ABLE-SCORE, a simplified risk score for major adverse cardiovascular outcomes in left ventricular hypertrabeculation: a multicenter longitudinal cohort study.

BACKGROUND: Left ventricular hypertrabeculation (LVHT) is a heterogeneous entity with life-threatening complications and variable prognosis. However, there are limited prediction models available to identify individuals at high risk of adverse outcomes, and the current risk score in LVHT is comparatively complex for clinical practice. This study aimed to develop and validate a simplified risk score to predict major adverse cardiovascular events (MACE) in LVHT. METHODS: This multicenter longitudinal cohort study consecutively enrolled morphologically diagnosed LVHT patients between January 2009 and December 2020 at Fuwai Hospital (derivation cohort, n = 300; internal validation cohort, n = 129), and between January 2014 and December 2022 at two national-level medical centers (external validation cohort, n = 95). The derivation/internal validation cohorts and the external validation cohort were followed annually until December 2022 and December 2023, respectively. MACE was defined as a composite of all-cause mortality, heart transplantation/left ventricular assist device implantation, cardiac resynchronization therapy, malignant ventricular arrhythmia, and thromboembolism. A simplified risk score, the ABLE-SCORE, was developed based on independent risk factors in the multivariable Cox regression predictive model for MACE, and underwent both internal and external validations to confirm its discrimination, calibration, and clinical applicability. RESULTS: A total of 524 LVHT patients (43.5 ± 16.6 years, 65.8% male) were included in the study. The ABLE-SCORE was established using four easily accessible clinical variables: age at diagnosis, N-terminal pro-brain natriuretic peptide levels, left atrium enlargement, and left ventricular ejection fraction ≤ 40% measured by echocardiography. The risk score showed excellent performance in discrimination, with Harrell's C-index of 0.821 [95% confidence interval (CI), 0.772-0.869], 0.786 (95%CI, 0.703-0.869), and 0.750 (95%CI, 0.644-0.856) in the derivation, internal validation, and external validation cohort, respectively. Calibration plots of the three datasets suggested accurate agreement between the predicted and observed 5-year risk of MACE in LVHT. According to decision curve analysis, the ABLE-SCORE displayed greater net benefits than the existing risk score for LVHT, indicating its strength in clinical applicability. CONCLUSIONS: A simplified and efficient risk score for MACE was developed and validated using a large LVHT cohort, making it a reliable and convenient tool for the risk stratification and clinical management of patients with LVHT.

Associations of 50 modifiable risk factors with atrial fibrillation using Mendelian randomization analysis.

BACKGROUND: Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF. METHODS: Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses. RESULTS: Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF. CONCLUSIONS: This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.

Association between Hematocrit and Acute Kidney Injury in Patients with Acute Myocardial Infarction.

Backgrounds: Hematocrit is found an independent risk factor for acute kidney injury (AKI) in certain patients, but this effect in patients with acute myocardial infarction (AMI) is unclear. We aim to identify the relationship between hematocrit and AKI in patients with AMI. Methods: The patient data for the discovery and validation cohorts were extracted from the electronic Intensive Care Unit database and the Medical Information Mart for Intensive Care III database, respectively, to identify the relationship between hematocrit and AKI. With normal hematocrit as the reference, patients were divided into five groups based on the initial hematocrit value. The primary outcome was AKI during hospitalization. A multivariable logistic regression and a marginal effect analysis were used to evaluate the relationship between hematocrit and AKI. Results: In this study, a total of 9692 patients diagnosed with AMI were included, with 7712 patients in the discovery cohort and 1980 patients in the validation cohort. In the discovery cohort, hematocrit in 30-33%, 27-30% or < 27% were independent risk factors for AKI in the multivariate logistic analysis, with odds ratio (OR) of 1.774 (95% confidence interval [CI]: 1.203-2.617, p = 0.004), 1.834 (95% CI: 1.136-2.961, p = 0.013) and 2.577 (95% CI: 1.510-4.397, p < 0.001), respectively. Additionally, in the validation cohort, low hematocrit levels independently contributed to an increased risk of AKI among patients with AMI. During the analysis of marginal effects, a significant negative linear relationship between hematocrit levels and AKI was observed. Conclusions: Decreased hematocrit was an independent risk factor for AKI in patients with AMI. The relationship between hematocrit and AKI was negative linear.

Sex Differences in the Epidemiology, Risk Factors, and Prognosis of Malignant Ventricular Arrhythmias in Sepsis Patients.

Background: Women are frequently underrepresented in clinical trials and databases focusing on ventricular arrhythmias (VAs). However, understanding sex-based differences in risk factors and the prognosis of VAs is essential for tailoring personalized prevention and treatment strategies. This study aimed to investigate sex differences in the epidemiology, risk factors, and prognosis of VAs in patients with sepsis. Methods: We conducted a comprehensive analysis of 27,139 sepsis patients (mean [SD] age, 66.6 [16.2] years; 15,626 [57.6%] male), among whom 1136 (4.2%) developed VAs during their hospitalization. We evaluated VAs incidence and potential risk elements in both male and female patients, along with in-hospital mortality. Results: Men had a significantly higher likelihood of developing VAs compared to women (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.50-1.94, p < 0.001). In the case of non-ischemic cardiomyopathy (NICM), the association with VAs was stronger in men than in women (relative risk ratio [RRR] = 1.63, 95% CI: 1.10-2.40, interaction p = 0.014). Furthermore, we observed significant sex-specific interactions in the relationship between incident VAs, congestive heart failure (CHF) (RRR = 1.35, 95% CI: 1.03-1.76, interaction p = 0.031), and pneumonia (RRR = 1.33, 95% CI: 1.02-1.74, interaction p = 0.036) when considering the adjusted model. The presence of VAs was associated with a nearly twofold increase in the risk of in-hospital mortality, a result that was observed in both sexes. Conclusions: In sepsis patients, the emergence of VAs independently escalates the risk of in-hospital mortality, with a notable correlation between male sex and an increased VAs risk. The impacts of CHF, NICM and pneumonia on incident VAs were significantly influenced by sex.

Association of stress hyperglycemia ratio and mortality in patients with sepsis: results from 13,199 patients.

BACKGROUND: The stress hyperglycemia ratio (SHR), adjusted for average glycemic status, is suggested for assessing actual blood glucose levels. Its link with adverse outcomes is known in certain populations, yet its impact on sepsis patients' prognosis is unclear. This study explores the association between SHR and mortality in sepsis. METHODS: We included 13,199 sepsis patients in this study and categorized SHR into distinct groups. Additionally, we utilized restricted cubic spline analysis to evaluate the correlation between SHR as a continuous variable and mortality. The primary outcome was 1-year all-cause mortality. Logistic regression and Cox proportional hazards models were employed to assess the associations between the SHR and both in-hospital mortality and 1-year mortality, respectively. RESULTS: Among the study participants, 4,690 (35.5%) patients died during the 1-year follow-up. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and 1-year mortality. Using an SHR of 0.99 as the reference point, the hazard ratio for predicted 1-year mortality increased by 1.17 (95% CI 1.08 to 1.27) per standard deviation above 0.99, whereas each standard deviation increase predicted the hazard ratio of 0.52 (95% CI 0.39 to 0.69) below 0.99. Furthermore, we found that SHR could enhance the predictive performance of conventional severity scores. CONCLUSION: There exists a U shaped association between SHR and mortality in sepsis patients, where both low and high SHR values are associated with an increased risk of poor outcomes.

Machine learning for the prediction of 1-year mortality in patients with sepsis-associated acute kidney injury.

INTRODUCTION: Sepsis-associated acute kidney injury (SA-AKI) is strongly associated with poor prognosis. We aimed to build a machine learning (ML)-based clinical model to predict 1-year mortality in patients with SA-AKI. METHODS: Six ML algorithms were included to perform model fitting. Feature selection was based on the feature importance evaluated by the SHapley Additive exPlanations (SHAP) values. Area under the receiver operating characteristic curve (AUROC) was used to evaluate the discriminatory ability of the prediction model. Calibration curve and Brier score were employed to assess the calibrated ability. Our ML-based prediction models were validated both internally and externally. RESULTS: A total of 12,750 patients with SA-AKI and 55 features were included to build the prediction models. We identified the top 10 predictors including age, ICU stay and GCS score based on the feature importance. Among the six ML algorithms, the CatBoost showed the best prediction performance with an AUROC of 0.813 and Brier score of 0.119. In the external validation set, the predictive value remained favorable (AUROC = 0.784). CONCLUSION: In this study, we developed and validated a ML-based prediction model based on 10 commonly used clinical features which could accurately and early identify the individuals at high-risk of long-term mortality in patients with SA-AKI.

Prognostic value of high-sensitivity C-reactive protein in patients undergoing percutaneous coronary intervention with different glycemic metabolism status.

BACKGROUND: High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). METHODS: In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. RESULTS: After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29-2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05-1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. CONCLUSION: Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status.

Prognostic significance of the stress hyperglycemia ratio in critically ill patients.

BACKGROUND: The stress hyperglycemia ratio (SHR) has demonstrated a noteworthy association with unfavorable cardiovascular clinical outcomes and heightened in-hospital mortality. Nonetheless, this relationship in critically ill patients remains uncertain. This study aims to elucidate the correlation between SHR and patient prognosis within the critical care setting. METHODS: A total of 8978 patients admitted in intensive care unit (ICU) were included in this study. We categorized SHR into uniform groups and assessed its relationship with mortality using logistic or Cox regression analysis. Additionally, we employed the restricted cubic spline (RCS) analysis method to further evaluate the correlation between SHR as a continuous variable and mortality. The outcomes of interest in this study were in-hospital and 1-year all-cause mortality. RESULTS: In this investigation, a total of 825 (9.2%) patients experienced in-hospital mortality, while 3,130 (34.9%) individuals died within the 1-year follow-up period. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and both in-hospital and 1-year mortality. Specifically, within the SHR range of 0.75-0.99, the incidence of adverse events was minimized. For each 0.25 increase in the SHR level within this range, the risk of in-hospital mortality rose by 1.34-fold (odds ratio [OR]: 1.34, 95% CI: 1.25-1.44), while a 0.25 decrease in SHR within 0.75-0.99 range increased risk by 1.38-fold (OR: 1.38, 95% CI: 1.10-1.75). CONCLUSION: There was a U-shaped association between SHR and short- and long-term mortality in critical ill patients, and the inflection point of SHR for poor prognosis was identified at an SHR value of 0.96.

Outcomes of catheter ablation in high-risk patients with Brugada syndrome refusing an implantable cardioverter defibrillator implantation.

AIMS: The aim of this study was to investigate the outcomes of catheter ablation (CA) in preventing arrhythmic events among patients with symptomatic Brugada syndrome (BrS) who declined implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: A total of 40 patients with symptomatic BrS were included in the study, of which 18 refused ICD implantation and underwent CA, while 22 patients received ICD implantation. The study employed substrate modification (including endocardial and epicardial approaches) and ventricular fibrillation (VF)-triggering pre-mature ventricular contraction (PVC) ablation strategies. The primary outcomes were a composite endpoint consisting of episodes of VF and sudden cardiac death during the follow-up period. The study population had a mean age of 43.8 ± 9.6 years, with 36 (90.0%) of them being male. All patients exhibited the typical Type 1 BrS electrocardiogram pattern, and 16 (40.0%) were carriers of an SCN5A mutation. The Shanghai risk scores were comparable between the CA and the ICD groups (7.05 ± 0.80 vs. 6.71 ± 0.86, P = 0.351). Ventricular fibrillation-triggering PVCs were ablated in 3 patients (16.7%), while VF substrates were ablated in 15 patients (83.3%). Epicardial ablation was performed in 12 patients (66.7%). During a median follow-up of 46.2 (17.5-73.7) months, the primary outcomes occurred more frequently in the ICD group than in the CA group (5.6 vs. 54.5%, Log-rank P = 0.012). CONCLUSION: Catheter ablation is an effective alternative therapy for improving arrhythmic outcomes in patients with symptomatic BrS who decline ICD implantation. Our findings support the consideration of CA as an alternative treatment option in this population.

The causal associations of non-alcoholic fatty liver disease with blood pressure and the mediating effects of cardiometabolic risk factors: A Mendelian randomization study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is prevalent in hypertensive people, but the causal effect remains unclear. We employed Mendelian randomization (MR) approach to assess the causality between NAFLD and different blood pressure (BP) parameters. METHOD AND RESULTS: Instrumental variables for genetically predicted NAFLD, including chronically elevated serum alanine aminotransferase levels (cALT) and imaging and biopsy-confirmed NAFLD, were obtained from a genome-wide association study (N = 164,197). Multiple MR methods were implemented, including Inverse variance weighted, MR-Egger, Maximum likelihood, Weighted median, Simple median, Penalised weighted median, MR-RAPS, and cML-MA. Outliers were detected using MR-PRESSO, and pleiotropy was assessed using MR-Egger intercept and Phenoscanner. Heterogeneity was quantified using Cochran's Q and Rucker's Q' tests. Potential shared risk factors were analyzed to reveal the mediating effect. A higher genetic predisposition to cALT was causally associated with an increased risk of elevated BP levels, resulting in 0.65 mmHg (95% CI, 0.42-0.87), 0.38 mmHg (95% CI, 0.25-0.50) and 0.33 mmHg (95% CI, 0.22-0.44) higher for systolic BP, diastolic BP and pulse pressure, respectively. When more stringent criteria were used, imaging and biopsy-confirmed NAFLD showed a 1.12 mmHg (95% CI, 0.94-1.30) increase in SBP and a 0.55 mmHg (95% CI, 0.39-0.70) increase in DBP. Risk factor and mediation analyses suggested type 2 diabetes and fasting insulin levels might mediate the causal relationship between NAFLD and BP. CONCLUSION: The two-sample MR analyses showed robust causal effects of genetically predicted NAFLD on 3 different BP indices. The shared genetic profile between NAFLD and BP may suggest important therapeutic targets and early interventions for cardiometabolic risk factors.

Development and Validation of Machine Learning-Based Models to Predict In-Hospital Mortality in Life-Threatening Ventricular Arrhythmias: Retrospective Cohort Study.

BACKGROUND: Life-threatening ventricular arrhythmias (LTVAs) are main causes of sudden cardiac arrest and are highly associated with an increased risk of mortality. A prediction model that enables early identification of the high-risk individuals is still lacking. OBJECTIVE: We aimed to build machine learning (ML)-based models to predict in-hospital mortality in patients with LTVA. METHODS: A total of 3140 patients with LTVA were randomly divided into training (n=2512, 80%) and internal validation (n=628, 20%) sets. Moreover, data of 2851 patients from another database were collected as the external validation set. The primary output was the probability of in-hospital mortality. The discriminatory ability was evaluated by the area under the receiver operating characteristic curve (AUC). The prediction performances of 5 ML algorithms were compared with 2 conventional scoring systems, namely, the simplified acute physiology score (SAPS-II) and the logistic organ dysfunction system (LODS). RESULTS: The prediction performance of the 5 ML algorithms significantly outperformed the traditional models in predicting in-hospital mortality. CatBoost showed the highest AUC of 90.5% (95% CI 87.5%-93.5%), followed by LightGBM with an AUC of 90.1% (95% CI 86.8%-93.4%). Conversely, the predictive values of SAPS-II and LODS were unsatisfactory, with AUCs of 78.0% (95% CI 71.7%-84.3%) and 74.9% (95% CI 67.2%-82.6%), respectively. The superiority of ML-based models was also shown in the external validation set. CONCLUSIONS: ML-based models could improve the predictive values of in-hospital mortality prediction for patients with LTVA compared with traditional scoring systems.

The Host E3-Ubiquitin Ligase TRIM28 Impedes Viral Protein GP4 Ubiquitination and Promotes PRRSV Replication.

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is a highly pathogenic porcine virus that brings tremendous economic losses to the global swine industry. PRRSVs have evolved multiple elegant strategies to manipulate the host proteins and circumvent against the antiviral responses to establish infection. Therefore, the identification of virus-host interactions is critical for understanding the pathogenesis of PRRSVs. Tripartite motif protein 28 (TRIM28) is a transcriptional co-repressor involved in the regulation of viral and cellular transcriptional programs; however, its precise role in regulating PRRSV infection remains unknown. In this study, we found that the mRNA and protein levels of TRIM28 were up-regulated in PRRSV-infected porcine alveolar macrophages (PAMs) and MARC-145 cells. Ectopic TRIM28 expression dramatically increased viral yields, whereas the siRNA-mediated knockdown of TRIM28 significantly inhibited PRRSV replication. Furthermore, we used a co-immunoprecipitation (co-IP) assay to demonstrate that TRIM28 interacted with envelope glycoprotein 4 (GP4) among PRRSV viral proteins. Intriguingly, TRIM28 inhibited the degradation of PRRSV GP4 by impeding its ubiquitination. Taken together, our work provides evidence that the host E3-ubiquitin ligase TRIM28 suppresses GP4 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM28, as a potential target in the development of anti-viral drugs against PRRSV.

Clinical use of tumor biomarkers in prediction for prognosis and chemotherapeutic effect in esophageal squamous cell carcinoma.

BACKGROUND: Growing evidence has indicated that tumor biomarkers, including cytokeratin 19 fragment antigen 21-1 (Cyfra21-1), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4), carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag) were reported to be commonly used in diagnosis and prognosis in esophageal squamous cell carcinoma (ESCC). However, which is the best marker for predicting prognosis remains unknown. Few papers focused on the relationship between tumor biomarkers and postoperative treatment in ESCC. METHODS: A total of 416 ESCC patients were enrolled in this study. The association between tumor markers and overall survival (OS) was analyzed using Kaplan-Meier method with log-rank test, followed by multivariate Cox regression models. RESULTS: The results of Cox multivariate analysis indicated that among these tumor biomarkers, CA19-9 (≥ 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (≥ 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS. For the ESCC patients with CA19-9 < 37, CEA < 5 or SCC-Ag < 1.5, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05), but this significant difference of OS between these two groups cannot be found in patients with CA19-9 ≥ 37, CEA ≥ 5 or SCC-Ag ≥ 1.5 (p > 0.05). CONCLUSIONS: CEA and CA19-9 maybe are superior to other tumor biomarkers as prognostic indicators in ESCC. CA19-9, CEA, SCC-Ag may be useful in predicting the therapeutic effect of postoperative chemotherapy in ESCC.

miR-221 and miR-222 synergistically regulate hepatocyte growth factor activator inhibitor type 1 to promote cell proliferation and migration in gastric cancer.

Gastric cancer is a common malignancy with limited treatment options and poor prognosis. Introduction of novel pathways of gastric cancer will provide candidates for target therapy. Hepatocyte growth factor activator inhibitor type 1 is an integral-membrane proteinase inhibitor. Hepatocyte growth factor activator inhibitor type 1 abnormality is found in various cancers and correlates with tumor progression and metastasis. However, the mechanisms underlying the dysregulation of hepatocyte growth factor activator inhibitor type 1 expression in gastric cancer remain unclear. Although microRNAs have been reported to be involved in the development of cancer, the roles of miR-221 and miR-222 in gastric cancer have not been reported yet. In this study, we showed that hepatocyte growth factor activator inhibitor type 1 protein was downregulated, while miR-221 and miR-222 were significantly increased in gastric cancer tissues. Bioinformatic predictions and luciferase assay verified that the 3'-untranslated region of the HAI-1 gene is a direct target site for miR-221 and miR-222. Overexpression of miR-221 and miR-222 in MGC-803 cells leads to the inhibition of hepatocyte growth factor activator inhibitor type 1 protein expression, thus promoting cell proliferation and migration; whereas knockdown of miR-221 and miR-222 showed opposite effects. Moreover, we found that the expression level of hepatocyte growth factor activator protein was increased when hepatocyte growth factor activator inhibitor type 1 was knocked down in MGC-803 cells. Thus, gastric cancer is probably an autocrine tumor, and the antitumor mechanism of hepatocyte growth factor activator inhibitor type 1 in vitro might be mediated by regulating the expression of hepatocyte growth factor activator protein. Therefore, our data illustrated a novel pathway comprising miR-221and miR-222 and hepatocyte growth factor activator inhibitor type 1 in gastric cancer, which is a potential target for future clinical use.

MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer.

BACKGROUND: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. METHODS: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. RESULTS: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR-520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. CONCLUSIONS: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC.

Direct targeting of HGF by miR-16 regulates proliferation and migration in gastric cancer.

MicroRNAs (miRNAs) have been reported to be involved in each stage of tumor development in various types of cancers. We have previously showed that miR-16 is downregulated in cancer and acts as a tumor suppressor. Other studies indicated that hepatocyte growth factor (HGF)/c-Met is implicated in proliferation, migration, and other pathophysiological processes. However, little is known about the relationship between miR-16 and HGF/c-Met in gastric cancer (GC). In the present study, we used bioinformatics tools and related experiments to search for miRNAs targeting HGF. Here, we found that miR-16 suppressed HGF protein expression by directly targeting 3'-untranslated region (UTR) of HGF mRNA. Subsequently, it was illustrated the downregulation of miR-16 promotes, while overexpressed of miR-16 significantly inhibits cell proliferation and migration by negatively regulating HGF/c-Met pathway. Moreover, the biological role of HGF in GC cells was determined by using HGF siRNA and HGF-overexpressing plasmid, respectively. To conclude, our results provide a potential target by using miR-16 for the future clinical treatment of GC.

Prognostic nomogram for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy followed by adjuvant chemotherapy.

OBJECTIVE: The aim of the study was to establish an effective prognostic nomogram for esophageal squamous cell carcinoma after radical esophagectomy followed by adjuvant chemotherapy in those previously untreated patients. METHODS: The clinicopathological data from 328 patients who underwent radical esophagectomy followed by adjuvant chemotherapy or not at the Tianjin Medical University Cancer Institute and Hospital between 2006 and 2010 were retrospectively studied. Nomograms which predicted survival of esophageal squamous cell carcinoma were established based on the Cox proportional hazards regression model. To determine its predictive accuracy and discriminatory capacity, the concordance index and calibration curve were calculated after bootstrapping in the internal validation. An external validation of 76 patients in 2011 was prospectively studied at the same institution. To verify the performance of the nomogram, the comparison between the nomogram and Tumor-Node-Metastasis staging system was conducted. RESULTS: The 5-year overall survival was 43.1% in the primary cohort. Based on multivariate analyses, five independent prognostic variables including gender, tumor length, T stage, N stage and chemotherapy cycles were selected to build the nomograms to predict disease-free survival and overall survival. The concordance index of the nomogram to predict overall survival was 0.71 (95% confidence interval, 0.63-0.79), which was superior to the predictive power of Tumor-Node-Metastasis staging system (0.64) in the primary cohort. Meanwhile, the calibration curve showed good accuracy between predictive and actual overall survival. In the validation cohort, the concordance index (0.77) and calibration plot displayed favorable performances. The other nomogram to predict disease-free survival also performed well. CONCLUSIONS: The prognostic nomogram provided individualized risk estimate of survival in patients after esophagectomy followed by adjuvant chemotherapy.

A Meta-Analysis of Palonosetron for the Prevention of Postoperative Nausea and Vomiting in Adults.

PURPOSE: The aim of this meta-analysis was to evaluate the effectiveness and adverse effects of palonosetron in the prevention of postoperative nausea and vomiting (PONV). DESIGN: A meta-analysis using a systematic search strategy was performed. METHODS: A meta-analysis of randomized controlled clinical trials was performed to compare palonosetron with first-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) or placebo to prevent PONV. Fixed or random effect models were used to combine homogenous data. FINDINGS: A total of 10 randomized controlled clinical trials including 1,827 patients were identified. The data showed statistically significant differences in favor of palonosetron (0.075 mg) in the prevention of acute PONV (P < .00001) and delayed PONV (P < .002), reducing the risk of PONV by 49% and 51%, respectively. Subgroup analyses indicated significant differences in favor of palonosetron compared with placebo (P < .00001) or first-generation 5-HT3RA (P = .002). There were no significant differences in the occurrence of headache, dizziness, and constipation between palonosetron and control groups (P = .85, P = .22, and P = .30, respectively). CONCLUSIONS: The results of this meta-analysis suggest that intravenous palonosetron could become a prophylactic antiemetic 5-HT3RA in the prevention of PONV compared with first-generation 5-HT3RAs or placebo. No increased risk of side effects with palonosetron were found.

The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer.

Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19 ± 0.70 vs. 3.65 ± 0.90 g/l, p = 0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p < 0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p < 0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p = 0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p = 0.027), tumor stage (p = 0.026) and distant metastasis (p = 0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2-13.0), 3.8 months (95% CI 2.3-5.3), and 2.3 months (95% CI 0.9-3.7), respectively (p = 0.000). Pretreatment plasma fibrinogen and platelet levels closely correlated with tumor progression, metastasis and overall survival in pancreatic cancer. The foundation of prognostic model may help us identify the greatest risk populations with pancreatic cancer.

Electrocardiographic tracking of left ventricular hypertrophy in hypertension: incidence and prognostic outcomes from the SPRINT trial.

BACKGROUND: This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data. METHODS: Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events. RESULTS: In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p<0.001) and increased LVH regression (14.89 vs. 11.89 per 1000-person years; adjusted p<0.001). Elevated ACE risk was notable in participants with pre-existing LVH [adjusted HR: 1.94 (95% CI: 1.25-2.99); p = 0.003], new-onset LVH [adjusted 1.74 (95% CI: 1.16-2.60); p = 0.007], and persistent LVH[adjusted HR: 1.96 (95% CI: 1.11-3.46); p = 0.020], compared to those without LVH. Intriguingly, LVH regression attenuated this risk increment [adjusted HR: 1.57 (95% CI: 0.98-2.53); p = 0.062]. Achieving a BP target of < 120/80 mmHg nullified the increased ACE risk in those with pre-existing LVH. CONCLUSIONS: Intensive BP control is instrumental in both reducing the emergence of LVH and fostering its regression. Pre-existing, new-onset LVH and persistent LV remain a predictor of adverse cardiovascular prognosis, whereas LVH regression and achieving on-treatment BP < 120/80 mmHg in pre-existing LVH individuals may further mitigate residual cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov Unique Identifier: NCT01206062.