as a sensitive biomarker in predicting the prognosis of BRCA patients and could exert positive influence in personalized immunotherapy.

BACKGROUND: Platelet distribution width (PDW) has been recognized as risk predictors of idiopathic pulmonary arterial hypertension. This study aims to investigate whether in-hospital PDW would be useful to predict all-cause death in patients with severe pulmonary hypertension due to chronic lung diseases (CLD-PH).METHODS: Early in-hospital PDW was measured in 67 severe CLD-PH patients who were confirmed by right heart catheterization and followed up. Event-free survival was estimated using the Kaplan–Meier method and analyzed with the log-rank test. Cox proportional hazards models were performed to determine the association between the PDW level and all-cause death.RESULTS: Pulmonary function test and echocardiography parameters were different among patients divided by 17% (the upper reference range of the PDW). There were no significant differences in both clinical variables and RHC parameters among patients with PDW ≥ or < 17%. During median of 2.4 (2.5, 3.7) years of follow-up, 44 patients died. A significant association was noted between in-hospital PDW level and the adjusted risk of all-cause mortality (hazard ratio [HR], 1.245; 95% confidence interval [CI], 1.099-1.409). Compared with those with PDW < 17%, the HR for all-cause death increased to 5.067 (95% CI: 2.420-10.609, P < 0.001) among patients with PDW ≥ 17 %. Higher levels of PDW were also associated with increased risk of all-cause death.CONCLUSIONS: In-hospital PDW was independently associated with all-cause death in patients with severe CLD-PH. This potentially could be used to estimate the severity of severe CLD-PH.

Protein arginine methyltransferase 5 (PRMT5) is the type II arginine methyltransferase that catalyzes the mono‐ and symmetrical dimethylation of protein substrates at the arginine residues. Emerging evidence reveals that PRMT5 is involved in the regulation of tumor cell proliferation and cancer development. However, the exact role of PRMT5 in human lung cancer cell proliferation and the underlying molecular mechanism remain largely elusive. Here, it is shown that PRMT5 promotes lung cancer cell proliferation through the Smad7‐STAT3 axis. Depletion or inhibition of PRMT5 dramatically dampens STAT3 activation and thus suppresses the proliferation of human lung cancer cells. Furthermore, depletion of Smad7 blocks PRMT5‐mediated STAT3 activation. Mechanistically, PRMT5 binds to and methylates Smad7 on Arg‐57, enhances Smad7 binding to IL‐6 co‐receptor gp130, and consequently ensures robust STAT3 activation. The findings position PRMT5 as a critical regulator of STAT3 activation, and suggest it as a potential therapeutic target for the treatment of human lung cancer., The role of protein arginine methyltransferase 5 (PRMT5) in Janus kinase (JAK)‐signal transducer and activator of transcription 3 (STAT3) signaling pathway and lung cancer cell proliferation is unveiled. PRMT5 symmetrically dimethylates Smad7 on Arginine‐57, promotes Smad7 binding to interleukin‐6 (IL‐6) co‐receptor glycoprotein 130 (gp130), and consequently ensures robust STAT3 activation in a transforming growth factor‐β (TGF‐β) independent manner. This finding positions PRMT5 as a promising therapeutic target for lung cancer treatment.

ObjectivesTo investigate the expression levels of aromatase cytochrome P450 enzyme (P450AROM) and related molecules—estrogen receptor-beta (ER-β), Ki-67, and p53—in prolactinoma tumor tissue from pre- and post-menopausal women, and to determine the associations of tumor invasiveness with expression levels of these genes.MethodsThis study recruited 90 patients with prolactinoma who underwent adenoidectomy between 2012 and 2017. Information was collected regarding clinical characteristics, hormones, laboratory tests, and magnetic resonance imaging-assessed tumor invasiveness. Expression levels of P450AROM, ER-β, Ki-67, and p53 were examined by immunohistochemistry in prolactinoma tissues.ResultsIncreased P450AROM expression was found in invasive prolactinoma tissues in post-menopausal women, compared with its expression in non-invasive prolactinoma tissues. ER-β level was significantly higher in patients resistant to treatment with bromocriptine, a dopamine agonist. However, there were no differences in rate of resistance to treatment (8.2% vs. 3.4%) or expression levels of P450AROM, Ki-67, p53, and ER-β between pre- and post-menopausal patients.ConclusionsOur results demonstrated that increased P450AROM expression in prolactinoma of post-menopausal women was positively associated with invasiveness. Moreover, ER-β level was higher in both pre- and post-menopausal patients who were resistant to dopamine agonist treatment.

OBJECTIVES Collagen is a core protein that maintains the homeostasis of the extracellular matrix (ECM), and its dysregulation in human cancers has attracted increasing attention. In tumors, increased lysyl oxidase (LOX)-catalyzed collagen cross-linking plays a critical role in collagen dysregulation. However, the expression patterns of LOX and collagen and their clinicopathological significance in oral squamous cell carcinoma (OSCC) have not been well established. METHODS The LOX mRNA expression in OSCC was measured by RT-PCR and bioinformatics analysis. LOX protein expression and total collagen content were identified by immunohistochemistry or Masson's trichrome staining in a retrospective cohort of primary OSCC samples, respectively. Moreover, the associations between LOX and collagen expression and various clinicopathological parameters or patient survival were assessed. RESULTS LOX mRNA was overexpressed in OSCC samples. Higher expression of LOX, collagen content or co-overexpression of LOX and collagen was significantly associated with aggressive clinicopathological features. Importantly, aberrant expression of LOX, collagen content, or both were markedly correlated with decreased overall and disease-free survival (P

Heat shock factor 1 (HSF1) is highly expressed in various malignancies and is a potential modulator of tumor progression. Emerging evidence suggests that HSF1 activation in stromal cells is closely related to poor patient prognosis. However, the role of HSF1 in oral squamous cell carcinoma (OSCC) remains elusive. We aimed to investigate the function of HSF1 in cancer-associated fibroblasts (CAFs) of the tumor microenvironment (TME) and in tumor development. In the present study, we found that HSF1 was highly expressed in both CAFs and tumor cells, and was significantly correlated with poor prognosis and overall survival. Moreover, HSF1 overexpression in CAFs resulted in a fibroblast-like phenotype of Cal27 cells, induced epithelial-mesenchymal transition (EMT), and promoted proliferation, migration and invasion in Cal27 cells. HSF1 knockdown attenuated features of CAFs and reduced EMT, proliferation, migration and invasion in Cal27 cells. Furthermore, HSF1 in CAFs promoted tumor growth in nude mice. Taken together, these data suggest that HSF1 expression in CAFs drive OSCC progression, and could serve as an independent prognostic marker of patients with OSCC. Thus, HSF1 is a potent mediator of OSCC malignancy.

Acute lung injury (ALI) is a life-threatening clinical syndrome in critically ill patients. The identification of novel biological markers for the early diagnosis of ALI and the development of more effective treatments are topics of current research. High mobility group box-1 protein (HMGB1) is a late inflammatory mediator associated with sepsis, malignancy, and immune disease. Levels of HMGB1 may reflect the severity of inflammation and tissue damage, indicating a potential role for HMGB1 as a prognostic biomarker in ALI, and a potential target for blocking inflammatory pathways. Several studies have shown that HMGB1 regulates autophagy. Autophagy, or type II programmed cell death, is an essential biological process that maintains cellular homeostasis. Studies have shown that HMGB1 and autophagy are involved in the pathogenesis of many lung diseases including ALI but the specific mechanisms underlying this association remain to be determined. This review aims to provide an update on the current status of the role of HMBG1 and autophagy in ALI.

On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP ALL. The basis for this accelerated approval was a single-arm trial. For the 86 patients in first and second complete remission with MRD ≥ 0.1%, conversion to MRD < 0.01% was achieved after one cycle of blinatumomab by 85.2% [95% confidence interval (CI): 73.8%, 93.0%] and 72.0% (95% CI: 50.6%, 87.9%), respectively, and the estimated median hematologic relapse-free survivals (RFS) were 35.2 months (95% CI: 0.4–53.5) and 12.3 months (95% CI: 0.7–42.3), respectively. Hematologic RFS was considered substantial independent of whether patients underwent subsequent allogeneic stem cell transplantation. The safety profile for blinatumomab was established in prior studies, and no new safety signals were observed in the new population. Cytokine release syndrome and neurotoxicity remain significant risks. The FDA is requiring confirmation of clinical benefit in a randomized trial.

Background: Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years.\ud \ud Objectives: This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF.\ud \ud Methods: The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro–B-type natriuretic peptide.\ud \ud Results: Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life—median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)—despite similar left ventricular ejection fraction and N-terminal pro–B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001).\ud \ud Conclusions: Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.

Objective To determine the prognostic implications and clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression and EGFRvIII nuclear translocation in Chinese human gliomas. Methods We retrospectively examined EGFRvIII expression and EGFRvIII nuclear translocation using immunohistochemistry in specimens of 240 Chinese patients with glioma, including 84 World Health Organization (WHO) II gliomas, 84 WHO III gliomas and 72 glioblastomas (WHO IV). Factors that correlated with EGFRvIII and EGFRvIII nuclear translocation expression were analyzed by the Chi-square test. Kaplan-Meier methodology and Cox regression were used for the survival analysis. Results Log-rank tests showed that patient age, Karnofsky performance scale (KPS) score, tumor grade, EGFRvIII expression, EGFRvIII nuclear translocation, 1p/19q codeletion, isocitrate dehydrogenase (IDH) mutation, Ki-67 labeling index and O6-methylguanine-DNA methyltransferase (MGMT) status (P

The aim of this study was to investigate the role of B7-H3 in prognosis of congenital heart disease (CHD) children patients. A total of 65 CHD patients within age 3-12 years who went to our hospital were included during August 2011 to December 2012. Demographic data including age, sex, weight, clinical basic information such as New York Heart Association (NYHA) class, pathological type were collected. Blood samples were collected and serum levels of B7-H3, C-reactive protein (CRP), N-Terminal Pro-Brain Natriuretic Peptide (NT-pro-BNP), and High-sensitivity Troponin T (hsTnT) were determined by enzyme-linked immunosorbent assay (ELISA). Characteristics including age, gender, weight, pathological type, NYHA class, and serum levels of hsTnT and CRP showed no significant difference between deceased and survival patients. However, serum levels of B7-H3 and NT-pro-BNP were significantly higher in deceased patients compared survival patients. Patients with high expressed B7-H3 had higher risks for total major cardiovascular events (MACE) occurrence compared with the lower group. Among the MACE events, significant difference was observed in rates of death, new onset of arrhythmias, and surgical, but not in NYHA class worsening and percutaneous intervention. Patients with higher levels if B7-H3 had significantly higher risk for mortality in the 5-year follow-up compared with the lower group, logic analysis was also conducted and results showed that B7-H3 might be an independent risk factor for 5-year mortality for CHD patients. B7-H3 was up-regulated in dead CHD patients, and serum levels of B7-H3 were related to long-term MACE and 5-year mortality of CHD patients.

Rho GTPase activating protein 9 (ARHGAP9), a member of RhoGAP family, has been identified as a RhoGAP for Cdc42 and Rac1. Here, we aimed to clarify the expression and functional role of ARHGAP9 in hepatocellular carcinoma (HCC). By analyzing TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) database, we found that ARHGAP9 expression was lower in HCC tissues than in normal liver tissues, and that patients with ARHGAP9 lower expression had a significant shorter overall survival time than those with ARHGAP9 higher expression. Cell counting kit-8 (CCK-8), transwell assays and in vivo experimental lung metastasis assay revealed that ARHGAP9 overexpression could inhibit HCC cell proliferation, migration and invasion, as well as HCC lung metastases. By next-generation RNA-sequencing, we identified that a transcription factor, Forkhead Box J2 (FOXJ2), was significantly induced by ARHGAP9 overexpression in HepG2 cells. Ectopic expression of FOXJ2 in HCC cell lines also exerted inhibitory effects on cell migration and invasion. Moreover, the inhibitory effects of ARHGAP9 on HCC cell migration and invasion was significantly attenuated by FOXJ2 knockdown. Luciferase reporter assay demonstrated that ARHGAP9 enhanced the transcription of E-cadherin (CDH1) via FOXJ2. Chromatin immunoprecipitation (ChIP) assay demonstrated that FOXJ2 modulated the transcription of E-cadherin (CDH1) by directly binding to its promoter. Furthermore, Pearson’s correlation analysis indicated that the mRNA levels of ARHGAP9 in HCC tissues were positively correlated with the mRNA levels of FOXJ2 and CDH1. These data clearly show that ARHGAP9/FOXJ2 inhibit cell migration and invasion during HCC development via inducing the transcription of CDH1.

Background Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. Results In the present work, we applied a rational computer‐aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC‐associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR‐378a‐3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and β‐catenin, affecting the β‐catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR‐378a‐3p and the impact of its abnormal expression on the cell growth and invasion of HCC. Conclusions A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR‐378a‐3p was a putative biomarker for diagnosis and prognosis of HCC., A rational computer‐aided biomarker discovery model has been successfully applied to screen microRNA biomarker for hepatocellular carcinoma based on their unique regulatory and influential power in the microRNA‐mRNA network. MiR‐378a‐3p was identified and validated as a biomarker for HCC diagnosis and prognosis, it was shown independently regulated several important transcription factors including PLAGL2 and β‐catenin, then affected the β‐catenin signaling, which could be the potential mechanism for its function as a tumor suppressor and its abnormal expression could affect the cell growth and invasion of HCC

Glioblastoma multiforme (GBM) is the most malignant glioma with a high death rate. N6-methyladenosine (m6A) RNA methylation plays an increasingly important role in tumors. The current study aimed to determine the function of the regulators of m6A RNA methylation in GBM. We evaluated the difference, interaction, and correlation of these regulators with TCGA database. HNRNPC, WTAP, YTHDF2 and, YTHDF1 were significantly upregulated in GBM. To explore the expression characteristics of regulators in GBM, we defined two subgroups through consensus cluster. HNRNPC, WTAP, and YTHDF2 were significantly upregulated in the cluster2 which had a good overall survival (OS). To investigate the prognostic value of regulators, we used lasso cox regression algorithm to screen an independent prognostic risk characteristic based on the expression of HNRNPC, ZC3H13, and YTHDF2. The prognostic feature between the low and high-risk groups was significantly different (P < 0.05), which could predict significance of prognosis (area under the curve (AUC) = 0.819). Moreover, we used western blot, RT-PCR, and immunohistochemical staining to verify the expression of HNRNPC was associated with malignancy and development of gliomas. Similarly, the high expression of HNRNPC had a good prognosis. In conclusion, HNRNPC is a vital participant in the malignant progression of GBM and might be valuable for prognosis.

Aims: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. Methods and results: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1–3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ −10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35–1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09–1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09–1.26; P < 0.001 vs. 1.07, 95% CI 1.02–1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. Conclusions: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. Clinical Trial Registration: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

Proprotein convertase subtilisin/kexin (PCSK) family member 3 (FURIN) has been suggested to be involved in the development of atherosclerosis. The aim of this study was to investigate the prognostic implication of FURIN in patients after acute myocardial infarction (AMI).This prospective study analyzed data from a total of 1312 consecutive patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction from August 2013 to June 2016. FURIN levels were analyzed in plasma obtained from AMI patients.The study included 1312 AMI patients. The patient population was predominantly male (63%) with a median age of 66 years (IQR: 19 years), and 59% were STEMI patients. During a follow-up of 2 years, 117 patients died, and 377 patients reached the combined endpoints of major adverse cardiac events (MACE). Patients with elevated FURIN levels had increased risk of MACE, all-cause mortality, recurrent MI and hospitalization for HF (log-rank test, p 0.0001). After adjusting for clinical risk factors and established markers, the association of FURIN concentrations with the risk of MACE and its individual components and cardiovascular death was statistically significant in the higher tertile of FURIN concentrations. After the addition of FURIN to the models, FURIN showed additive prognostic significance for 2-year clinical outcomes. Variable importance plots of the models showed that FURIN was of high importance to predict both occurrence of MACE and all-cause mortality.We found that FURIN was associated with all-cause mortality and recurrent cardiovascular events in AMI patients independent of conventional risk factors and established markers.

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8399), and 70.6% were New York Heart Association class II (n = 5919 of 8399). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, β-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual’s risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

Aims: The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods and results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) ‘mildly abnormal’ QRS (110–129 ms) and 6506 (54.9%) QRS

Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). Results: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73–0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62–0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82–1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43–0.65]; P Conclusions: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00853658, NCT01035255.

Chronic inflammation is the primary cause of gastric cancer (GC). NLRP3, as an important inflammasome component, has crucial roles in initiating inflammation. However, the potential roles of NLRP3 in GC is unknown. Here, we show that NLRP3 expression is markedly upregulated in GC, which promotes NLRP3 inflammasome activation and interleukin-1β (IL-1β) secretion in macrophages. In addition, NLRP3 binds to cyclin-D1 (CCND1) promoter and promotes its transcription in gastric epithelial cells. Consequently, NLRP3 enhances epithelial cells proliferation and GC tumorigenesis. Furthermore, we identify miR-22, which is constitutively expressed in gastric mucosa, as a suppressor of NLRP3. MiR-22 directly targets NLRP3 and attenuates its oncogenic effects in vitro and in vivo. However, Helicobacter pylori (H. pylori) infection suppresses miR-22 expression, while enhances NLRP3 expression, and that triggers uncontrolled proliferation of epithelial cells and the emergence of GC. Thus, our research describes a mechanism by which miR-22 suppresses NLRP3 and maintains homeostasis of gastric microenvironments and suggests miR-22 as a potential target for the intervention of GC.

Gastric cancer (GC) is a highly metastatic disease and one of the leading causes of cancer death in the world. Aberrant glycosylation is one of many molecular changes that accompany malignant transformation. This study was aimed at identification of glycan profiling changes in GC progression and its potential mechanisms. We employed a microarray with 91 lectins to compare the differential glycans in the three human GC cell lines, SGC-7901, BGC-823 and MGC-803. According to glycan-binding specificities of lectins, all GC cell lines expressed common sugar structures, such as mannose, galactose and fucose. Importantly, we found that the binding of Maackia amurensis lectin-I (MAL-I) to GC cells was proportional to their metastatic capacity. Further analysis revealed that the level of α2,3-linked sialic acids (α2-3Sia), which can be recognized by MAL-I, was significantly overexpressed in MGC-803 cells, while low expression was detected in SGC-7901 cells. In addition, the mRNA and protein expression levels of β-galactoside α2,3-sialyltransferase IV (ST3Gal-IV), which was related to the synthesis of α2-3Sia, were substantially increased in MGC-803 cells. Knockdown of ST3Gal-IV in MGC-803 cells led to a decreased level of α2-3Sia and decreased ability of invasion and migration. Exogenous expression of ST3Gal-IV in SGC-7901 cells enhanced cell migration, invasion and the content of α2-3Sia. Furthermore, the staining of MAL-I in GC tissues showed that high expression of α2-3Sia was closely correlated with lymph node metastasis, TNM stage and poor overall survival. These findings lead to better understanding of the function of α2-3Sia in the progression and metastasis of GC. This property may be important for developing new therapeutic approaches for GC.

// Chenghao Hu 1,* , Xiaoxia Dong 2,* , Junbo Wu 3,* , Feifan Xiao 4,* , Jun Shang 5 , Liang Liu 6 , Yuan Yang 7 , Dongmei Luo 8 , Qiuting Li 9 , Qian Song 4 , Jingcheng Yang 7 , Chengdong Zhang 7 , Li Shen 1 and Zhiguo Luo 1 1 Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, PR China 2 Department of Pharmacology, School of Basic Medicine, Hubei University of Medicine, Shiyan, Hubei, PR China 3 Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, PR China 4 First Clinical Academy, Guangxi Medical University, Nanning, Guangxi, PR China 5 Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, PR China 6 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, PR China 7 School of Life Sciences, Fudan University, Shanghai, PR China 8 School of Mathematics and Physics, Anhui University of Technology, Maanshan, Anhui, PR China 9 Department of Clinical Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China * These authors have contributed equally to this work Correspondence to: Li Shen, email: // Zhiguo Luo, email: // Keywords : gastric cancer, CD147, original research, meta-analysis Received : October 07, 2016 Accepted : February 06, 2017 Published : February 25, 2017 Abstract Gastric cancer (GC) is one of the most common malignancies worldwide. The expression of CD147 protein is associated with GC. However, the clinical role of CD147 in GC has not been investigated extensively. Hence, we focused on studying the association between the expression of CD147 and clinicopathological features of GC patients in this study. Firstly, sixteen publications (1752 cases and 391 controls) and one from our own original research (143 cases) were included in the meta-analysis to obtain a more precise estimation of the diagnostic value of CD147. The results showed that expression rate of CD147 in the GC group is higher than that in control group. Moreover, gender, TNM stage, lymph node metastasis, and depth of invasion are all associated with CD147. Further, sections of gastric tissue from 143 cases underwent immunohistochemical staining for evaluation of CD147 protein expression. Our retrospective analysis demonstrated CD147 protein expression was significantly associated with clinical N stage, and tumor stage. Meanwhile, it can also serve as an independent prognosis biomarker. In conclusion, our results support the role of CD147 as a good indicator of diagnosis and prognosis.

The aim of the present study was to investigate the prognostic value of genes that participate in the development of gastric adenocarcinoma, via exploring gene cross talk in disease-related pathways. Differentially expressed genes (DEGs) in the gastric samples were identified by analyzing the expression data downloaded from the GEO database. The DEGs were subjected to the human protein-protein interaction (PPI) network to construct the PPI network of DEGs, which was then used for the identification of key genes in cancer samples via the expression deviation score and degree in the network. A total of 635 DEGs, including 432 downregulated and 203 upregulated ones were screened in the gastric adenocarcinomas samples. The PPI network of DEGs comprised 590 DEGs and 4,299 interaction pairs. A total of 200 key genes were obtained, which were significantly enriched in six downregulated and six upregulated pathways. Cross talk genes in the connected pathways were analyzed, and the Kyoto Encyclopedia of Genes and Genomes pathways hsa00980 (Metabolism of xenobiotics by cytochrome P450) and hsa00982 (Drug metabolism) were reported to share 8 cross talk genes: ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B and CYP2C18. Among all cross talk genes, ADH7, ALDH3A1 and CLDN3 were the most specific genes. The high- and low-risk samples identified by the prognosis model presented a remarkable difference in total survival time, indicating its robustness and sensitivity as the prognosis genes for gastric adenocarcinoma. ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B, CYP2C18ADH7, ALDH3A1 and CLDN3 may be used as the prognosis markers and target biomarkers for chemotherapies in gastric adenocarcinoma.

The aim of the study was to determine whether the Full Outline of UnResponsiveness (FOUR) score, which includes eyes opening (E), motor function (M), brainstem reflex (B), and respiratory pattern (R), can be used as an alternate method to the Glasgow Coma Scale (GCS) in predicting intensive care unit (ICU) mortality in traumatic brain injury (TBI) patients.From January 2015 to June 2015, patients with isolated TBI admitted to the ICU were enrolled. Three advanced practice nurses administered the FOUR score, GCS, Acute Physiology and Chronic Health Evaluation II (APACHE II), and Therapeutic Intervention Scoring System (TISS) concurrently from ICU admissions. The endpoint of observation was mortality when the patients left the ICU. Data are presented as frequency with percentages, mean with standard deviation, or median with interquartile range. Each measurement tool used area under the receiver operating characteristic curve to compare the predictive power between these four tools. In addition, the difference between survival and death was estimated using the Wilcoxon rank sum test.From 55 TBI patients, males (72.73 %) were represented more than females, the mean age was 63.1 ± 17.9, and 19 of 55 observations (35 %) had a maximum FOUR score of 16. The overall mortality rate was 14.6 %. The area under the receiver operating characteristic curve was 74.47 % for the FOUR score, 74.73 % for the GCS, 81.78 % for the APACHE II, and 53.32 % for the TISS. The FOUR score has similar predictive power of mortality compared to the GCS and APACHE II. Each of the parameters-E, M, B, and R-of the FOUR score showed a significant difference between mortality and survival group, while the verbal and eye-opening components of the GCS did not.Having similar predictive power of mortality compared to the GCS and APACHE II, the FOUR score can be used as an alternative in the prediction of early mortality in TBI patients in the ICU.

Objective To study the brain protective effect of dexmedetomidine (DEX) during surgery in paediatric patients with congenital heart disease (CHD). Methods This randomized single-blind controlled study enrolled paediatric patients aged 0–3 years with CHD who underwent surgery and randomized them into two groups: one group received DEX and the control group received 0.9% NaCl during anaesthesia. Demographic data, heart rate (HR), mean arterial pressure (MAP) and central venous pressure (CVP) were recorded. Levels of neuron specific enolase (NES) and S-100β protein were determined using enzyme-linked immunosorbent assays. Results The study enrolled 80 paediatric patients with CHD. Compared with the control group, HR, MAP and CVP were significantly lower in the DEX group at all time-points except for T0. At all time-points except for T0, the levels of jugular venous oxygen saturation in the DEX group were significantly higher compared with the control group. At all time-points except for T0, the levels of arterial venous difference and cerebral extraction of oxygen were significantly lower in the DEX group compared with the control group. Levels of NES and S-100β protein in the DEX group were significantly lower compared with the control group at all time-points except for T0. Conclusion DEX treatment during surgery for CHD improved oxygen metabolism in brain tissues and reduced the levels of NES and S-100β protein.

Objectives This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Background Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown. Methods Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses. Results Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro–B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses. Conclusions These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients.

Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non–small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. Cancer Res; 76(13); 3676–83. ©2016 AACR.