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Baltimore Highlands, MD, United States

Reese J.B.,Johns Hopkins University | Porter L.S.,Duke University | Regan K.R.,Widener University | Keefe F.J.,Duke University | And 5 more authors.
Psycho-Oncology | Year: 2014

Background: We previously developed and piloted a telephone-based intimacy enhancement (IE) intervention addressing sexual concerns of colorectal cancer patients and their partners in an uncontrolled study. The current study tested the feasibility, acceptability, and preliminary efficacy of the IE intervention in a randomized, controlled trial. Methods: Twenty-three couples were randomized to either the four-session IE condition or to a wait list control condition and completed sexual and relationship outcomes measures. The IE intervention teaches skills for coping with sexual concerns and improving intimacy. Feasibility and acceptability were assessed through enrollment and post-treatment program evaluations, respectively. Effect sizes were calculated by comparing differences in average pre/post change scores across completers in the two groups (n = 18 couples). Results: Recruitment and attrition data supported feasibility. Program evaluations for process (e.g., ease of participation) and content (e.g., relevance) demonstrated acceptability. Engaging in intimacy-building activities and communication were the skills rated as most commonly practiced and most helpful. For patients, positive effects of the IE intervention were found for female and male sexual function, medical impact on sexual function, and self-efficacy for enjoying intimacy (≥.58); no effects were found on sexual distress or intimacy and small negative effects for sexual communication, and two self-efficacy items. For partners, positive IE effects were found for all outcomes; the largest were for sexual distress (.69), male sexual function (1.76), communication (.97), and two self-efficacy items (≥.87). Conclusions: The telephone-based IE intervention shows promise for couples facing colorectal cancer. Larger multi-site intervention studies are necessary to replicate findings. Copyright © 2014 John Wiley & Sons, Ltd. Source


Tomasetti C.,Johns Hopkins University | Marchionni L.,Johns Hopkins University | Nowak M.A.,Harvard University | Parmigiani G.,Dana-Farber Cancer Institute | And 2 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, how many such mutations are required for a normal human cell to progress to an advanced cancer? The best estimates for this number have been provided by mathematical models based on the relation between age and incidence. For example, the classic studies of Nordling [Nordling CO (1953) Br J Cancer 7(1):68-72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1-12] suggest that six or seven sequential mutations are required. Here, we describe a different approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data: incidence data for different groups of patients with the same cancer type were compared with respect to their somatic mutation rates. In two well-documented cancer types (lung and colon adenocarcinomas), we find that only three sequential mutations are required to develop cancer. This conclusion deepens our understanding of the process of carcinogenesis and has important implications for the design of future cancer genome-sequencing efforts. © 2015, National Academy of Sciences. All rights reserved. Source


Izumchenko E.,Johns Hopkins University | Sun K.,Shanghai JiaoTong University | Jones S.,Personal Genome Diagnostics (PGD) | Brait M.,Johns Hopkins University | And 8 more authors.
Cancer Prevention Research | Year: 2015

Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput PCR-based enrichment technology and next-generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty-nine samples were normal oralmucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies, and 50 were chemoradiation-naïve OSCCsamples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of premalignant lesions. Importantly, almost 60% of patients with leukoplakia with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese patients with OSCC with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that premalignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCCprogression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. ©2014 AACR. Source


Cardenas-Navia L.I.,Human Genome Research Institutes | Cruz P.,U.S. National Institutes of Health | Lin J.C.,Ludwig Center for Cancer Genetics and Therapeutics | Rosenberg S.A.,U.S. National Cancer Institute | Samuels Y.,Human Genome Research Institutes
Cancer Biology and Therapy | Year: 2010

Heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate signals between G-protein coupled receptors and their downstream pathways, and have been shown to be mutated in cancer. In particular, GNAQ was found to be frequently mutated in blue nevi of the skin and uveal melanoma, acting as an oncogene in its mutated form. To further examine the role of heterotrimeric G proteins in melanoma, we performed a comprehensive mutational analysis of the 35 genes in the heterotrimeric G protein gene family in a panel of 80 melanoma samples. somatic alterations in a G protein subunit were detected in 17% of samples spanning 7 genes. The highest rates of somatic, non-synonymous mutations were found in GNG10 and GNAZ, neither of which has been previously reported to be mutated in melanoma. Our study is the first systematic analysis of the heterotrimeric G proteins in melanoma and indicates that multiple mutated heterotrimeric G proteins may be involved in melanoma progression. © 2010 Landes Bioscience. Source


Lovejoy C.A.,Rockefeller University | Li W.,Rockefeller University | Reisenweber S.,Rockefeller University | Thongthip S.,Rockefeller University | And 25 more authors.
PLoS Genetics | Year: 2012

The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers. © 2012 Lovejoy et al. Source

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