Medicine and Health Sciences Commons^™

The Toxoplasma Gondii Cyst Wall Protein Cst1 Is Critical For Cyst Wall Integrity And Promotes Bradyzoite Persistence, Tadakimi Tomita, David J. Bzik, Yan Fen Ma, Barbara A. Fox

Dartmouth Scholarship

Toxoplasma gondii infects up to one third of the world's population. A key to the success of T. gondii as a parasite is its ability to persist for the life of its host as bradyzoites within tissue cysts. The glycosylated cyst wall is the key structural feature that facilitates persistence and oral transmission of this parasite. Because most of the antibodies and reagents that recognize the cyst wall recognize carbohydrates, identification of the components of the cyst wall has been technically challenging. We have identified CST1 (TGME49_064660) as a 250 kDa SRS (SAG1 related sequence) domain protein with a large …

Sensitization Of Human Cancer Cells To Gemcitabine By The Chk1 Inhibitor Mk-8776: Cell Cycle Perturbation And Impact Of Administration Schedule In Vitro And In Vivo, Ryan Montano, Ruth Thompson, Injae Chung, Huagang Hou, Nadeem Khan, Alan Eastman

Dartmouth Scholarship

Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.

Interactions Of Peptide Triazole Thiols With Env Gp120 Induce Irreversible Breakdown And Inactivation Of Hiv-1 Virions, Arangassery Bastian, Mark Contarino, Lauren D. Bailey, Rachna Aneja, Diogo Rodrigo Magalhaes Moreira, Kevin Freedman, Karyn Mcfadden, Caitlin Duffy, Ali Emileh

Dartmouth Scholarship

Background: We examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to specifically bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity.

Results: KR13, the sulfhydryl blocked KR13b and its parent non-sulfhydryl peptide triazole, HNG156, induced gp120 shedding but only KR13 induced p24 capsid protein release. The resulting virion post virolysis had an altered morphology, contained no gp120, but retained gp41 that bound to neutralizing gp41 antibodies. Remarkably, HIV-1 p24 release by KR13 was inhibited by enfuvirtide, which blocks formation of the gp41 6-helix bundle during membrane fusion, while …

Multicenter Study Comparing Shunt Type In The Norwood Procedure For Single-Ventricle Lesions: Three-Dimensional Echocardiographic Analysis., Gerald R. Marx, Girish S. Shirali, Jami C. Levine, Lin T. Guey, James F. Cnota, Jeanne M. Baffa, William L. Border, Steve Colan, Gregory Ensing, Mark K. Friedberg, David J. Goldberg, Salim F. Idriss, J Blaine John, Wyman W. Lai, Minmin Lu, Shaji C. Menon, Richard G. Ohye, David Saudek, Pierre C. Wong, Gail D. Pearson, Pediatric Heart Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The Pediatric Heart Network's Single Ventricle Reconstruction (SVR) trial randomized infants with single right ventricles (RVs) undergoing a Norwood procedure to a modified Blalock-Taussig or RV-to-pulmonary artery shunt. This report compares RV parameters in the 2 groups using 3-dimensional echocardiography.

METHODS AND RESULTS: Three-dimensional echocardiography studies were obtained at 10 of 15 SVR centers. Of the 549 subjects, 314 underwent 3-dimensional echocardiography studies at 1 to 4 time points (pre-Norwood, post-Norwood, pre-stage II, and 14 months) for a total of 757 3-dimensional echocardiography studies. Of these, 565 (75%) were acceptable for analysis. RV volume, mass, mass:volume ratio, ejection fraction, …

Predictors Of Disease Progression In Pediatric Dilated Cardiomyopathy., Kimberly M. Molina, Peter Shrader, Steven D. Colan, Seema Mital, Renee Margossian, Lynn A. Sleeper, Girish S. Shirali, Piers Barker, Charles E. Canter, Karen Altmann, Elizabeth Radojewski, Elif Seda Selamet Tierney, Jack Rychik, Lloyd Y. Tani, Pediatric Heart Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

Background: Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM.

Methods and results: The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using …

New Oral Anticoagulants Are Not Superior To Warfarin In Secondary Prevention Of Stroke Or Transient Ischemic Attacks, But Lower The Risk Of Intracranial Bleeding: Insights From A Meta-Analysis And Indirect Treatment Comparisons, Partha Sardar, Saurav Chatterjee, Wen-Chih Wu, Edgar Lichstein, Joydeep Ghosh, Shamik Aikat, Debabrata Mukherjee

Internal Medicine Faculty Publications

PURPOSE: Patients with Atrial Fibrillation (AF) and prior stroke are classified as high risk in all risk stratification schemes. A systematic review and meta-analysis was performed to compare the efficacy and safety of New Oral Anticoagulants (NOACs) to warfarin in patients with AF and previous stroke or transient ischemic attack (TIA).

METHODS: Three randomized controlled trials (RCTs), including total 14527 patients, comparing NOACs (apixaban, dabigatran and rivaroxaban) with warfarin were included in the analysis. Primary efficacy endpoint was ischemic stroke, and primary safety endpoint was intracranial bleeding. Random-effects models were used to pool efficacy and safety data across RCTs. RevMan …

Factors Impacting Echocardiographic Imaging After The Fontan Procedure: A Report From The Pediatric Heart Network Fontan Cross-Sectional Study., Richard V. Williams, Renee Margossian, Minmin Lu, Andrew M. Atz, Timothy J. Bradley, Michael Jay Campbell, Steven D. Colan, Dianne Gallagher, Wyman W. Lai, Gail D. Pearson, Ashwin Prakash, Girish S. Shirali, Meryl S. Cohen, Pediatric Heart Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

Echocardiographic image quality in Fontan survivors may be limited by a variety of factors. We sought to describe echocardiographic quality and factors associated with study quality in subjects participating in the Pediatric Heart Network Fontan Cross-Sectional Study. Echocardiograms were obtained at 7 clinical sites using a standard protocol. Quality grading and analysis were performed by a core laboratory. Univariate and multivariable modeling were performed to assess factors associated with quality and ability to obtain images sufficient for prespecified quantitative analysis. A total of 543 echocardiograms were obtained. The quality of echocardiograms improved over the duration of the study. The great …

Multi-Criteria Decision Analysis As An Innovative Approach To Managing Zoonoses: Results From A Study On Lyme Disease In Canada, Cécile Aenishaenslin, Valérie Hongoh, Hassane D. Cissé, Anne Gatewood Hoen

Dartmouth Scholarship

ackground: Zoonoses are a growing international threat interacting at the human-animal-environment interface and call for transdisciplinary and multi-sectoral approaches in order to achieve effective disease management. The recent emergence of Lyme disease in Quebec, Canada is a good example of a complex health issue for which the public health sector must find protective interventions. Traditional preventive and control interventions can have important environmental, social and economic impacts and as a result, decision-making requires a systems approach capable of integrating these multiple aspects of interventions. This paper presents the results from a study of a multi-criteria decision analysis (MCDA) approach for …

Sessile Serrated Adenomas In The Proximal Colon Are Likely To Be Flat, Large And Occur In Smokers, Tarun Rustagi, Priya Rangasamy, Matthew Myers, Melinda Sanders, Haleh Vaziri, George Y. Wu, John W. Birk, Petr Protiva, Joseph C. Anderson

Dartmouth Scholarship

Aim: To examine the epidemiology and the morphology of the proximal sessile serrated adenomas (SSAs).

Methods: We conducted a retrospective study to identify patients with SSAs using a university-based hospital pathology database query from January 2007 to April 2011. Data collected included: age, gender, ethnicity, body mass index, diabetes, smoking, family history of colorectal cancer, aspirin, and statin use. We collected data on morphology of SSAs including site (proximal or distal), size, and endoscopic appearance (flat or protuberant). We also compared proximal SSAs to proximal tubular adenomas detected during same time period.

Bioengineered Lysozyme Reduces Bacterial Burden And Inflammation In A Murine Model Of Mucoid Pseudomonas Aeruginosa Lung Infection, Charlotte C. Teneback, Thomas C. Scanlon, Matthew J. Wargo, Jenna L. Bement, Karl E. Griswold, Laurie W. Leclair

Dartmouth Scholarship

The spread of drug-resistant bacterial pathogens is a growing global concern and has prompted an effort to explore potential adjuvant and alternative therapies derived from nature's repertoire of bactericidal proteins and peptides. In humans, the airway surface liquid layer is a rich source of antibiotics, and lysozyme represents one of the most abundant and effective antimicrobial components of airway secretions. Human lysozyme is active against both Gram-positive and Gram-negative bacteria, ac

Early Echocardiographic Changes After Percutaneous Implantation Of The Edwards Sapien Transcatheter Heart Valve In The Pulmonary Position., Shahryar M. Chowdhury, Ziyad M. Hijazi, John Rhodes, Saibal Kar, Raj Makkar, Michael Mullen, Qi-Ling Cao, Lydia King, Jodi Akin, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVES: To evaluate echocardiographic changes after SAPIEN valve implantation in the pulmonary position.

BACKGROUND: The feasibility of the SAPIEN transcatheter pulmonary valve (TPV) has recently been demonstrated. We evaluated changes in pulmonary valve function and the right ventricle after SAPIEN TPV placement.

METHODS: We evaluated echocardiograms at baseline, discharge, 1 and 6 months after TPV placement in 33 patients from 4 centers. Pulmonary insufficiency severity was graded 0-4. TPV peak and mean gradients were measured. Right ventricular (RV) size and function were quantified using routine measures derived from color, spectral, and tissue Doppler indices and two-dimensional echocardiography.

RESULTS: At baseline, …

Ron Knockdown And Ron Monoclonal Antibody Imc-Ron8 Sensitize Pancreatic Cancer To Histone Deacetylase Inhibitors (Hdaci)., Yi Zou, Gillian M. Howell, Lisa E. Humphrey, J. Wang, Michael G. Brattain

Journal Articles: Eppley Institute

Recepteur d'origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA …

Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …

Id4 Deficiency Attenuates Prostate Development And Promotes Pin-Like Lesions By Regulating Androgen Receptor Activity And Expression Of Nkx3.1 And Pten, Pankaj Sharma, Ashley Knowell, Swathi Chinaranagari, Shravan Komaragiri, Peri Nagappan, Divya Patel, Mathew C. Havrda, Jaideep Chaudhary

Dartmouth Scholarship

Background: Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology. Methods: Histological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was …

Intracranial Injection Of Gammagard, A Human Ivig, Modulates The Inflammatory Response Of The Brain And Lowers AΒ In App/Ps1 Mice Along A Different Time Course Than Anti-AΒ Antibodies, Tiffany L. Sudduth, Abigail Greenstein, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Gammagard IVIg is a therapeutic approach to treat Alzheimer's disease currently in phase 3 clinical trials. Despite the reported efficacy of the approach the mechanism of action is poorly understood. We have previously shown that intracranial injection of anti-Aβ antibodies into the frontal cortex and hippocampus reveals important information regarding the time course of events once the agent is in the brain. In the current study we compared IVIg, mouse-pooled IgG, and the anti-Aβ antibody 6E10 injected intracranially into the frontal cortex and hippocampus of 7-month-old APP/PS1 mice. We established a time course of events ranging from 1 …

Cinacalcet As Adjunctive Therapy For Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets., Tarak Srivastava, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Secondary hyperparathyroidism from inadequate calcium absorption in the gut, is the underlying pathophysiology for rachitic changes in hereditary vitamin D-resistant rickets (HVDRR). We describe a novel use of Cinacalcet to treat a child with HVDRR in whom conventional modes of therapy had to be discontinued. Cinacalcet therapy with high-dose oral calcium effectively normalized the metabolic abnormalities and bone condition. The relative ease of administration of the calcimimetic as a once- or twice-daily oral preparation, compared with traditional intravenous calcium administration, should encourage its move to the frontline of treatment of the disorder.

Intra-Tumoral Heterogeneity In Metastatic Potential And Survival Signaling Between Iso-Clonal Hct116 And Hct116b Human Colon Carcinoma Cell Lines., Sanjib Chowdhury, Melanie Ongchin, Elizabeth Sharratt, Ivan Dominguez, J. Wang, Michael G. Brattain, Ashwani Rajput

Journal Articles: Eppley Institute

BACKGROUND: Colorectal cancer (CRC) metastasis is a leading cause of cancer-related deaths in the United States. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. Recent reports have stressed the importance of intra-tumoral heterogeneity in the development of a metastatic phenotype. The purpose of this study was to characterize the intra-tumoral phenotypic heterogeneity between two iso-clonal human colon cancer sublines HCT116 and HCT116b on their ability to undergo metastatic colonization and survive under growth factor deprivation stress (GFDS).

MATERIALS AND METHODS: HCT116 and HCT116b cells were transfected with green fluorescence protein and subcutaneously injected into …

Tgf-Beta Suppresses Vegfa-Mediated Angiogenesis In Colon Cancer Metastasis., Liying Geng, Anathbandhu Chaudhuri, G. Talmon, James L. Wisecarver, J. Wang

Journal Articles: Eppley Institute

The FET cell line, derived from an early stage colon carcinoma, is non-tumorigenic in athymic nude mice. Engineered FET cells that express TGF-α (FETα) display constitutively active EGFR/ErbB signaling. These cells readily formed xenograft tumors in athymic nude mice. Importantly, FETα cells retained their response to TGF-beta-mediated growth inhibition, and, like the parental FET cells, expression of a dominant negative TGF-beta type II receptor (DNRII) in FETα cells (FETα/DNRII) abrogated responsiveness to TGF-beta-induced growth inhibition and apoptosis under stress conditions in vitro and increased metastatic potential in an orthotopic model in vivo, which indicates metastasis suppressor activity of TGF-beta signaling …

Feasibility Of Tomotherapy-Based Image-Guided Radiotherapy To Reduce Aspiration Risk In Patients With Non-Laryngeal And Non-Pharyngeal Head And Neck Cancer, Nam P. Nguyen, Lexie Smith-Raymond, Vincent Vinh-Hung, Paul Vos, Rick Davis, Anand Desai, Thomas Sroka

Dartmouth Scholarship

Purpose: The study aims to assess the feasibility of Tomotherapy-based image-guided radiotherapy (IGRT) to reduce the aspiration risk in patients with non-laryngeal and non-hypopharyngeal cancer. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers was conducted. All patients had a modified barium swallow (MBS) prior to treatment, which was repeated one month following radiotherapy. Mean middle and inferior pharyngeal dose was recorded and correlated with the MBS results to determine aspiration risk.

Development Of A Diagnostic Test Set To Assess Agreement In Breast Pathology: Practical Application Of The Guidelines For Reporting Reliability And Agreement Studies (Grras), Natalia V. Oster, Patricia A. Carney, Kimberly H. Allison, Donald L. Weaver, Lisa Reisch, Gary Longton, Tracy Onega

Dartmouth Scholarship

Diagnostic test sets are a valuable research tool that contributes importantly to the validity and reliability of studies that assess agreement in breast pathology. In order to fully understand the strengths and weaknesses of any agreement and reliability study, however, the methods should be fully reported. In this paper we provide a step-by-step description of the methods used to create four complex test sets for a study of diagnostic agreement among pathologists interpreting breast biopsy specimens. We use the newly developed Guidelines for Reporting Reliability and Agreement Studies (GRRAS) as a basis to report these methods.

Association Of Impaired Linear Growth And Worse Neurodevelopmental Outcome In Infants With Single Ventricle Physiology: A Report From The Pediatric Heart Network Infant Single Ventricle Trial., Chitra Ravishankar, Victor Zak, Ismee A. Williams, David C. Bellinger, J William Gaynor, Nancy S. Ghanayem, Catherine D. Krawczeski, Daniel J. Licht, Lynn Mahony, Jane W. Newburger, Victoria L. Pemberton, Richard V. Williams, Renee Sananes, Amanda L. Cook, Teresa Atz, Svetlana Khaikin, Daphne T. Hsu, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVES: To describe neurodevelopmental outcomes in infants with single ventricle (SV) physiology and determine factors associated with worse outcomes.

STUDY DESIGN: Neurodevelopmental outcomes for infants with SV enrolled in a multicenter drug trial were assessed at 14 months of age using the Bayley Scales of Infant Development-II. Multivariable regression analysis was used to identify factors associated with worse outcomes.

RESULTS: Neurodevelopmental testing was performed at 14 ± 1 months in 170/185 subjects in the trial. Hypoplastic left heart syndrome was present in 59% and 75% had undergone the Norwood operation. Mean Psychomotor Developmental Index (PDI) and mental developmental index (MDI) …

Scanning In Situ Spectroscopy Pplatform For Imaging Surgical Breast Tissue Specimens, Venkataramanan Krishnaswamy, Ashley M. Laughney, Wendy A. Wells, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

A non-contact localized spectroscopic imaging platform has been developed and optimized to scan 1 x 1 cm² square regions of surgically resected breast tissue specimens with ~150-micron resolution. A color corrected, image-space telecentric scanning design maintained a consistent sampling geometry and uniform spot size across the entire imaging field. Theoretical modeling in ZEMAX allowed estimation of the spot size, which is equal at both the center and extreme positions of the field with ~5% variation across the designed waveband, indicating excellent color correction. The spot sizes at the center and an extreme field position were also measured experimentally using the …

Task Force #4--Adherence Issues And Behavior Changes: Achieving A Long-Term Solution. 33rd Bethesda Conference, Ira Ockene, Laura Hayman, Richard Pasternak, Eleanor Schron, Jacqueline Dunbar-Jacob

Laura L. Hayman

Adherence (equivalent to compliance) to lifestyle and medication recommendations for the prevention of cardiovascular disease (CVD) is a crucial element in the path from the science of risk-factor modification to the actual reduction of risk factors and consequent prevention of disease-related events. This Task Force Report presents an overview of the evidence supporting multilevel strategies for improving the adherence to lifestyle and pharmacologic interventions. Building on available adherence data and consistent with the theme of this Bethesda Conference, suggestions for advancing CVD prevention on both an individual and population level are also offered.

Lifestyle Factors, Medication Use And Risk For Ischaemic Heart Disease Hospitalisation: A Longitudinal Population-Based Study, Anthony S. Gunnell, K Einarsdottir, Daniel A. Galvao, S Joyce, S Tomlin, Vicki J. Graham, Caroline Mcintyre, Robert U. Newton, T Briffa

Research outputs 2013

Background:Lifestyle factors have been implicated in ischaemic heart disease (IHD) development however a limited number of longitudinal studies report results stratified by cardio-protective medication use.Purpose:This study investigated the influence of self-reported lifestyle factors on hospitalisation for IHD, stratified by blood pressure and/or lipid-lowering therapy.Methods:A population-based cohort of 14,890 participants aged 45+ years and IHD-free was identified from the Western Australian Health and wellbeing Surveillance System (2004 to 2010 inclusive), and linked with hospital administrative data. Adjusted hazard ratios for future IHD-hospitalisation were estimated using Cox regression.Results:Current smokers remained at higher risk for IHD-hospitalisation (adjusted HR=1.57; 95% CI: 1.22-2.03) after adjustment …

Health Literacy Influences Heart Failure Knowledge Attainment But Not Self-Efficacy For Self-Care Or Adherence To Self-Care Over Time, Aleda M.H. Chen, Karen S. Yehle, Nancy M. Albert, Kenneth F. Ferraro, Holly L. Mason, Matthew M. Murawski, Kimberly S. Plake

Pharmacy Practice Faculty Publications

Background. Inadequate health literacy may be a barrier to gaining knowledge about heart failure (HF) self-care expectations, strengthening self-efficacy for self-care behaviors, and adhering to self-care behaviors over time. Objective. To examine if health literacy is associated with HF knowledge, self-efficacy, and self-care adherence longitudinally. Methods. Prior to education, newly referred patients at three HF clinics (, age: years) completed assessments of health literacy, HF knowledge, self-efficacy, and adherence to self-care at baseline, 2, and 4 months. Repeated measures analysis of variance with Bonferroni-adjusted alpha levels was used to test longitudinal outcomes. Results. Health literacy was associated with HF knowledge …