STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability.

Given the integral role of stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs. STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress. SIGNIFICANCE: These findings provide clear mechanistic understanding of the role of STING in cell-cycle regulation, which may be exploited in cancer therapy because most normal cells express STING, while many tumor cells do not.See related commentary by Gius and Zhu, p. 1295.

PML plays both inimical and beneficial roles in HSV-1 replication.

After entry into the nucleus, herpes simplex virus (HSV) DNA is coated with repressive proteins and becomes the site of assembly of nuclear domain 10 (ND10) bodies. These small (0.1-1 µM) nuclear structures contain both constant [e.g., promyelocytic leukemia protein (PML), Sp100, death-domain associated protein (Daxx), and so forth] and variable proteins, depending on the function of the cells or the stress to which they are exposed. The amounts of PML and the number of ND10 structures increase in cells exposed to IFN-ß. On initiation of HSV-1 gene expression, ICP0, a viral E3 ligase, degrades both PML and Sp100. The earlier report that IFN-ß is significantly more effective in blocking viral replication in murine PML(+/+) cells than in sibling PML(-/-) cells, reproduced here with human cells, suggests that PML acts as an effector of antiviral effects of IFN-ß. To define more precisely the function of PML in HSV-1 replication, we constructed a PML(-/-) human cell line. We report that in PML(-/-) cells, Sp100 degradation is delayed, possibly because colocalization and merger of ICP0 with nuclear bodies containing Sp100 and Daxx is ineffective, and that HSV-1 replicates equally well in parental HEp-2 and PML(-/-) cells infected at 5 pfu wild-type virus per cell, but poorly in PML(-/-) cells exposed to 0.1 pfu per cell. Finally, ICP0 accumulation is reduced in PML(-/-) infected at low, but not high, multiplicities of infection. In essence, the very mechanism that serves to degrade an antiviral IFN-ß effector is exploited by HSV-1 to establish an efficient replication domain in the nucleus.

14q32-encoded microRNAs mediate an oligometastatic phenotype.

Oligometastasis is a clinically distinct subset of metastasis characterized by a limited number of metastases potentially curable with localized therapies. We analyzed pathways targeted by microRNAs over-expressed in clinical oligometastasis samples and identified suppression of cellular adhesion, invasion, and motility pathways in association with the oligometastatic phenotype. We identified miR-127-5p, miR-544a, and miR-655-3p encoded in the 14q32 microRNA cluster as co-regulators of multiple metastatic pathways through repression of shared target genes. These microRNAs suppressed cellular adhesion and invasion and inhibited metastasis development in an animal model of breast cancer lung colonization. Target genes, including TGFBR2 and ROCK2, were key mediators of these effects. Understanding the role of microRNAs expressed in oligometastases may lead to improved identification of and interventions for patients with curable metastatic disease, as well as an improved understanding of the molecular basis of this unique clinical entity.

Self-efficacy mediates the associations of social support and depression with treatment adherence in heart failure patients.

BACKGROUND: Nonadherence to treatment recommendations is a leading preventable cause of rehospitalization and premature mortality in chronic heart failure (HF) patients. PURPOSE: This study examined whether self-efficacy mediates the contributions of social support and depression to treatment adherence. METHODS: A sample of 252 HF outpatients with a mean age of 54 years completed self-report questionnaires assessing depression, perceived social support, self-efficacy, and treatment adherence. RESULTS: Self-efficacy mediated the associations of social support and depression with treatment adherence after adjusting for demographic (age, gender, marital status, education, and ethnicity) and medical (New York Heart Association Classification and comorbidity) covariates. CONCLUSION: Self-efficacy explains the influence of social support and depression on treatment adherence and may be a key target for interventions to improve disease management and self-care behaviors in HF patients.

Use of biotinylated plasmid DNA as a surrogate for HSV DNA to identify proteins that repress or activate viral gene expression.

ICP0, a key herpes simplex virus regulatory protein, functions first in the nucleus and then in the cytoplasm. The duration of its nuclear sojourn in cells transfected with DNA and then infected is related to the quantity of transfected DNA. Furthermore, ICP0 transactivates both viral genes and genes encoded by the transfected DNA. The data support the hypothesis that ICP0 is retained in the nucleus until it completes the replacement of repressive chromatin with effector proteins that enable transcription of both DNA templates.To identify the effector proteins, we transfected cells with biotinylated DNA encoding a nonviral gene and then infected the cells with wild-type virus. Proteins bound to transfected biotinylated plasmid recovered from mock-treated and infected cells were identified using mass spectrometry followed by appropriate database search. The transfected DNA from mock-infected cells yielded proteins associated with repression, whereas DNA recovered from infected cells included proteins known to enable transcription and proteins that have not been previously associated with that role. To test the hypothesis that the proteins hitherto not known to associate with viral gene expression are nevertheless essential, we tested the role of the DEAD-box helicase Ddx17. We report that Ddx17 plays a critical role in the expression of early and late viral genes. Thus, biotinylated DNA recovered from transfected infected cells can function as a surrogate for viral DNA and is a rich source of proteins that play a role in viral gene expression but which have not been previously identified in that role.

Avoidant coping moderates the association between anxiety and patient-rated physical functioning in heart failure patients.

Previous research has indicated that anxiety may be associated with adverse health outcomes in heart failure patients. Little research, however, has explored whether anxiety interacts with patients' coping strategies in their associations with physical functioning. The present study examined whether coping strategies moderated the association between anxiety and self-rated physical functioning in 273 heart failure patients. Hierarchical multiple regression analysis, adjusting for demographic and medical covariates, indicated that both anxiety (b=1.15, ß=0.46, P<0.001) and avoidant coping (b=0.43, ß=0.16, P<0.01) were significantly associated with poorer physical functioning in separate models. Results also demonstrated a significant interaction between avoidant coping and anxiety (b=0.56, ß=0.14, P<0.01), such that the association between anxiety and poorer physical functioning was stronger for patients who frequently used avoidant coping strategies than for those who avoided less frequently. Approach coping, however, was not directly associated with physical functioning, nor did it moderate the association between anxiety and physical functioning. The findings suggest that anxious heart failure patients who engage in avoidant coping may be at particular risk for physical dysfunction.

Utility of the Millon Behavioral Medicine Diagnostic to predict medication adherence in patients diagnosed with heart failure.

Medication non-adherence is common and a primary reason for poor medical outcomes among individuals with heart failure (HF). This study's aims were to determine whether depression, hostility, and the personality-based Millon Behavioral Medicine Diagnostic (MBMD) Medication Abuse scale were associated with medication adherence (e.g., beta-blockers, ACE inhibitors, diuretics, statins) beyond contributions of demographic, medical, and psychosocial variables in an ethnically-diverse sample of 105 men and women diagnosed with HF. In hierarchical regression, greater MBMD Medication Abuse scale scores were associated with poorer adherence above and beyond both depression (ß = .236, t[102] = 2.113, p = .037) and hostility (ß = .244, t[102] = 2.506, p = .014). The Medication Abuse scale also completely mediated the relationship between adherence and depression. These findings suggest that personality measures such as the MBMD and hostility scales might be utilized in future studies investigating predictors of adherence and also used clinically to predict medication adherence among HF patients.

Depression and anxiety predict decline in physical health functioning in patients with heart failure.

BACKGROUND: Few studies have examined the prospective influences of depression and anxiety on physical health functioning in heart failure (HF) patients. Prior studies were also limited by employing psychological measures containing somatic items confounded with HF symptoms. PURPOSE: This study examined whether depression, anxiety, social support, and their changes predicted the decline of physical functioning in HF patients over 6 months. METHODS: Participants were 238 HF patients among whom 164 provided follow-up data. The depression and anxiety measures did not contain somatic items. RESULTS: After controlling for baseline physical functioning and demographic and medical covariates, baseline depression and its increase, as well as baseline anxiety and its increase, independently predicted greater decline in physical functioning at 6 months. Social support and its change were not associated with either concurrent or follow-up physical functioning. CONCLUSIONS: Depression, anxiety, and their changes independently predicted the decline of physical health functioning over 6 months.

Acute pulmonary hypertension secondary to right ventricular pacing in a patient with sinus node dysfunction and severe ischemic cardiomyopathy.

Right ventricular pacing has been associated with worsening symptoms of heart failure in patients with cardiomyopathy. We describe a patient with severe ischemic cardiomyopathy and sinus node dysfunction who developed acute worsening of pulmonary hypertension immediately after right ventricular pacing.

Should stable UNOS Status 2 patients be transplanted?

BACKGROUND: Improved outcomes with contemporary medical therapy in patients with advanced heart failure brings into question the survival advantage of transplantation for patients in stable United Network for Organ Sharing (UNOS) Status 2. METHODS: Between January 1999 and June 2001, a total of 7,539 adult patients were listed for heart transplantation. Of those, 4,255 (56.4%) patients were listed as UNOS Status 2. Using a competing risk method, we computed probabilities of events while on the waiting list. Additionally, we used a time-dependent proportional hazards model to determine predictors of death before and after transplantation. RESULTS: Demographics included age >60 (72%), female sex (23%), ischemic causes for transplantation (49%), white race (85%), and median time on the waiting list (544 days). Laboratory and hemodynamic values included mean serum albumin of 3.9 g/dl, serum creatinine of 1.4 mg/dl, mean pulmonary artery pressure of 28 mm Hg, mean pulmonary capillary wedge pressure of 19 mm Hg, and mean cardiac output of 4.5 liter/min. Final outcomes on the waiting list for patients initially listed as UNOS Status 2 were transplantation (48%), removal from the list (11.5%), death (11.4%), and continued listing (29%). At 30 months after transplantation, survival was 81% for patients undergoing transplantation as Status 1A, 77% as Status 1B, and 83% as Status 2, and showed no difference among groups. At 365 days, survival analysis showed no difference for patients listed and undergoing transplantation as UNOS Status 2 compared with those still waiting as Status 2. CONCLUSION: In the current era of advances in medical and surgical therapies for heart failure, we found no survival benefit of cardiac transplantation at 1 year for patients initially listed as UNOS Status 2.

Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease.

BACKGROUND: Arterial compliance is related to left ventricular hypertrophy and risk for cardiovascular disease events; however, its association with coronary artery stenosis remains uncertain. We sought to assess the relation between lower extremity arterial compliance and presence of angiographically defined coronary artery disease. METHODS: Lower extremity arterial compliance was measured with the use of a noninvasive air plethysmography technique in 376 subjects undergoing routine diagnostic coronary angiography. RESULTS: Measures of calf arterial compliance were significantly associated with the presence of one or more stenoses > or =50% compared with no stenoses, even after adjustment for age, sex, smoking, diabetes, hypertension, hypercholesterolemia, and obesity (P =.03). Measures of thigh arterial compliance were also lower in subjects with disease, although this association did not reach statistical significance (P =.07). Receiver operator curves illustrate the incremental predictive ability of calf arterial compliance over and above age, sex, and conventional risk factors. CONCLUSIONS: Lower extremity arterial compliance is associated with presence of significant coronary stenoses in a cardiac catheterization laboratory referral population. This observation lends support for additional efforts to determine the utility of vascular stiffness measures in both clinical and pre-clinical populations to guide treatment and prevention efforts.

Factors affecting late survival after surgical remodeling of left ventricular aneurysms.

OBJECTIVES: Surgical remodeling of the left ventricle has involved various techniques of volume reduction. This study evaluates factors that influence long-term survival results with 3 operative methods. METHODS: From 1979 to 2000, 157 patients (134 men, mean age 61 years) underwent operations for class III or IV congestive heart failure, angina, ventricular tachyarrhythmia, and sudden death after anteroseptal myocardial infarction. The preoperative ejection fraction was 28% +/- 0.9% (mean +/- standard error), and the pulmonary artery occlusive pressure was 15 +/- 0.07 mm Hg. Cardiogenic shock was present in 26 patients (16%), and an intra-aortic balloon pump was used in 48 patients (30%). The type of procedure depended on the extent of endocardial disease and was aimed at maintaining the ellipsoid shape of the left ventricle cavity. In group I patients (n = 65), radical aneurysm resection and linear closure were performed. In group II patients (n = 70), septal dyskinesis was reinforced with a patch (septoplasty). In group III patients (n = 22), ventriculotomy closure was performed with an intracavitary oval patch. RESULTS: Hospital mortality was 16% (25/157) and was similar among the groups. Actuarial survival up to 18 years was better with a preoperative ejection fraction of 26% or greater (P =.004) and a pulmonary artery occlusive pressure of 17 mm Hg or less (P =.05). Survival was worse in patients who had intra-aortic balloon pump support (P =.03). Five-year survival for all patients in group III was higher than for patients in group II (67% vs 47%, P =.04). CONCLUSIONS: Factors that improved long-term survival after left ventricular surgical remodeling were intraventricular patch repair, preoperative ejection fraction of 26% or greater, and pulmonary artery occlusive pressure of 17 mm Hg or less without the need for balloon pump assist.