Digital Commons Network^™

Joint Effect Of Multiple Common Snps Predicts Melanoma Susceptibility, Shenying Fang, Jiali Han, Mingfeng Zhang, Li-E Wang, Qingyi Wei, Christopher I. Amos, Jeffrey E. Lee

Dartmouth Scholarship

Single genetic variants discovered so far have been only weakly associated with melanoma. This study aims to use multiple single nucleotide polymorphisms (SNPs) jointly to obtain a larger genetic effect and to improve the predictive value of a conventional phenotypic model. We analyzed 11 SNPs that were associated with melanoma risk in previous studies and were genotyped in MD Anderson Cancer Center (MDACC) and Harvard Medical School investigations. Participants with ≥15 risk alleles were 5-fold more likely to have melanoma compared to those carrying ≤6. Compared to a model using the most significant single variant rs12913832, the increase in predictive …

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.

Divergent Antibody Subclass And Specificity Profiles But Not Protective Hla-B Alleles Are Associated With Variable Antibody Effector Function Among Hiv-1 Controllers, Jennifer I. Lai, Anna F. Licht, Anne-Sophie Dugast, Todd Suscovich, Ickwon Choi, Chris Bailey-Kellogg, Galit Alter, Margaret E. Ackerman

Dartmouth Scholarship

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector …

Contrast Negation Differentiates Visual Pathways Underlying Dynamic And Invariant Facial Processing, Pamela M. Pallett, Ming Meng

Dartmouth Scholarship

Abstract Bruce and Young (1986) proposed a model for face processing that begins with structural encoding, followed by a split into two processing streams: one for the dynamic aspects of the face (e.g., facial expressions of emotion) and the other for the invariant aspects of the face (e.g., gender, identity). Yet how this is accomplished remains unclear. Here, we took a psychophysical approach using contrast negation to test the Bruce and Young model. Previous research suggests that contrast negation impairs processing of invariant features (e.g., gender) but not dynamic features (e.g., expression). In our first experiment, participants discriminated differences in …

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 …

Association Between In Utero Arsenic Exposure, Placental Gene Expression, And Infant Birth Weight: A Us Birth Cohort Study, Dennis Liang Fei, Devin C. Koestler, Zhigang Li, Camilla Giambelli, Avencia Sanchez-Mejias, Julie Gosse, Carmen J. Marsit, Margaret R. Karagas, David J. Robbins

Dartmouth Scholarship

Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels.

Methods: Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from …

Balancing The Presentation Of Information And Options In Patient Decision Aids: An Updated Review, Purva Abhyankar, Robert J. Volk, Jennifer Blumenthal-Barby, Paulina Bravo, Angela Buchholz, Elissa Ozanne, Dale C. Vidal, Nananda Col, Peep Stalmeier

Dartmouth Scholarship

Standards for patient decision aids require that information and options be presented in a balanced manner; this requirement is based on the argument that balanced presentation is essential to foster informed decision making. If information is presented in an incomplete/non-neutral manner, it can stimulate cognitive biases that can unduly affect individuals’ knowledge, perceptions of risks and benefits, and, ultimately, preferences. However, there is little clarity about what constitutes balance, and how it can be determined and enhanced. We conducted a literature review to examine the theoretical and empirical evidence related to balancing the presentation of information and options.

“Many Miles To Go …”: A Systematic Review Of The Implementation Of Patient Decision Support Interventions Into Routine Clinical Practice, Glyn Elwyn, Isabelle Scholl, Caroline Tietbohl, Mala Mann, Adrian G. K. Edwards, Catharine Clay

Dartmouth Scholarship

Two decades of research has established the positive effect of using patient-targeted decision support interventions: patients gain knowledge, greater understanding of probabilities and increased confidence in decisions. Yet, despite their efficacy, the effectiveness of these decision support interventions in routine practice has yet to be established; widespread adoption has not occurred. The aim of this review was to search for and analyze the findings of published peer-reviewed studies that investigated the success levels of strategies or methods where attempts were made to implement patient-targeted decision support interventions into routine clinical settings.

Delivering Patient Decision Aids On The Internet: Definitions, Theories, Current Evidence, And Emerging Research Areas, Aubri S. Hoffman, Robert J. Volk, Anton Saarimaki, Christine Stirling, Linda C. Li, Martin Härter, Geetanjali R. Kamath, Hilary Llewellyn-Thomas

Dartmouth Scholarship

Background: In 2005, the International Patient Decision Aids Standards Collaboration identified twelve quality dimensions to guide assessment of patient decision aids. One dimension — the delivery of patient decision aids on the Internet — is relevant when the Internet is used to provide some or all components of a patient decision aid. Building on the original background chapter, this paper provides an updated definition for this dimension, outlines a theoretical rationale, describes current evidence, and discusses emerging research areas. Methods: An international, multidisciplinary panel of authors examined the relevant theoretical literature and empirical evidence through 2012. Results: The updated definition …

Serine/Threonine Kinase 17a Is A Novel Candidate For Therapeutic Targeting In Glioblastoma, Pingping Mao, Mary P. Hever-Jardine, Gilbert J. Rahme, Eric Yang, Janice Tam, Anita Kodali, Bijesh Biswal, Camilo E. Fadul, Arti Gaur, Mark A. Israel, Michael J. Spinella

Dartmouth Scholarship

STK17A is a relatively uncharacterized member of the death-associated protein family of serine/threonine kinases which have previously been associated with cell death and apoptosis. Our prior work established that STK17A is a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner. In this study we have uncovered an additional, unanticipated role for STK17A as a candidate promoter of cell proliferation and survival in glioblastoma (GBM). Unexpectedly, it was found that STK17A is highly overexpressed in a grade-dependent manner in gliomas compared to normal brain and other cancer cell types with the …

X-Linked Mtmr8 Diversity And Evolutionary History Of Sub-Saharan Populations, Damian Labuda, Vania Yotova, Jean-François Lefebvre, Claudia Moreau, Gerd Utermann, Scott M. Williams

Dartmouth Scholarship

The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary …

Findings From The Peutz-Jeghers Syndrome Registry Of Uruguay, Asadur Tchekmedyian, Christopher I. Amos, Sherri J. Bale, Dakai Zhu, Stefan Arold, Joaquin Berrueta, Natalie Nabon, Thomas Mcgarrity

Dartmouth Scholarship

Background: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Methods: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. Results and discussion: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal …

On The Evolution Of The Serotonin Transporter Linked Polymorphic Region (5-Httlpr) In Primates, Seth D. Dobson, Lauren J.N Brent

Dartmouth Scholarship

Some allelic variants of the serotonin transporter linked polymorphic region (5-HTTLPR) result in lower levels of expression of the serotonin transporter gene (SLC6A4). These low-expressing (LE) alleles are associated with mental-health disorders in a minority of humans that carry them. Humans are not the only primates that exhibit this polymorphism; other species, including some monkeys, also have LE and high-expressing (HE) variants of 5-HTTLPR. We propose a behavioral genetic framework to explain the adaptive evolution of this polymorphism in primates, including humans. We hypothesize that both LE and HE alleles are maintained by balancing selection in species characterized …

Diet And Toenail Arsenic Concentrations In A New Hampshire Population With Arsenic-Containing Water, Kathryn L. Cottingham, Roxanne Karimi, Joann F. Gruber, M Scot Zens, Vicki Sayarath, Carol L. Folt, Tracy Punshon, J. Steven Morris, Margaret R. Karagas

Dartmouth Scholarship

Background: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest.

Methods: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) …

Socially Excluded Individuals Fail To Recruit Medial Prefrontal Cortex For Negative Social Scenes, Katherine E. Powers, Dylan D. Wagner, Catherine J. Norris, Todd F. Heatherton

Dartmouth Scholarship

Converging behavioral evidence suggests that people respond to experiences of social exclusion with both defensive and affiliative strategies, allowing them to avoid further distress while also encouraging re-establishment of positive social connections. However, there are unresolved questions regarding the cognitive mechanisms underlying people's responses to social exclusion. Here, we sought to gain insight into these behavioral tendencies by using functional magnetic resonance imaging (fMRI) to examine the impact of social exclusion on neural responses to visual scenes that varied on dimensions of sociality and emotional valence. Compared to socially included participants, socially excluded participants failed to recruit dorsomedial prefrontal cortex …

The Dartmouth Database Of Children’S Faces: Acquisition And Validation Of A New Face Stimulus Set, Kirsten A. Dalrymple, Jesse Gomez, Brad Duchaine

Dartmouth Scholarship

Facial identity and expression play critical roles in our social lives. Faces are therefore frequently used as stimuli in a variety of areas of scientific research. Although several extensive and well-controlled databases of adult faces exist, few databases include children’s faces. Here we present the Dartmouth Database of Children’s Faces, a set of photographs of 40 male and 40 female Caucasian children between 6 and 16 years-of-age. Models posed eight facial expressions and were photographed from five camera angles under two lighting conditions. Models wore black hats and black gowns to minimize extra-facial variables. To validate the images, independent raters …

Interictal Neurocognitive Processing Of Visual Stimuli In Migraine: Evidence From Event-Related Potentials, Marla J. S Mickleborough, Christine M. Chapman, Andreea Simina Toma, Jeremy H. M Chan, Grace Truong, Todd C. Handy

Dartmouth Scholarship

Research has established decreased sensory habituation as a defining feature in migraine, while decreased cognitive habituation has only been found with regard to cognitive assessment of the relative probability of the occurrence of a stimulus event. Our study extended the investigation of interictal habituation in migraine to include cognitive processing when viewing of a series of visually-complex images, similar to those we encounter on the internet everyday. We examined interictal neurocognitive function in migraine from a habituation perspective, using a novel paradigm designed to assess how the response to a series of images changes over time. Two groups of participants--migraineurs …

The Composite Effect For Inverted Faces Is Reliable At Large Sample Sizes And Requires The Basic Face Configuration, Tirta Susilo, Constantin Rezlescu, Bradley Duchaine

Dartmouth Scholarship

Abstract The absence of the face composite effect (FCE) for inverted faces is often considered evidence that holistic processing operates only on upright faces. However, such absence might be explained by power issues: Most studies that have failed to find the inverted FCE tested 24 participants or less. Here we find that the inverted FCE exists reliably when we tested at least 60 participants. The inverted FCE was ∼ 18% the size of the upright FCE, and it was unaffected by testing order: It did not matter whether participants did the upright condition first (Experiment 1, n = 64) or …

Recurrent Tissue-Specific Mtdna Mutations Are Common In Humans, David C. Samuels, Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A. Thornton-Wells, Jason H. Moore, Tia M. Hughes, Robert D. Hoffman, Jonathan L. Haines, Deborah G. Murdock, Douglas P. Mortlock, Scott M. Williams

Dartmouth Scholarship

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in …

Adam17-Mediated Processing Of Tnf-Α Expressed By Antiviral Effector Cd8+ T Cells Is Required For Severe T-Cell-Mediated Lung Injury, Matthew P. Deberge, Kenneth H. Ely, Guang-Shing Cheng, Richard I. Enelow

Dartmouth Scholarship

Influenza infection in humans evokes a potent CD8+ T-cell response, which is important for clearance of the virus but may also exacerbate pulmonary pathology. We have previously shown in mice that CD8+ T-cell expression of TNF-a is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF-a is first expressed as a transmembrane protein that is then proteolytically processed to release a soluble form, we sought to characterize the role of TNF-a processing in CD8+ T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-a by …

Killerflip: A Novel Lytic Peptide Specifically Inducing Cancer Cell Death, B Pennarun, G. Gaidos, O Bucur, A Tinari

Dartmouth Scholarship

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killer FLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using …

Pre-Diagnosis Oophorectomy, Estrogen Therapy And Mortality In A Cohort Of Women Diagnosed With Breast Cancer, Hazel B. Nichols, Amy Trentham-Dietz, Polly A. Newcomb, Kathleen M. Egan, Linda J. Titus, John M. Hampton, Kala Visvanathan

Dartmouth Scholarship

Introduction:

Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women.

Methods:

We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% …

An Expanded View Of The Eukaryotic Cytoskeleton, James B. Moseley

Dartmouth Scholarship

A rich and ongoing history of cell biology research has defined the major polymer systems of the eukaryotic cytoskeleton. Recent studies have identified additional proteins that form filamentous structures in cells and can self-assemble into linear polymers when purified. This suggests that the eukaryotic cytoskeleton is an even more complex system than previously considered. In this essay, I examine the case for an expanded definition of the eukaryotic cytoskeleton and present a series of challenges for future work in this area.

A Population-Based Case–Control Study Of Urinary Arsenic Species And Squamous Cell Carcinoma In New Hampshire, Usa, Diane Gilbert-Diamond, Zhigang Li, Ann E. Perry, Steven K. Spencer, A Jay Gandolfi, Margaret R. Karagas

Dartmouth Scholarship

Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States.

Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population.

Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and …

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 …

Identification Of Cell Cycle–Regulated Genes Periodically Expressed In U2os Cells And Their Regulation By Foxm1 And E2f Transcription Factors, Gavin D. Grant, Lionel Brooks Iii, Xiaoyang Zhang, J. Matthew Mahoney, Viktor Martyanov, Tammara A. Wood, Gavin Sherlock, Chao Cheng, Michael L. Whitfield

Dartmouth Scholarship

We identify the cell cycle–regulated mRNA transcripts genome-wide in the osteosarcoma-derived U2OS cell line. This results in 2140 transcripts mapping to 1871 unique cell cycle–regulated genes that show periodic oscillations across multiple synchronous cell cycles. We identify genomic loci bound by the G2/M transcription factor FOXM1 by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and associate these with cell cycle–regulated genes. FOXM1 is bound to cell cycle–regulated genes with peak expression in both S phase and G2/M phases. We show that ChIP-seq genomic loci are responsive to FOXM1 using a real-time luciferase assay in live cells, showing that FOXM1 strongly …

Impact Of Treatment Response Metrics On Photodynamic Therapy Planning And Outcomes In A Three-Dimensional Model Of Ovarian Cancer, Sriram Anbil, Imran Rizvi, Jonathan P. Celli, Nermina Alagic, Brian W. Pogue, Tayyaba Hasan

Dartmouth Scholarship

Common methods to characterize treatment efficacy based on morphological imaging may misrepresent outcomes and exclude effective therapies. Using a three-dimensional model of ovarian cancer, two functional treatment response metrics are used to evaluate photodynamic therapy (PDT) efficacy: total volume, calculated from viable and nonviable cells, and live volume, calculated from viable cells. The utility of these volume-based metrics is corroborated using independent reporters of photodynamic activity: viability, a common fluorescence-based ratiometric analysis, and photosensitizer photobleaching, which is characterized by a loss of fluorescence due in part to the production of reactive species during PDT. Live volume correlated with both photobleaching …

Mapping Disease At An Approximated Individual Level Using Aggregate Data: A Case Study Of Mapping New Hampshire Birth Defects, Xun Shi, Stephanie Miller, Kevin Mwenda, Akikazu Onda

Dartmouth Scholarship

Limited by data availability, most disease maps in the literature are for relatively large and subjectively-defined areal units, which are subject to problems associated with polygon maps. High resolution maps based on objective spatial units are needed to more precisely detect associations between disease and environmental factors. Method: We propose to use a Restricted and Controlled Monte Carlo (RCMC) process to disaggregate polygon-level location data to achieve mapping aggregate data at an approximated individual level. RCMC assigns a random point location to a polygon-level location, in which the randomization is restricted by the polygon and controlled by the background (e.g., …

Patchy ‘Coherence’: Using Normalization Process Theory To Evaluate A Multi-Faceted Shared Decision Making Implementation Program (Magic), Amy Lloyd, Natalie Joseph-Williams, Adrian Edwards, Andrew Rix, Glyn Elwyn

Dartmouth Scholarship

Implementing shared decision making into routine practice is proving difficult, despite considerable interest from policy-makers, and is far more complex than merely making decision support interventions available to patients. Few have reported successful implementation beyond research studies. MAking Good Decisions In Collaboration (MAGIC) is a multi-faceted implementation program, commissioned by The Health Foundation (UK), to examine how best to put shared decision making into routine practice. In this paper, we investigate healthcare professionals' perspectives on implementing shared decision making during the MAGIC program, to examine the work required to implement shared decision making and to inform future efforts. The MAGIC …