Medicine and Health Sciences Commons^™

Targeted Dna Damage At Individual Telomeres Disrupts Their Integrity And Triggers Cell Death, Luxi Sun, Rong Tan, Jianquan Xu, Justin Laface, Ying Gao, Yanchun Xiao, Myriam Attar, Carola Neumann, Guo-Min Li, Bing Su, Yang Liu, Satoshi Nakajima, Arthur S. Levine, Li Lan

Markey Cancer Center Faculty Publications

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.

Trustworthy Guidelines – Excellent; Customized Care Tools – Even Better, Glyn Elwyn, Casey Quinlan, Albert Mulley, Thomas Agoritsas, Per Olav Vandvik, Gordon Guyatt

Dartmouth Scholarship

Background:

The ability to do online searches for health information has led to concerns that patients find the results confusing and that they often lead to expectations for treatments that have little supportive evidence. At the same time, the science of summarizing research evidence has advanced to the point where it is increasingly possible to quantify treatment tradeoffs and to describe the balance between harms and benefits for individual patients.

Discussion:

Trustworthy clinical practice guidelines provide evidence-based recommendations to health care practitioners based on assessments of study-level averages. In an effort to customize the use of evidence and ensure that …

Inflammatory Muscle Diseases., Marinos Dalakas

Department of Medicine Faculty Papers

No abstract provided.

Efficacy Of Galactose And Adalimumab In Patients With Resistant Focal Segmental Glomerulosclerosis: Report Of The Font Clinical Trial Group., Howard Trachtman, Suzanne Vento, Emily Herreshoff, Milena Radeva, Jennifer Gassman, Daniel T. Stein, Virginia J. Savin, Mukut Sharma, Jochen Reiser, Changli Wei, Michael Somers, Tarak Srivastava, Debbie S. Gipson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Patients with resistant focal segmental glomerulosclerosis (FSGS) who are unresponsive to corticosteroids and other immunosuppressive agents are at very high risk of progression to end stage kidney disease. In the absence of curative treatment, current therapy centers on renoprotective interventions that reduce proteinuria and fibrosis. The FONT (Novel Therapies for Resistant FSGS) Phase II clinical trial (NCT00814255, Registration date December 22, 2008) was designed to assess the efficacy of adalimumab and galactose compared to standard medical therapy which was comprised of lisinopril, losartan, and atorvastatin.

METHODS: Key eligibility criteria were biopsy confirmed primary FSGS or documentation of a causative …

Genome-Wide Meta-Analysis In Alopecia Areata Resolves Hla Associations And Reveals Two New Susceptibility Loci, Regina C. Betz, Lynn Petukhova, Stephan Ripke, Hailiang Huang, Androniki Menelaou, Silke Redeler, Tim Becker, Stefanie Heilmann, Tarek Yamany, Madeleine Duvic, Maria Hordinsky, David Norris, Vera H. Price, Julian Mackay-Wiggan, Annemieke De Jong, Gina M. Destefano, Susanne Moebus, Markus Böhm, Ulrike Blume-Peytavi, Hans Wolff, Gerhard Lutz, Roland Kruse, Li Bian, Christopher I. Amos

Dartmouth Scholarship

Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ ATXN2 (12q24.12). Candidate susceptibility gene expression …

Consumption Of Sutherlandia Frutescens By Hiv-Seropositive South African Adults: An Adaptive Double-Blind Randomized Placebo Controlled Trial., Douglas Wilson, Kathy Goggin, Karen Williams, Mary M. Gerkovich, Nceba Gqaleni, James Syce, Patricia Bartman, Quinton Johnson, William R. Folk

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sutherlandia frutescens (L.) R. Br. is widely used as an over the counter complementary medicine and in traditional medications by HIV seropositive adults living in South Africa; however the plant's safety has not been objectively studied. An adaptive two-stage randomized double-blind placebo controlled study was used to evaluate the safety of consuming dried S. frutescens by HIV seropositive adults with CD4 T-lymphocyte count of >350 cells/μL.

METHODS: In Stage 1 56 participants were randomized to S. frutescens 400, 800 or 1,200 mg twice daily or matching placebo for 24 weeks. In Stage 2 77 additional participants were randomized to …

Sex Differences In Clinical Features Of Early, Treated Parkinson's Disease, Erika F. Augustine, Adriana Pérez, Rohit Dhall, Chizoba C. Umeh, Aleksandar Videnovic, Franca Cambi, Anne-Marie A. Wills, Jordan J. Elm, Richard M. Zweig, Lisa M. Shulman, Martha A. Nance, Jacquelyn Bainbridge, Oksana Suchowersky

Neurology Faculty Publications

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial.

METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between …

Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …

New York State: Comparison Of Treatment Outcomes For Unruptured Cerebral Aneurysms Using An Instrumental Variable Analysis, Kimon Bekelis, Symeon Missios, Shannon Coy, Robert J. Singer, Todd A. Mackenzie

Dartmouth Scholarship

Background:

There is wide regional variation in the predominant treatment for unruptured cerebral aneurysms. We investigated the association of elective surgical clipping and endovascular coiling with mortality, readmission rate, length of stay, and discharge to rehabilitation.

Methods and Results:

We performed a cohort study involving patients with unruptured cerebral aneurysms, who underwent surgical clipping or endovascular coiling from 2009 to 2013 and were registered in the Statewide Planning and Research Cooperative System database. An instrumental variable analysis was used to investigate the association of treatment technique with outcomes. Of the 4643 patients undergoing treatment, 3190 (68.7%) underwent coiling, and 1453 …

Dumbbell-Pcr: A Method To Quantify Specific Small Rna Variants With A Single Nucleotide Resolution At Terminal Sequences., Shozo Honda, Yohei Kirino

Computational Medicine Center Faculty Papers

Recent advances in next-generation sequencing technologies have revealed that cellular functional RNAs are not always expressed as single entities with fixed terminal sequences but as multiple isoforms bearing complex heterogeneity in both length and terminal sequences, such as isomiRs, the isoforms of microRNAs. Unraveling the biogenesis and biological significance of heterogenetic RNA expression requires distinctive analysis of each RNA variant. Here, we report the development of dumbbell PCR (Db-PCR), an efficient and convenient method to distinctively quantify a specific individual small RNA variant. In Db-PCR, 5'- and 3'-stem-loop adapters are specifically hybridized and ligated to the 5'- and 3'-ends of …

Characterization Of A Prefusion-Specific Antibody That Recognizes A Quaternary, Cleavage-Dependent Epitope On The Rsv Fusion Glycoprotein, Morgan S.A Gilman, Syed M. Moin, Vicente Mas, Man Chen, Nita K. Patel, Kari Kramer, Qing Zhu, Stephanie C. Kabeche, Azad Kumar, Concepción Palomo, Tim Beaumont, Ulrich Baxa, Nancy D. Ulbrandt, José A. Melero, Barney S. Graham, Jason S. Mclellan

Dartmouth Scholarship

Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains …

Improving Early Infant Hiv Diagnosis In Kenya: Study Protocol Of A Cluster-Randomized Efficacy Trial Of The Hitsystem., Sarah Finocchario-Kessler, Kathy Goggin, Samoel Khamadi, Brad Gautney, Jacinda K. Dariotis, Charles Bawcom, An-Lin Cheng, Niaman Nazir, Catherine Martin, Andrea Ruff, Michael Sweat, Vincent Okoth

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Early infant diagnosis among human immunodeficiency virus (HIV)-exposed infants is a critical component of prevention of mother-to-child transmission programs. Barriers to early infant diagnosis include poor uptake, low retention at designated re-testing intervals, delayed test results, passive systems of communication, and poor linkage to treatment. This study will evaluate the HIV Infant Tracking System (HITSystem), an eHealth intervention that streamlines communication and accountability between the key early infant diagnosis stakeholders: HIV+ mothers and their HIV-exposed infants, healthcare providers, and central laboratory personnel. It is hypothesized that the HITSystem will significantly improve early infant diagnosis retention at 9 and 18 …

Copd: Do Imaging Measurements Of Emphysema And Airway Disease Explain Symptoms And Exercise Capacity?, Miranda Kirby, Damien Pike, Don D Sin, Harvey O Coxson, David G Mccormack, Grace Parraga

Medical Biophysics Publications

PURPOSE: To determine the role of imaging measurements of emphysema and airway disease in determining chronic obstructive pulmonary disease (COPD) symptoms and exercise limitation in patients with COPD, particularly in patients with mild-to-moderate disease.

MATERIALS AND METHODS: Participants (n = 116) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade U (unclassified) or grade I-IV COPD provided informed consent to an ethics board-approved HIPAA-compliant protocol and underwent spirometry and plethysmography, completed the St George's Respiratory Questionnaire (SGRQ), completed a 6-minute walk test for the 6-minute walk distance (6MWD), and underwent hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging and …

Altered Lysosomal Proteins In Neural-Derived Plasma Exosomes In Preclinical Alzheimer Disease, Edward J. Goetzl, Adam Boxer, Janice B. Schwartz, Erin L. Abner, Ronald C. Petersen, Bruce L. Miller, Dimitrios Kapogiannis

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.

METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.

RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane …

Recessive Mutations In Polr1c Cause A Leukodystrophy By Impairing Biogenesis Of Rna Polymerase Iii., Isabelle Thiffault, Nicole I Wolf, Diane Forget, Kether Guerrero, Luan T. Tran, Karine Choquet, Mathieu Lavallée-Adam, Christian Poitras, Bernard Brais, Grace Yoon, Laszlo Sztriha, Richard I. Webster, Dagmar Timmann, Bart P. Van De Warrenburg, Jürgen Seeger, Alíz Zimmermann, Adrienn Máté, Cyril Goizet, Eva Fung, Marjo S. Van Der Knaap, Sébastien Fribourg, Adeline Vanderver, Cas Simons, Ryan J. Taft, John R. Yates, Benoit Coulombe, Geneviève Bernard

Manuscripts, Articles, Book Chapters and Other Papers

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first …

A Randomized Controlled Trial Of Exercise In Spinal And Bulbar Muscular Atrophy., Joseph A Shrader, Ilona Kats, Angela Kokkinis, Cris Zampieri, Ellen Levy, Galen O Joe, Joshua G. Woolstenhulme, Bart E Drinkard, Michaele R Smith, Willie Ching, Laboni Ghosh, Derrick Fox, Sungyoung Auh, Alice B Schindler, Kenneth H Fischbeck, Christopher Grunseich

Physical Therapy and Health Care Sciences Faculty Publications

OBJECTIVE: To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA).

METHODS: Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up …

Fetal, Neonatal, Infant, And Child International Growth Standards: An Unprecedented Opportunity For An Integrated Approach To Assess Growth And Development., Cutberto Garza

Global Health Faculty Publications

The recent publication of fetal growth and gestational age-specific growth standards by the International Fetal and Newborn Growth Consortium for the 21st Century Project and the previous publication by the WHO of infant and young child growth standards based on the WHO Multicentre Growth Reference Study enable evaluations of growth from ∼9 wk gestation to 5 y. The most important features of these projects are the prescriptive approach used for subject selection and the rigorous testing of the assertion that growth is very similar among geographically and ethnically diverse nonisolated populations when health, nutrition, and other care needs are met …

Hand Use Predicts The Structure Of Representations In Sensorimotor Cortex., Naveed Ejaz, Masashi Hamada, Jörn Diedrichsen

Brain and Mind Institute Researchers' Publications

Fine finger movements are controlled by the population activity of neurons in the hand area of primary motor cortex. Experiments using microstimulation and single-neuron electrophysiology suggest that this area represents coordinated multi-joint, rather than single-finger movements. However, the principle by which these representations are organized remains unclear. We analyzed activity patterns during individuated finger movements using functional magnetic resonance imaging (fMRI). Although the spatial layout of finger-specific activity patterns was variable across participants, the relative similarity between any pair of activity patterns was well preserved. This invariant organization was better explained by the correlation structure of everyday hand movements than …

Changes In Visual And Sensory-Motor Resting-State Functional Connectivity Support Motor Learning By Observing., Heather R Mcgregor, Paul L Gribble

Brain and Mind Institute Researchers' Publications

Motor learning occurs not only through direct first-hand experience but also through observation (Mattar AA, Gribble PL. Neuron 46: 153-160, 2005). When observing the actions of others, we activate many of the same brain regions involved in performing those actions ourselves (Malfait N, Valyear KF, Culham JC, Anton JL, Brown LE, Gribble PL. J Cogn Neurosci 22: 1493-1503, 2010). Links between neural systems for vision and action have been reported in neurophysiological (Strafella AP, Paus T. Neuroreport 11: 2289-2292, 2000; Watkins KE, Strafella AP, Paus T. Neuropsychologia 41: 989-994, 2003), brain imaging (Buccino G, Binkofski F, Fink GR, Fadiga L, …

Clinical Utility Of Lactate Dehydrogenase In Determining The Severity Of Hemolysis In Sickle Cell Anemia., Samir K. Ballas

Cardeza Foundation for Hematologic Research

No abstract provided.

Paracrine Effect Of Nrg1 And Hgf Drives Resistance To Mek Inhibitors In Metastatic Uveal Melanoma., Hanyin Cheng, Mizue Terai, Ken Kageyama, Shinji Ozaki, Peter Mccue, Takami Sato, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and …

Beta-Blocker Use And 30-Day All-Cause Readmission In Medicare Beneficiaries With Systolic Heart Failure, Vikas Bhatia, Kumar Sanam, Taimoor Hashim, Prakash Deedwania, Wilbert S. Aronow, Ross Fletcher, Ali Ahmed

NYMC Faculty Publications

BACKGROUND: Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act.

METHODS: Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction

RESULTS: Beta-blocker use was not associated with 30-day all-cause readmission (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.64-1.18) or heart failure readmission (HR 0.95; 95% CI, 0.57-1.58), but was significantly associated with lower …

Can Dentistry Have Two Contracts With The Public?, David A. Nash

Oral Health Science Faculty Publications

The social contract is an implicit agreement between parts of society and society as a whole. Since the Middle Ages, the learned professions, recently including dentistry, have had a covenantal relationship with the public based on trust, exchanging monopoly privileges for benefiting the public good. Unlike commercial trade in commodities, professional relationships are grounded in ensuring an adequate level of oral health to all. A second contract is emerging where dentists relate to society as business operators, exchanging commodity services for a price. Recent actions by the Federal Trade Commission and the U.S. Supreme Court make it unlikely that dentistry …

Placental Dna Methylation Related To Both Infant Toenail Mercury And Adverse Neurobehavioral Outcomes, Jennifer Zeynab Joukhadar Maccani, Devin C. Koestler, Barry Lester, E Andres Houseman, David A. Armstrong, Karl T. Kelsey, Carmen J. Marsit

Dartmouth Scholarship

Background:

Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.

Objectives:

We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.

Methods:

The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU …

Influence Of Linker Length And Composition On Enzymatic Activity And Ribosomal Binding Of Neomycin Dimers, Derrick Watkins, Sunil Kumar, Keith D. Green, Dev P. Arya, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The human and bacterial A site rRNA binding as well as the aminoglycoside-modifying enzyme (AME) activity against a series of neomycin B (NEO) dimers is presented. The data indicate that by simple modifications of linker length and composition, substantial differences in rRNA selectivity and AME activity can be obtained. We tested five different AMEs with dimeric NEO dimers that were tethered via triazole, urea, and thiourea linkages. We show that triazole-linked dimers were the worst substrates for most AMEs, with those containing the longer linkers showing the largest decrease in activity. Thiourea-linked dimers that showed a decrease in activity by …

Vascular Regulation Via Kir Channels And Na+ /K+-Atpase, Anne R. Crecelius, Frank A. Dinenno

Health and Sport Science Faculty Publications

Despite the longstanding knowledge that blood flow increases in proportion to metabolic activity of skeletal muscle, the underlying mechanisms that govern this response have only recently been identified.¹ Given the role of endothelial cells in mediating exercise hyperemia,² interest has been focused on endothelium-derived vasodilation occurring via the synthesis of nitric oxide (NO) and vasodilating prostaglandins (PGs; i.e. prostacyclin) or endothelium- derived hyperpolarization. A number of studies performed in humans have established a minimal-to-modest role for NO and PGs during mild- and moderate- intensity exercise. In animal preparations, prevention of hyperpolarization attenuates contraction-induced hyperemia; however, performing similar studies …

Long-Term Oncological Outcomes Of A Phase Ii Trial Of Neoadjuvant Chemohormonal Therapy Followed By Radical Prostatectomy For Patients With Clinically Localised, High-Risk Prostate Cancer., Jonathan L. Silberstein, Stephen A. Poon, Daniel D. Sjoberg, Alexandra C. Maschino, Andrew J. Vickers, Aaron Bernie, Badrinath R. Konety, William Kevin Kelly, James A. Eastham

Department of Urology Faculty Papers

OBJECTIVE: To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer.

PATIENTS AND METHODS: In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only.

RESULTS: In all, 34 patients were enrolled and followed for a median of 13.1 years. …

Risk Analysis Of Prostate Cancer In Practical, A Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci., Ali Amin Al Olama, Sara Benlloch, Antonis C Antoniou, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, Kenneth Muir, Johanna Schleutker, Brian E Henderson, Christopher Haiman, Fredrick R Schumacher, Nora Pashayan, Paul D P Pharoah, Elaine A Ostrander, Janet L Stanford, Jyotsna Batra, Judith A Clements, Suzanne K Chambers, Maren Weischer, Børge G Nordestgaard, Sue A Ingles, Karina D Sorensen, Torben F Orntoft, Jong Y Park, Cezary Cybulski, Christiane Maier, Thilo Doerk, Joanne L Dickinson, Lisa Cannon-Albright, Hermann Brenner, Timothy R Rebbeck, Charnita Zeigler-Johnson, Tomonori Habuchi, Stephen N Thibodeau, Kathleen A Cooney, Pierre O Chappuis, Pierre Hutter, Radka P Kaneva, William D Foulkes, Maurice P Zeegers, Yong-Jie Lu, Hong-Wei Zhang, Robert Stephenson, Angela Cox, Melissa C Southey, Amanda B Spurdle, Liesel Fitzgerald, Daniel Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Michelle Guy, Tokhir Dadaev, Sarah J Little, Koveela Govindasami, Emma Sawyer, Rosemary Wilkinson, Kathleen Herkommer, John L Hopper, Aritaya Lophatonanon, Antje E Rinckleb, Zsofia Kote-Jarai, Rosalind A Eeles, Douglas F Easton

Department of Medical Oncology Faculty Papers

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.

METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.

RESULTS: The prostate cancer risk for men in the top 1% of the …

Hla-Dqa1 And Plcg2 Are Candidate Risk Loci For Childhood-Onset Steroid-Sensitive Nephrotic Syndrome., Rasheed A. Gbadegesin, Adebowale Adeyemo, Nicholas J A Webb, Larry A A. Greenbaum, Asiri Abeyagunawardena, Shenal Thalgahagoda, Arundhati Kale, Debbie Gipson, Tarak Srivastava, Jen-Jar Lin, Deepa Chand, Tracy E. Hunley, Patrick D. Brophy, Arvind Bagga, Aditi Sinha, Michelle N. Rheault, Joanna Ghali, Kathy Nicholls, Elizabeth Abraham, Halima S. Janjua, Abiodun Omoloja, Gina-Marie Barletta, Yi Cai, David D. Milford, Catherine O'Brien, Atif Awan, Vladimir Belostotsky, William E. Smoyer, Alison Homstad, Gentzon Hall, Guanghong Wu, Shashi Nagaraj, Delbert Wigfall, John Foreman, Michelle P. Winn, Mid-West Pediatric Nephrology Consortium

Manuscripts, Articles, Book Chapters and Other Papers

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were …

Obesity Early In Adulthood Increases Risk But Does Not Affect Outcomes Of Hepatocellular Carcinoma, Manal M. Hassan, Reham Abdel-Wahab, Ahmed Kaseb, Ahmed Shalaby, Alexandria Phan, Hashem El-Serag, Ernest Hawk, Jeff Morris, Kanwal Pratap Singh Raghav, Ju-Seog Lee, Jean-Nicolas Vauthey, Gehan Bortus, Harrys Torres, Christopher Amos, Robert Wolff, Donghui Li

Dartmouth Scholarship

Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to accurately determine body mass index (BMI), and many factors contribute to the development of HCC. We performed a case–control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC.