Digital Commons Network^™

Transarterial Chemoembolization Is Ineffective For Neuroendocrine Tumors Metastatic To The Caudate Lobe: A Single Institution Review., Lawrence A Shirley, Megan Mcnally, Ravi Chokshi, Natalie Jones, Patrick Tassone, Gregory Guy, Hooman Khabiri, Carl Schmidt, Manisha Shah, Mark Bloomston

Oncology Articles

BACKGROUND: Caudate lobe liver metastases occur commonly in patients with neuroendocrine tumors. It is unknown, however, how these lesions respond to regional therapy and how their presence impacts outcomes. We reviewed our experience treating these lesions using transarterial chemoembolization (TACE).

METHODS: We reviewed radiographic response to TACE in 86 patients with metastatic neuroendocrine tumors to the liver. We determined the impact of caudate lesions on outcomes in comparison to the cohort of patients without caudate lesions, as well as response of caudate lesions to TACE versus lesions elsewhere in the liver.

RESULTS: Caudate lesions were identified in 45 (52%) patients. …

Multimodal Frontostriatal Connectivity Underlies Individual Differences In Self-Esteem, Robert S. Chavez, Todd F. Heatherton

Dartmouth Scholarship

A heightened sense of self-esteem is associated with a reduced risk for several types of affective and psychiatric disorders, including depression, anxiety and eating disorders. However, little is known about how brain systems integrate self-referential processing and positive evaluation to give rise to these feelings. To address this, we combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to test how frontostriatal connectivity reflects long-term trait and short-term state aspects of self-esteem. Using DTI, we found individual variability in white matter structural integrity between the medial prefrontal cortex and the ventral striatum was related to trait measures of …

Central Line-Associated Blood Stream Infections In Pediatric Intensive Care Units: Longitudinal Trends And Compliance With Bundle Strategies., Jeffrey D. Edwards, Carolyn T. Herzig, Hangsheng Liu, Monika Pogorzelska-Maziarz, Philip Zachariah, Andrew W. Dick, Lisa Saiman, Patricia W. Stone, E. Yoko Furuya

College of Nursing Faculty Papers & Presentations

BACKGROUND: Knowing the temporal trend central line-associated bloodstream infection (CLABSI) rates among U.S. pediatric intensive care units (PICUs), the current extent of central line bundle compliance, and the impact of compliance on rates is necessary to understand what has been accomplished and can be improved in CLABSI prevention.

METHODS: This is a longitudinal study of PICUs in National Healthcare Safety Network hospitals and a cross-sectional survey of directors and managers of infection prevention and control departments regarding PICU CLABSI prevention practices, including self-reported compliance with elements of central line bundles. Associations between 2011-2012 PICU CLABSI rates and infection prevention practices …

Immune Reconstitution But Persistent Activation After 48 Weeks Of Antiretroviral Therapy In Youth With Pre-Therapy Cd4 >350 In Atn 061., Bret J. Rudy, Bill G. Kapogiannis, Carol Worrell, Kathleen E. Squires, James Bethel, Su Li, Craig M. Wilson, Allison Agwu, Patricia Emmanuel, Georgine Price, Stephanie Hudey, Maureen M. Goodenow, John W. Sleasman

Department of Medicine Faculty Papers

BACKGROUND: Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited.

DESIGN: Adolescent Trials Network 061 examined changes over 48 weeks of cART in T-cell subsets and markers of T-cell and macrophage activation in subjects with pre-therapy CD4 > 350 cells/mm. All subjects had optimal viral suppression from weeks 24 through 48.

METHODS: Subjects (n = 48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls.

RESULTS: Significant increases over 48 weeks were noted in all CD4 populations, …

Loss Of Cbl And Cbl-B Ubiquitin Ligases Abrogates Hematopoietic Stem Cell Quiescence And Sensitizes Leukemic Disease To Chemotherapy., Wei An, Scott A. Nadeau, Bhopal C. Mohapatra, Dan Feng, Neha Zutshi, Matthew D. Storck, Priyanka Arya, James E. Talmadge, Jane L. Meza, Vimla Band, Hamid Band

Journal Articles: Pathology and Microbiology

Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution …

Powerful Anti-Tumor And Anti-Angiogenic Activity Of A New Anti-Vascular Endothelial Growth Factor Receptor 1 Peptide In Colorectal Cancer Models, Valeria Cicatiello, Ivana Apicella, Laura Tudisco, Valeria Tarallo, Luigi Formisano, Annamaria Sandomenico, Younghee Kim, Ana Bastos-Carvalho, Augusto Orlandi, Jayakrishna Ambati, Menotti Ruvo, Roberto Bianco, Sandro De Falco

Ophthalmology and Visual Science Faculty Publications

To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit …

Inflammatory Muscle Diseases., Marinos C Dalakas

Department of Neurology Faculty Papers

No abstract provided.

Evidence For Patterns Of Selective Urban Migration In The Greater Indus Valley (2600-1900 Bc): A Lead And Strontium Isotope Mortuary Analysis, Benjamin Valentine, George D. Kamenov, Jonathan Mark Kenoyer, Vasant Shinde, Veena Mushrif-Tripathy, Erik Otarola-Castillo, John Krigbaum

Dartmouth Scholarship

Just as modern nation-states struggle to manage the cultural and economic impacts of migration, ancient civilizations dealt with similar external pressures and set policies to regulate people’s movements. In one of the earliest urban societies, the Indus Civilization, mechanisms linking city populations to hinterland groups remain enigmatic in the absence of written documents. However, isotopic data from human tooth enamel associated with Harappa Phase (2600-1900 BC) cemetery burials at Harappa (Pakistan) and Farmana (India) provide individual biogeochemical life histories of migration. Strontium and lead isotope ratios allow us to reinterpret the Indus tradition of cemetery inhumation as part of a …

Eleven Years Of Data On The Jefferson Scale Of Empathy-Medical Student Version (Jse-S): Proxy Norm Data And Tentative Cutoff Scores., Mohammadreza Hojat, Joseph S. Gonnella

Department of Psychiatry and Human Behavior Faculty Papers

OBJECTIVE: This study was designed to provide typical descriptive statistics, score distributions and percentile ranks of the Jefferson Scale of Empathy-Medical Student version (JSE-S) of male and female medical school matriculants to serve as proxy norm data and tentative cutoff scores.

SUBJECTS AND METHODS: The participants were 2,637 students (1,336 women and 1,301 men) who matriculated at Sidney Kimmel (formerly Jefferson) Medical College between 2002 and 2012, and completed the JSE at the beginning of medical school. Information extracted from descriptive statistics, score distributions and percentile ranks for male and female matriculants were used to develop proxy norm data and …

Antiviral Activity Of The Human Cathelicidin, Ll-37, And Derived Peptides On Seasonal And Pandemic Influenza A Viruses., Shweta Tripathi, Guangshun Wang, Mitchell White, Li Qi, Jeffery Taubenberger, Kevan L. Hartshorn

Journal Articles: Pathology and Microbiology

Human LL-37, a cationic antimicrobial peptide, was recently shown to have antiviral activity against influenza A virus (IAV) strains in vitro and in vivo. In this study we compared the anti-influenza activity of LL-37 with that of several fragments derived from LL-37. We first tested the peptides against a seasonal H3N2 strain and the mouse adapted H1N1 strain, PR-8. The N-terminal fragment, LL-23, had slight neutralizing activity against these strains. In LL-23V9 serine 9 is substituted by valine creating a continuous hydrophobic surface. LL-23V9 has been shown to have increased anti-bacterial activity compared to LL-23 and we now show slightly …

Plasma Tnf-Α And Soluble Tnf Receptor Levels After Doxorubicin With Or Without Co-Administration Of Mesna-A Randomized, Cross-Over Clinical Study, John Hayslip, Emily Van Meter Dressler, Heidi L. Weiss, Tammy J. Taylor, Mara D. Chambers, Teresa Noel, Sumitra Miriyala, Jeriel T. R. Keeney, Xiaojia Ren, Rukhsana Sultana, Mary Vore, D. Allan Butterfield, Daret St. Clair, Jeffrey A. Moscow

Markey Cancer Center Faculty Publications

PURPOSE: Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.

METHODS: Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast …

Can Polychlorinated Biphenyl (Pcb) Signatures And Enantiomer Fractions Be Used For Source Identification And To Age Date Occupational Exposure?, David Megson, Jean Françios Focant, Donald G. Patterson, Matthew Robson, Maeve C. Lohan, Paul J. Worsfold, Sean Comber, Robert Kalin, Eric Reiner, Gwen O'Sullivan

School of Geography, Earth and Environmental Sciences

Detailed polychlorinated biphenyl (PCB) signatures and chiral Enantiomer Fractions (EFs) of CB-95, CB-136 and CB-149 were measured for 30 workers at a transformer dismantling plant. This was undertaken to identify sources of exposure and investigate changes to the PCB signature and EFs over different exposure periods. Approximately 1.5 g of serum was extracted and PCB signatures were created through analysis by comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry (GC×GC-TOFMS) and EFs calculated following analysis by gas chromatography with high resolution mass spectrometry (GC-HRMS). A total of 84 PCBs were identified in the serum samples with concentrations of the 7 …

Molecular Dyes Used For Surgical Specimen Margin Orientation Allow For Intraoperative Optical Assessment During Breast Conserving Surgery, David M. Mcclatchy, Venkataramanan Krishnaswamy, Stephen C. Kanick, Jonathan T. Elliott, Wendy A. Wells, Richard J. Barth Jr., Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

A variety of optical techniques utilizing near-infrared (NIR) light are being proposed for intraoperative breast tumor margin assessment. However, immediately following a lumpectomy excision, the margins are inked, which preserves the orientation of the specimen but prevents optical interrogation of the tissue margins. Here, a workflow is proposed that allows for both NIR optical assessment following full specimen marking using molecular dyes which have negligible absorption and scattering in the NIR. The effect of standard surgical inks in contrast to molecular dyes for an NIR signal is shown. Further, the proposed workflow is demonstrated with full specimen intraoperative imaging on …

Preempting Performance Challenges: The Effects Of Inoculation Messaging On Attacks To Task Self-Efficacy, Ben Jackson, Josh Compton, Ryan Whiddett, David R. Anthony, James A. Dimmock

Dartmouth Scholarship

Although inoculation messages have been shown to be effective for inducing resistance to counter-attitudinal attacks, researchers have devoted relatively little attention toward studying the way in which inoculation theory principles might support challenges to psychological phenomena other than attitudes (e.g., self-efficacy). Prior to completing a physical (i.e., balance) task, undergraduates (N = 127, M_age = 19.20, SD = 2.16) were randomly assigned to receive either a control or inoculation message, and reported their confidence in their ability regarding the upcoming task. During the task, a confederate provided standardized negative feedback to all participants regarding their performance, and following …

Translation Initiation Complex Eif4f Is A Therapeutic Target For Dual Mtor Kinase Inhibitors In Non-Hodgkin Lymphoma., Christos Demosthenous, Jing Jing Han, Mary J Stenson, Matthew J Maurer, Linda E Wellik, Brian Link, Kristen Hege, Ahmet Dogan, Eduardo Sotomayor, Thomas Witzig, Mamta Gupta

Medicine Faculty Publications

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor …

Can Shared Decision-Making Reduce Medical Malpractice Litigation? A Systematic Review, Marie-Anne Durand, Benjamin Moulton, Elizabeth Cockle, Mala Mann, Glyn Elwyn

Dartmouth Scholarship

Background: To explore the likely influence and impact of shared decision-making on medical malpractice litigation and patients’ intentions to initiate litigation.

Methods: We included all observational, interventional and qualitative studies published in all languages, which assessed the effect or likely influence of shared decision-making or shared decision-making interventions on medical malpractice litigation or on patients ’ intentions to litigate. The following databases were searched from inception until January 2014: CINAHL, Cochrane Register of Controlled Trials, Cochrane Da tabase of Systematic Reviews, EMBASE, HMIC, Lexis library, MEDLINE, NHS Economic Evaluation Database, Open SIGLE, PsycINFO and Web of Knowledge. We also hand …

Loregic: A Method To Characterize The Cooperative Logic Of Regulatory Factors, Daifeng Wang, Koon-Kiu Yan, Cristina Sisu, Chao Cheng, Joel Rozowsky, William Meyerson, Mark B. Gerstein

Dartmouth Scholarship

The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet’s observed gene expression pattern across many conditions. …

Identifying Cases Of Undiagnosed, Clinically Significant Copd In Primary Care: Qualitative Insight From Patients In The Target Population, Nancy K. Leidy, Katherine Kim, Elizabeth D. Bacci, Barbara P. Yawn, David M. Mannino, Byron M. Thomashow, R. Graham Barr, Stephen I. Rennard, Julia F. Houfek, Meilan K. Han, Catherine A. Meldrum, Barry J. Make, Russ P. Bowler, Anna W. Steenrod, Lindsey T. Murray, John W. Walsh, Fernando Martinez

Preventive Medicine and Environmental Health Faculty Publications

BACKGROUND: Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations.

AIMS: This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care.

METHODS: Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the …

Management Of The Hospitalized Transplant Patient., Brian P. Boerner, Vijay Shivaswamy, Whitney Goldner, Jennifer Larsen

Journal Articles: Diabetes, Endocrinology & Metabolism

Significant hyperglycemia is commonly observed immediately after solid organ and bone marrow transplant as well as with subsequent hospitalizations. Surgery and procedures are well known to cause pain and stress leading to secretion of cytokines and other hormones known to aggravate insulin action. Immunosuppression required for transplant and preexisting risk are also major factors. Glucose control improves outcomes for all hospitalized patients, including transplant patients, but is often more challenging to achieve because of frequent and sometimes unpredictable changes in immunosuppression doses, renal function, and nutrition. As a result, risk of hypoglycemia can be greater in this patient group when …

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective P38Αmapk Inhibitor That Attenuates Disease Progression In Alzheimer's Disease Mouse Models, Saktimayee M. Roy, Valerie L. Grum-Tokars, James P. Schavocky, Faisal Saeed, Agnieszka Staniszewski, Andrew F. Teich, Ottavio Arancio, Adam D. Bachstetter, Scott J. Webster, Linda J. Van Eldik, George Minasov, Wayne F. Anderson, Jeffrey C. Pelletier, D. Martin Watterson

Spinal Cord and Brain Injury Research Center Faculty Publications

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, …

Chaperone Hsp47 Drives Malignant Growth And Invasion By Modulating An Ecm Gene Network, Jieqing Zhu, Gaofeng Xiong, Hanjiang Fu, B. Mark Evers, Binhua P. Zhou, Ren Xu

Markey Cancer Center Faculty Publications

The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were …

Implementing A Patient-Initiated Review System In Rheumatoid Arthritis: A Qualitative Evaluation., Sue Child, Victoria A. Goodwin, Mark G. Perry, Christian A. Gericke, Richard Byng

Peninsula Medical School

BACKGROUND: The management of Rheumatoid Arthritis (RA), a chronic relapsing condition primarily affecting joints usually entails regular hospital reviews with a specialist. These reviews can occur when the patient is well. This study forms part of a service evaluation of a system wide implementation of a patient initiated review appointment system which we have called Direct Access (DA). The aim was to explore the experiences of patients and staff of a DA system in order to understand the process of the implementation and to identify potential improvements. METHODS: Twenty-three patients with RA that had completed one year of follow-up on …

Machine Learning Methods Enable Predictive Modeling Of Antibody Feature:Function Relationships In Rv144 Vaccinees, Ickwon Choi, Amy W. Chung, Todd J. Suscovich, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapha, Jaranit Kaewkungwal, Robert J. O'Connell, Donald Francis, Merlin L. Robb, Nelson L. Michael, Jerome H. Kim, Galit Alter, Margaret E. Ackerman, Chris Bailey-Kellogg

Dartmouth Scholarship

The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine …

Transcriptional Activity Of The Islet Β Cell Factor Pdx1 Is Augmented By Lysine Methylation Catalyzed By The Methyltransferase Set7/9, Aarthi V. Maganti, Bernhard Maier, Sarah A. Tersey, Megan L. Sampley, Amber L. Mosley, Sabire Özcan, Boobalan Pachaiyappan, Patrick M. Woster, Chad S. Hunter, Roland Stein, Raghavendra G. Mirmira

Molecular and Cellular Biochemistry Faculty Publications

The transcription factor Pdx1 is crucial to islet β cell function and regulates target genes in part through interaction with coregulatory factors. Set7/9 is a Lys methyltransferase that interacts with Pdx1. Here we tested the hypothesis that Lys methylation of Pdx1 by Set7/9 augments Pdx1 transcriptional activity. Using mass spectrometry and mutational analysis of purified proteins, we found that Set7/9 methylates the N-terminal residues Lys-123 and Lys-131 of Pdx1. Methylation of these residues occurred only in the context of intact, full-length Pdx1, suggesting a specific requirement of secondary and/or tertiary structural elements for catalysis by Set7/9. Immunoprecipitation assays and mass …

Myocardial Feature Tracking Reduces Observer-Dependence In Low-Dose Dobutamine Stress Cardiovascular Magnetic Resonance., Andreas Schuster, Matthias Paul, Nuno Bettencourt, Shazia T. Hussain, Geraint Morton, Shelby Kutty, Boris Bigalke, Amedeo Chiribiri, Divaka Perera, Eike Nagel, Philipp Beerbaum

Journal Articles: Cardiology

OBJECTIVES: To determine whether quantitative wall motion assessment by CMR myocardial feature tracking (CMR-FT) would reduce the impact of observer experience as compared to visual analysis in patients with ischemic cardiomyopathy (ICM).

METHODS: 15 consecutive patients with ICM referred for assessment of hibernating myocardium were studied at 3 Tesla using SSFP cine images at rest and during low dose dobutamine stress (5 and 10 μg/kg/min of dobutamine). Conventional visual, qualitative analysis was performed independently and blinded by an experienced and an inexperienced reader, followed by post-processing of the same images by CMR-FT to quantify subendocardial and subepicardial circumferential (Eccendo and …

Practical Management Of Anticoagulation In Patients With Atrial Fibrillation., Richard J Kovacs, Greg C Flaker, Sherry J Saxonhouse, John U. Doherty, Kim K Birtcher, Adam Cuker, Bruce L Davidson, Robert P Giugliano, Christopher B Granger, Amir K Jaffer, Bella H Mehta, Edith Nutescu, Kim A Williams

Department of Medicine Faculty Papers

Anticoagulation for atrial fibrillation has become more complex due to the introduction of new anticoagulant agents, the number and kinds of patients requiring therapy, and the interactions of those patients in the matrix of care. The management of anticoagulation has become a "team sport" involving multiple specialties in multiple sites of care. The American College of Cardiology, through the College's Anticoagulation Initiative, convened a roundtable of experts from multiple specialties to discuss topics important to the management of patients requiring anticoagulation and to make expert recommendations on issues such as the initiation and interruption of anticoagulation, quality of anticoagulation care, …

Targeted Single Molecule Sequencing Methodology For Ovarian Hyperstimulation Syndrome., Funda Orkunoglu-Suer, Arthur F. Harralson, David Frankfurter, Paul Gindoff, Travis J. O'Brien

Genomics and Precision Medicine Faculty Publications

BACKGROUND: One of the most significant issues surrounding next generation sequencing is the cost and the difficulty assembling short read lengths. Targeted capture enrichment of longer fragments using single molecule sequencing (SMS) is expected to improve both sequence assembly and base-call accuracy but, at present, there are very few examples of successful application of these technologic advances in translational research and clinical testing. We developed a targeted single molecule sequencing (T-SMS) panel for genes implicated in ovarian response to controlled ovarian hyperstimulation (COH) for infertility.

RESULTS: Target enrichment was carried out using droplet-base multiplex polymerase chain reaction (PCR) technology (RainDance®) …

Lipid-Induced Epigenomic Changes In Human Macrophages Identify A Coronary Artery Disease-Associated Variant That Regulates Ppap2b Expression Through Altered C/Ebp-Beta Binding, Michael E. Reschen, Kyle J. Gaulton, Da Lin, Elizabeth J. Soilleux, Andrew J. Morris, Susan S. Smyth, Christopher A. O'Callaghan

Gill Heart & Vascular Institute Faculty Publications

Genome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno-precipitation (ChIP-seq) in primary human macrophages before …

Core Intended Learning Outcomes For Tackling Health Inequalities In Undergraduate Medicine., Ae Williamson, R Ayres, J Allen, U Macleod

Peninsula Medical School

BACKGROUND: Despite there being a concerted effort in recent years to influence what doctors can do to tackle health inequalities in the UK, there has been limited policy focus on what undergraduate students need to learn at medical school in preparation for this. This project led by members of the Health Inequalities Group of the Royal College of General Practitioners in collaboration with the Institute of Health Equity, University College London sought to fill this gap. DISCUSSION: We conducted a Delphi poll using our teaching and stakeholder networks. We identified 5 areas for learning focusing on key knowledge and skills. …

Molecular Effects Of Cancer-Associated Somatic Mutations On The Structural And Target Recognition Properties Of Keap1., Halema Khan, Ryan C Killoran, Anne Brickenden, Jingsong Fan, Daiwen Yang, Wing-Yiu Choy

Biochemistry Publications

Kelch-like ECH-associated protein 1 (Keap1) plays an important regulatory role in the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent oxidative stress response pathway. It functions as a repressor of Nrf2, a key transcription factor that initiates the expression of cytoprotective enzymes during oxidative stress to protect cells from damage caused by reactive oxygen species. Recent studies show that mutations of Keap1 can lead to aberrant activation of the antioxidant pathway, which is associated with different types of cancers. To gain a mechanistic understanding of the links between Keap1 mutations and cancer pathogenesis, we have investigated the molecular effects of a …