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1.  Longitudinal Associations Between Neighborhood Physical and Social Environments and Incident Type 2 Diabetes Mellitus 
JAMA internal medicine  2015;175(8):1311-1320.
Neighborhood environments may influence the risk for developing type 2 diabetes mellitus (T2DM), but, to our knowledge, no longitudinal study has evaluated specific neighborhood exposures.
To determine whether long-term exposures to neighborhood physical and social environments, including the availability of healthy food and physical activity resources and levels of social cohesion and safety, are associated with incident T2DM during a 10-year period.
We used data from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study of adults aged 45 to 84 years at baseline (July 17, 2000, through August 29, 2002). A total of 5124 participants free of T2DM at baseline underwent 5 clinical follow-up examinations from July 17, 2000, through February 4, 2012. Time-varying measurements of neighborhood healthy food and physical activity resources and social environments were linked to individual participant addresses. Neighborhood environments were measured using geographic information system (GIS)- and survey-based methods and combined into a summary score. We estimated hazard ratios (HRs) of incident T2DM associated with cumulative exposure to neighborhood resources using Cox proportional hazards regression models adjusted for age, sex, income, educational level, race/ethnicity, alcohol use, and cigarette smoking. Data were analyzed from December 15, 2013, through September 22, 2014.
Incident T2DM defined as a fasting glucose level of at least 126 mg/dL or use of insulin or oral antihyperglycemics.
During a median follow-up of 8.9 years (37 394 person-years), 616 of 5124 participants (12.0%) developed T2DM (crude incidence rate, 16.47 [95% CI, 15.22-17.83] per 1000 person-years). In adjusted models, a lower risk for developing T2DM was associated with greater cumulative exposure to indicators of neighborhood healthy food (12%; HR per interquartile range [IQR] increase in summary score, 0.88 [95% CI, 0.79-0.98]) and physical activity resources (21%; HR per IQR increase in summary score, 0.79 [95% CI, 0.71-0.88]), with associations driven primarily by the survey exposure measures. Neighborhood social environment was not associated with incident T2DM (HR per IQR increase in summary score, 0.96 [95% CI, 0.88-1.07]).
Long-term exposure to residential environments with greater resources to support physical activity and, to a lesser extent, healthy diets was associated with a lower incidence of T2DM, although results varied by measurement method. Modifying neighborhood environments may represent a complementary, population-based approach to prevention of T2DM, although further intervention studies are needed.
PMCID: PMC4799846  PMID: 26121402
2.  Short Communication: Coronary Heart Disease Risk by Framingham Risk Score in Hepatitis C and HIV/Hepatitis C-Coinfected Persons 
We compared the Framingham risk score (FRS) for 10-year coronary heart disease (CHD) risk in age- and race-matched hepatitis C virus (HCV)-infected and HCV-uninfected persons: 114,073 HCV-infected (111,436 HCV-monoinfected and 2,637 HIV/HCV-coinfected) and 122,996 HCV-uninfected (121,380 HIV and HCV-uninfected and 1,616 HIV-monoinfected) males without cardiovascular disease, diabetes, or hepatitis B. In unadjusted analyses, FRS was similar between the HCV-infected and HCV-uninfected groups [median (interquartile range, IQR) risk points 13 (10–14) vs. 13 (10–14), p=0.192]. Cholesterol levels were lower and current smoking more prevalent in the HCV groups (both HCV and HIV/HCV) compared with the uninfected groups (p<0.001 for both). Prevalence of non-FRS CHD risk factors, such as substance abuse and chronic kidney disease, in the cohort was high, and differed by HCV and HIV status. Adjusting for age, race/ethnicity, body mass index, chronic kidney disease, drug and alcohol use, and HIV status, HCV infection was associated with minimally lower FRS (β=−0.095 risk points, p<0.001), suggesting a small but significant difference in 10-year CHD risk estimation in HCV-infected as compared to HCV-uninfected persons when measuring risk by FRS. Given the complex relationship between HCV, HIV, and CHD risk factors, some of which are not captured by the FRS, the FRS may underestimate CHD risk in HCV-monoinfected and HIV/HCV-coinfected persons. HCV- and HIV/HCV-specific risk scores may be needed to optimize CHD risk stratification.
PMCID: PMC4505770  PMID: 25858663
4.  The Association of Menopausal Age and NT-proBrain Natriuretic Peptide: The Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.Y.)  2015;22(5):527-533.
Menopausal age could affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before 45 years of age) and menopausal age with NT-pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure (HF).
Our cross-sectional study included 2275 postmenopausal women, aged 45–85 years, without clinical CVD (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis.
There were 561 women with early menopause. The median NT-proBNP value was 79.0 (41.1–151.6) pg/ml for all participants with values of 83.4 (41.4–164.9) pg/ml and 78.0 (40.8–148.3) pg/ml for women with and without early menopause respectively. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause respectively. There were no significant interactions between menopausal age and ethnicity. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP while each year increase in menopausal age was associated with a 0.7% decrease in NT-proBNP.
Early menopause is associated with greater NT-proBNP levels while each year increase in menopausal age is associated with lower NT-proBNP levels in postmenopausal women.
PMCID: PMC4387119  PMID: 25290536
Menopause; NT-proBNP; Sex hormones
5.  Unfolded DapA forms aggregates when diluted into free solution, confounding comparison with folding by the GroEL/GroES chaperonin system 
FEBS letters  2015;589(4):497-499.
A recent hydrogen-deuterium exchange study of folding of the GroEL/GroES-dependent bacterial enzyme DapA has suggested that the DapA folding pathway when free in solution may differ from the folding pathway used in the presence of the GroEL/GroES chaperonin. Here, we have investigated whether DapA aggregation might be occurring in free solution under the conditions of the exchange experiment, as this would confound interpretation of the pathway predictions. Dynamic light scattering data, sedimentation analysis and refolding yield indicate that significant aggregation occurs upon dilution of DapA from denaturant, bringing into question the earlier conclusion that different folding pathways occur in the absence and presence of the chaperonin system.
PMCID: PMC4410871  PMID: 25601566
Dap; GroEL; aggregation; light scattering; protein folding
7.  Age at Menopause and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.Y.)  2014;21(6):585-591.
To evaluate associations of early menopause (menopause occurring before 45 years of age) and age at menopause with incident heart failure (HF) in post-menopausal women. We also explored associations of early, and age at menopause with left ventricular (LV) measures of structure and function in post-menopausal women.
We included 2947 post-menopausal women, aged 45-84 years, without known cardiovascular disease (2000-2002), from the Multi-Ethnic study of Atherosclerosis. Cox-Proportional hazards models were used to examine associations of early, and age at menopause with incident HF. In 2123 post-menopausal women in whom cardiac magnetic resonance imaging was obtained at baseline, we explored associations of early, and age at menopause with LV measures using multivariable linear regression.
Over a median follow-up of 8.5 years, we observed 71 HF events. There were no significant interactions with ethnicity for incident HF (Pinteraction>0.05). In adjusted analysis, early menopause was associated with increased risk of incident HF [1.66 (1.01-2.73)], while each year increase in age at menopause was associated with decreased risk of incident HF [0.96 (0.94-0.99)]. We observed significant interactions between early menopause and ethnicity for LV mass to volume ratio (LVMVR), Pinteraction=0.02. In Chinese-American women, early menopause was associated with higher LVMVR (+0.11, p=0.0002), while each year increase in age at menopause was associated with lower LVMVR (−0.004, p=0.04) at baseline.
An older menopausal age is independently associated with decreased risk of incident HF. Concentric LV remodelling, indicated by a higher LVMVR was present in Chinese-American women with early menopause at baseline.
PMCID: PMC4031284  PMID: 24423934
Menopause; Heart failure; Estrogen
8.  Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder 
British Journal of Cancer  2015;112(10):1626-1635.
Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy.
Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (±biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan–Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model.
Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P<0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4–127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature.
Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in >80% of the selected patients.
PMCID: PMC4430712  PMID: 25897675
bladder cancer; transitional cell carcinoma; radiotherapy; chemotherapy; cystectomy; organ preservation
10.  Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma 
British Journal of Cancer  2013;110(1):256-263.
Patients with stage I testicular seminoma are typically diagnosed at a young age and treatment is associated with low relapse and mortality rates. The long-term risks of adjuvant radiotherapy in this patient group are therefore particularly relevant.
We identified patients and obtained treatment details from 12 cancer centres (11 United Kingdom, 1 Norway) and ascertained second cancers and mortality through national registries. Data from 2629 seminoma patients treated with radiotherapy between 1960 and 1992 were available, contributing 51 151 person-years of follow-up.
Four hundred and sixty-eight second cancers (excluding non-melanoma skin cancers) were identified. The standardised incidence ratio (SIR) was 1.61 (95% confidence interval (CI): 1.47–1.76, P<0.0001). The SIR was 1.53 (95% CI: 1.39–1.68, P<0.0001) when the 32 second testicular cancers were also excluded. This increase was largely due to an excess risk to organs in the radiation field; for pelvic–abdominal sites the SIR was 1.62 (95% CI: 1.43–1.83), with no significant elevated risk of cancers in organs elsewhere. There was no overall increase in mortality with a standardised mortality ratio (SMR) of 1.06 (95% CI: 0.98–1.14), despite an increase in the cancer-specific mortality (excluding testicular cancer deaths) SMR of 1.46 (95% CI: 1.30–1.65, P<0.0001).
The prognosis of stage I seminoma is excellent and it is important to avoid conferring long-term increased risk of iatrogenic disease such as radiation-associated second cancers.
PMCID: PMC3887279  PMID: 24263066
seminoma; radiotherapy; carboplatin; metastasis
11.  Pro-HEART – A Randomized Clinical Trial to Test the Effectiveness of a High Protein Diet Targeting Obese Individuals with Heart Failure: Rationale, Design and Baseline Characteristics 
Contemporary clinical trials  2013;36(2):10.1016/j.cct.2013.08.004.
There is ample research to support the potential benefits of a high protein diet on clinical outcomes in overweight/obese, diabetic subjects. However, nutritional management of overweight/obese individuals with heart failure (HF) and type 2 diabetes mellitus (DM) or metabolic syndrome (MS) is poorly understood and few clinical guidelines related to nutritional approaches exist for this subgroup. This article describes the design, methods, and baseline characteristics of study participants enrolled in Pro-HEART, a randomized clinical trial to determine the short term and long term effects of a high protein diet (30% protein [~110 g/day], 40% carbohydrates [150 g/day], 30% fat [~50 g/day]) versus a standard protein diet (15% protein [~55 g/day], 55% carbohydrates [~200 g/day], 30% fat [~50 g/day]) on body weight and adiposity, cardiac structure and function, functional status, lipid profile, glycemic control, and quality of life. Between August, 2009 and May, 2013, 61 individuals agreed to participate in the study; 52 (85%) - mean age 58.2 ± 9.8 years; 15.4% Blacks; 57.7% Whites; 19.2% Hispanics; 7.7% Asians; 73.1% male; weight 112.0 ± 22.6 kilograms- were randomized to a 3-month intensive weight management program of either a high protein or standard protein diet; data were collected at baseline, 3 months, and 15 months. This study has the potential to reveal significant details about the role of macronutrients in weight management of overweight/obese individuals with HF and DM or MS.
PMCID: PMC3844022  PMID: 23958597
Heart failure; Obesity; Nutrition; Clinical trial
12.  Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up 
British Journal of Cancer  2013;109(3):651-657.
Radical three-dimensional conformal radiotherapy (CFRT) with initial androgen suppression (AS) is a standard management for localised prostate cancer (PC). This pilot study evaluated the role of dose escalation and appropriate target volume margin. Here, we report long-term follow-up.
Eligible patients had T1b-T3b N0 M0 PC. After neoadjuvant AS, they were randomised to CFRT, giving (a) 64 Gy with either a 1.0- or 1.5-cm margin and (b) ±10 Gy boost to the prostate alone.
One hundred and twenty-six men were randomised and treated. Median follow-up was 13.7 years. The median age was 66.6 years at randomisation. Median presenting prostate-specific antigen (PSA) was 14 ng ml−1. Sixty-four out of 126 patients developed PSA failure. Forty-nine out of 126 patients restarted AS, 34 out of 126 developed metastases and 28 out of 126 developed castrate-resistant prostate cancer (CRPC). Fifty-one out of 126 patients died; 19 out of 51 died of PC. Median overall survival (OS) was 14.4 years. Although escalated dose results were favourable, no statistically significant differences were seen between the randomised groups; PSA control (hazard ratio (HR): 0.77 (95% confidence interval (CI): 0.47–1.26)), development of CRPC (HR: 0.81 (95% CI: 0.40–1.65)), PC-specific survival (HR: 0.59 (95% CI:0.23–1.49)) and OS (HR: 0.81 (95% CI: 0.47–1.40)). There was no evidence of a difference in PSA control according to margin size (HR: 1.01 (95% CI: 0.61–1.66)).
Long-term follow-up of this small pilot study is compatible with a benefit from dose escalation, but confirmation from larger trials is required. There was no obvious detriment using the smaller radiotherapy margin.
PMCID: PMC3738135  PMID: 23880826
prostate cancer; radiotherapy; dose escalation; phase III randomised controlled trial
13.  Intact Skeletal Muscle Mitochondrial Enzyme Activity but Diminished Exercise Capacity in Advanced Heart Failure Patients on Optimal Medical and Device Therapy 
A skeletal myopathy, perhaps attributable to neuro-endocrine excitation or disuse, has been described in heart failure (HF) patients, and is thought to contribute to their exercise limitation. Our purpose was to assess biochemical and morphometric characteristics of skeletal muscles of HF patients on optimal HF therapy. A secondary purpose was to explore the effects of clonidine, which interrupts the neuro-endocrine excitation, on these same muscle characteristics.
Methods and Results
Eleven HF patients (50.8±3.4 years, peak VO2 11.6±2.5 ml/kg/min) underwent two vastus lateralis biopsies (pre/post clonidine). Baseline values were compared to biopsies in 11 age-matched, healthy controls. Scatter plots of individual values for each mitochondrial enzyme revealed almost complete overlap between HF and control groups; mean values, although tending to be greater in controls versus HF patients, were not significantly different. The proportion of type 1 fibers was diminished in 10 of 11 patients. There was no difference in any of the variables after 3 months clonidine versus placebo.
In HF patients treated with optimal medical and device therapy, characteristic abnormalities of mitochondrial enzyme activity are not found, but muscle fiber type shifts are present. The remaining severe impairment in exercise capacity cannot be attributed to mitochondrial abnormalities.
PMCID: PMC3710307  PMID: 23575739
14.  Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors 
British Journal of Cancer  2013;108(11):2399-2406.
Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk.
We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956–2003.
Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97–15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35–0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003).
In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.
PMCID: PMC3681009  PMID: 23652303
Hodgkin lymphoma; breast cancer; supradiaphragmatic radiotherapy
15.  Temporal Trends in Treatment and Outcomes for Advanced Heart Failure with Reduced Ejection Fraction from 1993-2010: Findings from a University Referral Center 
Circulation. Heart failure  2013;6(3):411-419.
Randomized trials have demonstrated the efficacy of several new therapies for heart failure (HF) with reduced ejection fraction over the preceding two decades. This study investigates whether these therapeutic advances have translated into improvement in outcomes for patients with advanced HF referred to a heart transplant center.
Methods and Results
Patients with HF (n=2507) referred to a single university center were analyzed in three 6-year eras during which medical and device therapies were evolving: 1993-1998 (era 1), 1999-2004 (era 2), and 2005-2010 (era 3). Impaired hemodynamics and comorbidities were more frequent at time of referral in later eras, whereas other HF severity parameters where similar or improved. Successive eras had greater utilization of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, aldosterone antagonists, implantable cardioverter defibrillators, and cardiac resynchronization therapy, consistent with evolving evidence and guideline-recommendations over the study period. All-cause mortality and sudden death were significantly lower in era 2 and 3 compared to era 1. After multivariable risk adjustment, era 3 had significantly decreased 2- and 3-year all-cause mortality risk and significantly decreased 1- and 3-year sudden death risk compared to era 1. However, progressive HF death and the combined outcome of mortality / urgent transplant / ventricular assist device were modestly increased in the latter eras.
Over the past two decades, patients with advanced HF referred to and managed at a tertiary university referral center have benefited from advances in HF medications and devices, as evidenced by improvements in overall survival and sudden death risk.
PMCID: PMC3674961  PMID: 23479563
heart failure; mortality; therapy
16.  Association between inflammatory biomarkers and adiposity in obese patients with heart failure and metabolic syndrome 
Obesity, type 2 diabetes mellitus (DM) and metabolic syndrome (MS) are common in patients with heart failure (HF). Studies investigating the association between known biomarkers and adiposity in patient populations are limited. The aim of the present study was to investigate the association between C-reactive protein (CRP) and leptin with adiposity in a sub-group of overweight/obese patients with HF, DM and/or MS. A total of 36 patients (mean age, 56.72±9.78 years; ranging between 27 and 76 years of age; 80.6% male; 52.8% Caucasian) were enrolled and their height, weight, waist circumference and body composition (e.g. percentage body fat and lean mass), as well as the levels of CRP and leptin, were assessed. The results demonstrated that there was a significant association between CRP and leptin, CRP and body mass index (BMI) and gender and percentage body fat (P<0.05, for all associations). Analysis of leptin and CRP levels revealed that patients in the highest BMI quartile (BMI, 40.3–61.2) had higher CRP levels (4.83 μg/ml vs. 3.03 μg/ml; P=0.033) and higher leptin levels (44.97 ng/ml vs. 24.64 ng/ml; P=0.042) compared with patients in the lower BMI quartile (BMI, 28.6–32.4). In conclusion, among obese patients with HF, DM and/or MS, an association between CRP and leptin was identified, providing further evidence that metabolic and inflammatory mechanisms are involved in these diseases. Future investigation to assess the potential impact of inflammation and adiposity, and the role of dietary interventions and weight loss on clinical outcomes in this population of chronically ill patients is warranted.
PMCID: PMC4061200  PMID: 24944619
heart failure; biomarkers; C-reactive protein; leptin; obesity
17.  A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact 
Genetic epidemiology  2011;35(6):549-556.
Genome Wide Association Studies have identified several Single Nucleotide Polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where P∼N(0,σP2). Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, PK∼N(0,σK2), and the residual polygenic component due to the postulated but as yet unknown genetic variants, PU∼N(0,σU2). The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist.
PMCID: PMC3950816  PMID: 21769933
18.  A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease 
Amin Al Olama, Ali | Kote-Jarai, Zsofia | Schumacher, Fredrick R. | Wiklund, Fredrik | Berndt, Sonja I. | Benlloch, Sara | Giles, Graham G. | Severi, Gianluca | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Hunter, David J. | Henderson, Brian E. | Thun, Michael J. | Gaziano, Michael | Giovannucci, Edward L. | Siddiq, Afshan | Travis, Ruth C. | Cox, David G. | Canzian, Federico | Riboli, Elio | Key, Timothy J. | Andriole, Gerald | Albanes, Demetrius | Hayes, Richard B. | Schleutker, Johanna | Auvinen, Anssi | Tammela, Teuvo L.J. | Weischer, Maren | Stanford, Janet L. | Ostrander, Elaine A. | Cybulski, Cezary | Lubinski, Jan | Thibodeau, Stephen N. | Schaid, Daniel J. | Sorensen, Karina D. | Batra, Jyotsna | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Gardiner, Robert A. | Maier, Christiane | Vogel, Walther | Dörk, Thilo | Brenner, Hermann | Habuchi, Tomonori | Ingles, Sue | John, Esther M. | Dickinson, Joanne L. | Cannon-Albright, Lisa | Teixeira, Manuel R. | Kaneva, Radka | Zhang, Hong-Wei | Lu, Yong-Jie | Park, Jong Y. | Cooney, Kathleen A. | Muir, Kenneth R. | Leongamornlert, Daniel A. | Saunders, Edward | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | Govindasami, Koveela | O'Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Artitaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Virtamo, Jarmo | Le Marchand, Loic | Campa, Daniele | Kaaks, Rudolf | Lindstrom, Sara | Diver, W. Ryan | Gapstur, Susan | Yeager, Meredith | Cox, Angela | Stern, Mariana C. | Corral, Roman | Aly, Markus | Isaacs, William | Adolfsson, Jan | Xu, Jianfeng | Zheng, S. Lilly | Wahlfors, Tiina | Taari, Kimmo | Kujala, Paula | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Frikke-Schmidt, Ruth | Bojesen, Stig E. | FitzGerald, Liesel M. | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Rinckleb, Antje | Luedeke, Manuel | Herkommer, Kathleen | Meyer, Andreas | Serth, Jürgen | Marthick, James R. | Patterson, Briony | Wokolorczyk, Dominika | Spurdle, Amanda | Lose, Felicity | McDonnell, Shannon K. | Joshi, Amit D. | Shahabi, Ahva | Pinto, Pedro | Santos, Joana | Ray, Ana | Sellers, Thomas A. | Lin, Hui-Yi | Stephenson, Robert A. | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Chanock, Stephen | Gronberg, Henrik | Haiman, Christopher A. | Kraft, Peter | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2012;22(2):408-415.
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 × 10−8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
PMCID: PMC3526158  PMID: 23065704
19.  Production of RNA for Transcriptomic Analysis from Mouse Spinal Cord Motor Neuron Cell Bodies by Laser Capture Microdissection 
Preparation of high-quality RNA from cells of interest is critical to precise and meaningful analysis of transcriptional differences among cell types or between the same cell type in health and disease or following pharmacologic treatments. In the spinal cord, such preparation from motor neurons, the target of interest in many neurologic and neurodegenerative diseases, is complicated by the fact that motor neurons represent <10% of the total cell population. Laser capture microdissection (LMD) has been developed to address this problem. Here, we describe a protocol to quickly recover, freeze, and section mouse spinal cord to avoid RNA damage by endogenous and exogenous RNases, followed by staining with Azure B in 70% ethanol to identify the motor neurons while keeping endogenous RNase inhibited. LMD is then used to capture the stained neurons directly into guanidine thiocyanate lysis buffer, maintaining RNA integrity. Standard techniques are used to recover the total RNA and measure its integrity. This material can then be used for downstream analysis of the transcripts by RNA-seq and qRT-PCR.
PMCID: PMC4089401  PMID: 24457537
Neuroscience; Issue 83; Laser capture microdissection; Motor neuron; Spinal cord; Azure B; RNA; RNA-seq; qRT-PCR
20.  Long-term functional donor site morbidity of the free radial forearm flap in head and neck cancer survivors 
To assess the functional donor site morbidity of the forearm free flap in patients surviving at least 2 years after ablative head and neck cancer surgery in a tertiary care centre.
This study involved nine long-term survivors (2 year post-operative) who had forearm free flaps to reconstruct head and neck defects. All flaps were raised from the non-dominant arm. The non-donor side acted as a control for all patients. Objective measurements were as follows: grip, tip pinch and key pinch strength measured with dynamometers; flexion, extension, radial and ulnar deviation and pronation and supination range of motion at the wrist measured with goniometry; A timed manual dexterity task was performed with a grooved pegboard test, and sensation of the radial nerve was tested with Semmes Weinstein monofilaments. Subjective measurements included a validated patient questionnaire of hand function and opinions of scar appearance as well as a validated scar assessment from two different observers.
Pronation at the wrist, manual dexterity and sensation were found to be significantly reduced in the donor side compared to the non-donor side. Inter-rater agreement between the two observers was found to be poor, except for an acceptable correlation between overall scar opinions. No correlations were found between any subjective or objective items or between the patient’s and the observers’ subjective evaluations.
Donor site morbidity can be demonstrated with objective testing however this is accepted and well tolerated by head and neck cancer patients.
PMCID: PMC3895707  PMID: 24418459
Radial forearm flap; Donor-site; Morbidity; Long-term
21.  Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array 
Eeles, Rosalind A | Olama, Ali Amin Al | Benlloch, Sara | Saunders, Edward J | Leongamornlert, Daniel A | Tymrakiewicz, Malgorzata | Ghoussaini, Maya | Luccarini, Craig | Dennis, Joe | Jugurnauth-Little, Sarah | Dadaev, Tokhir | Neal, David E | Hamdy, Freddie C | Donovan, Jenny L | Muir, Ken | Giles, Graham G | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J | Gapstur, Susan | Chanock, Stephen J | Berndt, Sonja I | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J | Travis, Ruth | Campa, Daniele | Ingles, Sue A | John, Esther M | Hayes, Richard B | Pharoah, Paul DP | Pashayan, Nora | Khaw, Kay-Tee | Stanford, Janet | Ostrander, Elaine A | Signorello, Lisa B | Thibodeau, Stephen N | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright,  | Brenner, Hermann | Park, Jong Y | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda B | Clements, Judith A | Teixeira, Manuel R | Dicks, Ed | Lee, Andrew | Dunning, Alison | Baynes, Caroline | Conroy, Don | Maranian, Melanie J | Ahmed, Shahana | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A | Sawyer, Emma J | Morgan, Angela | Dearnaley, David P | Horwich, Alan | Huddart, Robert A | Khoo, Vincent S | Parker, Christopher C | Van As, Nicholas J | Woodhouse, J | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin | Lophatananon, Artitaya | Cox, Angela | Southey, Melissa | Hopper, John L | English, Dallas R | Aly, Markus | Adolfsson, Jan | Xu, Jiangfeng | Zheng, Siqun | Yeager, Meredith | Kaaks, Rudolf | Diver, W Ryan | Gaudet, Mia M | Stern, Mariana | Corral, Roman | Joshi, Amit D | Shahabi, Ahva | Wahlfors, Tiina | Tammela, Teuvo J | Auvinen, Anssi | Virtamo, Jarmo | Klarskov, Peter | Nordestgaard, Børge G | Røder, Andreas | Nielsen, Sune F | Bojesen, Stig E | Siddiq, Afshan | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika | Karyadi, Danielle | Blot, William J | Zheng, Wei | Cai, Qiuyin | McDonnell, Shannon K | Rinckleb, Antje | Drake, Bettina | Colditz, Graham | Wokolorczyk, Dominika | Stephenson, Robert A | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Sellers, Thomas A | Lin, Hui-Yi | Slavov, Chavdar | Mitev, Vanio | Lose, Felicity | Srinivasan, Srilakshmi | Maia, Sofia | Paulo, Paula | Lange, Ethan | Cooney, Kathleen A | Antoniou, Antonis | Vincent, Daniel | Bacot, François | Tessier,  | Kote-Jarai, Zsofia | Easton, Douglas F
Nature genetics  2013;45(4):10.1038/ng.2560.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
PMCID: PMC3832790  PMID: 23535732
22.  Abnormalities of Calcium Handling Proteins in Skeletal Muscle Mirror those of the Heart in Humans with Heart Failure: a Shared Mechanism? 
Journal of cardiac failure  2012;18(9):724-733.
In the failing human heart, abnormalities of Ca2+ cycling have been described, but there is scant knowledge about Ca2+ handling in the skeletal muscle of humans with HF. We tested the hypothesis that in humans with HF, Ca2+ cycling proteins in skeletal muscle are abnormal.
Methods and Results
Ten advanced HF patients (50.4±3.7 years), and 9 age matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a, which is responsible for Ca2+ sequestration into the sarcoplasmic reticulum(SR), was lower in HF vs controls (4.8±0.5vs7.5±0.8AU, p=0.01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF vs controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8±0.1vs3.9±0.9AU, p=0.004). Dihydropyridine receptors were reduced in HF, (2.1±0.4vs3.6±0.5AU, p=0.04). We tested the hypothesis that these abnormalities of Ca2+ handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients.
In chronic HF, marked abnormalities of Ca2+ handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca2+-calmodulin-dependent-protein kinase II.
PMCID: PMC3437990  PMID: 22939042
exercise intolerance; sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a; sympathetic nerve activity; oxidative stress
23.  The Obesity Paradox in Men versus Women with Systolic Heart Failure 
Obesity is common in heart failure (HF) and associated with improved outcomes, often termed the “obesity paradox”. Although fat distribution varies by sex, the role of obesity in the outcomes of women compared to men with HF has not been well-studied. In a cohort of advanced systolic HF patients followed at a single university center, 2718 patients had body mass index (BMI) measured at baseline and 469 HF patients had waist circumference (WC) measured at baseline. Elevated BMI was defined as ≥25 kg/m2. High WC was defined as ≥88 cm in women and ≥102 cm in men. The primary outcome was death, urgent heart transplant, or ventricular assist device placement. Mean age was 53.0 ± 12.4, 25% of subjects were women, and LVEF was 22.9 ± 7.19. In men, 2-year event-free survival was better for high vs. normal BMI (63.2 vs. 53.5% p<0.001) and for high vs. normal WC (78.8% vs. 63.1%, p=0.01). In women, 2-year event-free survival was better in elevated vs. normal BMI groups (67.1% vs. 56.6%, p=0.01), but similar in WC groups. In multivariate analyses, normal BMI and normal WC were associated with higher risk of primary outcome in both men (BMI 1.34, WC 2.02) and women (BMI 1.38, WC 2.99). In advanced HF, high BMI and WC were associated with improved outcomes in both sexes. Further investigation of the interaction between body composition and sex in HF outcomes is warranted.
PMCID: PMC3377856  PMID: 22497678
Cardiomyopathy; mortality; adiposity; gender
24.  Relation between Hemoglobin A1c and Outcomes in Heart Failure Patients with and without Diabetes Mellitus 
The American Journal of Cardiology  2012;109(12):1767-1773.
Among patients with diabetes mellitus (DM) in the general population, elevated glycosylated hemoglobin (HbA1c) increases the risk of developing heart failure (HF). However, in patients with established HF, the association of HbA1c level with outcomes is not well established. This study investigated the relation between HbA1c and outcomes in HF patients with and without diabetes. We studied 845 advanced HF patients followed at the Ahmanson-UCLA Cardiomyopathy Center, stratified by presence (n=358) or absence (n=487) of DM and by DM-specific HbA1c quartiles (Q) (Diabetics: Q1≤6.4%, Q2 6.5–7.2%, Q3 7.3–8.5%, Q4≥8.6%; Non-diabetics: Q1≤5.6%, Q2 5.7–6.0%, Q3 6.1–6.5%, Q4≥6.6%). The primary outcomes analyzed were death and death/urgent heart transplantation (Utx). In the cohort with DM, 2-year event-free survival was 61% and 65% for Q3 and Q4 compared to 48% and 42% in Q1 and Q2 (p=0.005). In the cohort without DM, there was no difference in outcomes by HbA1c Q. Risk-adjusted analysis in the diabetic cohort showed significantly increased hazard ratio (HR) of death/Utx in Q1 and Q2 compared to Q4. For every unit HbA1c increase, there was a 15% decreased HR of death/Utx and all-cause mortality (p=0.006 and p=0.036, respectively). In the cohort without DM, multivariable models revealed similar HR among HbA1c Q. In this cohort of patients with advanced HF, higher HbA1c levels were associated with improved outcomes in patients with diabetes. This relationship was not observed in patients without DM. Further investigations into mechanisms underlying the relationship between HbA1c, DM, and survival in advanced HF are warranted.
PMCID: PMC3367080  PMID: 22459300
diabetes; heart failure; glycosylated hemoglobin; outcomes
25.  RNA-Seq Profiling of Spinal Cord Motor Neurons from a Presymptomatic SOD1 ALS Mouse 
PLoS ONE  2013;8(1):e53575.
Mechanisms involved with degeneration of motor neurons in amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) are poorly understood, but genetically inherited forms, comprising ∼10% of the cases, are potentially informative. Recent observations that several inherited forms of ALS involve the RNA binding proteins TDP43 and FUS raise the question as to whether RNA metabolism is generally disturbed in ALS. Here we conduct whole transcriptome profiling of motor neurons from a mouse strain, transgenic for a mutant human SOD1 (G85R SOD1-YFP), that develops symptoms of ALS and paralyzes at 5–6 months of age. Motor neuron cell bodies were laser microdissected from spinal cords at 3 months of age, a time when animals were presymptomatic but showed aggregation of the mutant protein in many lower motor neuron cell bodies and manifested extensive neuromuscular junction morphologic disturbance in their lower extremities. We observed only a small number of transcripts with altered expression levels or splicing in the G85R transgenic compared to age-matched animals of a wild-type SOD1 transgenic strain. Our results indicate that a major disturbance of polyadenylated RNA metabolism does not occur in motor neurons of mutant SOD1 mice, suggesting that the toxicity of the mutant protein lies at the level of translational or post-translational effects.
PMCID: PMC3536741  PMID: 23301088

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