Medicine and Health Sciences Commons^™

Two Novel Genetic Variants In The Mineralocorticoid Receptor Gene Associated With Spontaneous Preterm Birth, Inge Christiaens, Q. Wei Ang, Lindsay N. Gordon, Xin Fang, Scott Williams

Dartmouth Scholarship

Background: Preterm birth is the leading cause of mortality and morbidity in newborn infants. Its etiology is multifactorial with genes and environmental factors, including chronic maternal stress, contributing to its risk. Our objective was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in the stress response are associated with spontaneous preterm birth using a candidate gene approach.

Methods: A total of 210 cases (singleton spontaneous preterm birth at <37 >weeks) and 412 controls (singleton term birth at 38–42 weeks without a history of preterm birth) were studied. High quality maternal DNA was available from saliva samples of 190 cases …

Task Force 2: Pediatric Cardiology Fellowship Training In Noninvasive Cardiac Imaging., Shubhika Srivastava, Beth F. Printz, Tal Geva, Girish S. Shirali, Paul M. Weinberg, Pierre C. Wong, Peter Lang

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Task Force 2: Pediatric Cardiology Fellowship Training In Noninvasive Cardiac Imaging. Spctpd/Acc/Aap/Aha., Shubhika Srivastava, Beth F Printz, Tal Geva, Girish S. Shirali, Paul M Weinberg, Pierre C Wong, Peter Lang, Society Of Pediatric Cardiology Training Program Directors, American College Of Cardiology, American Academy Of Pediatrics, American Heart Association

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Confident Difference Criterion: A New Bayesian Differentially Expressed Gene Selection Algorithm With Applications., Fang Yu, Ming-Hui Chen, Lynn Kuo, Heather Talbott, John S. Davis

Journal Articles: Obstetrics & Gynecology

BACKGROUND: Recently, the Bayesian method becomes more popular for analyzing high dimensional gene expression data as it allows us to borrow information across different genes and provides powerful estimators for evaluating gene expression levels. It is crucial to develop a simple but efficient gene selection algorithm for detecting differentially expressed (DE) genes based on the Bayesian estimators.

RESULTS: In this paper, by extending the two-criterion idea of Chen et al. (Chen M-H, Ibrahim JG, Chi Y-Y. A new class of mixture models for differential gene expression in DNA microarray data. J Stat Plan Inference. 2008;138:387-404), we propose two new gene …

Increased Expression Of Fatty Acid Synthase Provides A Survival Advantage To Colorectal Cancer Cells Via Upregulation Of Cellular Respiration, Yekaterina Y. Zaytseva, Jennifer W. Harris, Mihail I. Mitov, Ji Tae Kim, D. Allan Butterfield, Eun Young Lee, Heidi L. Weiss, Tianyan Gao, B. Mark Evers

Markey Cancer Center Faculty Publications

Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells …

Truncating Mutation In The Autophagy Gene Uvrag Confers Oncogenic Properties And Chemosensitivity In Colorectal Cancers, Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo-Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo-Min Li, Sue Ellen Martin, Keigo Machida, Chengyu Liang

Toxicology and Cancer Biology Faculty Publications

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG^FS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG^FS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG^FS can …

Change In Overactive Bladder Symptoms After Surgery For Stress Urinary Incontinence In Women, Halina Zyczynski, Michael E Albo, Howard B Goldman, Clifford Y Wai, Larry T Sirls, Linda Brubaker, Peggy Norton, R E Varner, Maude Carmel, Hae-Young Kim

NYMC Faculty Publications

OBJECTIVE: To assess change in overactive bladder (OAB) symptoms up to 5 years after surgery and to identify associated predictors of change from baseline.

METHODS: This is a secondary analysis of data from three multicenter urinary incontinence (UI) surgical trials of women with stress-predominant mixed UI assigned to Burch colposuspension, autologous fascial sling, or retropubic or transobturator midurethral slings. The primary outcome was improvement of 70% or greater from baseline in symptoms measured by the Urinary Distress Inventory-Irritative subscale. Surgical groups were compared within respective trials. Generalized linear models were fit using 1-year and up to 5-year data.

RESULTS: Significant …

Tract-Based Spatial Statistics In Preterm-Born Neonates Predicts Cognitive And Motor Outcomes At 18 Months., E G Duerden, J Foong, V Chau, H Branson, K J Poskitt, R E Grunau, A Synnes, J G Zwicker, S P Miller

Brain and Mind Institute Researchers' Publications

BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age.

MATERIALS AND METHODS: Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at …

Transient Visual Responses Reset The Phase Of Low-Frequency Oscillations In The Skeletomotor Periphery., Daniel K Wood, Chao Gu, Brian D Corneil, Paul L Gribble, Melvyn A Goodale

Brain and Mind Institute Researchers' Publications

We recorded muscle activity from an upper limb muscle while human subjects reached towards peripheral targets. We tested the hypothesis that the transient visual response sweeps not only through the central nervous system, but also through the peripheral nervous system. Like the transient visual response in the central nervous system, stimulus-locked muscle responses (< 100 ms) were sensitive to stimulus contrast, and were temporally and spatially dissociable from voluntary orienting activity. Also, the arrival of visual responses reduced the variability of muscle activity by resetting the phase of ongoing low-frequency oscillations. This latter finding critically extends the emerging evidence that the feedforward visual sweep reduces neural variability via phase resetting. We conclude that, when sensory information is relevant to a particular effector, detailed information about the sensorimotor transformation, even from the earliest stages, is found in the peripheral nervous system.

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Infusion Of Reconstituted High-Density Lipoprotein, Csl112, In Patients With Atherosclerosis: Safety And Pharmacokinetic Results From A Phase 2a Randomized Clinical Trial, Pierluigi Tricoci, Denise M. D'Andrea, Paul A. Gurbel, Zhenling Yao, Marina Cuchel, Brion Winston, Robert Schott, Robert Weiss, Michael A. Blazing, Louis Cannon, Alison L. Bailey, Dominick J. Angiolillo, Andreas Gille, Charles L. Shear, Samuel D. Wright, John H. Alexander

Gill Heart & Vascular Institute Faculty Publications

Background CSL112 is a new formulation of human apolipoprotein A‐I (apoA‐I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double‐blind, multicenter, dose‐ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.

Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2‐hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA‐I plasma …

Federally Qualified Health Centers’ Capacity And Readiness For Research Collaborations: Implications For Clinical-Academic-Community Partnerships, Heather M. Brandt, Vicki M. Young, Dayna A. Campbell, Seul Ki Choi, Jessica S. Seel, Daniela B. Friedman

Faculty Publications

BACKGROUND: Federally qualified health centers (FQHCs) provide a health care safety net for underserved populations and contribute unique expertise to research that could further enhance quality of patient care. The purpose of this research was to assess interest in, readiness to, and capacity for conducting research in FQHCs in South Carolina (SC). METHODS: A Web-based survey was administered to 20 FQHCs across SC. Fourteen representatives of FQHCs completed the 39-item survey that assessed research experience and interest, partnerships and funding, barriers and benefits to research participation, training and technical assistance needs, and research capacity. RESULTS: FQHCs are interested in conducting …

Pharmacodynamics Of Folic Acid Receptor Targeted Antiretroviral Nanotherapy In Hiv-1-Infected Humanized Mice., Pavan Puligujja, Mariluz Araínga, Prasanta Dash, Diana L. Palandri, R. Lee Mosley, Santhi Gorantla, Larisa Y Poluektova, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Long-acting nanoformulated antiretroviral therapy (nanoART) can sustain plasma drug levels and improve its biodistribution. Cell targeted-nanoART can achieve this and bring drug efficiently to viral reservoirs. However, whether such improvements affect antiretroviral responses remains unknown. To these ends, we tested folic acid (FA)-linked poloxamer407-coated ritonavir-boosted atazanavir (FA-nanoATV/r) nanoparticles for their ability to affect chronic HIV-1 infection in humanized mice. Following three, 100mg/kg FA-nanoATV/r intramuscular injections administered every other week to infected animals, viral RNA was at or below the detection limit, cell-associated HIV-1p24 reduced and CD4+ T cell counts protected. The dosing regimen improved treatment outcomes more than two fold …

Intracellular Listeria Monocytogenes Comprises A Minimal But Vital Fraction Of The Intestinal Burden Following Foodborne Infection, Grant S. Jones, Kate M. Bussell, Tanya Myers-Morales, Abigail M. Fieldhouse, Elsa N. Bou Ghanem, Sarah E. F. D'Orazio

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Listeria monocytogenes is a highly adaptive bacterium that replicates as a free-living saprophyte in the environment as well as a facultative intracellular pathogen that causes invasive foodborne infections. The intracellular life cycle of L. monocytogenes is considered to be its primary virulence determinant during mammalian infection; however, the proportion of L. monocytogenes that is intracellular in vivo has not been studied extensively. In this report, we demonstrate that the majority of wild-type (strain EGDe) and mouse-adapted (InlA^m-expressing) L. monocytogenes recovered from the mesenteric lymph nodes (MLN) was extracellular within the first few days after foodborne infection. In addition, …

Amphiphilic Tobramycin Analogues As Antibacterial And Antifungal Agents, Sanjib K. Shrestha, Marina Y. Fosso, Keith D. Green, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C₁₂ and C₁₄ chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter …

Census-Based Socioeconomic Indicators For Monitoring Injury Causes In The Usa: A Review, Nathaniel Bell, Amanda Arrington, Swann Arp Adams

Faculty Publications

BACKGROUND:

Unlike the UK or New Zealand, there is no standard set of census variables in the USA for characterising socioeconomic (SES, socioeconomic status) inequalities in health outcomes, including injury. We systematically reviewed existing US studies to identify conceptual and methodological strengths and limitations of current approaches to determine those most suitable for research and surveillance.

METHODS:

We searched seven electronic databases to identify census variables proposed in the peer-reviewed literature to monitor injury risk. Inclusion criteria were that numerator data were derived from hospital, trauma or vital statistics registries and that exposure variables included census SES constructs.

RESULTS:

From …

Prevalence Of And Risk Factors For Intracranial Abnormalities In Unprovoked Seizures., Peter S. Dayan, Kathleen Lillis, Jonathan Bennett, Gregory P. Conners, Pam Bailey, James Callahan, Cigdem Akman, Neil Feldstein, Joshua Kriger, W Allen Hauser, Nathan Kuppermann

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: Prospective data are lacking to determine which children might benefit from prompt neuroimaging after unprovoked seizures. We aimed to determine the prevalence of, and risk factors for, relevant intracranial abnormalities in children with first, unprovoked seizures.

METHODS: We conducted a 6-center prospective study in children aged >28 days to 18 years with seemingly unprovoked seizures. Emergency department (ED) clinicians documented clinical findings on a standardized form. Our main outcome was the presence of a clinically relevant intracranial abnormality on computed tomography (CT) or MRI, defined as those that might change management, either emergently, urgently, or nonurgently.

RESULTS: …

J-Wave Syndromes: Brugada And Early Repolarization Syndromes., Charles Antzelevitch, Gan-Xin Yan

Department of Medicine Faculty Papers

A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada syndrome and early repolarization syndromes. Brugada syndrome and early repolarization syndromes differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J-wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these 2 inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, and molecular, ionic, …

Sex And Race And/Or Ethnicity Differences In Patients Undergoing Radiofrequency Ablation For Barrett's Esophagus: Results From The U.S. Rfa Registry., Sarina Pasricha, Nan Li, William J. Bulsiewicz, Richard I. Rothstein, Anthony Infantolino, Atilla Ertan, Daniel S. Camara, Evan S. Dellon, George Triadafilopoulos, Charles J. Lightdale, Ryan D. Madanick, William D. Lyday, Raman V. Muthusamy, Bergein F. Overholt, Nicholas J. Shaheen

Department of Medicine Faculty Papers

BACKGROUND: Little is known about differences in Barrett's esophagus (BE) characteristics by sex and race and/or ethnicity or these differences in response to radiofrequency ablation (RFA).

OBJECTIVE: We compared disease-specific characteristics, treatment efficacy, and safety outcomes by sex and race and/or ethnicity in patients treated with RFA for BE.

DESIGN: The U.S. RFA patient registry is a multicenter collaboration reporting processes and outcomes of care for patients treated with RFA for BE.

PATIENTS: Patients enrolled with BE.

INTERVENTIONS: RFA.

MAIN OUTCOME MEASUREMENTS: We assessed safety (stricture, bleeding, perforation, hospitalization), efficacy (complete eradication of intestinal metaplasia [CEIM]), complete eradication of dysplasia, …

The Rise And Fall Of Poly(Adp-Ribose): An Enzymatic Perspective., John M. Pascal, Tom Ellenberger

Department of Biochemistry and Molecular Biology Faculty Papers

Human cells respond to DNA damage with an acute and transient burst in production of poly(ADP-ribose), a posttranslational modification that expedites damage repair and plays a pivotal role in cell fate decisions. Poly(ADP-ribose) polymerases (PARPs) and glycohydrolase (PARG) are the key set of enzymes that orchestrate the rise and fall in cellular levels of poly(ADP-ribose). In this perspective, we focus on recent structural and mechanistic insights into the enzymes involved in poly(ADP-ribose) production and turnover, and we highlight important questions that remain to be answered.

Association Between Arsenic Exposure From Drinking Water And Longitudinal Change In Blood Pressure Among Heals Cohort Participants, Jieying Jiang, Mengling Liu, Faruque Parvez, Binhuan Wang, Fen Wu, Mahbub Eunus, Sripal Bangalore, Jonathan D. Newman, Alauddin Ahmed, Tariqul Islam, Muhammed Rakibuz-Zaman, Rabiul Hasan, Golam Sarwar, Diane Levy, Vesna Slavkovich, Maria Argos, Molly Scannell Bryan, Shohreh F. Farzan, Richard B. Hayes, Joseph H. Graziano, Habibul Ahsan, Yu Chen

Dartmouth Scholarship

Background:

Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking.

Method:

We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure …

Scarnas Regulate Splicing And Vertebrate Heart Development., Prakash Patil, Nataliya Kibiryeva, Tamayo Uechi, Jennifer A. Marshall, James E. O'Brien, Michael Artman, Naoya Kenmochi, Douglas C. Bittel

Manuscripts, Articles, Book Chapters and Other Papers

Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived …

Age At Onset In Patients With Medically Refractory Temporal Lobe Epilepsy And Mesial Temporal Sclerosis: Impact On Clinical Manifestations And Postsurgical Outcome., Ali Akbar Asadi-Pooya, Michael R. Sperling

Department of Neurology Faculty Papers

PURPOSE: To evaluate the demographic and clinical manifestations and postsurgical outcome of childhood-onset mesial temporal sclerosis and temporal lobe epilepsy (MTS-TLE) and establishing the potential differences as compared to the patients with adult-onset MTS-TLE.

METHOD: In this retrospective study all patients with a clinical diagnosis of medically refractory TLE due to mesial temporal sclerosis, who underwent epilepsy surgery at Jefferson comprehensive epilepsy center, were recruited. Patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was classified into two groups; seizure-free or relapsed. Clinical manifestations and outcome were compared between patients with childhood-onset MTS-TLE (i.e., age at …

Transcatheter Aortic Valve Replacement: A Physician-Patient's Story, Herbert L Fred

The Texas Heart Institute Journal

No abstract provided.

Modified Maze Procedure For Atrial Fibrillation As An Adjunct To Elective Cardiac Surgery: Predictors Of Mid-Term Recurrence And Echocardiographic Follow-Up, Claudia Loardi, Francesco Alamanni, Fabrizio Veglia, Claudia Galli, Alessandro Parolari, Marco Zanobini

The Texas Heart Institute Journal

The radiofrequency maze procedure achieves sinus rhythm in 45%–95% of patients treated for atrial fibrillation. This retrospective study evaluates mid-term results of the radiofrequency maze—performed concomitant to elective cardiac surgery—to determine sinus-rhythm predictive factors, and describes the evolution of patients' echocardiographic variables.

From 2003 through 2011, 247 patients (mean age, 64 ± 9.5 yr) with structural heart disease (79.3% mitral disease) and atrial fibrillation underwent a concomitant radiofrequency modified maze procedure. Patients were monitored by 24-hour Holter at 3, 6, 12, and 24 months, then annually. Eighty-four mitral-valve patients underwent regular echocardiographic follow-up. Univariate and multivariate analysis for risk factors …

Primary Prevention Of Sudden Cardiac Death In Adults With Transposition Of The Great Arteries: A Review Of Implantable Cardioverter-Defibrillator Placement, Sandeep S Sodhi, Ari M Cedars

The Texas Heart Institute Journal

Transposition of the great arteries encompasses a set of structural congenital cardiac lesions that has in common ventriculoarterial discordance. Primarily because of advances in medical and surgical care, an increasing number of children born with this anomaly are surviving into adulthood. Depending upon the subtype of lesion or the particular corrective surgery that the patient might have undergone, this group of adult congenital heart disease patients constitutes a relatively new population with unique medical sequelae. Among the more common and difficult to manage are cardiac arrhythmias and other sequelae that can lead to sudden cardiac death. To date, the question …

Successful Use Of Therapeutic Hypothermia In A Pregnant Patient, Kevin N Oguayo, Ola O Oyetayo, David Stewart, Steven M Costa, Richard O Jones

The Texas Heart Institute Journal

Out-of-hospital cardiac arrest is a leading cause of death in the United States. Pregnant women are not immune to cardiac arrest, and the treatment of such patients can be difficult. Pregnancy is a relative contraindication to the use of therapeutic hypothermia after cardiac arrest.

A 20-year-old woman who was 18 weeks pregnant had an out-of-hospital cardiac arrest. Upon her arrival at the emergency department, she was resuscitated and her circulation returned spontaneously, but her score on the Glasgow Coma Scale was 3. After adequate family discussion of the risks and benefits of therapeutic hypothermia, a decision was made to initiate …

Impact Of Insulin Resistance On Neointimal Tissue Proliferation After 2nd-Generation Drug-Eluting Stent Implantation, Takaaki Komatsu, Isao Yaguchi, Sachiko Komatsu, Shiro Nakahara, Sayuki Kobayashi, Yoshihiko Sakai, Isao Taguchi

The Texas Heart Institute Journal

Percutaneous coronary intervention is established as an effective treatment for patients with ischemic heart disease; in particular, drug-eluting stent implantation is known to suppress in-stent restenosis. Diabetes mellitus is an independent risk factor for restenosis, so reducing insulin resistance is being studied as a new treatment approach. In this prospective study, we sought to clarify the factors associated with in-stent restenosis after percutaneous coronary intervention, and we evaluated the homeostasis model assessment of insulin resistance (HOMA-IR) index as a predictor of restenosis.

We enrolled 136 consecutive patients who underwent elective percutaneous coronary intervention at our hospital from February 2010 through …

Numerical Chromosomal Instability Mediates Susceptibility To Radiation Treatment, Samuel F. Bakhoum, Lilian Kabeche, Matthew D. Wood, Christopher D. Laucius

Dartmouth Scholarship

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which …

Samhd1 Is A Single-Stranded Nucleic Acid Binding Protein With No Active Site-Associated Nuclease Activity., Kyle J. Seamon, Zhiqiang Sun, Luda S. Shlyakhtenko, Yuri L. Lyubchenko, James T. Stivers

Journal Articles: Pharmaceutical Sciences

The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been a series of conflicting reports as to whether the enzyme also possesses single-stranded DNA and/or RNA 3'-5' exonuclease activity. SAMHD1 was purified using three chromatography steps, over which the DNase activity was largely separated from the dNTPase activity, but the RNase activity persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants of SAMHD1 with no dNTPase activity retained the exonuclease activities. Thus, the exonuclease activity cannot be associated with any …