Citations

Abstract Increased angiogenesis and tumor-induced immune evasion are two mechanisms by which clear cell renal cell carcinoma (ccRCC) proliferate and metastasize; however, the relationship between these pathways in human ccRCC is poorly understood. We conducted a nested case–control study using 98 archived tumor samples from patients diagnosed with primary ccRCC between 1990 and 2006, half of which were identified by immunohistochemistry (IHC) as either programmed death ligand 1 (PDL-1)–positive or PDL-1–negative. RNAs were extracted from the formalin-fixed paraffin-embedded tumor slides and the expression of the VEGFA, VEGFR1, VEGFR2, and PDL-1 genes was quantified. We assessed the presence of tumor-infiltrating lymphocytes (TIL) by IHC for CD3, and then analyzed the relationship among VEGFA, VEGFR1, VEGFR2, CD3, and PDL-1. When analyzed as a continuous variable, PDL-1 protein expression by IHC inversely correlates with the expression of the three VEGF-related genes: VEGFA (r = −0.23; P = 0.01), VEGFR1 (r = −0.34; P < 0.001), and VEGFR2 (r = −0.23; P = 0.01). When dichotomized, the PDL-1–positive cohort trended toward a lower expression of VEGFA (fold change = 0.72; P = 0.056) and VEGFR1 (fold change = 0.69; P = 0.057). In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = −0.18; P = 0.089). In conclusion, this is the first demonstration of an inverse association between the angiogenesis and PDL-1 pathways in tumor samples from primary ccRCC, and this relationship may be related to the immunosuppressive effects of VEGF signaling. Cancer Immunol Res; 1(6); 378–85. ©2013 AACR.

Abstract Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967

This study was to evaluate the efficacy and safety of acupuncture for chronic functional constipation. Randomized controlled trials were searched in several databases. The primary outcome was a change in the number of weekly spontaneous bowel movements. The secondary outcomes included colonic transit activity, effective rate, Cleveland Clinic Score, and health-related quality of life score. Meta-analysis was done by using RevMan 5.1. After strict screening, 15 RCTs were included, containing 1256 participants. All of them were conducted in China and published in Chinese journals. Meta-analysis indicated that acupuncture for chronic functional constipation was probably as effective as conventional medical therapy in the change of bowel movements. For the colonic transit activity, acupuncture might be the same as conventional medical therapy and could be better than sham acupuncture. For the Cleveland Clinic Score, acupuncture was unlikely inferior to conventional medical therapy and the deep acupuncture was better than normal depth acupuncture in abdominal region. No obvious adverse event was associated with acupuncture for constipation. In conclusion, acupuncture for chronic functional constipation is safe and may improve weekly spontaneous bowel movements, quality of life, and relevant symptoms. However, the evidence was limited by the small sample size and the methodological quality.

ABSTRACTBackgroundPrescription drug abuse has prompted considerable concern. We evaluated a retrospective drug utilization review program to reduce controlled substance use among individuals with high‐risk utilization.MethodsWe analyzed pharmacy claims from a large pharmaceutical benefits manager. For each eligible member, we calculated a controlled substance score based on the number and type of claims, prescribers and pharmacies, and utilization patterns over three months. Two state health plans sent controlled substance letters to prescribers of members meeting or exceeding a plan‐ and pre‐specified controlled substance score. Two different state health plans did not send such letters. We used a difference‐in‐difference design and generalized estimating equations to quantify the impact of the program on the mean difference in reduction of the controlled substance score over six months.ResultsEligible members in the intervention and comparison states had similar baseline mean controlled substance scores (19.0 vs. 18.6, p = 0.36). Adjusting for individuals' age, sex and pharmacy risk group score, reductions in the mean controlled substance score were greater in the intervention than comparison cohort (5.67 vs. 4.31, p = 0.01), corresponding with a 34.0% reduction in the intervention cohort compared to a 25.5% reduction in the comparison cohort. Changes were driven primarily by reductions in the number of controlled substance claims filled (30.5% vs. 23.1%, p = 0.01), as well as by a non‐statistically significant trend towards reductions in the number of prescribers and pharmacies used (26.9% vs. 20.1%, p = 0.07).ConclusionsRetrospective drug utilization review programs may reduce controlled substance scores and claims among individuals with patterns suggesting high‐risk utilization. Copyright © 2013 John Wiley & Sons, Ltd.

The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry assay. The GENICA breast cancer case–control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.

AbstractWe have analyzed the thermodynamic properties of the von Willebrand factor (VWF) A3 domain using urea‐induced unfolding at variable temperature and thermal unfolding at variable urea concentrations to generate a phase diagram that quantitatively describes the equilibrium between native and denatured states. From this analysis, we were able to determine consistent thermodynamic parameters with various spectroscopic and calorimetric methods that define the urea–temperature parameter plane from cold denaturation to heat denaturation. Urea and thermal denaturation are experimentally reversible and independent of the thermal scan rate indicating that all transitions are at equilibrium and the van't Hoff and calorimetric enthalpies obtained from analysis of individual thermal transitions are equivalent demonstrating two‐state character. Global analysis of the urea–temperature phase diagram results in a significantly higher enthalpy of unfolding than obtained from analysis of individual thermal transitions and significant cross correlations describing the urea dependence of and that define a complex temperature dependence of the m‐value. Circular dichroism (CD) spectroscopy illustrates a large increase in secondary structure content of the urea‐denatured state as temperature increases and a loss of secondary structure in the thermally denatured state upon addition of urea. These structural changes in the denatured ensemble make up ∼40% of the total ellipticity change indicating a highly compact thermally denatured state. The difference between the thermodynamic parameters obtained from phase diagram analysis and those obtained from analysis of individual thermal transitions illustrates that phase diagrams capture both contributions to unfolding and denatured state expansion and by comparison are able to decipher these contributions.