Medicine and Health Sciences Commons^™

Syndecan 4 Is Required For Endothelial Alignment In Flow And Atheroprotective Signaling, Nicolas Baeyens, Mary Jo Mulligan-Kehoe, Federico Corti, David D. Simon, Tyler D. Ross, John M. Rhodes, Thomas Z. Wang

Dartmouth Scholarship

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4−/−) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4−/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression …

E2f4 Regulatory Program Predicts Patient Survival Prognosis In Breast Cancer, Sari S. Khaleel, Erik H. Andrews, Matthew Ung, James Direnzo, Chao Chung

Dartmouth Scholarship

Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures. We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score …

Unencapsulated Streptococcus Pneumoniae From Conjunctivitis Encode Variant Traits And Belong To A Distinct Phylogenetic Cluster, Michael D. Valentino, Abigail Manson Mcguire, Jason W. Rosch, Paulo J.M Bispo, Corinna Burnham, Christine M. Sanfilippo, Robert A. Carter, Michael E. Zegans, Bernard Beall, Ashlee M. Earl, Elaine I. Tuomanen, Timothy W. Morris, Wolfgaang Haas, Michael S. Gilmore

Dartmouth Scholarship

Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the United States. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with …

Role Of A Genetic Variant On The 15q25.1 Lung Cancer Susceptibility Locus In Smoking-Associated Nasopharyngeal Carcinoma, Xuemei Ji, Weidong Zhang, Jiang Gui, Xia Fan, Weiwei Zhang, Yafang Li, Guangyu An, Dakai Zhu, Qiang Hu

Dartmouth Scholarship

Background: The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods: In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and …

A Dietary-Wide Association Study (Dwas) Of Environmental Metal Exposure In Us Children And Adults, Matthew A. Davis, Diane Gilbert-Diamond, Margaret R. Karagas, Zhigang Li, Jason H. Moore, Scott M. Williams, H. Robert Frost

Dartmouth Scholarship

Background: A growing body of evidence suggests that exposure to toxic metals occurs through diet but few studies have comprehensively examined dietary sources of exposure in US populations.

Purpose: Our goal was to perform a novel dietary-wide association study (DWAS) to identify specific dietary sources of lead, cadmium, mercury, and arsenic exposure in US children and adults.

Methods: We combined data from the National Health and Nutrition Examination Survey with data from the US Department of Agriculture’s Food Intakes Converted to Retail Commodities Database to examine associations between 49 different foods and environmental metal exposure. Using blood and urinary biomarkers …

Stag2 Promotes Error Correction In Mitosis By Regulating Kinetochore–Microtubule Attachments, Marianna Kleyman, Lilian Kabeche, Duane A. Compton

Dartmouth Scholarship

Mutations in the STAG2 gene are present in ∼20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, …

Human And Helicobacter Pylori Coevolution Shapes The Risk Of Gastric Disease, Nuri Kodaman, Alvaro Pazos, Barbara G. Schneider, M. Blanca Piazuelo, Robertino Mera, Rafal S. Sobota

Dartmouth Scholarship

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster …

Novel Roles For Actin In Mitochondrial Fission, Anna L. Hatch, Pinar S. Gurel, Henry N. Higgs

Dartmouth Scholarship

Mitochondrial dynamics, including fusion, fission and translocation, are crucial to cellular homeostasis, with roles in cellular polarity, stress response and apoptosis. Mitochondrial fission has received particular attention, owing to links with several neurodegenerative diseases. A central player in fission is the cytoplasmic dynamin-related GTPase Drp1, which oligomerizes at the fission site and hydrolyzes GTP to drive membrane ingression. Drp1 recruitment to the outer mitochondrial membrane (OMM) is a key regulatory event, which appears to require a pre-constriction step in which the endoplasmic reticulum (ER) and mitochondrion interact extensively, a process termed ERMD (ER-associated mitochondrial division). It is unclear how ER-mitochondrial …