Renal nerve stimulation identifies renal innervation and optimizes the strategy for renal denervation in canine.

BACKGROUND: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. METHODS: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. RESULTS: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). CONCLUSIONS: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

Activating transcription factor 4 regulates angiogenesis under lipid overload via methionine adenosyltransferase 2A-mediated endothelial epigenetic alteration.

Lipid overload is intimately connected with the change of endothelial epigenetic status which impacts cellular signaling activities and endothelial function. Activating transcription factor 4 (ATF4) is involved in the regulation of lipid metabolism and meanwhile an epigenetic modifier. However, the role of ATF4 in the angiogenesis under lipid overload is not well understood. Here, to induce lipid overload status, we employed high-fat diet (HFD)-induced obese mouse model in vivo and palmitic acid (PA) to stimulate endothelial cells in vitro. Compared with mice fed with normal chow diet (NCD), HFD-induced obese mice showed angiogenic defects evidenced by decline in (1) blood flow recovery after hind limb ischemia, (2) wound healing speed after skin injury, (3) capillary density in injured tissues and matrigel plugs, and (4) endothelial sprouts of aortic ring. ATF4 deficiency aggravated above angiogenic defects in mice while ATF4 overexpression improved the blunted angiogenic response. Mechanistically, lipid overload lowered the H3K4 methylation levels at the regulatory regions of NOS3 and ERK1 genes, leading to reduced angiogenic signaling activity. Methionine adenosyltransferase 2A (MAT2A) is identified as a target of ATF4 and formed complex with ATF4 to direct lysine methyltransferase 2A (MLL1) to the regulatory regions of both genes for the maintenance of the H3K4 methylation level and angiogenic signaling activity. Here, we uncovered a novel metabolic-epigenetic coupling orchestrated by the ATF4-MAT2A axis for angiogenesis. The ATF4-MAT2A axis links lipid overload milieu to altered epigenetic status of relevant angiogenic signaling in endothelial cells, suggesting a potential therapeutic target for angiogenesis impaired by lipid overload.

STING recognition of cytoplasmic DNA instigates cellular defense.

How the cell recognizes cytosolic DNA including DNA-based microbes to trigger host-defense-related gene activation remains to be fully resolved. Here, we demonstrate that STING (stimulator of interferon genes), an endoplasmic reticulum translocon-associated transmembrane protein, acts to detect cytoplasmic DNA species. STING homodimers were able to complex with self- (apoptotic, necrotic) or pathogen-related ssDNA and dsDNA and were indispensible for HSV-1-mediated transcriptional activation of a wide array of innate immune and proinflammatory genes in addition to type I IFN. Our data indicate that STING instigates cytoplasmic DNA-mediated cellular defense gene transcription and facilitates adoptive responses that are required for protection of the host. In contrast, chronic STING activation may manifest inflammatory responses and possibly autoimmune disease triggered by self-DNA.

The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction.

Stromal cell-derived factor-1 (SDF-1) is a well-characterized cytokine that protects heart from ischaemic injury. However, the beneficial effects of native SDF-1, in terms of promoting myocardial repair, are limited by its low concentration in the ischaemic myocardium. Annexin V (AnxA5) can precisely detect dead cells in vivo. As massive cardiomyocytes die after MI, we hypothesize that AnxA5 can be used as an anchor to carry SDF-1 to the ischaemic myocardium. In this study, we constructed a fusion protein consisting of SDF-1 and AnxA5 domains. The receptor competition assay revealed that SDF-1-AnxA5 had high binding affinity to SDF-1 receptor CXCR4. The treatment of SDF-1-AnxA5 could significantly promote phosphorylation of AKT and ERK and induce chemotactic response, angiogenesis and cell survival in vitro. The binding membrane assay and immunofluorescence revealed that AnxA5 domain had the ability to specifically recognize and bind to cells injured by hypoxia. Furthermore, SDF-1-AnxA5 administered via peripheral vein could accumulate at the infarcted myocardium in vivo. The treatment with SDF-1-AnxA5 attenuated cell apoptosis, enhanced angiogenesis, reduced infarcted size and improved cardiac function after mouse myocardial infarction. Our results suggest that the bifunctional SDF-1-AnxA5 can specifically bind to dead cells. The systemic administration of bifunctional SDF-1-AnxA5 effectively provides cardioprotection after myocardial infarction.

Cutting Edge: Innate Immune Augmenting Vesicular Stomatitis Virus Expressing Zika Virus Proteins Confers Protective Immunity.

Zika virus (ZIKV) has become a serious public health concern because of its link to brain damage in developing human fetuses. Recombinant vesicular stomatitis virus (rVSV) was shown to be a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. In this study, we generated rVSVs (wild-type and attenuated VSV with mutated matrix protein [VSVm] versions) that express either the full length ZIKV envelope protein (ZENV) alone or include the ZENV precursor to the membrane protein upstream of the envelope protein, and our rVSV-ZIKV constructs showed efficient immunogenicity in murine models. We also demonstrated maternal protective immunity in challenged newborn mice born to female mice vaccinated with VSVm-ZENV containing the transmembrane domain. Our data indicate that rVSVm may be a suitable strategy for the design of effective vaccines against ZIKV.

The triglyceride paradox in the mortality of coronary artery disease.

BACKGROUND: The role of triglyceride (TG) in secondary prevention of patients with coronary artery disease (CAD) was debated. In the present study, we assessed the association between admission TG levels and long-term mortality risk in CAD patients. METHODS: A retrospective analysis was conducted from a single registered database. 3061 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into 3 categories by the tertiles of admission serum TG levels. The primary end point in this study was all-cause mortality and the secondary end point was cardiovascular mortality. RESULTS: The mean follow-up time was 26.9 ± 13.6 months and death events occurred in 258 cases and cardiovascular death events occurred in 146 cases. Cumulative survival curves indicated that the risk of all-cause death decreased with increasing TG level (Tertile 1 vs. Tertile 2 vs. Tertile 3 = 10.3% vs. 8.6% vs. 6.3%, log rank test for overall p = 0.001). Cox regression analysis showed an independent correlation between TG level and risk of all-cause mortality [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.86] and cardiovascular mortality (HR 0.67, 95% CI 0.51-0.89) in total patients with CAD. Subgroup analysis found the similar results in patients with acute coronary syndrome and acute myocardial infarction. CONCLUSIONS: This study found an inverse association between TG levels and mortality risk in CAD patients, which suggests that the "TG paradox" may exist in CAD patients. TRIAL REGISTRATION: ChiCTR, ChiCTR-OOC-17010433 . Registered 17 February 2017 - Retrospectively registered.

Influence of age on the effect of reduced renal function on outcomes in patients with coronary artery disease.

BACKGROUND: Ageing is a risk factor for both coronary artery disease (CAD) and reduced renal function (RRF), and it is also associated with poor prognosis in patients with CAD or RRF. However, little is known about whether the impact of RRF on clinical outcomes are different in CAD patients at different age groups. This study aimed to investigate whether ageing influences the effect of RRF on long-term risk of death in patients with CAD. METHODS: A retrospective analysis was conducted using data from a single-center cohort study. Three thousand and two consecutive patients with CAD confirmed by coronary angiography were enrolled. RRF was defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min. The primary endpoint in this study was all-cause mortality. RESULTS: The mean follow-up time was 29.1 ± 12.5 months and death events occurred in 275 cases (all-cause mortality: 9.2%). The correlation analysis revealed a negative correlation between eGFR and age (r = - 0.386, P < 0.001). Comparing the younger group (age ≤ 59) with the elderly one (age ≥ 70), the prevalence of RRF increased from 5.9 to 27.5%. Multivariable Cox regression revealed that RRF was independently associated with all-cause mortality in all age groups, and the relative risks in older patients were lower than those in younger ones (age ≤ 59 vs. age 60-69 vs. age ≥ 70: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.04-6.37 vs. HR 2.00, 95% CI 1.17-3.42 vs. HR 1.46, 95% CI 1.06-2.02). There was a significant trend for HRs for all-cause mortality according to the interaction terms for RRF and age group (RRF*age [≤59] vs. RRF*age [60-69] vs. RRF*age [≥70]: HR 1.00[reference] vs. HR 0.60, 95% CI 0.23-1.54 vs. HR 0.32, 95% CI 0.14-0.75; P for trend = 0.010). CONCLUSIONS: RRF may have different impacts on clinical outcomes in CAD patients at different age groups. The association of RRF with the risk of all-cause mortality was attenuated with ageing.

Efficacy of Different Types of Exercise-Based Cardiac Rehabilitation on Coronary Heart Disease: a Network Meta-analysis.

BACKGROUND: Exercise-based cardiac rehabilitation (CR) has been recognized as an essential component of the treatment for coronary heart disease (CHD). Determining the efficacy of modern alternative treatment methods is the key to developing exercise-based CR programs. METHODS: Studies published through June 6, 2016, were identified using MEDLINE, EMBASE, and the Cochrane Library. English-language articles regarding the efficacy of different modes of CR in patients with CHD were included in this analysis. Two investigators independently reviewed abstracts and full-text articles and extracted data from the studies. According to the categories described by prior Cochrane reviews, exercise-based CR was classified into center-based CR, home-based CR, tele-based CR, and combined CR for this analysis. Outcomes included all-cause mortality, cardiovascular death, recurrent fatal and/or nonfatal myocardial infarction, recurrent cardiac artery bypass grafting, recurrent percutaneous coronary intervention (PCI), and hospital readmissions. RESULTS: Sixty randomized clinical trials (n = 19,411) were included in the analysis. Network meta-analysis (NMA) demonstrated that only center-based CR significantly reduced all-cause mortality (center-based: RR = 0.76 [95% CI 0.64-0.90], p = 0.002) compared to usual care. Other modes of CR were not significantly different from usual care with regard to their ability to reduce mortality. Treatment ranking indicated that combined CR exhibited the highest probability (86.9%) of being the most effective mode, but this finding was not statistically significant due to the small sample size (combined: RR = 0.50 [95% CI 0.20-1.27], p = 0.146). CONCLUSIONS: Current evidence suggests that center-based CR is acceptable for patients with CHD. As home- and tele-based CR can save time, money, effort, and resources and may be preferred by patients, their efficacy should be investigated further in subsequent studies.

The impact of age on the implementation of evidence-based medications in patients with coronary artery disease and its prognostic significance: a retrospective cohort study.

BACKGROUND: Elderly patients with coronary artery disease (CAD) frequently complicated with more cardiovascular risk factors, but received fewer evidence-based medications (EBMs). This study explored the association of EBMs compliance in different age groups and the risk of long-term death. METHODS: A retrospective analysis was conducted from a single registered database. 2830 consecutive patients with CAD were enrolled and grouped into 3 categories by age. The primary end point was all-cause mortality and secondary endpoint is cardiovascular mortality. RESULTS: The mean follow-up time was 30.25 ± 11.89 months and death occurred in 270 cases,including 150 cases of cardiac death. Cumulative survival curves indicated that the incidence rates of all-cause death and cardiovascular death increased with age (older than 75 years old vs. 60 to 75 years old vs. younger than 60 years old, mortality: 18.7% vs. 9.6% vs. 4.1%, p < 0.001; cardiovascular mortality: 10.3% vs. 5.1% vs. 2.7%, p < 0.001). The percentage of elderly patients using no EBMs was significantly higher than the percentages in the other age group (7.7% vs. 4.6% vs. 2.2%,p < 0.05). Cox regression analysis revealed the benefit of combination EBMs (all-cause mortality: hazard ratio [HR] 0.15, 95% CI 0.08-0.27; cardiac mortality: HR 0.08, 95% CI 0.04-0.19) for older CAD patients. Similar trends were found about different kinds of EBMs in elderly patients. CONCLUSIONS: Elderly patients with CAD had higher risk of death but a lower degree of compliance with EBMs usage. Elderly CAD patients could receive more clinical benefits by using EBMs.

No modifying effect of nutritional status on statins therapy in relation to all-cause death in older patients with coronary artery disease.

BACKGROUND: Statins therapy in the secondary prevention of coronary artery disease (CAD) is associated with a lower risk of adverse cardiovascular events. However, little is known regarding the association of elderly patients with nutritional risk on statin therapy. AIMS: To investigate whether older patients with CAD who were at nutritional risk gain similar survival benefit from statins therapy as their counterparts without nutritional risk. METHODS: We conducted a retrospective hospital-based cohort study among 1705 patients with CAD who were older than 65 years of age, using coronary heart disease database from 2008 to 2012. Nutritional status of included patients was gauged using the geriatric nutritional risk index. After stratification by nutritional status, the hazard of all-cause death was compared between those with or without statins therapy. RESULTS: Of the 1705 patients included in the study (mean age 72 years; 73% male), all-cause death occurred in 146 (9.2%) patients with statins use and in 33 (26.2%) patients without statins use. The rate of all-cause death was higher in patients not receiving statins irrespective of nutritional status. After adjustments for potential confounders, the HR with statins use was 0.33 (95% CI 0.20-0.55) in patients without nutritional risk and 0.47 (95% CI 0.22-1.00) in patients with nutritional risk. No interaction effect was detected between nutritional status and statins use in relation to all-cause death (P value for interaction effect 0.516). CONCLUSION: Despite of the patient's nutritional status, statins therapy as a secondary prevention in elderly CAD patients was associated with decreased risk of all-cause death.

Body Composition and Mortality in Coronary Artery Disease With Mild Renal Insufficiency in Chinese Patients.

OBJECTIVE: Obesity is a risk factor for both coronary artery disease (CAD) and chronic renal insufficiency (RI); patients with CAD are prone to obesity and RI. In this study, we try to analyze the effect of body composition on death in CAD patients with mild RI. DESIGN: Retrospective cohort study. SUBJECTS: A total of 1,591 consecutive CAD patients confirmed by coronary angiography were enrolled and met the mild RI criteria by estimated glomerular filtration rate: 60-90 mL/min. MAIN OUTCOME MEASUREMENTS: The influence of body composition on mortality of CAD was detected in different body compositions, including body mass index (BMI), body fat (BF), and lean mass index (LMI). The end points were all-cause mortality. Cox models were used to evaluate the relationship of quintiles of body compositions with all-cause mortality. RESULTS: A survival curve showed that the risk of death was higher in the low BMI group than in the high BMI group (log-rank for overall P = .002); LMI was inversely correlated with risk of death, such that a lower LMI was associated with a higher risk of death (log-rank for overall P < .001). No significant correlation was observed between BF and risk of death. Multifactorial correction show that LMI was still inversely correlated with risk of death (quintile 1: reference; quintile 2: hazard ratio [HR]: 0.49, 95% confidence interval [CI]: 0.26-0.92; quintile 3: HR: 0.35, 95% CI: 0.17-0.70; quintile 4: HR: 0.41, 95% CI: 0.20-0.85; quintile 5: HR: 0.28, 95% CI: 0.12-0.67). CONCLUSION: For CAD patients with mild RI, BMI or BF was unrelated to risk of death, while LMI was inversely correlated with risk of death. A weak "obesity paradox" was observed in this study.

The influence of body composition on the N-terminal pro-B-type natriuretic peptide level and its prognostic performance in patients with acute coronary syndrome: a cohort study.

BACKGROUND: Whether body composition is associated with the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and its prognostic performance in acute coronary syndrome (ACS) remains unknown. We aimed to investigate the influence of body composition on the NT-proBNP level and its prognostic performance among ACS patients. METHODS: In total, 1623 ACS patients with NT-proBNP data were enrolled. Percent body fat and lean mass index were estimated using the Clínica Universidad de Navarra-Body Adiposity Estimator equation. Patients were divided into three groups according to the tertiles of sex-specific body mass index, percent body fat, or lean mass index. The endpoints were death from any cause and cardiovascular death. RESULTS: Body mass index was inversely correlated with NT-proBNP levels (ß = -0.036, P = 0.003). Lean mass index, but not percent body fat, was inversely associated with NT-proBNP levels (ß of lean mass index = -0.692, P = 0.002). During a median follow-up of 23 months, 161 all-cause deaths occurred, and of these, 93 (57.8 %) were attributed to cardiovascular causes. Multivariate Cox analysis showed that the NT-proBNP level independently predicted all-cause mortality or cardiovascular death in the lower body mass index, lean mass index, and percent body fat groups. However, the prognostic performance of NT-proBNP was attenuated in patients with high body mass index, lean mass index, and percent body fat. In the subgroup of patients with diabetes, inverse associations between NT-proBNP levels and body mass index or body composition were not observed. In addition, the negative influence of high body mass index and body composition on the prognostic performance of the NT-proBNP level appeared to be attenuated. CONCLUSIONS: Body mass index and lean mass index, but not percent body fat, are inversely associated with NT-proBNP levels. The prognostic performance of this biomarker may be compromised in patients with high body mass index, percent body fat, or lean mass index. Additionally, the influence of body composition on the NT-proBNP level and its prognostic performance might be attenuated in diabetic patients with ACS.

The influence of body composition on renal function in patients with coronary artery disease and its prognostic significance: a retrospective cohort study.

OBJECTIVE: We try to analyse the effect of renal functions on death in CAD patients with different body compositions. METHODS: A retrospective analysis was conducted in 2989 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into two categories: basically preserved renal function (PRF) (eGFR ≥60 ml/min) and obviously reduced renal function (RRF) (eGFR <60 ml/min). The influence of renal insufficiency on mortality of CAD was detected in every tertile of body composition, including body mass index (BMI), body fat (BF) and lean mass index (LMI). The end points were all-cause mortality. RESULTS: The mean follow-up time was 29.1 ± 12.5 months and death events occurred in 271 cases. The percentage of patients with RRF was positively correlated with BF and inversely correlated with the LMI, but no relationship to BMI. The survival curves showed that the risk of death was significantly higher in the RRF patients in all subgroups stratified using BMI, BF, or LMI (log rank test, all p < 0.001). The COX multivariate regression analysis showed that the risk of death was significantly higher in the RRF patients with high BF (HR 1.95, CI 1.25-3.05) and low LMI (HR 1.82, CI 1.19-2.79). Meanwhile, risk of death was significantly higher in RRF patients with a high BMI (HR 2.08, CI 1.22-3.55) or low BMI (HR 1.98, CI 1.28-3.08) but this risk was not significant in patients with a medium BMI (HR 1.12, 0.65-1.94). The subgroup analysis of patients with acute coronary syndrome (ACS) showed similar results. CONCLUSIONS: For patients with CAD, renal insufficiency was positively correlated with BF, inversely correlated with LMI, and unrelated to BMI. The effect of renal insufficiency on the risk of death of CAD was related to body composition.

Relation between serum calcium levels and mortality in patients with coronary artery disease.

OBJECTIVES: Calcium has a critical role in a spectrum of biological processes related to cardiovascular disease. This study aimed to evaluate associations of baseline serum calcium levels with both short-term and long-term outcomes in CAD patients. MATERIALS AND METHODS: 3109 consecutive patients with angiography confirmed CAD, admitted to West China hospital of Sichuan University between July 2008 and September 2012 were enrolled and were categorized into quartiles according to admission serum calcium to determine the association of serum calcium level with in-hospital and long-term mortality by multivariable Logistic and Cox regression analysis respectively. RESULTS: The admission serum calcium was normally distributed with a mean level of 2.20±0.15 mmol/L. A total of 259 deaths, including 58 in-hospital deaths, occurred during a mean follow-up of 20 months. Patients in the upper quartiles of serum calcium, as compared to the lowest quartile of serum calcium, were presented with lower in-hospital mortality [HR was 0.391 (95% CI: 0.188-0.812), 0.231(95% CI: 0.072-0.501) and 0.223 (95% CI: 0.093-0.534) for three upper quartiles versus lowest quartile respectively] and long-term mortality [HR was 0.614 (95% CI: 0.434-0.869), 0.476(95% CI: 0.294-0.698) and 0.553 (95% CI: 0.349-0.777) respectively]. Similar association between serum calcium and long-term mortality as showed in total cohort were also obtained when restricting analyses to subgroups: stable CAD patients, ACS patients and discharged patients. CONCLUSIONS: As a widely available clinical index, serum calcium was an independent predictor of both in-hospital and long-term mortality among CAD patients. Further studies are warranted to determine mechanisms and whether patients with hypocalcaemia could benefit from calcium supplement.

Association Between Bisphosphonates Therapy and Incident Myocardial Infarction: Meta-analysis and Trial Sequential Analysis.

BACKGROUND: Bisphosphonates have shown potential to inhibit atherosclerosis in animal experiments; however, whether bisphosphonates therapy lowers the risk of incidence of myocardial infarction (MI) is debated. We performed the meta-analysis and trial sequential analysis (TSA) to investigate the relation between bisphosphonates therapy and incident MI. METHODS: Pubmed and Embase databases were systematically searched in April 2015 to identify studies, which compared the incidence of MI in subjects receiving bisphosphonates with that in subjects not receiving the agents. Meta-analysis was conducted using random effects model in consideration of statistical heterogeneity between studies. Reliability of the results from meta-analysis was examined using TSA. RESULTS: Six observational studies (n = 440261) and 3 randomized control trials (RCTs, n = 11,024) met the eligible criteria. In the pooled analysis of observational studies, bisphosphonates therapy was not associated with reduced risk of MI either using unadjusted estimates (relative risk 0.93, 95% confidence interval (CI), 0.75-1.15) or estimates adjusted for confounding factors (hazard ratio 1.01, 95% CI, 0.84-1.21). Furthermore, hazard of incident MI did not differ between alendronate users and nonusers. TSA showed that evidence from observational studies firmly precluded the association between bisphosphonates and incident MI. Pooled analysis of RCTs also suggested no benefits of decrease in incident MI associated with bisphosphonates therapy (relative risk 1.05, 95% CI, 0.53-2.09). However, TSA demonstrated that evidence from RCTs was insufficient to draw a conclusion. CONCLUSIONS: Despite the encouraging findings from animal studies, bisphosphonates therapy is not associated with reduced risk of MI.

Current problems in renal denervation and a hope to break the stage.

Renal denervation (RDN) is currently confronted with the considerable heterogeneity of different post-procedural blood pressure responses. The challenges predominantly arise from not only the lack of selection of appropriate responders but also the absence of detection for the successful endpoints of intervention. In this paper, we summarize the significant characteristics of potentially appropriate hypertensive patients and propose a hopeful way to improve the accuracy of RDN, that is, the application of three-dimensional reconstruction technology combined with electrical renal nerve stimulation to guide the radiofrequency catheter ablation, which may promote the development of selective and accurate RDN in real-world clinical practice. This paper focuses on two current critical concerns of renal denervation (RDN): appropriate patient selection and the improvement in the accuracy of selective RDN. A hopeful way of accurate RDN may be the combination of 3D electroanatomic mapping systems for the renal artery with modified renal nerve stimulation (RNS) techniques and technology for appropriate hypertensive candidates.

Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis.

Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms that may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell lines, governed by the Stimulator of Interferon Genes (STING), which controls self or viral DNA-triggered cytokine production. Our results indicate that STING-dependent signaling is habitually defective in majority of ovarian cancer cells examined, frequently through the suppression of STING and/or the cyclic dinucleotide (CDN) enzyme Cyclic GMP-AMP synthase (cGAS) expression, by epigenetic processes. However, STING-independent, dsRNA-activated innate immune cytokine production, which require RIG-I/MDA5, were largely unaffected. Such defects enabled ovarian cancer cells to avoid DNA damage-mediated cytokine production, which would alert the immunosurveillance system. Loss of STING signaling also rendered ovarian cancer cells highly susceptible to viral oncolytic γ34.5 deleted-HSV1 (Herpes simplex virus) infection in vitro and in vivo. IMPLICATIONS: STING signaling evaluation in tumors may help predict disease outcome and possibly dictate the efficacy of oncoviral and other types of cancer therapies.

The impact of renal function on the prognostic value of N-terminal pro-B-type natriuretic peptide in patients with coronary artery disease.

BACKGROUND: The impact of renal function on the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) remains unclear in coronary artery disease (CAD). This study sought to investigate the value of using NT-proBNP level to predict prognoses of CAD patients with different estimated glomerular filtration rates (eGFRs). METHODS: A retrospective analysis was conducted from a single registered database. 2087 consecutive patients with CAD confirmed by coronary angiography were enrolled. The primary endpoint was allcause mortality. RESULTS: The mean follow-up time was 26.4 ± 11.9 months and death events occurred in 197 cases. The NT-proBNP levels increased with the deterioration of renal function, as well as the optimal cutoff values based on eGFR stratification to predict endpoint outcome (179.4 pg/mL, 1443.0 pg/mL, 3478.0 pg/mL, for eGFR ≥ 90, 60-90 and < 60 mL/min/1.73 m2, respectively). Compared with the routine cut-off value or overall optimal one, stratified optimal ones had superior predictive ability for endpoint in each eGFR group (all with the highest Youden's J statistics). And the prognostic value became weaker as eGFR level decreased (eGFR ≥ 90 vs. 60-90 vs. < 60 mL/min/1.73 m2, odds ratio [OR] 7.7; 95% confidence interval [CI] 1.7-33.9 vs. OR 4.8; 95% CI 2.7-8.5 vs. OR 3.0; 95% CI 1.5-6.2). CONCLUSIONS: This study demonstrated that NT-proBNP exhibits different predictive values for prognosis for CAD patients with different levels of renal function. Among the assessed values, the NT-proBNP cut-off value determined using renal function improve the accuracy of the prognosis prediction of CAD. Moreover, lower eGFR is associated with a higher NT-proBNP cut-off value for prognostic prediction.

Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells.

The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Cytosolic STING activators, including CDNs, constitute cellular danger-associated molecular patterns (DAMPs) only generated by viral infection or following DNA damage events that rendered tumor cells highly immunogenic. Our data shed insight into the molecular mechanisms that drive appropriate anti-tumor adaptive immune responses, while averting harmful autoinflammatory disease, and provide a therapeutic strategy for cancer treatment.

Prevalence and Prognostic Significance of Right Ventricular Dysfunction in Patients With Hypertrophic Cardiomyopathy.

Few data are available regarding the prevalence and clinical significance of right ventricular systolic dysfunction (RVSD) in hypertrophic cardiomyopathy (HC) patients. This study aimed to evaluate right ventricular (RV) systolic function by cardiovascular magnetic resonance and explore the prevalence and prognostic significance of RVSD in HC patients. A total of 226 patients with HC assessed by cardiovascular magnetic resonance were included in this retrospective study. RVSD was defined by RV ejection fraction (RVEF) ≤45% and was present in 26 (11.5%) patients. Association between RVSD, clinical characteristics, and outcomes were analyzed. RVEF was significantly lower in patients with RVSD than without RVSD (36.2 ± 7.0% vs 60.5 ± 7.4%, p < 0.001). There was a positive correlation between RVEF and left ventricular ejection fraction (r = 0.45; p < 0.001). During a mean follow-up of 30.5 ± 23.9 months, there were 22 (9.7 %) all-cause mortality, including 12 (5.3%) cardiovascular death. Kaplan-Meier analysis showed a significantly higher risk for cardiovascular mortality in patients with RVSD (p = 0.026), but no significant difference in all-cause mortality (p = 0.118) and heart failure related rehospitalization (p = 0.485). On multivariate Cox regression analysis, RVSD (hazard ratio 5.36; confidence interval 1.39 to 20.77; p = 0.015) and RVEF (hazard ratio 0.94; confidence interval 0.89 to 0.98; p = 0.011) were independent predictors of cardiovascular mortality. In conclusion, RVSD is a common phenotype and a strong independent predictor of cardiovascular mortality in HC patients.