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Turner K.M.,Ludwig Institute for Cancer Research | Deshpande V.,University of California at San Diego | Beyter D.,University of California at San Diego | Koga T.,Ludwig Institute for Cancer Research | And 19 more authors.
Nature | Year: 2017

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

King W.C.,University of Pittsburgh | Engel S.G.,Neuropsychiatric Institute | Elder K.A.,Oregon Health And Science University | Chapman W.H.,East Carolina Medical Center | And 3 more authors.
Surgery for Obesity and Related Diseases | Year: 2012

Background: This study characterizes the walking limitations of bariatric surgery candidates by age and body mass index (BMI) and determines factors independently associated with walking capacity. The setting was multi-institutional at research university hospitals in the United States. Methods: Participants of the Longitudinal Assessment of Bariatric Surgery study (n=2458; age 1878 yr, BMI 3394 kg/m 2) attended a preoperative research visit. Their walking capacity was measured by self-report and the 400 m Long Distance Corridor Walk (LDCW). Results: Almost two thirds (64%) of subjects reported limitations with walking several blocks, 48% had an objectively defined mobility deficit, and 16% reported at least some walking aid use. In multivariate analysis, BMI, older age, lower income, and greater bodily pain were independently associated (P <.05) with walking aid use, physical discomfort during the LDCW, an inability to complete the LDCW, and a slower time to complete the LDCW. Female gender, Hispanic ethnicity (but not race), greater heart rate at rest, a history of smoking, several co-morbidities (history of stroke, ischemic heart disease, diabetes, asthma, sleep apnea, venous edema with ulcerations), and depressive symptoms were also independently related (P <.05) to at least one measure of reduced walking capacity. Conclusions: Walking limitations are common in bariatric surgery candidates, even among the least severely obese and youngest patients. Physical activity counseling must be tailored to individuals' abilities. Although several factors identified in the present study (eg, BMI, age, pain, co-morbidities) should be considered, directly assessing the patient's walking capacity will facilitate appropriate goal setting. © 2012 American Society for Metabolic and Bariatric Surgery. All rights reserved.

King W.C.,University of Pittsburgh | Hsu J.Y.,University of Pittsburgh | Belle S.H.,University of Pittsburgh | Courcoulas A.P.,University of Pittsburgh | And 7 more authors.
Surgery for Obesity and Related Diseases | Year: 2012

Background: Numerous studies have reported that bariatric surgery patients report more physical activity (PA) after surgery than before; however, the quality of the PA assessment has been questionable. Methods: The Longitudinal Assessment of Bariatric Surgery-2 is a 10-center longitudinal study of adults undergoing bariatric surgery. Of 2458 participants, 455 were given an activity monitor, which records the steps per minute, and an exercise diary before and 1 year after surgery. The mean number of steps/d, active min/d, and high-cadence min/wk were calculated for 310 participants who wore the monitor <10 hr/d for <3 days at both evaluations. Pre- and postoperative PA were compared for differences using the Wilcoxon signed-rank test. Generalized estimating equations were used to identify independent preoperative predictors of postoperative PA. Results: PA increased significantly (P <.0001) from before to after surgery for all PA measures. The median values before and after surgery were 7563 and 8788 steps/d, 309 and 340 active min/d, and 72 and 112 high-cadence min/wk, respectively. However, depending on the PA measure, 24-29% of participants were <5% less active postoperatively than preoperatively. Controlling for surgical procedure, gender, age, and body mass index, more PA preoperatively independently predicted for more PA postoperatively (P <.0001, for all PA measures). Less pain, not having asthma, and the self-report of increasing PA as a weight loss strategy preoperatively also independently predicted for more high-cadence min/wk postoperatively (P <.05). Conclusions: The majority of adults increase their PA level after bariatric surgery. However, most remain insufficiently active, and some become less active. Increasing PA, addressing pain, and treating asthma before surgery might have a positive effect on postoperative PA. © 2012 American Society for Metabolic and Bariatric Surgery.

Galvez V.,University of New South Wales | Galvez V.,Hospital Road | Galvez V.,University of Barcelona | Galvez V.,Bellvitge Biomedical Research Institute IDIBELL | And 11 more authors.
Journal of ECT | Year: 2011

Objectives: To report a case of hypomania induced by transcranial direct current stimulation (tDCS) given with an extracephalic reference electrode. Transcranial direct current stimulation is a noninvasive brain stimulation technique in which a weak current is applied through the scalp to produce changes in neuronal excitability in the underlying cerebral tissue. Recent clinical trials have shown promising results with left anodal prefrontal tDCS in treating depression. When the reference cathodal electrode in tDCS is moved from the cranium to an extracephalic position, larger areas of both cerebral hemispheres are stimulated, with potential implications for both efficacy and safety. Methods: We report the case of a 33-year-old female with bipolar II disorder, on mood stabilizer medication, who had previously participated in a clinical trial of tDCS given with a bifrontal electrode montage for the treatment of major depression without incident, but became hypomanic when she received a later course of tDCS given with a frontoextracephalic configuration. Factors contributing to the development of hypomania in the second course of tDCS are examined. Results: No substantial differences were found in the patient's clinical presentation between the 2 tDCS courses to explain the emergence of hypomania only after the second course. The different montage used in the second course appeared to be the main contributory factor in the induction of hypomania. Conclusions: The reported case suggests that frontoextracephalic tDCS has antidepressant properties and the potential to induce hypomanic symptoms. In particular, it raises the question of whether frontoextracephalic tDCS requires additional precautions when administered to bipolar patients compared to bifrontal tDCS. © 2011 by Lippincott Williams & Wilkins.

Cherbuin N.,Australian National University | Sachdev P.,University of New South Wales | Sachdev P.,Neuropsychiatric Institute | Anstey K.J.,Australian National University
American Journal of Geriatric Psychiatry | Year: 2010

Objective: To identify neuropsychological predictors of transition from healthy cognitive aging to mild cognitive impairment (MCI) or any mild cognitive disorder (any-MCD) in a community-based longitudinal study of aging. Design: Longitudinal Participants: Two thousand eighty-two individuals, aged 60-64 years and participating in a prospective epidemiologic study of mental health, and aging were assessed at two time points 4 years apart for MCI using the International Consensus Criteria, the clinical dementia rating scale (CDR, 0.5), or any of a suite of criteria sets for MCDs (any-MCD). Measurements: Logistic regression was used to assess the neuropsychological predictors of conversion to diagnosis including the Mini-Mental State Examination, immediate and delayed recall (IR and DR), Digit Backward, Spot-the-Word (STW), Symbol Digits Modalities Test (SDMT), simple and choice reaction time, and reaction time variability. Results: Of the 2,082 Participants with no cognitive impairment in the first wave of data collection, 18 Participants were diagnosed with MCI, 32 with CDR 0.5, and 64 Participants presented with any-MCD 4 years later. The main neuropsychological predictors of conversion identified in multivariate analyses were measures of IR/DR, STW, Symbol Digit Modalities Task, and reaction time variability. Conclusions: Although most measures were significant predictors of conversion to MCI or any-MCD when assessed independently, four tests (IR/DR, STW, SDMT, and simple reaction time variability) accounted for the explained variance in diagnosis when all tests were assessed together. When predictive value, stability across clinical categories, and psychometric characteristics were considered together, the reaction time variability measure was the best predictor of future cognitive disorder. © 2010 American Association for Geriatric Psychiatry.

Gautam P.,Australian National University | Cherbuin N.,Australian National University | Sachdev P.S.,University of New South Wales | Sachdev P.S.,Neuropsychiatric Institute | And 3 more authors.
Neuroradiology | Year: 2013

Introduction: The study investigated sex differences in cortical thickness in middle-aged (MA, 44-48 years old, n = 397) and early old-aged (OA, 64-68 years old, n = 398) adults in a community-based sample. Methods: T1-weighted three-dimensional structural magnetic resonance imaging scans were acquired in a Fast Field Echo sequence, and cortical thickness was measured with a surface-based segmentation procedure ( Results: Results showed that after correcting for age, MA males had predominantly thicker superior temporal cortices, while MA females had thicker occipital, posterior cingulate, precentral, and postcentral cortices. Sex differences in OA adults were less prominent than those in MA adults with females showing thicker temporal and posterior cingulate cortices and males showing thicker rostral middle frontal regions. Between-cohort comparisons revealed that when compared with MA males, OA males showed many regions with significantly thinner cortices, but this pattern was less pronounced for OA females. Our results suggest that sex differences in cortical thickness are age specific, as larger differences in cortical thickness were found in MA compared to OA adults. Conclusion: The results of the present study indicate that the inconsistencies in sexual dimorphism that have been reported in the literature are partly due to the variable and transitory nature of cortical thickness differences with age. © 2013 Springer-Verlag Berlin Heidelberg.

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