Medicine and Health Sciences Commons^™

Secretion Of Rhoptry And Dense Granule Effector Proteins By Nonreplicating Toxoplasma Gondii Uracil Auxotrophs Controls The Development Of Antitumor Immunity, Barbara A. Fox, Kiah L. Sanders, Leah M. Rommereim, Rebekah B. Guevara, David J. Bzik

Dartmouth Scholarship

Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α⁺ dendritic cells, the IL-12/interferon-gamma (IFN-γ) T_H1 axis, as well as CD4⁺ and CD8 …

Consistency Of Hemoglobin A1c Testing And Cardiovascular Outcomes In Medicare Patients With Diabetes, Philip P. Goodney, Karina A. Newhall, Kimon Bekelis, Daniel Gottlieb, Richard Comi, Sushela Chaudrain, Adrienne E. Faerber, Todd A. Mackenzie, Jonathan S. Skinner

Dartmouth Scholarship

Background:

Annual hemoglobin A1c testing is recommended for patients with diabetes mellitus. However, it is unknown how consistently patients with diabetes mellitus receive hemoglobin A1c testing over time, or whether testing consistency is associated with adverse cardiovascular outcomes.

Methods and Results:

We identified 1 574 415 Medicare patients (2002–2012) with diabetes mellitus over the age of 65. We followed each patient for a minimum of 3 years to determine their consistency in hemoglobin A1C testing, using 3 categories: low (testing in 0 or 1 of 3 years), medium (testing in 2 of 3 years), and high (testing in all 3 …

Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib

Dartmouth Scholarship

Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …

Intact Cohesion, Anaphase, And Chromosome Segregation In Human Cells Harboring Tumor-Derived Mutations In Stag2, Jung-Sik Kim, Xiaoyuan He, Bernardo Orr, Gordana Wutz, Victoria Hill, Jan-Michael Peters, Duane A. Compton, Todd Waldman

Dartmouth Scholarship

Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 …

Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p13.1 Breast–Ovarian Cancer Susceptibility Locus, Kate Lawrenson, Siddhartha Kar, Karen Mccue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalie Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fionna Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Sandra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B.M Claes, Gemo Study Collaborators, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diaz, Jennifer A. Doherty

Dartmouth Scholarship

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 X 10^-20), ER-negative BC (P = 1.1 X 10^-13), BRCA1 -associated BC (P = 7.7 X 10^-16) and triple negative BC (P-diff = 2 X 10^-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 X 10^{-3 …}

Patterns Of Human Herpesvirus-8 Oral Shedding Among Diverse Cohorts Of Human Herpesvirus-8 Seropositive Persons, Rachel A. Bender Ignacio, Jason D. Goldman, Amalia S. Magaret, Stacy Selke, Meei-Li Huang, Soren Gantt, Christine Johnston, Warren Phipps, Joshua Schiffer, Richard Zuckerman

Dartmouth Scholarship

Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication (“shedding”) at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons.