Neural Crest Cell-Autonomous Roles Of Fibronectin In Cardiovascular Development., Xia Wang, Sophie Astrof

Department of Medicine Faculty Papers

The chemical and mechanical properties of extracellular matrices (ECMs) modulate diverse aspects of cellular fates; however, how regional heterogeneity in ECM composition regulates developmental programs is not well understood. We discovered that fibronectin 1 (Fn1) is expressed in strikingly non-uniform patterns during mouse development, suggesting that regionalized synthesis of the ECM plays cell-specific regulatory roles during embryogenesis. To test this hypothesis, we ablated Fn1 in the neural crest (NC), a population of multi-potent progenitors expressing high levels of Fn1. We found that Fn1 synthesized by the NC mediated morphogenesis of the aortic arch artery and differentiation of NC cells into …

Surface-Initiated Polymerizations For The Rapid Sorting Of Rare Cancer Cells, Jacob L. Lilly

Theses and Dissertations--Chemical and Materials Engineering

Cancer metastasis directly accounts for an estimated 90% of all cancer related deaths and is correlated with the presence of malignant cells in systemic circulation. This observed relationship has prompted efforts to develop a fluid biopsy, with the goal of detecting these rare cells in patient peripheral blood as surrogate markers for metastatic disease as a partial replacement or supplement to tissue biopsies. Numerous platforms have been designed, yet these have generally failed to support a reliable fluid biopsy due to poor performance parameters such as low throughput, low purity of enriched antigen positive cells, and insufficiently low detection thresholds …

The Role Of Fat Grafting And Adipose-Derived Stem Cells In Breast Reconstruction, Krishna S. Vyas

Theses and Dissertations--Clinical and Translational Science

Fat grafting is a common surgical procedure that involves the transfer of fat from one area of the body to another in order to improve contour deformities, such as in breast reconstruction. Advantages of the technique include using autologous tissue rather than a foreign body and the added benefit of having liposuction to remove fat from an undesirable location. Although adipose tissue could be the ideal soft tissue filler, fat grafting is plagued by tremendous variability in long-term retention, with volume survival rates of 20-80%, resulting in suboptimal outcomes and repetitive procedures.

The mechanisms contributing to long-term fat graft survival …

Overcoming Treatment Resistance In Heterogeneous Tumors, Nikhil Hebbar

Theses and Dissertations--Toxicology and Cancer Biology

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains …

Effect Of Fluid Temperature And Volume On Thermoregulation In The Heat, Michelle M. Johannsen

Graduate Student Theses, Dissertations, & Professional Papers

The link between thermoregulation, hydration status, and exercise performance in hot humid environments is controversial. The purpose of this study was to evaluate the effects of volume and temperature of ingested fluid on hydration status, thermoregulation and exercise performance. Recreationally active males (N=11, 24.7±5.9 years; VO₂max=58.2±6.0 mL/kg/min) completed two 3-hour intermittent exercise trials in the heat (31^o WBGT=35.5°C with 50% humidity). Participants consumed either 1 mL/kg body weight (BW) of room temperature water (35.5°C; ROOM) or 0.5 mL/kg of an ice slurry mixture (~0°C; COLD) every ten minutes throughout the trials in a randomized crossover design. Subjects …

Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations Of Conps’ Pharmacokinetics, Efficacy, And Mechanisms Of Action, Philip R. Mcdonagh Iii

Theses and Dissertations

Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH₂), dextran T10-polyethylene …

Introducing Novel Combinatorial Targeted Therapies In Multiple Types Of Cancer, Mehrad Tavallai

Theses and Dissertations

The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, …

Attitudes Toward Breast Cancer Genetic Testing In Five Special Population Groups, Amelie G. Ramirez, Patricia Chalela, Kipling J. Gallion, Edgar Muñoz, Alan E. Holden, Linda Burhansstipanov, Selina A. Smith, Evaon Wong-Kim, Stephen W. Wyatt, Lucina Suarez

Journal of Health Disparities Research and Practice

Purpose: This study examined interest in and attitudes toward genetic testing in 5 different population groups.

Methods: The survey included African American, Asian American, Latina, Native American, and Appalachian women with varying familial histories of breast cancer. A total of 49 women were interviewed in person. Descriptive and nonparametric statistical techniques were used to assess ethnic group differences.

Results: Overall, interest in testing was high. All groups endorsed more benefits than risks. There were group differences regarding endorsement of specific benefits and risks: testing to “follow doctor recommendations” (p=0.017), “concern for effects on family” (p=0.044), “distrust of modern medicine” (p=0.036), …

Racial Disparities In The Association Between Stress And Preterm Birth, Saba W. Masho, Sarah Kye Price, Patricia Anne Kinser, Nancy Jallo

Journal of Health Disparities Research and Practice

Background: High levels of maternal stress have been linked to preterm births. However, findings from previous studies are inconsistent due to the varied use of stress measures. This study examined the effect of maternal stress on preterm birth, using both psychosocial and physiological measures.

Methods: This study was conducted among 231 pregnant women enrolled during their first prenatal care visit. Presence of stress was assessed at enrollment using the Perceived Stress Scale (PSS) and Stressful Life Events Inventory (SLEI). Samples of maternal salivary cortisol were obtained during the first trimester and birth outcomes were ascertained at delivery. Multiple …

Community Based Participatory Research: The Application And Lessons Learned From A Study With Lgb College Students, Caitlin M. Stover

Journal of Health Disparities Research and Practice

Lesbian, gay, and bisexual (LGB) individuals are members of a vulnerable group where health disparities have been identified. To gain a better understanding of the LGB college student healthcare experience and its contribution to the healthcare disparities found in LGB population, a community based participatory research (CBPR) approach was used to fill the gap. This paper will outline the CBPR process with an emphasis on how the principle investigator applied the tenets of CBPR when working with a local LGB college community. Several lessons learned from the research process are also shared in this paper.

Understanding How Components Of Black Racial Identity And Racial Realities May Impact Healthcare Utilization: A Randomized Study, Alexander M. Chaitoff, Thomas Wickizer, Ismail White

Journal of Health Disparities Research and Practice

Purpose: Studies have suggested that even when minority groups have potential access to healthcare, they may have inadequate utilization (realized access). This study explores the application of a theory from the social psychology and political science literatures concerning how racial centrality and racial realities, specifically amongst Blacks, may influence patients’ healthcare utilization preferences.

Methods: We created a survey with two (pseudo) randomized, controlled experimental treatments designed to assess whether racialized hospital and physician characteristics elicited a preference from Black or White respondents, as well as questions aimed at understanding participants’ different beliefs and levels of knowledge about past and current …

Nucleus Accumbens Deep Brain Stimulation In A Rat Model Of Binge Eating, W. T. Doucette, J. Y. Khokhar, A. I. Green

Dartmouth Scholarship

Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for …

Hdac6 Activity Is A Non-Oncogene Addiction Hub For Inflammatory Breast Cancers, Preeti Putcha, Jiyang Yu, Ruth Rodriguez-Barrueco, Laura Saucedo-Cuevas, Patricia Villagrasa, Eva Murga-Penas, Steven N. Quayle, Min Yang, Veronica Castro, David Llobet-Navas, Daniel Birbaum, Pascal Finetti, Wendy A. Woodward, Francois Bertucci, Mary Alpaugh, Andrea Califano, Jose Silva

College of Science & Mathematics Departmental Research

Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles’ heel of IBC cells.

Differing Cognitive Strategies Between Evidence-Based Medicine And Evidence-Based Practice, James P. Meza Md, Phd

Clinical Research in Practice: The Journal of Team Hippocrates

Clinical care requires both evidence-based medicine (abstract, not applied, knowledge) and evidence-based practice (derived from knowledge of a specific patient's concerns). Clinical Research in Practice encourages an apprenticeship model that embraces both.

Impact Of Sleep And Circadian Disruption On Energy Balance And Diabetes: A Summary Of Workshop Discussions, Deanna M. Arble, Joseph Bass, Cecilia Diniz Behn, Matthew P. Butler, Etienne Challet, Charles Czeisler, Christopher M. Depner, Joel Elmquist, Paul Franken, Michael A. Grandner, Erin C. Hanlon, Alex C. Keene, Michael J. Joyner, Ilia Karatsoreos, Philip A. Kern, Samuel Klein, Christopher J. Morris, Allan I. Pack, Satchidananda Panda, Louis J. Ptacek, Naresh M. Punjabi, Paolo Sassone-Corsi, Frank A. Scheer, Richa Saxena, Elizabeth R. Seaquest, Matthew S. Thimgan, Eve Van Cauter, Kenneth P. Wright

Clinical and Translational Science Faculty Publications

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact …

Mechanisms And Intervention Strategies For Alcohol And Hiv-Antiretroviral Therapy-Induced Liver Injury., Hridgandh Donde

Electronic Theses and Dissertations

Chronic alcohol consumption is a leading cause of liver disease and liver-related death worldwide. Alcoholic liver disease includes, hepatic steatosis, steatohepatitis and ultimately fibrosis and cirrhosis. Emerging evidence has established the important role of the “gut-liver” axis in the development of alcoholic liver disease (ALD). Our recent work indicated that chronic alcohol induced perturbations in the gut microbiome and consequent changes in fatty acids have a major impact on the development of intestinal barrier dysfunction and ALD. The aim of this study was to investigate whether treatment with tributyrin - a butyrate prodrug results in protection against ALD in terms …

Prediction Of Laser Ablation In Brain: Sensitivity, Calibration, And Validation, Samuel J. Fahrenholtz

Dissertations and Theses (Open Access)

The surgical planning of MR-guided laser induced thermal therapy (MRgLITT) stands to benefit from predictive computational modeling. The dearth of physical model parameter data leads to modeling uncertainty. This work implements a well-accepted framework with three key steps for model-building: model-parameter sensitivity analysis, model calibration, and model validation.

The sensitivity study is via generalized polynomial chaos (gPC) paired with a transient finite element (FEM) model. Uniform probability distribution functions (PDFs) capture the plausible range of values suggested by the literature for five model parameters. The five PDFs are input separately into the FEM model to gain a probabilistic sensitivity response …

Redirecting T Cells With Chimeric Antigen Receptors To Target Cd123+ Leukemia, Radhika Thokala

Dissertations and Theses (Open Access)

ABSTRAC

REDIRECTING T CELLS WITH CHIMERIC ANTIGEN RECEPTORS TO TARGET CD123+ LEUKEMIA

Radhika Thokala, Ph.D*

Advisory Professor: Dean Anthony Lee, M.D, Ph.D

CD123 or interleukin receptor alpha (IL-3Rα) is expressed on hematological malignancies such as acute myeloid leukemia (AML) and some acute lymphoblastic leukemia (ALL). Significantly, CD123 is over-expressed on leukemic stem cells (LSCs) compared to normal hematopoietic stem cells and thus targeting this tumor- associated antigen (TAA) provides the potential to prevent relapse. The prototyical chimeric antigen receptor (CAR) is fashioned by …

Fibronectin Signals Through Integrin Α5Β1 To Regulate Cardiovascular Development In A Cell Type-Specific Manner., Dongying Chen, Xia Wang, Dong Liang, Julie Gordon, Ashok Mittal, Nancy Manley, Karl Degenhardt, Sophie Astrof

Department of Medicine Faculty Papers

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in …

Extrapolating Evidence About Preventing Recurrent Cellulitis For An Individual Patient Concern, Christina L. Benkert D.O., Amrit K. Basi, Kristina L. Bahrou M.D., Catherine R. Cherri M.D., Suraiya K. Azom M.D., Nicholus H. Yee M.D.

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Thomas KS, Crook AM, Nunn AJ, et al. Penicillin to prevent recurrent leg cellulitis, N Engl J Med. 2013, May 2;368(18):1695-1703. doi: 10.1056/NEJMoa1206300