Citations

Abstract Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

ABSTRACTBackgroundThe authors sought to estimate incremental economic impact of atrial fibrillation (AF) and the timing of its onset in myocardial infarction (MI) patients.HypothesisConcurrent AF and its timing are associated with higher costs in MI patients.MethodsThis retrospective cohort study included incident MI patients from Olmsted County, Minnesota, treated between November 1, 2002, and December 31, 2010. We compared inflation‐adjusted standardized costs accumulated between incident MI and end of follow‐up among 3 groups by AF status and timing: no AF, new‐onset AF (within 30 days after index MI), and prior AF. Multivariate adjustment of median costs accounted for right‐censoring in costs.ResultsThe final study cohort had 1389 patients, with 989 in no AF, 163 in new‐onset AF, and 237 in prior AF categories. Median follow‐up times were 3.98, 3.23, and 2.55 years, respectively. Mean age at index was 67 years, with significantly younger patients in the no AF group (64 years vs 76 and 77 years, respectively; P < 0.001). New‐onset and prior AF patients had more comorbid conditions (hypertension, heart failure, and chronic obstructive pulmonary disease). After accounting for differences in baseline characteristics, we found adjusted median (95% confidence interval) costs of $73 000 ($69 000‐$76 000) for no AF; $85 000 ($81 000‐$89 000) for new‐onset AF; and $97 000 ($94 000‐$100 000) for prior AF. Inpatient costs composed the largest share of total median costs (no AF, 82%; new‐onset AF, 84%; prior AF, 83%).ConclusionsAtrial fibrillation frequently coexists with MI and imposes incremental costs, mainly attributable to inpatient care. Timing of AF matters, as prior AF was found to be associated with higher costs than new‐onset AF.

The large diversity and volume of extracellular RNA (exRNA) data that will form the basis of the exRNA Atlas generated by the Extracellular RNA Communication Consortium pose a substantial data integration challenge. We here present the strategy that is being implemented by the exRNA Data Management and Resource Repository, which employs metadata, biomedical ontologies and Linked Data technologies, such as Resource Description Framework to integrate a diverse set of exRNA profiles into an exRNA Atlas and enable integrative exRNA analysis. We focus on the following three specific data integration tasks: (a) selection of samples from a virtual biorepository for exRNA profiling and for inclusion in the exRNA Atlas; (b) retrieval of a data slice from the exRNA Atlas for integrative analysis and (c) interpretation of exRNA analysis results in the context of pathways and networks. As exRNA profiling gains wide adoption in the research community, we anticipate that the strategies discussed here will increasingly be required to enable data reuse and to facilitate integrative analysis of exRNA data.

Abstract The oncogenic EGFR/HER2/K-RAS “pathway” activation is pivotal in driving uncontrolled cell proliferation, aggressive tumor growth and systemic metastasis. Guided by studies in Drosophila, SIAH (seven-in-absentia homologue), the most downstream gatekeeper required for proper RAS signaling and tumor cell survival, was identified as a suitable target for anti-neoplastic therapy. We have shown that anti-SIAH-based therapy leads to the complete blockade of tumorigenesis in highly aggressive pancreatic, lung and breast cancer cells expressing a proteolysis deficient mutant protein, SIAHPD, at the onset of tumor initiation. In this study, we aim to determine if this anti-SIAH strategy is effective against well-established and late-stage pancreatic and triple negative breast (TNBC) tumors in a xenograft mouse model in vivo. We established stable cancer cell lines with doxycycline (DOX)-inducible SIAH2PD expression. One million MiaPaCa-SIAH2PD or MDA-MB-231-SIAH2PD cells were injected subcutaneously bilaterally in the dorsal scapular areas or bilaterally into the mammary fat pads, respectively, in 4-week-old female athymic nude mice. Tumor growth was monitored 3 times per week. Once tumors reached certain volume, SIAH2PD expression was induced via oral DOX treatment. Tumor growth in these mice was compared to control. Immunohistochemical (IHC) and immunofluorescence (IF) staining for endogenous SIAH and FLAG-tagged exogenous SIAH2PD were performed on formalin-fixed, paraffin-embedded sections of tumor tissue. Expression of SIAH2PD blocks oncogenic K-RAS signaling and K-RAS-mediated tumor growth in established pancreatic (MiaPaCa) and triple negative breast (MDA-MB-231) tumors in athymic nude mice. The immunohistochemical (IHC) and immunofluorescent (IF) staining reveals that in control tumors there is high expression of endogenous SIAH and none of SIAH2PD, while in tumors responding to treatment there is pronounced SIAH2PD and diminished endogenous SIAH expression. Oncogenic HER2/EGFR/K-RAS activation promote neoplastic transformation and tumorigenesis. In this study, we have identified a new vulnerability in the oncogenic K-RAS signaling pathway and we have demonstrated a novel and effective way to block K-RAS-driven tumor growth in well-established pancreatic adenocarcinoma and TNBC tumors in a xenograft model. In the follow-up studies, we hope to develop a small molecule inhibitor against SIAH, test their efficacy against patient-derived stage IV and II tumors in our “xenopatient” models. In the future, we aim to translate these exciting findings to the cancer clinics to benefit our cancer patients with metastatic diseases in VA. Citation Format: Minglei Bian, Vasilena Zheleva, Xiaofei Gao, Justin Odanga, Monica Njogu, Zena Urban, Bruce Knudsen, Richard A. Hoefer, Roger R. Perry, Amy H. Tang. Inhibition of late-stage tumor growth of human pancreatic and triple-negative breast cancer by blocking the most downstream “gatekeeper” signaling module, SIAH E3 ligase, in the oncogenic ERBB/ K-RAS signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4366. doi:10.1158/1538-7445.AM2015-4366

Abstract Background: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. Methods: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. Results: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2; HR, 1.10; 95% CI, 1.06–1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). Conclusions: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. Cancer Epidemiol Biomarkers Prev; 24(8); 1229–38. ©2015 AACR.

Context HepPar-1 and Arginase-1 are urea cycle enzymes used to distinguish hepatocellular carcinoma from other carcinomas. HepPar-1, but not Arginase-1, is known to be immunoreactive with normal human small intestine. Objectives To better define and compare the immunohistochemical staining patterns of HepPar-1 and Arginase-1 in adenocarcinomas arising in the small intestine, including the ampullary region. Design Staining for HepPar-1 and Arginase-1 was performed on 20 nonampullary small intestinal adenocarcinomas and 32 adenocarcinomas from the ampullary region. Ampullary adenocarcinomas were divided into intestinal morphology (15), pancreatobiliary morphology (14), and unclassifiable (3). Nonneoplastic small intestinal mucosa and colorectal adenocarcinomas were used as control groups. Results HepPar-1 stained 12 of 20 nonampullary small intestinal adenocarcinomas, with a median of 63% of cells staining in positive cases. It also stained 11 of 15 ampullary carcinomas with intestinal morphology, with a median of 75% of cells staining in positive cases. Two of 14 ampullary carcinomas with pancreatobiliary morphology were positive for HepPar-1. Arginase-1 showed positivity in 2 ampullary region carcinomas and diffuse positivity in 1 duodenal adenocarcinoma. Two of 22 colorectal carcinomas stained for HepPar-1 with none positive for Arginase-1. Conclusions HepPar-1, but not Arginase-1, usually shows positivity in small intestinal adenocarcinomas and ampullary adenocarcinomas with intestinal morphology, but only rarely shows positivity in ampullary adenocarcinomas with pancreatobiliary morphology. HepPar-1 positivity in metastatic adenocarcinoma with intestinal morphology is suggestive of an upper gastrointestinal primary site.

BACKGROUNDThere is little research regarding characteristics of effective continuing medical education (CME) presentations in hospital medicine (HM). Therefore, we sought to identify associations between validated CME teaching effectiveness scores and characteristics of CME presentations in the field of HM.DESIGN/SETTINGThis was a cross‐sectional study of participants and didactic presentations from a national HM CME course in 2014.MEASUREMENTSParticipants provided CME teaching effectiveness (CMETE) ratings using an instrument with known validity evidence. Overall CMETE scores (5‐point scale: 1 = strongly disagree; 5 = strongly agree) were averaged for each presentation, and associations between scores and presentation characteristics were determined using the Kruskal‐Wallis test. The threshold for statistical significance was set at P < 0.05.RESULTSA total of 277 out of 368 participants (75.3%) completed evaluations for the 32 presentations. CMETE scores (mean [standard deviation]) were significantly associated with the use of audience response (4.64 [0.16]) versus no audience response (4.49 [0.16]; P = 0.01), longer presentations (≥30 minutes: 4.67 [0.13] vs <30 minutes: 4.51 [0.18]; P = 0.02), and larger number of slides (≥50: 4.66 [0.17] vs <50: 4.55 [0.17]; P = 0.04). There were no significant associations between CMETE scores and use of clinical cases, defined goals, or summary slides.CONCLUSIONSTo our knowledge, this is the first study regarding associations between validated teaching effectiveness scores and characteristics of effective CME presentations in HM. Our findings, which support previous research in other fields, indicate that CME presentations may be improved by increasing interactivity through the use of audience response systems and allowing longer presentations. Journal of Hospital Medicine 2015;10:569–573. © 2015 Society of Hospital Medicine

ABSTRACT Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25-hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at-risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non-white populations. © 2015 American Society for Bone and Mineral Research.