Citations

Abstract To identify novel genetic loci influencing interindividual variation in red blood cell (RBC) traits in African-Americans, we conducted a genome-wide association study (GWAS) in 2315 individuals, divided into discovery (n = 1904) and replication (n = 411) cohorts. The traits included hemoglobin concentration (HGB), hematocrit (HCT), RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Patients were participants in the electronic MEdical Records and GEnomics (eMERGE) network and underwent genotyping of ~1.2 million single-nucleotide polymorphisms on the Illumina Human1M-Duo array. Association analyses were performed adjusting for age, sex, site, and population stratification. Three loci previously associated with resistance to malaria—HBB (11p15.4), HBA1/HBA2 (16p13.3), and G6PD (Xq28)—were associated (P ≤ 1 × 10−6) with RBC traits in the discovery cohort. The loci replicated in the replication cohort (P ≤ 0.02), and were significant at a genome-wide significance level (P < 5 × 10−8) in the combined cohort. The proportions of variance in RBC traits explained by significant variants at these loci were as follows: rs7120391 (near HBB) 1.3% of MCHC, rs9924561 (near HBA1/A2) 5.5% of MCV, 6.9% of MCH and 2.9% of MCHC, and rs1050828 (in G6PD) 2.4% of RBC count, 2.9% of MCV, and 1.4% of MCH, respectively. We were not able to replicate loci identified by a previous GWAS of RBC traits in a European ancestry cohort of similar sample size, suggesting that the genetic architecture of RBC traits differs by race. In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans.

Objectives To determine the prevalence range for sarcopenic obesity and its relationship with sex, age, and ethnicity. Design Cross‐sectional analysis of a population‐based sample. Setting Noninstitutionalized persons in the U nited S tates participating in the N ational H ealth and N utrition E xamination S urveys 1999–2004. Participants Subsample of 4,984 subjects aged 60 and older with dual‐energy X‐ray absorptiometry body composition data. Measurements Eight definitions of sarcopenic obesity identified from six studies found using a systematic literature review ( B aumgartner, B ouchard, D avison, Z oico, L evine, K im‐1,2,3) were applied to the sample. Results were stratified according to sex, age, and ethnicity. Results Prevalence of sarcopenic obesity ranged from 4.4% to 84.0% in men and from 3.6% to 94.0% in women. Prevalence was higher in men using definitions from Baumgartner (17.9% vs 13.3%, P < .001), Levine (14.2% vs 6.6%, P < .001), and Kim‐1 (30.0% vs 9.3%, P < .001); lower for men using the Davison (4.4% vs 11.1%, P < .001) and Kim‐2 (83.7% vs 94.0%) definitions; and the same for men and women using the Bouchard (45.3% vs 44.3%, P = .32) and Kim‐3 (75.6% vs 77.0%, P = .51) definitions. For all but one definition, sarcopenic obesity increased with each decade and was lower in non‐ H ispanic blacks than whites. Conclusion Prevalence of sarcopenic obesity in older adults varies up to 26‐fold depending on current research definitions. Such a high degree of variability suggests the need to establish consensus criteria that can be reliably applied across clinical and research settings.

Abstract Purpose: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. Experimental Design: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. Clin Cancer Res; 19(9); 2368–80. ©2013 AACR.

Abstract Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS‐PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome‐specific synthetic reviews and recommendations prepared by NPS‐PIA workgroups on depression, apathy, sleep, agitation, and psychosis.

Background. Previous reports have shown a positive association between serum calcium level and prostate cancer mortality. However, there is no data regarding whether higher serum calcium levels are associated with increased risk of biochemical recurrence (BCR) following salvage radiation therapy (SRT) for prostate cancer. Herein, we evaluate the association between pretreatment serum calcium levels and BCR in a cohort of men who underwent SRT. Methods. We evaluated 165 patients who underwent SRT at our institution. Median dose was 65.0 Gy (range: 54.0–72.4 Gy). We considered serum calcium as both a continuous variable and a 3-level categorical variable (low [≤9.0 mg/dL], moderate [>9.0 mg/dL and ≤9.35 mg/dL], and high [>9.35 mg/dL]) based on sample tertiles. Results. We observed no evidence of a linear association between serum calcium and BCR (relative risk (RR): 0.96, P=0.76). Compared to men with low calcium, there was no significantly increased risk of BCR for men with moderate (RR: 0.94, P=0.79) or high (RR: 1.08, P=0.76) serum calcium levels. Adjustment for clinical, pathological, and SRT characteristics in multivariable analyses did not alter these findings. Conclusion. Our results provide evidence that pretreatment serum calcium is unlikely to be a useful tool in predicting BCR risk following SRT.

Abstract New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. Clin Cancer Res; 19(11); 2817–23. ©2013 AACR.