Medicine and Health Sciences Commons^™

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 …

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 …

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 …

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 …

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 …

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