Medicine and Health Sciences Commons^™

Integrative Analysis Of Survival-Associated Gene Sets In Breast Cancer, Frederick S. Varn, Matthew H. Ung, Shao Ke Lou, Chao Cheng

Dartmouth Scholarship

Patient gene expression information has recently become a clinical feature used to evaluate breast cancer prognosis. The emergence of prognostic gene sets that take advantage of these data has led to a rich library of information that can be used to characterize the molecular nature of a patient’s cancer. Identifying robust gene sets that are consistently predictive of a patient’s clinical outcome has become one of the main challenges in the field. We inputted our previously established BASE algorithm with patient gene expression data and gene sets from MSigDB to develop the gene set activity score (GSAS), a metric that …

The Gas Cylinder, The Motorcycle And The Village Health Team Member: A Proof-Of-Concept Study For The Use Of The Microsystems Quality Improvement Approach To Strengthen The Routine Immunization System In Uganda, Dorothy A. Bazos, Lea R. Ayers Lafave, Gautham Suresh, Kevin C. Shannon, Fred Nuwaha, Mark E. Splaine

Dartmouth Scholarship

Although global efforts to support routine immunization (RI) system strengthening have resulted in higher immunization rates, the World Health Organization (WHO) estimates that the proportion of children receiving recommended DPT3 vaccines has stagnated at 80% for the past 3 years (WHO Fact sheet-Immunization coverage 2014, WHO, 2014). Meeting the WHO goal of 90% national DPT3 coverage may require locally based strategies to support conventional approaches. The Africa Routine Immunization Systems Essentials-System Innovation (ARISE-SI) initiative is a proof-of-concept study to assess the application of the Microsystems Quality Improvement Approach for generating local solutions to strengthen RI systems and reach those unreached …

Identification Of A Family Of Fatty Acid-Speciated Sonic Hedgehog Proteins, Whose Members Display Differential Biological Properties, Jun Long, Robert Tokhunts, William M. Old, Stephane Houel, Jezabel Rodgriguez-Blanco, Samer Singh, Neal Schilling, Anthony J. Capobianco, Natalie G. Ahn, David J. Robbins

Dartmouth Scholarship

Hedgehog (HH) proteins are proteolytically processed into a biologically active form that is covalently modified by cholesterol and palmitate. However, most studies of HH biogenesis have characterized protein from cells in which HH is overexpressed. We purified Sonic Hedgehog (SHH) from cells expressing physiologically relevant levels and showed that it was more potent than SHH isolated from overexpressing cells. Furthermore, the SHH in our preparations was modified with a diverse spectrum of fatty acids on its amino termini, and this spectrum of fatty acids varied dramatically depending on the growth conditions of the cells. The fatty acid composition of SHH …

Spectral Gene Set Enrichment (Sgse), H Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes …

Macroscopic-Imaging Technique For Subsurface Quantification Of Near-Infrared Markers During Surgery, Michael Jermyn, Kolbein Kolste, Julien Pichette, Guillaume Sheehy, Leticia Angulo-Rodriguez, Keith D. Paulsen, David W. Roberts, Brian C. Wilson, Kevin Petrecca, Frederic Leblond

Dartmouth Scholarship

Obtaining accurate quantitative information on the concentration and distribution of fluorescent markers lying at a depth below the surface of optically turbid media, such as tissue, is a significant challenge. Here, we introduce a fluorescence reconstruction technique based on a diffusion light transport model that can be used during surgery, including guiding resection of brain tumors, for depth-resolved quantitative imaging of near-infrared fluorescent markers. Hyperspectral fluorescence images are used to compute a topographic map of the fluorophore distribution, which yields structural and optical constraints for a three-dimensional subsequent hyperspectral diffuse fluorescence reconstruction algorithm. Using the model fluorophore Alexa Fluor 647 …

Belief About Nicotine Selectively Modulates Value And Reward Prediction Error Signals In Smokers, Xiaosi Gu, Terry Lohrenz, Ramiro Salas, Philip R. Baldwin, Alireza Soltani

Dartmouth Scholarship

Little is known about how prior beliefs impact biophysically described processes in the presence of neuroactive drugs, which presents a profound challenge to the understanding of the mechanisms and treatments of addiction. We engineered smokers' prior beliefs about the presence of nicotine in a cigarette smoked before a functional magnetic resonance imaging session where subjects carried out a sequential choice task. Using a model-based approach, we show that smokers' beliefs about nicotine specifically modulated learning signals (value and reward prediction error) defined by a computational model of mesolimbic dopamine systems. Belief of "no nicotine in cigarette" (compared with "nicotine in …

Predicting Functional And Regulatory Divergence Of A Drug Resistance Transporter Gene In The Human Malaria Parasite, Geoffrey H. Siwo, Asako Tan, Katrina A. Button-Simons, Upeka Samarakoon, Lisa A. Checkley, Richard S. Pinapati, Michael T. Ferdig

Dartmouth Scholarship

Background:

The paradigm of resistance evolution to chemotherapeutic agents is that a key coding mutation in a specific gene drives resistance to a particular drug. In the case of resistance to the anti-malarial drug chloroquine (CQ), a specific mutation in the transporter pfcrt is associated with resistance. Here, we apply a series of analytical steps to gene expression data from our lab and leverage 3 independent datasets to identify pfcrt-interacting genes. Resulting networks provide insights into pfcrt’s biological functions and regulation, as well as the divergent phenotypic effects of its allelic variants in different genetic backgrounds.

Results:

To …

Tumor Cell Targeting By Iron Oxide Nanoparticles Is Dominated By Different Factors In Vitro Versus In Vivo, Christian Ndong, Jennifer A. Tate, Warren C. Kett, Jaya Batra, Eugene Demidenko, Lionel D. Lewis, P. Jack Hoopes, Tillmann U. Gerngross, Karl E. Griswold

Dartmouth Scholarship

Realizing the full potential of iron oxide nanoparticles (IONP) for cancer diagnosis and therapy requires selective tumor cell accumulation. Here, we report a systematic analysis of two key determinants for IONP homing to human breast cancers: (i) particle size and (ii) active vs passive targeting. In vitro, molecular targeting to the HER2 receptor was the dominant factor driving cancer cell association. In contrast, size was found to be the key determinant of tumor accumulation in vivo, where molecular targeting increased tumor tissue concentrations for 30 nm but not 100 nm IONP. Similar to the in vitro results, PEGylation …

Scoliosis Related Information On The Internet In China: Can Patients Benefit From This Information?, Hongda Bao, Feng Zhu, Fei Wang, Zhen Liu, Mike H. Bao, Shouyu He, Zezhang Zhu, Yong Qiu

Dartmouth Scholarship

Background: There has been an increasing popularity of searching health related information online in recent years. Despite that considerable amount of scoliosis patients have shown interest in obtaining scoliosis information through Internet, previous studies have demonstrated poor quality of online information. However, this conclusion may vary depending on region and culture. Since China has a restricted Internet access outside of its borders, the aim of this study is to evaluate the quality of scoliosis information available online using recognized scoring systems and to analyze the Internet as a source of health information in China.

Methods: A survey-based questionnaire was distributed …

Directed Evolution Of A Yeast-Displayed Hiv-1 Sosip Gp140 Spike Protein Toward Improved Expression And Affinity For Conformational Antibodies, Sebastian K. Grimm, Michael B. Battles, Margaret E. Ackerman

Dartmouth Scholarship

Design of an envelope-based immunogen capable of inducing a broadly neutralizing anti- body response is thought to be key to the development of a protective HIV-1 vaccine. How- ever, the broad diversity of viral variants and a limited ability to produce native envelope have hampered such design efforts. Here we describe adaptation of the yeast display sys- tem and use of a combinatorial protein engineering approach to permit directed evolution of HIV envelope variants. Because the intrinsic instability and complexity of this trimeric glyco- protein has greatly impeded the development of immunogens that properly represent the structure of native envelope, …

Measuring Organisational Readiness For Patient Engagement (More): An International Online Delphi Consensus Study, Linda J. M. Oostendorp, Marie-Anne Durand, Amy Lloyd, Glyn Elwyn

Dartmouth Scholarship

Widespread implementation of patient engagement by organisations and clinical teams is not a reality yet. The aim of this study is to develop a measure of organisational readiness for patient engagement designed to monitor and facilitate a healthcare organisation’s willingness and ability to effectively implement patient engagement in healthcare. The development of the MORE (Measuring Organisational Readiness for patient Engagement) scale was guided by Weiner’s theory of organisational readiness for change. Weiner postulates that an organisation’s readiness is determined by both the willingness and ability to implement the change (i.e. in this context: patient engagement). A first version of the …

Next-Generation Raman Tomography Instrument For Non-Invasive In Vivo Bone Imaging, Jennifer-Lynn H. Demers, Francis W. L. Esmonde-White, Karen A. Esmonde-White, Michael D. Morris, Brian Pogue

Dartmouth Scholarship

Combining diffuse optical tomography methods with Raman spectroscopy of tissue provides the ability for in vivo measurements of chemical and molecular characteristics, which have the potential for being useful in diagnostic imaging. In this study a system for Raman tomography was developed and tested. A third generation microCT coupled system was developed to combine 10 detection fibers and 5 excitation fibers with laser line filtering and a Cytop reference signal. Phantom measurements of hydroxyapatite concentrations from 50 to 300 mg/ml had a linear response. Fiber placement and experiment design was optimized using cadaver animals with live animal measurements acquired to …

The Role Of Il-27 In Susceptibility To Post-Influenza Staphylococcus Aureus Pneumonia, Keven M. Robinson, Benjamin Lee, Erich V Scheller, Sivanarayana Mandalapu, Richard I. Enelow

Dartmouth Scholarship

Influenza is a common respiratory virus and Staphylococcus aureus frequently causes secondary pneumonia during influenza infection, leading to increased morbidity and mortality. Influenza has been found to attenuate subsequent Type 17 immunity, enhancing susceptibility to secondary bacterial infections. IL-27 is known to inhibit Type 17 immunity, suggesting a potential critical role for IL-27 in viral and bacterial co-infection.

Macroscopic Optical Imaging Technique For Wide-Field Estimation Of Fluorescence Depth In Optically Turbid Media For Application In Brain Tumor Surgical Guidance, Kolbein K. Kolste, Stephen C. Kanick, Pablo A. Valdés, Michael Jermyn, Brian C. Wilson, David W. Roberts, Keith D. Paulsen, Frederic Leblond

Dartmouth Scholarship

A diffuse imaging method is presented that enables wide-field estimation of the depth of fluorescent molecular markers in turbid media by quantifying the deformation of the detected fluorescence spectra due to the wavelength-dependent light attenuation by overlying tissue. This is achieved by measuring the ratio of the fluorescence at two wavelengths in combination with normalization techniques based on diffuse reflectance measurements to evaluate tissue attenuation variations for different depths. It is demonstrated that fluorescence topography can be achieved up to a 5 mm depth using a near-infrared dye with millimeter depth accuracy in turbid media having optical properties representative of …

Somatic Experiencing: Using Interoception And Proprioception As Core Elements Of Trauma Therapy, Peter Payne, Peter A. A. Levine, Mardi A. Crane-Godreau

Dartmouth Scholarship

Here we present a theory of human trauma and chronic stress, based on the practice of Somatic Experiencing(®) (SE), a form of trauma therapy that emphasizes guiding the client's attention to interoceptive, kinesthetic, and proprioceptive experience. SE™ claims that this style of inner attention, in addition to the use of kinesthetic and interoceptive imagery, can lead to the resolution of symptoms resulting from chronic and traumatic stress. This is accomplished through the completion of thwarted, biologically based, self-protective and defensive responses, and the discharge and regulation of excess autonomic arousal. We present this theory through a composite case study of …

Shbg Gene Polymorphism (Rs1799941) Associates With Metabolic Syndrome In Children And Adolescents, Marquitta J. White, Fatih Eren, Deniz Agirbasli, Scott M. Williams, Mehmet Agirbasli

Dartmouth Scholarship

Background: Metabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents.

Methods: Genetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish …

Fungal Mediator Tail Subunits Contain Classical Transcriptional Activation Domains, Zhongle Liu, Lawrence C. Myers

Dartmouth Scholarship

Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their …

Price Subsidies, Diagnostic Tests, And Targeting Of Malaria Treatment: Evidence From A Randomized Controlled Trial, Jessica Cohen, Pascaline Dupas, Simone Schaner

Dartmouth Scholarship

Both under- and over-treatment of communicable diseases are public bads. But efforts to decrease one run the risk of increasing the other. Using rich experimental data on household treatment- seeking behavior in Kenya, we study the implications of this trade-off for subsidizing life-saving antimalarials sold over-the-counter at retail drug outlets. We show that a very high subsidy (such as the one under consideration by the international community) dramatically increases access, but nearly one-half of subsidized pills go to patients without malaria. We study two ways to better target subsidized drugs: reducing the subsidy level, and introducing rapid malaria tests over-the-counter. …

Total Pancreatectomy With Islet Autologous Transplantation: The Cure For Chronic Pancreatitis?, Samuel J. Kesseli, Kerrington A. Smith, Timothy B. Gardner

Dartmouth Scholarship

Chronic pancreatitis (CP) is a debilitating disease that leads to varying degrees of pancreatic endocrine and exocrine dysfunction. One of the most difficult symptoms of CP is severe abdominal pain, which is often challenging to control with available analgesics and therapies. In the last decade, total pancreatectomy with autologous islet cell transplantation has emerged as a promising treatment for the refractory pain of CP and is currently performed at approximately a dozen centers in the United States. While total pancreatectomy is not a new procedure, the endocrine function-preserving autologous islet cell isolation and re-implantation have made the prospect of total …

Il-1Α Signaling Is Critical For Leukocyte Recruitment After Pulmonary Aspergillus Fumigatus Challenge, Alayna K. Caffrey, Margaret M. Lehmann, Julianne M. Zickovich, Vanessa Espinosa, Kelly M. Shepardson, Christopher P. Watschke, Kimberly M. Hilmer, Arsa Thammahong, Bridget M. Barker, Amariliz Rivera, Robert A. Cramer, Joshua J. Obar

Dartmouth Scholarship

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines …

Validating Estimates Of Prevalence Of Non-Communicable Diseases Based On Household Surveys: The Symptomatic Diagnosis Study, Spencer L. James, Minerva Romero, Dolores Ramírez-Villalobos, Sara Gómez

Dartmouth Scholarship

Easy-to-collect epidemiological information is critical for the more accurate estimation of the prevalence and burden of different non-communicable diseases around the world. Current measurement is restricted by limitations in existing measurement systems in the developing world and the lack of biometry tests for non-communicable diseases. Diagnosis based on self-reported signs and symptoms (“Symptomatic Diagnosis,” or SD) analyzed with computer-based algorithms may be a promising method for collecting timely and reliable information on non-communicable disease prevalence. The objective of this study was to develop and assess the performance of a symptom-based questionnaire to estimate prevalence of non-communicable diseases in low-resource areas.

Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated With Distinct Subsets Of Systemic Sclerosis Patients In Three Independent Cohorts, Michael E. Johnson, J. Matthew Mahoney, Jaclyn Taroni, Jennifer L. Sargent, Eleni Marmarelis, Ming-Ru Wu, John Varga, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Genome-wide expression profiling in systemic sclerosis (SSc) has identified four ‘intrinsic’ subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a …

Assessments Of The Extent To Which Health‐Care Providers Involve Patients In Decision Making: A Systematic Review Of Studies Using The Option Instrument, Nicolas Couët, Sophie Desroches, Hubert Robitaille, Hugues Vaillancourt, Annie Leblanc, Stéphane Turcotte, Glyn Elwyn, France Légaré

Dartmouth Scholarship

Background: We have no clear overview of the extent to which health-care providers involve patients in the decision-making process during consultations. The Observing Patient Involvement in Decision Making instrument (OPTION) was designed to assess this. Objective: To systematically review studies that used the OPTION instrument to observe the extent to which health-care providers involve patients in decision making across a range of clinical contexts, including different health professions and lengths of consultation. We conducted online literature searches in multiple databases (2001-12) and gathered further data through networking.

Microarray Enriched Gene Rank, Eugene Demidenko

Dartmouth Scholarship

We develop a new concept that reflects how genes are connected based on microarray data using the coefficient of determination (the squared Pearson correlation coefficient). Our gene rank combines a priori knowledge about gene connectivity, say, from the Gene Ontology (GO) database, and the microarray expression data at hand, called the microarray enriched gene rank, or simply gene rank (GR). GR, similarly to Google PageRank, is defined in a recursive fashion and is computed as the left maximum eigenvector of a stochastic matrix derived from microarray expression data. An efficient algorithm is devised that allows computation of GR for 50 …

Cohort Of Birth Modifies The Association Between Fto Genotype And Bmi, James Niels Rosenquist, Steven F. Lehrer, A. James O'Malley, Alan M. Zaslavsky, Jordan W. Smoller, Nicholas A. Christakis

Dartmouth Scholarship

A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this …

In Vivo Cigarette Smoke Exposure Decreases Ccl20, Slpi, And Bd-1 Secretion By Human Primary Nasal Epithelial Cells, James Jukosky, Benoit J. Gosselin, Leah Foley, Tenzin Dechen, Steven Fiering, Mardi A. Crane-Godreau

Dartmouth Scholarship

Smokers and individuals exposed to second-hand cigarette smoke have a higher risk of developing chronic sinus and bronchial infections. This suggests that cigarette smoke (CS) has adverse effects on immune defenses against pathogens. Epithelial cells are important in airway innate immunity and are the first line of defense against infection. Airway epithelial cells not only form a physical barrier but also respond to the presence of microbes by secreting antimicrobials, cytokines, and chemokines. These molecules can lyse infectious microorganisms and/or provide signals critical to the initiation of adaptive immune responses. We examined the effects of CS on antimicrobial secretions of …

The Erv41–Erv46 Complex Serves As A Retrograde Receptor To Retrieve Escaped Er Proteins, Aya Shibuya, Neil Margulis, Romain Christiano, Tobias C. Walther, Charles Barlowe

Dartmouth Scholarship

Signal-dependent sorting of proteins in the early secretory pathway is required for dynamic retention of endoplasmic reticulum (ER) and Golgi components. In this study, we identify the Erv41–Erv46 complex as a new retrograde receptor for retrieval of non–HDEL-bearing ER resident proteins. In cells lacking Erv41–Erv46 function, the ER enzyme glucosidase I (Gls1) was mislocalized and degraded in the vacuole. Biochemical experiments demonstrated that the luminal domain of Gls1 bound to the Erv41–Erv46 complex in a pH-dependent manner. Moreover, in vivo disturbance of the pH gradient across membranes by bafilomycin A1 treatment caused Gls1 mislocalization. Whole cell proteomic analyses of deletion …

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes …

Exposure To Kynurenic Acid During Adolescence Increases Sign-Tracking And Impairs Long-Term Potentiation In Adulthood, Nicole E. Deangeli, Travis P. Todd, Stephen E. Chang, Hermes H. Yeh, Pamela W. Yeh, David J. Bucci

Dartmouth Scholarship

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and …

Relaxation Techniques For People With Chronic Obstructive Pulmonary Disease: A Systematic Review And A Meta-Analysis, Eleonora Volpato, Paolo Banfi, Sheena M. Rogers, Francesco Pagnini

Dartmouth Scholarship

Chronic Obstructive Pulmonary Disease (COPD) people suffer from severe physical impairments, which often elicit significant psychological distress and impact their quality of life. This meta-analysis aimed to assess evidence from the scientific literature on the effects of relaxation techniques. Methods. We investigated 9 databases to select 25 RCTs. Studies included both inpatients and outpatients with COPD. Both respiratory and psychological outcomes were considered.