Medicine and Health Sciences Commons^™

Acute Hypersensitivity Of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma To Low-Dose 5-Aza Deoxycytidine Is Associated With Global Dna Damage-Associated P53 Activation, Anti-Pluripotency And Dna Demethylation, Bijesh K. Biswal, Maroun J. Beyrouthy, Mary P. Hever-Jardine, David Armstrong, Craig R. Tomlinson, Brock C. Christensen, Carmen J. Marsit, Michael J. Spinella

Dartmouth Scholarship

Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low- dose 5-aza induces a p53 transcriptional signature distinct from …

On The Interplay Of Telomeres, Nevi And The Risk Of Melanoma, Clara Bodelon, Ruth M. Pfeiffer, Valentina Bollati, Julien Debbache, Donato Calista, Paola Ghiorzo, Maria Concetta Fargnoli, Giovanna Bianchi-Scarra, Ketty Peris, Mirjam Hoxha, Amy Hutchinson, Laura Burke, Shenying Fang, Margaret A. Tucker, Alisa M. Goldstein, Jeffrey E. Lee, Qingyi Wei, Sharon A. Savage, Xiaohong R. Yang, Christopher Amos, Maria Teresa Landi

Dartmouth Scholarship

The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or …

Multiple Subject Barycentric Discriminant Analysis (Musubada): How To Assign Scans To Categories Without Using Spatial Normalization, Hervé Abdi, Lynne J. Williams, Andrew C. Connolly, M. Ida Gobbini

Dartmouth Scholarship

We present a new discriminant analysis (DA) method called Multiple Subject Barycentric Discriminant Analysis (MUSUBADA) suited for analyzing fMRI data because it handles datasets with multiple participants that each provides different number of variables (i.e., voxels) that are themselves grouped into regions of interest (ROIs). Like DA, MUSUBADA (1) assigns observations to predefined categories, (2) gives factorial maps displaying observations and categories, and (3) optimally assigns observations to categories. MUSUBADA handles cases with more variables than observations and can project portions of the data table (e.g., subtables, which can represent participants or ROIs) on the factorial maps. Therefore MUSUBADA can …

Microrna Mir-155 Affects Antiviral Effector And Effector Memory Cd8 T Cell Differentiation, Ching-Yi Tsai, S. Rameeza Allie, Weijun Zhang, Edward J. Usherwood

Dartmouth Scholarship

MicroRNAs are key regulators of the immune response, but their role in CD8 T cell differentiation in vivo is not known. We show that miR-155 is important in both effector and memory antiviral CD8 T cell responses. Without miR-155, there was a weaker effector response and a skewing toward memory precursor cells. At the memory stage, miR-155-deficient CD8 T cells preferentially differentiated into central memory cells and were capable of mounting a potent secondary response.

Myeloid-Derived Suppressor Cells In Murine Retrovirus-Induced Aids Inhibit T- And B-Cell Responses In Vitro That Are Used To Define The Immunodeficiency, Kathy A. Green, W. James Cook, William R. Green

Dartmouth Scholarship

Myeloid-derived suppressor cells (MDSCs) have been characterized in several disease settings, especially in many tumor systems. Compared to their involvement in tumor microenvironments, however, MDSCs have been less well studied in their responses to infectious disease processes, in particular to retroviruses that induce immunodeficiency. Here, we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on infection by the LP-BM5 retrovirus, which causes murine acquired immunodeficiency. These MDSCs express a cell surface marker signature (CD11b Gr-1 Ly6C ) characteristic of monocyte-type MDSCs. Such MDSCs profoundly inhibit immune responsiveness by a cell dose- and …

Building A Strategic Framework For Comparative Effectiveness Research In Complementary And Integrative Medicine, Claudia M. Witt, Margaret Chesney, Richard Gliklich, Lawrence Green, George Lewith, Bryan Luce, Anne Mccaffrey, Shelly Rafferty Withers, Harold C. Sox, Sean Tunis, Brian M. Berman

Dartmouth Scholarship

The increasing burden of chronic diseases presents not only challenges to the knowledge and expertise of the professional medical community, but also highlights the need to improve the quality and relevance of clinical research in this domain. Many patients now turn to complementary and integrative medicine (CIM) to treat their chronic illnesses; however, there is very little evidence to guide their decision-making in usual care. The following research recommendations were derived from a CIM Stakeholder Symposium on Comparative Effectiveness Research (CER): (1) CER studies should be made a priority in this field; (2) stakeholders should be engaged at every stage …

Chapter 11: Genome-Wide Association Studies, William S. Bush, Jason H. Moore

Dartmouth Scholarship

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

Joint Effect Of Genetic And Lifestyle Risk Factors On Type 2 Diabetes Risk Among Chinese Men And Women, Raquel Villegas, Ryan Delahanty, Yu-Tang Gao, Jirong Long, Scott M. Williams, Yong-Bing Xiang, Hui Cai, Hong-Lan Li, Frank Hu, Qiuyin Cai, Wei Zheng, Xiao-Ou Shu

Dartmouth Scholarship

More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) …

Building A Statistical Model For Predicting Cancer Genes, Ivan P. Gorlov, Christopher J. Logothetis, Shenying Fang, Olga Y. Gorlova, Christopher Amos

Dartmouth Scholarship

More than 400 cancer genes have been identified in the human genome. The list is not yet complete. Statistical models predicting cancer genes may help with identification of novel cancer gene candidates. We used known prostate cancer (PCa) genes (identified through KnowledgeNet) as a training set to build a binary logistic regression model identifying PCa genes. Internal and external validation of the model was conducted using a validation set (also from KnowledgeNet), permutations, and external data on genes with recurrent prostate tumor mutations. We evaluated a set of 33 gene characteristics as predictors. Sixteen of the original 33 predictors were …

Quantitative, Spectrally-Resolved Intraoperative Fluorescence Imaging, Pablo A. Valdés, Frederic Leblond, Valerie L. Jacobs, Brian C. Wilson, Keith D. Paulsen, David W. Roberts

Dartmouth Scholarship

Intraoperative visual fluorescence imaging (vFI) has emerged as a promising aid to surgical guidance, but does not fully exploit the potential of the fluorescent agents that are currently available. Here, we introduce a quantitative fluorescence imaging (qFI) approach that converts spectrally-resolved data into images of absolute fluorophore concentration pixel-by-pixel across the surgical field of view (FOV). The resulting estimates are linear, accurate, and precise relative to true values, and spectral decomposition of multiple fluorophores is also achieved. Experiments with protoporphyrin IX in a glioma rodent model demonstrate in vivo quantitative and spectrally-resolved fluorescence imaging of infiltrating tumor margins for the …

Effect Of Genetic Variants, Especially Cyp2c9 And Vkorc1, On The Pharmacology Of Warfarin, Erik Fung, Nikolaos Patsopoulos, Steven Belknap, Daniel O'Rourke, John Robb, Jeffrey L. Anderson, Nicholas W. Shworak, Jason H. Moore

Dartmouth Scholarship

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in …

Privacy In Mobile Technology For Personal Healthcare, Sasikanth Avancha, Amit Baxi, David Kotz

Dartmouth Scholarship

Information technology can improve the quality, efficiency, and cost of healthcare. In this survey, we examine the privacy requirements of \emphmobile\/ computing technologies that have the potential to transform healthcare. Such \emphmHealth\/ technology enables physicians to remotely monitor patients' health, and enables individuals to manage their own health more easily. Despite these advantages, privacy is essential for any personal monitoring technology. Through an extensive survey of the literature, we develop a conceptual privacy framework for mHealth, itemize the privacy properties needed in mHealth systems, and discuss the technologies that could support privacy-sensitive mHealth systems. We end with a list of …

Comparative Study Of Influenza Virus Replication In Mdck Cells And In Primary Cells Derived From Adenoids And Airway Epithelium, Natalia A. Ilyushina, Mine R. Ikizler, Yoshihiro Kawaoka, Larisa G. Rudenko

Dartmouth Scholarship

Although clinical trials with human subjects are essential for determination of safety, infectivity, and immunogenicity, it is de- sirable to know in advance the infectiousness of potential candidate live attenuated influenza vaccine strains for human use. We compared the replication kinetics of wild-type and live attenuated influenza viruses, including H1N1, H3N2, H9N2, and B strains, in Madin-Darby canine kidney (MDCK) cells, primary epithelial cells derived from human adenoids, and human bron- chial epithelium (NHBE cells). Our data showed that despite the fact that all tissue culture models lack a functional adaptive im- mune system, differentiated cultures of human epithelium exhibited …

Regulatory T-Cells And Associated Pathways In Metastatic Renal Cell Carcinoma (Mrcc) Patients Undergoing Dc-Vaccination And Cytokine-Therapy, Adrian Schwarzer, Benita Wolf, Jan L. Fisher, Thomas Schwaab, Sven Olek, Udo Baron, Craig R. Tomlinson, John D. Seigne, Nancy A. Crosby, Jiang Gui, Thomas H. Hampton, Camilo E. Fadul, John A. Heaney, Marc S. Ernstoff

Dartmouth Scholarship

Purpose: To evaluate CD4+CD25+FOXP3+ T regulatory cells (TREG) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating TREG combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.

Design: Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. TREG phenotype was examined using flow cytometry (FCM). TREG were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip …

Genetic Association Analysis Of Complex Diseases Incorporating Intermediate Phenotype Information, Yafang Li, Jian Huang, Christopher I. Amos

Dartmouth Scholarship

Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate …

In Utero Exposures, Infant Growth, And Dna Methylation Of Repetitive Elements And Developmentally Related Genes In Human Placenta, Charlotte S. Wilhelm-Benartzi, E. Andres Houseman, Matthew A. Maccani, Graham M. Poage, Devin C. Koestler, Scott M. Langevin, Luc A. Gagne, Carolyn E. Banister, James F. Padbury, Carmen J. Marsit

Dartmouth Scholarship

BACKGROUND:

Fetal programming describes the theory linking environmental conditions during embryonic and fetal development with risk of diseases later in life. Environmental insults in utero may lead to changes in epigenetic mechanisms potentially affecting fetal development.

OBJECTIVES:

We examined associations between in utero exposures, infant growth, and methylation of repetitive elements and gene-associated DNA in human term placenta tissue samples.

METHODS:

Placental tissues and associated demographic and clinical data were obtained from subjects delivering at Women and Infants Hospital in Providence, Rhode Island (USA). Methylation levels of long interspersed nuclear element-1 (LINE-1) and the Alu element AluYb8 were determined in …

Understanding Sharing Preferences And Behavior For Mhealth Devices, Aarathi Prasad, Jacob Sorber, Timothy Stablein, Denis Anthony, David Kotz

Dartmouth Scholarship

mHealth devices offer many potential benefits to patients, health providers and others involved in the patients' healthcare. If patients are not in control of the collection and sharing of their personal health information, they will have privacy concerns even while enjoying the benefits of the devices. We investigated patients' willingness to share their personal health information, collected using mHealth devices, with their family, friends, third parties and the public. Our findings are based on a user study conducted with 41 participants. The best way to understand people's privacy concerns is to give them the opportunity to use the device and …

Thr 163 Phosphorylation Causes Mcl-1 Stabilization When Degradation Is Independent Of The Adjacent Gsk3-Targeted Phosphodegron, Promoting Drug Resistance In Cancer, Shanna K. Nifoussi, Julie A. Vrana, Aaron M. Domina, Alfredo De Biasio, Jingang Gui, Mark A. Gregory, Stephen R. Hann, Ruth W. Craig

Dartmouth Scholarship

The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a …

Influenza-Infected Neutrophils Within The Infected Lungs Act As Antigen Presenting Cells For Anti-Viral Cd8+ T Cells, Matthew M. Hufford, Graham Richardson, Haixia Zhou, Balaji Manicassamy, Adolfo Garcia-Sastre, Richard I. Enelow, Thomas J. Braciale

Dartmouth Scholarship

Influenza A virus (IAV) is a leading cause of respiratory tract disease worldwide. Anti-viral CD8⁺ T lymphocytes responding to IAV infection are believed to eliminate virally infected cells by direct cytolysis but may also contribute to pulmonary inflammation and tissue damage via the release of pro-inflammatory mediators following recognition of viral antigen displaying cells. We have previously demonstrated that IAV antigen expressing inflammatory cells of hematopoietic origin within the infected lung interstitium serve as antigen presenting cells (APC) for infiltrating effector CD8⁺ T lymphocytes; however, the spectrum of inflammatory cell types capable of serving as APC was not …

Rice Consumption And Urinary Arsenic Concentrations In U.S. Children, Matthew A. Davis, Todd A. Mackenzie, Kathryn L. Cottingham, Diane Gilbert-Diamond, Tracy Punshon, Margaret R. Karagas

Dartmouth Scholarship

Background: In adult populations, emerging evidence indicates that humans are exposed to arsenic by ingestion of contaminated foods such as rice, grains, and juice; yet little is known about arsenic exposure among children.

Objectives: Our goal was to determine whether rice consumption contributes to arsenic exposure in U.S. children.

Methods: We used data from the nationally representative National Health and Nutrition Examination Survey (NHANES) to examine the relationship between rice consumption (measured in 0.25 cups of cooked rice per day) over a 24-hr period and subsequent urinary arsenic concentration among the 2,323 children (6–17 years of age) who participated in …

Predicting The Difficulty Of Pure, Strict, Epistatic Models: Metrics For Simulated Model Selection, Ryan J. Urbanowicz, Jeff Kiralis, Jonathan M. Fisher, Jason H. Moore

Dartmouth Scholarship

Background:

Algorithms designed to detect complex genetic disease associations are initially evaluated using simulated datasets. Typical evaluations vary constraints that influence the correct detection of underlying models (i.e. number of loci, heritability, and minor allele frequency). Such studies neglect to account for model architecture (i.e. the unique specification and arrangement of penetrance values comprising the genetic model), which alone can influence the detectability of a model. In order to design a simulation study which efficiently takes architecture into account, a reliable metric is needed for model selection.

Results:

We evaluate three metrics as predictors of relative model detection difficulty derived …

Quantifying The Clinical Significance Of Cannabis Withdrawal, David J. Allsop, Jan Copeland, Melissa M. Norberg, Shanlin Fu, Anna Molnar, John Lewis, Alan J. Budney

Dartmouth Scholarship

Background and Aims:

Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.

Methods and Results:

A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment …

Design Of A Prostate Cancer Patient Navigation Intervention For A Veterans Affairs Hospital, Narissa J. Nonzee, June M. Mckoy, Alfred W. Rademaker, Peter Byer, Thanh H. Luu, Dachao Liu, Elizabeth A. Richey

Dartmouth Scholarship

Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago.

The Human Brain Intracerebral Microvascular System: Development And Structure, Miguel Marín-Padilla

Dartmouth Scholarship

The capillary from the meningeal inner pial lamella play a crucial role in the development and structural organization of the cerebral cortex extrinsic and intrinsic microvascular compartments. Only pial capillaries are capable of perforating through the cortex external glial limiting membrane (EGLM) to enter into the nervous tissue, although incapable of perforating the membrane to exit the brain. Circulatory dynamics and functional demands determine which capillaries become arterial and which capillaries become venous. The perforation of the cortex EGLM by pial capillaries is a complex process characterized by three fundamental stages: (1) pial capillary contact with the EGLM with fusion …

Herpes Simplex Virus 34.5 Interferes With Autophagosome Maturation And Antigen Presentation In Dendritic Cells, Philipe A. M. Gobeil, David A. Leib

Dartmouth Scholarship

The cellular autophagy response induced by herpes simplex virus 1 (HSV-1) is countered by the viral γ34.5 protein. γ34.5 modulates autophagy by binding to the host autophagy protein Beclin-1 and through this binding inhibits the formation of autophagosomes in fibroblasts and neurons. In contrast, in this study dendritic cells (DCs) infected with HSV-1 showed an accumulation of autophagosomes and of the long-lived protein p62. No such accumulations were observed in DCs infected with a γ34.5-null virus or a virus lacking the Beclin-binding domain (BBD) of γ34.5. To explore this further, we established stably transduced DC lines to show that γ34.5 …

Automatic And Robust Calibration Of Optical Detector Arrays For Biomedical Diffuse Optical Spectroscopy, Michael A. Mastanduno, Shudong Jiang, Roberta Diflorio-Alexander, Brian W. Pogue, Keith Paulsen

Dartmouth Scholarship

The design and testing of a new, fully automated, calibration approach is described. The process was used to calibrate an image-guided diffuse optical spectroscopy system with 16 photomultiplier tubes (PMTs), but can be extended to any large array of optical detectors and associated imaging geometry. The design goals were accomplished by developing a routine for robust automated calibration of the multi-detector array within 45 minutes. Our process was able to characterize individual detectors to a median norm of the residuals of 0.03 V for amplitude and 4.4 degrees in phase and achieved less than 5% variation between all the detectors …

Measuring Infertility In Populations: Constructing A Standard Definition For Use With Demographic And Reproductive Health Surveys, Maya N. Mascarenhas, Hoiwan Cheung, Colin D. Mathers, Gretchen A. Stevens

Dartmouth Scholarship

Background: Infertility is a significant disability, yet there are no reliable estimates of its global prevalence. Studies on infertility prevalence define the condition inconsistently, rendering the comparison of studies or quantitative summaries of the literature difficult. This study analyzed key components of infertility to develop a definition that can be consistently applied to globally available household survey data.

Methods: We proposed a standard definition of infertility and used it to generate prevalence estimates using 53 Demographic and Health Surveys (DHS). The analysis was restricted to the subset of DHS that contained detailed fertility information collected through the reproductive health calendar. …

Breast Milk From Tanzanian Women Has Divergent Effects On Cell-Free And Cell-Associated Hiv-1 Infection In Vitro, Magdalena A. Lyimo, Matilda Ngarina Mosi, Molly L. Housman, Muhammad Zain-Ul-Abideen, Frederick V. Lee, Alexandra L. Howell, Ruth I. Connor

Dartmouth Scholarship

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively …

The Mre11 Nuclease Is Critical For The Sensitivity Of Cells To Chk1 Inhibition, Ruth Thompson, Ryan Montano, Alan Eastman

Dartmouth Scholarship

The Chk1 kinase is required for the arrest of cell cycle progression when DNA is damaged, and for stabilizing stalled replication forks. As a consequence, many Chk1 inhibitors have been developed and tested for their potential to enhance DNA damage-induced tumor cell killing. However, inhibition of Chk1 alone, without any additional exogenous agent, can be cytotoxic. Understanding the underlying mechanisms of this sensitivity is critical for defining which patients might respond best to therapy with Chk1 inhibitors. We have investigated the mechanism of sensitivity in U2OS osteosarcoma cells. Upon incubation with the Chk1 inhibitor MK-8776, single-stranded DNA regions (ssDNA) and …

Tryptophan Hydroxylase-1 Regulates Immune Tolerance And Inflammation, Elizabeth C. Nowak, Victor C. De Vries, Anna Wasiuk, Cory Ahonen, Kathryn A. Bennett, Isabelle Le Mercier, Dae-Gon Ha, Randolph J. Noelle

Dartmouth Scholarship

Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control in ammatory responses and immune tolerance. Here we report the novel nding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 de ciency breaks allograft tolerance, induces tumor remission, and intensi es neuroin ammation, respectively. All of these effects of Tph-1 de ciency are independent of its downstream product serotonin. Because …