Citations

ABSTRACT Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase‐1 (HO‐1) expression on vaccine response and outcome of influenza infection. HO‐1‐deficient and wild‐type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus ) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adeno‐viral‐based influenza vaccine. A genome‐wide association study evaluated the expression of single‐nucleotide polymorphisms (SNPs) in the HO‐1 gene and the response to influenza vaccination in healthy humans. HO‐1‐deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P =0.016). HO‐1‐deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P =0.02). One SNP in HO‐1 and one SNP in the constitutively expressed isoform HO‐2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers ( P =0.017 and 0.014, respectively). HO‐1 deficient mice were paired with sex‐ and age‐matched WT controls. HO‐1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO‐1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.—Cummins, N. W., Weaver, E. A., May, S. M., Croatt, A. J., Foreman, O., Kennedy, R. B., Poland, G. A., Barry, M. A., Nath, K. A., Badley, A. D. Heme oxygenase‐1 regulates the immune response to influenza virus infection and vaccination in aged mice. FASEB J. 26, 2911–2918 (2012). www.fasebj.org

Health care provider’s acceptance of telemonitoring is pivotal for implementation. The aim of this study was to determine provider’s feelings about telemonitoring using a qualitative method. In regard to method, we interviewed physicians, nurse practitioners, and registered nurses to explore their attitudes toward telemonitoring. Thematic and content analysis strategies were used to identify core concepts and develop categories for coding interview data. Results reveal that providers view telemonitoring as most appropriate for specific types of patients, especially older patients with chronic medical conditions. Telemonitoring offers reassurance to patients and providers. Some providers expressed concerns about excessive information that at times may not be clinically useful. In conclusion, home telemonitoring provides reassurance to patients and health care providers. Taking provider preferences into consideration when implementing telemonitoring may improve provider acceptance of this form of care.

With new technologies, multiple types of genomic data are commonly collected on a single set of samples. However, standard analysis methods concentrate on a single data type at a time and ignore the relationships between genes, proteins, and biochemical reactions that give rise to complex phenotypes. In this paper, we propose a novel integrative model to incorporate multiple types of genomic data into an association analysis with a complex phenotype. The method combines path analysis and stochastic search variable selection into a Bayesian hierarchical model that simultaneously identifies both direct and indirect genomic effects on the phenotype. Results from a simulation study and application of the Bayesian model to a pharmacogenomic study of the drug gemcitabine demonstrate greater sensitivity to detect genomic effects in some simulation scenarios, when compared to the standard single data type analysis. Further research is required to extend and modify this integrative modeling framework to increase computational efficiency to best capitalize on the wealth of information available across multiple genomic data types. Genet. Epidemiol. 36:352–359, 2012. © 2012 Wiley Periodicals, Inc.

AbstractRecently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.

The purpose of this study was to compare return visits made by patients within 2 weeks after using retail nurse practitioner clinics to return visits made by similar patients after using standard medical office clinics. Retail medicine clinics have become widely available. However, their impact on return visit rates compared to standard medical office visits for similar patients has not been extensively studied. Electronic medical records of adult primary care patients seen in a large group practice in Minnesota in 2009 were analyzed for this study. Patients who were treated for sinusitis were selected. Two groups of patients were studied: those who used one of 2 retail walk-in clinics staffed by nurse practitioners and a comparison group who used one of 4 regular office clinics. The dependent variable was a return office visit to any site within 2 weeks. Multiple logistic regression analysis was used to adjust for case-mix differences between groups. Unadjusted odds of return visits were lower for retail clinic patients than for standard office care patients. After adjustment for case mix, patients with more outpatient visits in the previous 6 months had higher odds of return visits within 2 weeks (2–6 prior visits: odds ratio [OR]=1.99, P =0.00; 6 or more prior visits: OR=6.80, P =0.00). The odds of a return visit within 2 weeks were not different by clinic type after adjusting for propensity to use services (OR=1.17, P =0.28). After adjusting for case mix differences, return visit rates did not differ by clinic type. ( Population Health Management 2012;15:216–219)

Abstract Background: Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single-nucleotide polymorphism (SNP) individually may not be well suited to detect small effects of multiple SNPs, such as those operating within the same biologic pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes. Methods: To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWAS (N cases = 2,813, N deaths = 1,116), with a novel Principal Component-Gamma GSA method. Analysis was completed for all cases and then separately for high-grade serous histologic subtype. Results: Analysis of the high-grade serous subjects resulted in 43 gene sets with P < 0.005 (1.7%); of these, 21 gene sets had P < 0.10 in both GWAS, including intracellular signaling pathway (P = 7.3 × 10−5) and macrolide binding (P = 6.2 × 10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (P = 6.3 × 10−4) and macrolide binding (P = 1.0 × 10−3). Of 18 gene sets with P < 0.005 (0.7%), eight had P < 0.10 in both GWAS. Conclusion: This research detected novel gene sets associated with EOC survival. Impact: Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies. Cancer Epidemiol Biomarkers Prev; 21(3); 529–36. ©2012 AACR.

ABSTRACT Introduction Peyronie’s disease (PD) is characterized by fibrotic plaque formation within the tunica albuginea, leading to penile deformity, angulation, painful erections, and often, erectile dysfunction. There is limited knowledge of its etiology and pathophysiology. Currently, there is no standardization for reporting the evaluation and treatment outcomes. No consensus exists on the ideal management of PD. Aim The aim of this study is to review the use of radiation therapy (RT) for the treatment of PD. Methods This study used a review of the literature and informed expert opinion. Main Outcome Measures The main outcome measures are the reported improvement with regard to pain, curvature, plaque size, and erectile function as well as a review of the safety profile of RT. Results Radiation has been used for the empirical treatment of PD with mixed results throughout the literature. Low-dose RT in the early stages of PD seems to be effective in patients with painful erections not improving with time or with the use of oral or intralesional therapies. Comparison with other current medical therapies is difficult due to the absence of criteria for therapeutic success and the absence of randomized, controlled trials. Multiple studies have demonstrated varied results in terms of curvature reduction, plaque volume, and sexual functioning. The absence of the use of validated means of measuring penile deformity and sexual function, the limited relevance of plaque and pain improvement combined with the potential negative consequences of radiation on erectile tissue structure and function lead us to make a recommendation that RT not be used for the management of PD. Conclusions In clinical practice, mixed success for RT has led to the recommendation against its use as a treatment modality for PD.