Resnick M.J.,The Surgical Center |
Resnick M.J.,Vanderbilt University |
Koyama T.,Center for Quantitative science |
Fan K.-H.,Center for Quantitative science |
And 9 more authors.
New England Journal of Medicine | Year: 2013
BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.) Copyright © 2013 Massachusetts Medical Society.
PubMed | Levine Cancer Institute, Center for Quantitative science, Tennessee Valley Healthcare System and, Vanderbilt University and 2 more.
Type: Journal Article | Journal: Blood | Year: 2015
The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment.
PubMed | Center for Quantitative science and Vanderbilt University
Type: Journal Article | Journal: Bioinformatics (Oxford, England) | Year: 2015
We previously developed dmGWAS to search for dense modules in a human protein-protein interaction (PPI) network; it has since become a popular tool for network-assisted analysis of genome-wide association studies (GWAS). dmGWAS weights nodes by using GWAS signals. Here, we introduce an upgraded algorithm, EW_dmGWAS, to boost GWAS signals in a node- and edge-weighted PPI network. In EW_dmGWAS, we utilize condition-specific gene expression profiles for edge weights. Specifically, differential gene co-expression is used to infer the edge weights. We applied EW_dmGWAS to two diseases and compared it with other relevant methods. The results suggest that EW_dmGWAS is more powerful in detecting disease-associated signals.
Hoffman R.M.,University of New Mexico |
Hoffman R.M.,New Mexico VA Healthcare System |
Koyama T.,Center for Quantitative science |
Fan K.-H.,Center for Quantitative science |
And 9 more authors.
Journal of the National Cancer Institute | Year: 2013
Background No randomized trials have compared survival outcomes for men with localized prostate cancer (PC) being treated with radical prostatectomy (RP) or external beam radiotherapy (EBRT). The goal of the study, therefore, was to estimate the association of RP (compared with EBRT) with overall and PC mortality. Methods We analyzed an observational cohort from the population-based Prostate Cancer Outcomes Study, which included men aged 55 to 74 years diagnosed with localized PC between October 1994 and October 1995 who underwent either RP (n = 1164) or EBRT (n = 491) within 1 year of diagnosis. Patients were followed until death or study end (December 31, 2010). Overall and disease-specific mortality were assessed with multivariable survival analysis, with propensity scores to adjust for potential treatment selection confounders (demographics, comorbidities, and tumor characteristics). All statistical tests were two-sided. Results After 15 years of follow-up, there were 568 deaths, including 104 from PC. RP was associated with statistically significant advantages for overall (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.53 to 0.70, P <.0001.) and disease-specific mortality (HR = 0.35, 95% CI = 0.26 to 0.49, P <.0001.). Mortality benefits for RP were also observed within treatment propensity quintiles, when subjects were pair-matched on propensity scores, and in subgroup analyses based on age, tumor characteristics, and comorbidity. Conclusions Population-based observational data on men diagnosed with localized PC in the mid-1990s suggest a mortality benefit associated with RP vs EBRT. Possible explanations include residual selection bias or a true survival advantage. Results might be less applicable for men facing treatment decisions today. © The Author 2013. Published by Oxford University Press. All rights reserved.
Guo Y.,Center for Quantitative science |
Long J.,Vanderbilt University |
He J.,Vanderbilt University |
Li C.-I.,Center for Quantitative science |
And 4 more authors.
BMC Genomics | Year: 2012
Background: Exome sequencing using next-generation sequencing technologies is a cost efficient approach to selectively sequencing coding regions of human genome for detection of disease variants. A significant amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment.Result: We performed whole exome sequencing on 22 subjects using Agilent SureSelect capture reagent and 6 subjects using Illumina TrueSeq capture reagent. We also downloaded sequencing data for 6 subjects from the 1000 Genomes Project Pilot 3 study. Using these data, we examined the quality of SNPs detected outside target regions by computing consistency rate with genotypes obtained from SNP chips or the Hapmap database, transition-transversion (Ti/Tv) ratio, and percentage of SNPs inside dbSNP. For all three platforms, we obtained high-quality SNPs outside target regions, and some far from target regions. In our Agilent SureSelect data, we obtained 84,049 high-quality SNPs outside target regions compared to 65,231 SNPs inside target regions (a 129% increase). For our Illumina TrueSeq data, we obtained 222,171 high-quality SNPs outside target regions compared to 95,818 SNPs inside target regions (a 232% increase). For the data from the 1000 Genomes Project, we obtained 7,139 high-quality SNPs outside target regions compared to 1,548 SNPs inside target regions (a 461% increase).Conclusions: These results demonstrate that a significant amount of high quality genotypes outside target regions can be obtained from exome sequencing data. These data should not be ignored in genetic epidemiology studies. © 2012 Guo et al.; licensee BioMed Central Ltd.
PubMed | Center for Quantitative science and Vanderbilt Medical Center
Type: Journal Article | Journal: European journal of radiology | Year: 2016
Crossed cerebellar diaschisis (CCD) is most commonly investigated using hemodynamic PET and SPECT imaging. However, noninvasive MRI offers advantages of improved spatial resolution, allowing hemodynamic changes to be compared directly with structural findings and without concerns related to ionizing radiation exposure. The aim of this study was to evaluate relationships between CCD identified from cerebral blood flow (CBF)-weighted arterial spin labeling (ASL) MRI with cerebrovascular reactivity (CVR)-weighted blood oxygenation level dependent (BOLD) MRI, Wallerian degeneration, clinical motor impairment, and corticospinal tract involvement.Subjects (n=74) enrolled in an ongoing observational stroke trial underwent CBF-weighted ASL and hypercapnic CVR-weighted BOLD MRI. Hemispheric asymmetry indices for basal cerebellar CBF, cerebellar CVR, and cerebral peduncular area were compared between subjects with unilateral supratentorial infarcts (n=18) and control subjects without infarcts (n=16). CCD required (1) supratentorial infarct and (2) asymmetric cerebellar CBF (>95% confidence interval relative to controls).In CCD subjects (n=9), CVR (p=0.04) and cerebral peduncular area (p<0.01) were significantly asymmetric compared to controls. Compared to infarct subjects not meeting CCD criteria (n=9), CCD subjects had no difference in corticospinal tract location for infarct (p=1.0) or motor impairment (p=0.08).CCD correlated with cerebellar CVR asymmetry and Wallerian degeneration. These findings suggest that noninvasive MRI may be a useful alternative to PET or SPECT to study structural correlates and clinical consequences of CCD following supratentorial stroke.
Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer
PubMed | Washington University in St. Louis, Sloan Kettering Cancer Center, Mayo Medical School, Stanford University and 5 more.
Type: Clinical Trial | Journal: The Annals of thoracic surgery | Year: 2014
Fluorodeoxyglucose-positron emission tomography (FDG-PET) is recommended for diagnosis and staging of non-small cell lung cancer (NSCLC). Meta-analyses of FDG-PET diagnostic accuracy demonstrated sensitivity of 96% and specificity of 78% but were performed in select centers, introducing potential bias. This study evaluates the accuracy of FDG-PET to diagnose NSCLC and examines differences across enrolling sites in the national American College of Surgeons Oncology Group (ACOSOG) Z4031 trial.Between 2004 and 2006, 959 eligible patients with clinical stage I (cT1-2 N0 M0) known or suspected NSCLC were enrolled in the Z4031 trial, and with a baseline FDG-PET available for 682. Final diagnosis was determined by pathologic examination. FDG-PET avidity was categorized into avid or not avid by radiologist description or reported maximum standard uptake value. FDG-PET diagnostic accuracy was calculated for the entire cohort. Accuracy differences based on preoperative size and by enrolling site were examined.Preoperative FDG-PET results were available for 682 participants enrolled at 51 sites in 39 cities. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% confidence interval, 79 to 85) and specificity was 31% (95% confidence interval, 23% to 40%). Positive and negative predictive values were 85% and 26%, respectively. Accuracy improved with lesion size. Of 80 false-positive scans, 69% were granulomas. False-negative scans occurred in 101 patients, with adenocarcinoma being the most frequent (64%), and 11 were 10 mm or less. The sensitivity varied from 68% to 91% (p=0.03), and the specificity ranged from 15% to 44% (p=0.72) across cities with more than 25 participants.In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared with published studies.
PubMed | Center for Quantitative science, University of Oxford, Vanderbilt University and Huazhong University of Science and Technology
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016
The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC).Using a panel of molecularly defined CRC cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.BET inhibitors as monotherapy moderately reduced CRC cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized CRC cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo. A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous CRC xenografts. ` Conclusions: Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in CRC and propose an effective combination strategy for the treatment of CRC.
PubMed | The Johns Hopkins Medical Institutions, University of Washington, Center for Quantitative science, Case Western Reserve University and 2 more.
Type: Journal Article | Journal: Cancer research | Year: 2016
Esophageal adenocarcinoma is a deadly cancer with increasing incidence in the United States, but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pretreatment esophageal adenocarcinoma and 49 nonmalignant biopsy tissues from patients undergoing endoscopy for Barretts esophagus. In this cohort, we identified 21 novel candidate esophageal adenocarcinoma-associated fusions occurring in 3.33% to 11.67% of esophageal adenocarcinomas. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pretreatment esophageal adenocarcinoma (N = 115) and nonmalignant (N = 183) biopsy tissues. In particular, we observed RPS6KB1-VMP1 gene fusion as a recurrent event occurring in approximately 10% of esophageal adenocarcinoma cases. Notably, esophageal adenocarcinoma cases harboring RPS6KB1-VMP1 fusions exhibited significantly poorer overall survival as compared with fusion-negative cases. Mechanistic investigations established that the RPS6KB1-VMP1 transcript coded for a fusion protein, which significantly enhanced the growth rate of nondysplastic Barretts esophagus cells. Compared with the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1-VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1-VMP1 as a genetic fusion that promotes esophageal adenocarcinoma by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas. Cancer Res; 76(19); 5628-33. 2016 AACR.
PubMed | Center for Quantitative science
Type: | Journal: BMC genomics | Year: 2012
Exome sequencing using next-generation sequencing technologies is a cost efficient approach to selectively sequencing coding regions of human genome for detection of disease variants. A significant amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment.We performed whole exome sequencing on 22 subjects using Agilent SureSelect capture reagent and 6 subjects using Illumina TrueSeq capture reagent. We also downloaded sequencing data for 6 subjects from the 1000 Genomes Project Pilot 3 study. Using these data, we examined the quality of SNPs detected outside target regions by computing consistency rate with genotypes obtained from SNP chips or the Hapmap database, transition-transversion (Ti/Tv) ratio, and percentage of SNPs inside dbSNP. For all three platforms, we obtained high-quality SNPs outside target regions, and some far from target regions. In our Agilent SureSelect data, we obtained 84,049 high-quality SNPs outside target regions compared to 65,231 SNPs inside target regions (a 129% increase). For our Illumina TrueSeq data, we obtained 222,171 high-quality SNPs outside target regions compared to 95,818 SNPs inside target regions (a 232% increase). For the data from the 1000 Genomes Project, we obtained 7,139 high-quality SNPs outside target regions compared to 1,548 SNPs inside target regions (a 461% increase).These results demonstrate that a significant amount of high quality genotypes outside target regions can be obtained from exome sequencing data. These data should not be ignored in genetic epidemiology studies.