NEUROTOXINS FROM MARINE ALGAE AND CYANOBACTERIA

F Thomas, Professor
University Of California San Diegocity: La Jolla country: United States (us)

Grant 2R01NS053398-10A1 from National Institute Of Neurological Disorders And Stroke

Abstract: Natural products have played pivotal roles in neuropharmacology due to their potent and selective targeting of specific biochemical pathways and receptors, and are highly useful as probe substances and therapeutic leads. Marine cyanobacteria are exceptionally rich in diverse natural product structures, many of which are toxic or have other biological properties. We propose to continue our productive collaboration between a natural products chemist (Gerwick) and a neuropharmacologist (Murray), expanding on our previous investigations of these life forms for their new and biologically-insightful neuroactive compounds. Thus, we have the long range goals of 1) developing new compounds to serve as novel tools for pharmacology and cell biology, 2) describing new putative environmental toxins so that appropriate actions can be taken should outbreaks occur, and 3) development of neuroactive substances as potential therapeutic lead compounds, especially in the treatment of stroke-induced brain injury. To accomplish these goals we have the following four specific aims 1) to collect 250 samples of cyanobacteria and algae, and produce high quality focused fraction libraries for screening in assays designed to detect neuroactive natural products, 2) to evaluate the above diverse extracts using high throughput spontaneous Ca2+ oscillation and Na+ influx assays in cerebrocortical neurons, 3) to use innovative and accelerated methods to isolate and structurally characterize new neuroactive substances from marine cyanobacteria testing positively in the screening assays, featuring nanoscale NMR and MSn methods, 4) to further define the molecular pharmacology of several cyanobacterial toxins discovered during prior support. Additionally, to evaluate the influence of newly discovered cyanobacterial ligands on neurite outgrowth, spinogenesis and synaptogenesis in neocortical neurons. Select compounds active in these in vitro assays will be advanced into a mouse model for focal stroke. This will require the production of additional supplies or analogs of these newly discovered compounds, including radioisotope-labeled analogs to be used in radioligand binding and distribution assays. Completion of these aims will increase our knowledge of the unique and neuroactive natural products produced by marine cyanobacteria and algae. The past two cycles of support for this collaborative program have been highly productive, and we now have a mature, well functioning, and highly effective program. We continue to refine our approaches and thinking as applied to the discovery and utility of novel marine neuroactive substances, and this leads us in new research directions for the proposed coming grant period, such as the application of voltage-gated sodium channel activators that promote neurite outgrowth in neocortical neurons to the potential treatment of stroke-induced brain injury. This project focuses on describing the natural neuroactive compounds present in marine algae and cyanobacteria, and this impacts human health in three areas 1) this research will find neuroactive compounds that work by new mechanisms, thus allowing a better of how cells communicate and react to their environment, 2) some of these neuroactive compounds may lead to new therapies for diseases such as stroke, epilepsy, pain control, schizophrenia, and cognitive disorders, and 3) by fully describing the structures and pharmacology of some of these toxic natural products, this research can help reduce human exposures and suggest treatment options in case of exposure

Keywords: Agonist; Algae; Algal Blooms; analog; antillatoxin; Area; Binding (Molecular Function); Biochemical Pathway; Biological; Biological Assay; Biological Factors; Brain; Brain Injuries; Cardiovascular Diseases; Cells; Cellular biology; Chemicals; Cognition Disorders; Collaborations; cyanobacterial toxin; Cyanobacterium; design; Development; Disease; Disease Outbreaks; Environment; Environmental Health; Epilepsy; Evolution; exposed human population; Funding; gambierol; Glutamate Receptor; Goals; Grant; Health; Human; in vitro Assay; innovation; Investigation; Ion Channel; kalkitoxin; Knowledge; Label; Lead; Libraries; Life; Ligands; Marine Toxins; Marines; Mediating; Methods; Molecular; mouse model; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; nanoscale; neocortical; nervous system disorder; Neurites; neuron development; neuronal growth; Neuronal Plasticity; Neurons; Neuropharmacology; Neurotoxins; novel; Pain management; Pharmacology; Play; Production; programs; Property; public health medicine (field); Radioisotopes; radioligand; receptor; Receptor Signaling; relating to nervous system; Research; Role; Sampling; Schizophrenia; Screening procedure; Signal Pathway; Sodium Channel; stroke; Structure; synaptogenesis; Targeted Toxins; Testing; Therapeutic; therapeutic target; Thinking, function; tool; Toxic effect; Toxic Environmental Substances; Toxin; voltage; Water; Work

Relevance: This project focuses on describing the natural neuroactive compounds present in marine algae and cyanobacteria, and this impacts human health in three areas: 1) this research will find neuroactive compounds that work by new mechanisms, thus allowing a better of how cells communicate and react to their environment, 2) some of these neuroactive compounds may lead to new therapies for diseases such as stroke, epilepsy, pain control, schizophrenia, and cognitive disorders, and 3) by fully describing the structures and pharmacology of some of these toxic natural products, this research can help reduce human exposures and suggest treatment options in case of exposure

Project start date: 2001-07-01

Project end date: 2016-06-30

Budget start date: 1-JUL-2011

Budget end date: 30-JUN-2012

PFA/PA: PA-10-067

2R01NS053398-10A1 (2011): $516280

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Grants awarded to F Thomas

VISUALIZATION OF ENDODERMAL CELL MIGRATION DURING ZEBRAFISH GASTRULATION

F Thomas, Associate Professor
University Of California Irvinecity: Irvine country: United States (us)

Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project seeks to track the movements of the Zebrafish endodermal cells during gastrulation. Video imaging with take place over a 6 hour time frame, and endodermal cells will be visualized using GFP. Videos will then be analyzed for the speed, polarity and migration of cells over the course of this time frame

Keywords: body movement; Brachydanio rerio; Cell Locomotion; Cell Migration; cell motility; Cell Movement; Cellular Migration; Computer Retrieval of Information on Scientific Projects Database; CRISP; Danio rerio; Endoderm Cell; Endodermal Cell; Funding; gastrulation; Grant; Hour; Image; Imagery; imaging; Institution; Investigators; Motility; Motility, Cellular; Movement; National Institutes of Health; National Institutes of Health (U.S.); NIH; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Speed; Speed (motion); Time; United States National Institutes of Health; Visualization; Zebra Danio; Zebra Fish; Zebrafish

Project start date: 2010-08-01

Project end date: 2011-07-31

Budget start date: 1-AUG-2010

Budget end date: 31-JUL-2011

5P41RR003155-25_6926 (2010): $1815

LIVE IMAGING OF CRANIAL NEURAL CREST CELLS IN THE ZEBRAFISH EMBRYO

F Thomas, Associate Professor
University Of California Irvinecity: Irvine country: United States (us)

Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Describe the behavior of cranial neural crest cells in live zebrafish embryos in order to better understand how cell behavior influences morphogenetic events and how changes in this behavior may result in craniofacial malformations

Keywords: Behavior; behavior influence; behavioral influence; Brachydanio rerio; cell behavior; Cephalic; Computer Retrieval of Information on Scientific Projects Database; Cranial; craniofacial; craniofacies; CRISP; Danio rerio; Embryo; Embryonic; Event; Funding; Grant; Image; imaging; Institution; Investigators; Life; malformation; National Institutes of Health; National Institutes of Health (U.S.); Neural Crest Cell; NIH; Research; Research Personnel; Research Resources; Researchers; Resources; Source; United States National Institutes of Health; Zebra Danio; Zebra Fish; Zebrafish

Project start date: 2010-08-01

Project end date: 2011-07-31

Budget start date: 1-AUG-2010

Budget end date: 31-JUL-2011

5P41RR003155-25_6925 (2010): $35355

HUMAN IMMUNOLOGIC MONITORING

F Thomas, Associate Professor
University Of Chicagocity: Chicago country: United States (us)

Abstract: The specific recognition of tumor antigens by CD8+ T cells, and the binding of monoclonal antibodies to tumor targets represent the main effector mechanisms for immune-mediated tumor rejection. The exquisite specificity of these interactions has earned cancer immunotherapy the designation as a targeted therapy. Excitement in this area was reinforced by the FDA approval of several monoclonal antibodies, such as Herceptin for breast cancer and Rituxan for lymphoma, as well as two cytokines, interleukin-2 and interferon-a, for the treatment of melanoma and kidney cancer. In addition, allogeneic bone marrow transplantation has therapeutic effects through a cell-mediated graft-versus-tumor immune response. However, the efficacy of these therapies is still suboptimal. Improving upon the effectiveness of current agents, developing new immunotherapeutic interventions (such as anti-cancer vaccines), and elucidating the mechanism of success versus failure of investigational treatments, all require careful monitoring of scientific endpoints. The main purpose of the Human Immunologic Monitoring Facility is to perform such assays in the context of clinical trials in cancer patients. As such, it serves as a specialized laboratory for evaluating pharmacodynamic parameters in response to agents or interventions that impact on immune cells. This service enables a range of clinical cancer researchers, who don´t necessarily have laboratory expertise themselves, to measure immunologic endpoints in participating study subjects. The Facility also monitors biologic effects of other pharmacologic agents (such as signal transduction inhibitors) using lymphocytes or other hematopoietic cells as a surrogate tissue. Finally, the technologists of our Core interface with the cGMP Facility to carry out the preparation of clinical-grade products, such as cancer vaccines, for administration to patients. Thus, this Facility lies at the heart of our clinical/translational effort in cancer immunotherapy, and is vital for the scientific investigation of additional novel agents

Keywords: Allogeneic Bone Marrow Transplantation; Area; Binding (Molecular Function); Biological Assay; Biological Monitoring; Cancer Center Support Grant; cancer immunotherapy; Cancer Patient; Cancer Vaccines; CD8B1 gene; Cells; Clinical; Clinical Trials; Cyclic GMP; cytokine; Effectiveness; Failure (biologic function); Graft-Versus-Tumor Induction; Heart; Hematopoietic; Human; Immune; Immune response; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; improved; Interferons; Interleukin-2; Intervention; Investigation; Investigational Therapies; Laboratories; Lymphocyte; Lymphoma; malignant breast neoplasm; Malignant Neoplasms; Measures; Mediating; melanoma; Monitor; Monoclonal Antibodies; novel; Patients; Pharmacodynamics; Preparation; Renal carcinoma; Research Personnel; response; Roche brand of rituximab; Roche brand of trastuzumab; Services; Signal Transduction Inhibitor; Specificity; Study Subject; success; T-Lymphocyte; Therapeutic Effect; Time; Tissues; Treatment Efficacy; tumor; Tumor Antigens; University of Chicago Cancer Research Center

Budget start date: 1-APR-2011

Budget end date: 31-MAR-2012

5P30CA014599-36_9023 (2011): $128319

CALCIUM REGULATION OF SECRETION IN NEUROENDOCRINE CELLS

F Thomas
University Of Wisconsin Madisoncity: Madison country: United States (us)

Grant 2R01DK040428-23 from National Institute Of Diabetes And Digestive And Kidney Diseases

Abstract: The secretion of neurotransmitters, neuropeptides and peptide hormones occurs by Ca2+dependent vesicle exocytosis. The machinery that mediates vesicle fusion with the plasma membrane is well-characterized and consists of complexes of the vesicle SNARE VAMP-2/synaptobrevin with the plasma membrane SNAREs syntaxin-1 and SNAP-25. SNARE complexes are acted upon by Ca2+bound synaptotagmin to drive membrane fusion. While these final steps in Ca2+triggered vesicle fusion have been extensively studied, there remain important gaps in understanding key events that precede fusion. These events are termed priming and they confer competence to docked vesicles for Ca2+triggered fusion. Priming is thought to involve the progressive assembly of trans SNARE complexes but the precise pathway utilized and the factors that regulate it have not been characterized. Genetic and biochemical studies indicate that members of the CAPS/Munc13 family of proteins operate in priming. Our proposed research will obtain a molecular of the mechanism of CAPS function in priming dense-core vesicle (DCV) exocytosis. This work is based on major advances during the previous project period, which discovered that CAPS promotes trans SNARE complex formation in vitro and interacts with each of the 3 SNARE proteins. Moreover, CAPS undergoes tetramer formation, which suggests a mechanism for catalyzing SNARE complex assembly. CAPS is present on the plasma membrane and on DCVs in a central location for controlling DCV exocytosis. We propose biochemical, cell biological and biophysical studies on the molecular events that mediate CAPS function in priming. Our specific aims will be to (1) determine whether the priming activity of CAPS is mediated through its interactions with VAMP-2, syntaxin-1 and SNAP-25; (2) determine whether CAPS promotes trans SNARE complex assembly in neuroendocrine cells; and (3) determine whether CAPS oligomerization and DCV binding play critical roles for CAPS function in priming. Highlights of the work include imaging of CAPS and SNAREs at sites of exocytosis, reconstituting priming by CAPS on artificial membranes, and structural studies of CAPS tetramers and its SNARE-binding domain. Completion of this work will provide a molecular of priming and fill an important gap in our understanding of the pathway for regulated vesicle exocytosis. Neurotransmitters, peptide hormones, and inflammatory mediators are secreted from neural, endocrine and mast cells by the regulated fusion of vesicles with the plasma membrane. We will study key proteins that are needed for this process. Because a variety of diseases involve excessive or inadequate secretion, this work will contribute basic knowledge about these conditions and set the stage for developing therapies

Keywords: Address; Artificial Membranes; base; Binding (Molecular Function); Binding Proteins; Biochemical; Biochemical Genetics; Biological; Calcium; Cell membrane; Cells; Competence; Complex; Dense Core Vesicle; Disease; Docking; Endocrine; Endocrine system; Event; Exocytosis; Family; Fluorescence Resonance Energy Transfer; Genetic; Homologous Protein; Image; In Vitro; Inflammation Mediators; insight; Knowledge; Lead; Link; Location; mast cell; Mediating; member; Membrane; Membrane Fusion; Molecular; monomer; Mutagenesis; mutant; Mutation; Nervous system structure; Neuroendocrine Cell; Neurons; Neuropeptides; Neurotransmitters; Pathway interactions; PC12 Cells; peptide hormone; Physiological; Play; Positioning Attribute; prevent; Process; Protein Family; Proteins; public health relevance; reconstitution; Regulation; relating to nervous system; Research; Role; S-nitro-N-acetylpenicillamine; Signaling Molecule; Site; SNAP receptor; Staging; Synaptic plasticity; Synaptic Vesicles; synaptotagmin; syntaxin; syntaxin 1; target SNARE proteins; therapy development; Total Internal Reflection Fluorescent; VAMP-2; Vesicle; vesicle-associated membrane protein; Work

Relevance: Neurotransmitters, peptide hormones, and inflammatory mediators are secreted from neural, endocrine and mast cells by the regulated fusion of vesicles with the plasma membrane. We will study key proteins that are needed for this process. Because a variety of diseases involve excessive or inadequate secretion, this work will contribute basic knowledge about these conditions and set the stage for developing therapies

Project start date: 1998-06-10

Project end date: 2016-03-31

Budget start date: 1-APR-2011

Budget end date: 31-MAR-2012

PFA/PA: PA-10-067

2R01DK040428-23 (2011): $312861

ADMINISTRATIVE CORE

F Thomas
Massachusetts General Hospitalcity: Boston country: United States (us)

Abstract: The objective of Core A, the Administrative Core, is to provide centralized scientific and administrative management, financial control services and clerical and materials management support to all Projects and Cores. The Administrative Core will provide necessary support for the organization and conduct of the Steering Committee Meetings, the annual meetings of the External Advisory Board, on-going administration of the overall grant and coordination with NCI and collaborating institutions

Keywords: Grant; Institution; meetings; Office of Administrative Management; Proton Radiation; Radiation therapy; Research Personnel; Services; symposium; Telephone; Therapeutic Studies

Budget start date: 1-AUG-2011

Budget end date: 31-JUL-2012

5P01CA021239-32_9003 (2011): $277097

PROGRAM 3 (IMMUNOLOGY AND CANCER)

F Thomas, Associate Professor
University Of Chicagocity: Chicago country: United States (us)

Abstract: The Immunology and Cancer Program (Program 3) has been an integral component of the UCCRC for more than 20 years. It has 19 members from 5 departments, and is supported by a total of $7,660,269 in peer-reviewed funding (annual direct costs), with $2,154,936 from the NCI. Over the past grant period, program members have produced a total of 387 peer-reviewed publications, including 11% that were intraprogrammatic and 15% that were interprogrammatic collaborations. It is well established that tumors can express antigens that can be recognized by specific T cells or antibodies. Established immunologic therapies in the clinic include allogeneic bone marrow or blood stem cell transplantation, the monoclonal antibodies Herceptin and Rituxan, and the cytokines IL-2 and IFN-cc. However, as fundamental knowledge of the immune system continues to increase at a rapid pace, the potential for improving upon existing immune-based therapies, as well as for developing new immunotherapeutic approaches, continues to expand. The overall goals of the Immunology and Cancer Program are to foster the best possible research that has relevance for the cancer setting, to support an environment that brings new immunology concepts into preclinical models of anti-tumor immunity, and to translate fundamental discoveries into clinical application. A major accomplishment of the Program is the expansion of the clinical/translational component. These goals are supported by severa key Core Facilities, in particular the Flow Cytometry, Fitch Monoclonal Antibody, Immunohistochemistry, and the Human Immunologic Monitoring Cores. The Immunology and Cancer Program also depends on the services of the cGMP Facility (a UCCRC developing core) for preparation of clinical-grade immunotherapeutic products for clinical administration. By incorporating detailed scientific endpoint monitoring into clinical studies, new key information is being generated that has led to the development of new hypotheses that can then be interrogated back in the basic laboratory. Thus, the Immunology and Cancer Program has evolved into a clear example of bi-directional translational research

Keywords: Address; Allogenic; Antibodies; antigen processing; Antigens; Autoimmunity; B-Lymphocytes; Back; base; bench to bedside; Blood; Bone Marrow; Cancer Center Support Grant; Cancer Immunology Science; Cancer Vaccine Related Development; Cancer Vaccines; Cells; Clinic; Clinical; clinical application; Clinical Research; Clinical Trials; Collaborations; Core Facility; Cross Presentation; Cyclic GMP; cytokine; Development; Direct Costs; Effector Cell; Environment; Failure (biologic function); Flow Cytometry; Fostering; fundamental research; Funding; Generations; Goals; Grant; Human; Immune; Immune response; Immune system; Immune Tolerance; Immunohistochemistry; Immunologic Monitoring; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; improved; in vivo; Inflammation; insight; Interferons; Interleukin-2; Investigation; Knowledge; Laboratories; Lymphocyte; Malignant Neoplasms; member; Memory; Monitor; Monoclonal Antibodies; mouse model; Mus; Natural Immunity; neoplastic cell; novel; Pathway interactions; Patients; Peer Review; Pre-Clinical Model; Preparation; Program Research Project Grants; programs; Publications; Regulation; Research; Research Activity; Research Personnel; response; Roche brand of rituximab; Roche brand of trastuzumab; Role; Secondary to; Services; Signal Transduction; Site; Stem cell transplant; success; System; T cell differentiation; T cell response; T-Lymphocyte; Therapeutic; trafficking; Translating; Translational Research; tumor; Tumor Antigens; Tumor Immunity; tumor immunology; United States National Institutes of Health; University of Chicago Cancer Research Center

Budget start date: 1-APR-2011

Budget end date: 31-MAR-2012

5P30CA014599-36_0004 (2011): $24797

F Thomas, Professor In Residence
University Of California San Franciscocity: San Francisco country: United States (us)

Grant 5R01AG028832-05 from National Institute On Aging

Abstract: The exponential increase in hip fracture incidence with age cannot be explained either by the age-related decrease in area! bone mineral density (aBMD) or by the increase of fall risk with age. Recent studies have outlined age-related changes in hip structure that appear to result in increased fragility but that may not be reflected in bone density measurements. We propose to examine the effect of aging on proximal femoral structure and strength and to relate these measures to hip fracture risk. To accomplish this end, we will carry out two studies using quantitative computed tomography (QCT) a longitudinal study to examine age-related changes in proximal femoral geometry and strength and a prospective study relating these properties to incident hip fracture. The analytical methods will include structural analysis of the hip from high resolution QCT scans and patient specific finite element modeling (FEM) to estimate hip strength in loading conditions simulating a single-legged stance and a fall to the side. Our longitudinal cohort will be a subset of 500 patients selected from the 5000 elderly subjects in the Age Gene/Environment -Reykjavik (AGES-R) study. In the prospective fracture study the AGES-R fracture registry will be employed to determine which of the subjects scanned at baseline have sustained fracture of the hip. The scans of these subjects will be analyzed along with a set of gender and age-matched controls. In this study, we expect to derive clinically relevant information regarding the effect regarding how the structural characteristics of the proximal femur and its strength change with age and how they contribute to fracture risk

Keywords: Accounting; Age; age effect; age related; aging gene; analytical method; Anthropometry; Area; Body Weight; bone; Bone Density; bone geometry; bone strength; Characteristics; Clinical; clinically relevant; cohort; Data; density; Development; Elderly; Elements; Environment; Evaluation; Failure (biologic function); fall risk; falls; Femur; Finite Element Analysis; Fracture; frailty; Gender; Height; Hip Fractures; Hip region structure; image registration; improved; Incidence; indexing; Lateral; Longitudinal Studies; Maps; Measurement; Measures; men; Modeling; Muscle; Neck; Non-linear Models; Patients; Performance; programs; Property; prospective; Prospective Studies; Registries; Research Personnel; Resolution; Risk; Scanning; Side; Simulate; Structure; Structure of greater trochanter of femur; Study models; System; Techniques; time interval; Trochanters; Visit; Woman; X-Ray Computed Tomography

Project start date: 2007-07-15

Project end date: 2012-04-30

Budget start date: 1-JUL-2011

Budget end date: 30-APR-2012

5R01AG028832-05 (2011): $347323

STAGES OF REGULATED EXOCYTOSIS

F Thomas
University Of Wisconsin Madisoncity: Madison country: United States (us)

Grant 5R01DK025861-32 from National Institute Of Diabetes And Digestive And Kidney Diseases

Abstract: Regulated vesicle exocytosis is a Ca2+dependent membrane fusion event of key physiological importance for integration of the nervous, endocrine and immune systems. Because of its central role and involvement in disease, it is important to identify the proteins and mechanisms that are utilized for Ca2+regulated vesicle exocytosis. In neural & endocrine cells, the SNARE proteins VAMP-2, Syntaxin-1 & SNAP-25 constitute the core fusion machinery. SNAREs execute fusion by forming trans complexes between docked vesicles and the plasma membrane. However, not all docked vesicles are fusion-competent and a priming step is needed to promote a fusion-ready state. The assembly of SNARE complexes is fundamental to priming but poorly understood. The principal goal of our proposed research is to elucidate vesicle priming reactions. To do so, we will determine the mechanism of proteins that catalyze priming. Genetic studies indicate that Munc-13 and CAPS, which have sequence homology in a MUN domain, mediate vesicle priming possibly in concert with Munc-18. We found that Munc-13 exhibits a novel interaction with Syntaxin by binding the SNARE motif- containing H3 domain, which is different from the previously-suggested N-terminal Syntaxin binding. Further studies of this interaction and its role will likely shift the current paradigm for a molecular model of priming. We will exploit our findings that purified Munc-13 proteins reconstitute priming in permeabilized cells, promote SNARE-dependent liposome fusion, and stimulate SNARE complex formation in vitro to elucidate a new mechanism for Munc-13 function. This mechanism will be critically evaluated in neural, neuroendocrine and mast cells. The specific aims for this project are 1) To fully characterize Munc-13-Syntaxin interactions and generate mutant proteins deficient in binding; 2.) To determine the mechanism by which Munc-13 promotes SNARE complex assembly in vitro; 3) To critically assess the functional role of the new Munc-13 mechanism for priming in PC12 neuroendocrine, hippocampal neuronal, and RBL-2H3 mast cells; and 4) To determine how multiple MUN domain proteins (Munc-13 & CAPS) contribute to priming in secretory cells. Completion of the proposed work will provide major new insight into vesicle priming, Munc-13 mechanisms, and the fusion machinery for regulated vesicle exocytosis. Neurotransmitters, peptide hormones, and inflammatory mediators are secreted from neural, endocrine and mast cells by the regulated fusion of vesicles with the plasma membrane. We will study key protein interactions that are needed to convert vesicles into a fusion-ready state. Because mutations in these proteins result in human disease (e.g., in immune system function), the work will contribute to understanding the underlying basis of these pathologies

Keywords: Amines; base; Binding (Molecular Function); Binding Sites; Biological Assay; Cell membrane; cell preparation; Cells; Complex; Dense Core Vesicle; Disease; Docking; Endocrine; Endocrine system; Event; Exhibits; Exocytosis; Fluorescence Resonance Energy Transfer; Genetic; Glutamates; Goals; Health; Hippocampus (Brain); human disease; Immune system; In Vitro; in vivo; Inflammation Mediators; insight; Lead; Length; Liposomes; mast cell; Mediating; Membrane; Membrane Fusion; Modeling; molecular modeling; Molecular Models; Mutagenesis; mutant; Mutation; N-terminal; Nervous system structure; Neuroendocrine Cell; Neurons; Neurosecretory Systems; neurotransmitter release; Neurotransmitters; novel; Pathology; Pathway interactions; peptide hormone; Peptide Signal Sequences; Physiological; Property; protein function; Proteins; Reaction; reconstitution; relating to nervous system; Research; Role; S-nitro-N-acetylpenicillamine; Secretory Cell; sensor; Sequence Homology; Site; SNAP receptor; Staging; Synaptic Vesicles; synaptotagmin; syntaxin; syntaxin 1; syntaxin 13; syntaxin binding protein 1; System; Tertiary Protein Structure; Testing; VAMP-2; Vesicle; Work

Relevance: Neurotransmitters, peptide hormones, and inflammatory mediators are secreted from neural, endocrine and mast cells by the regulated fusion of vesicles with the plasma membrane. We will study key protein interactions that are needed to convert vesicles into a fusion-ready state. Because mutations in these proteins result in human disease (e.g., in immune system function), the work will contribute to understanding the underlying basis of these pathologies

Project start date: 1979-07-01

Project end date: 2014-03-31

Budget start date: 1-APR-2011

Budget end date: 31-MAR-2012

PFA/PA: PA-07-070

5R01DK025861-32 (2011): $407702

COUNTERING IMMUNE RESISTANCE IN THE MELANOMA TUMOR MICROENVIRONMENT

F Thomas, Associate Professor
University Of Chicagocity: Chicago country: United States (us)

Grant 5R01CA127475-05 from National Cancer Institute

Abstract: Recent observations have indicated that features of the melanoma tumor microenvironment likely determine whether tumor regression versus resistance occurs in response to a successfully generated anti-tumor T cell response. Our preliminary gene expression profiling data on the melanoma tumor microenvironment from patients with advanced disease have suggested two categories of downstream defects failure to recruit activated T cells into metastatic sites, and presence of immunosuppressive mechanisms in the microenvironment of tumors that have indeed recruited T cells. T cell trafficking has been associated with expression of specific chemokines within tumor sites. Identified immune resistance mechanisms include expression of the inhibitory ligand PD-L1 on the tumor cells themselves, the presence of FoxP3+ regulatory T cells, the tryptophan-catabolizing enzyme IDO expressed by dendritic-like cells and endothelial cells, and the anergy-promoting conditions of having poor B7 expression by APC populations. An additional observation has linked high levels of Notch signaling in melanoma tumors with resistance to immunotherapy and poor T cell recruitement, thus offering a potential link between tumor cell biology and establishment of features of the surrounding microenvironment. These observations have crystalized into the following Specific Aims 1. To examine the relative contribution of PD-1, regulatory T cells, IDO, and anergy in limiting immune-mediated tumor regression in a mouse preclinical model 2. To identify cell types producing specific chemokines in the tumor microenvironment and determine the role of selected chemokines in T cell recruitment; and 3. To investigate the role of Notch signaling in melanoma tumor cells in establishing the tumor microenvironment and mediating resistance to T cell-mediated killing. The ultimate goal of this work is to develop strategies to facilitate the effector phase of the anti-tumor immune response by overcoming limitations within the melanoma tumor microenvironment, thus identifying approaches with potential for future clinical application

Keywords: A Mouse; Adoptive Transfer; advanced disease; anergy; Apoptotic; base; biological signal transduction; cancer metastasis; cancer progression; Categories; Cell Communication and Signaling; Cell Signaling; cell type; Cells; chemoattractant cytokine; chemokine; Chemokine (C-C motif) Ligand 3; Clinical; clinical applicability; clinical application; Closure by Ligation; Cytokines, Chemotactic; Data; Defect; Disease Progression; Endothelial Cells; Environment; Enzymes; failure; Failure (biologic function); Favorable Clinical Outcome; FLR; Future; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; Genes; Goals; Homologous Chemotactic Cytokines; host response; Human; Human, General; Immune; immune resistance; Immune response; immune therapy; Immunologically Directed Therapy; immunoresponse; Immunosuppressants; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); immunosuppressive; Immunosuppressive Agents; Immunosuppressive Effect; Immunotherapy; In Vitro; in vivo; Injection of therapeutic agent; Injections; Intercrines; Intracellular Communication and Signaling; ITX; Killings; L-Tryptophan; Levotryptophan; Ligands; Ligation; Light; Link; Malignant Melanoma; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; melanoma; Melanoma Cell; Melanoma Vaccine; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Mice; MIP 1alpha; MIP-1 Alpha; MIP-1a; Modeling; Murine; Mus; Natural immunosuppression; Neoplasm Metastasis; neoplasm progression; neoplastic cell; neoplastic progression; notch; notch protein; notch receptors; Outcome; Patients; Pattern; Phase; Phenotype; Photoradiation; Play; Population; Pre-Clinical Model; Preclinical Models; prevent; preventing; Profilings, Gene Expression; Progressive Disease; recruit; Recruitment Activity; Regulatory T-Lymphocyte; Relative; Relative (related person); Resistance; resistance mechanism; resistant; resistant mechanism; response; Role; Secondary Neoplasm; Secondary Tumor; Series; Signal Transduction; Signal Transduction Systems; Signaling; SIS cytokines; Site; Small Inducible Cytokine A3; social role; Stem Cell Inhibitor; System; System, LOINC Axis 4; T cell response; T-Cell Subsets; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; trafficking; Transcript; Transcript Expression Analyses; Transcript Expression Analysis; Tryptophan; tumor; Tumor Cell; Tumor Cell Biology; Tumor Cell Migration; Tumor Immunity; tumor progression; Vaccine Clinical Trial; Work; Xenograft Model

Project start date: 2007-04-01

Project end date: 2012-01-31

Budget start date: 1-FEB-2011

Budget end date: 31-JAN-2012

5R01CA127475-05 (2011): $262485

IMPROVING THE THERAPEUTIC RATIO OF PROTON RADIATION THERAPY

F Thomas
Massachusetts General Hospitalcity: Boston country: United States (us)

Abstract: Protons have a physical dose advantage over photons (x-rays), the most commonly used type of radiation therapy for cancer patients, because they do not exit beyond the tumor target and thus irradiate less normal tissue. Irradiation of normal tissue yields no possible benefit for the patient; it can only increase the risk of treatment related side effects during and long after the end of treatment. While proton radiation therapy has been used in selective clinical sites with significant improvements in clinical outcome, we believe that research into better control of the finite range of the proton in the patient can yield additional clinical gains. The major objective of this project, Improving the Therapeutic Ratio of Proton Radiation Therapy in Challenging Clinical Sites, is to perform clinical trials employing improved control of the proton range in challenging clinical scenarios. We believe that these research advances should translate into further improvement in outcome in not only these particular diseases, but at multiple other anatomic sites where proton radiation therapy is increasingly being employed. The potential impact for public health is higher cancer cure rates and/or reduced treatment side effects, particularly in children, who are at the highest risk of late radiation therapy-induced side effects, which can be reduced with the use of protons. The specific aims are to conduct phase II clinical studies in patients with unresectable liver tumors, pediatric medulloblastoma and rhabdomyosarcoma, spine and skull base sarcomas, and paranasal sinus tumors in which we will (1) use the end of range of the proton more effectively, (2) investigate the clinical use of magnetically scanned proton beams and intensity-modulated proton therapy, (3) confirm the tolerability and effectiveness of hypofractionated radiation dose escalation for unresectable liver tumors, (4) critically assess the importance of an adaptive proton radiation therapy strategy in response to tumor and normal tissue responses to radiation therapy in one anatomic site, and (5) compare treatment-related morbidity with photons and protons in these selected pediatric malignancies and in adult paranasal sinus tumors. The physical tools necessary to achieve these clinical goals will be investigated in Projects 3 and 4. The initial use of many of these physical tools in Project 2 will be important for their later use in Project 1, Proton Dose Escalation and Proton vs. Photon Randomized Trials for Non-Small Cell Lung Cancer

Keywords: Adult; Adverse effects; Anatomic Sites; Anesthesia procedures; BAY 54-9085; Cancer Patient; chemotherapy; Child; Childhood; Childhood Medulloblastomas; Childhood Rhabdomyosarcoma; Clinical; Clinical Research; clinical research site; Clinical Trials; cohort; Complex; Correlative Study; Devices; Disease; Dose; Effectiveness; Goals; Hepatic; high risk; improved; Investigation; irradiation; Length; Liver neoplasms; Malignant Neoplasms; medulloblastoma; Morbidity - disease rate; Neutrons; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Outcome; Paranasal Sinus Neoplasms; Patients; Phase; phase 2 study; Photons; Physics; Positioning Attribute; prospective; Protocols documentation; proton beam; Proton Radiation; Protons; public health medicine (field); Quality-of-Life Assessment; Radiation; Radiation therapy; randomized trial; Relative (related person); Research; response; Rhabdomyosarcoma; Risk; sarcoma; Scanning; Sinus; skull base; Testing; Therapeutic; Therapeutic Studies; tool; Toxic effect; Translating; treatment planning; tumor; Tumor Tissue; Unresectable; Vertebral column; X-Ray Computed Tomography

Budget start date: 1-AUG-2011

Budget end date: 31-JUL-2012

5P01CA021239-32_0008 (2011): $579305

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MEASURING HUMAN EXPOSURE TO PBDES

F Thomas, Associate Professor
Boston University Medical Campuscity: Boston country: United States (us)

Grant 5R01ES015829-04 from National Institute Of Environmental Health Sciences

Abstract: Polybrominated diphenyl ethers (PBDEs) are commonly used as fire retardants in consumer products such as electronics and furniture containing polyurethane foam. Structurally similar to polychlorinated biphenyls (PCBs), several PBDE congeners perturb hormonal signaling and are toxic to the nervous and reproductive systems of developing animals. Human body burdens have increased over the last several decades and are highest in the United States (US), where levels are more than an order of magnitude higher than in Asian and European populations in which PBDE levels are associated with decreased birth outcomes and increased risk of cryptorchidism. Diet and the indoor environment (dust, air) are likely important factors that contribute to personal exposure, but the predominant route of exposure is not known. Indeed, in a 2006 report on PBDEs, the US Environmental Protection Agency identified the "need for improved understanding of exposure to these chemicals and the associated hazards." We propose a comprehensive approach to examining human exposure to PBDEs. The proposed study has been designed to address a range of important gaps that exist in the PBDE research base and would represent the most complete assessment of human PBDE exposure to date. In a cohort of fifty Massachusetts residents, we will conduct three rounds of exposure sampling (at six month intervals) and examine three microenvironments the home, workplace, and car. During each sampling round, we will concurrently assess PBDEs at multiple steps of the exposure-response continuum by (a) estimating the PBDE content of consumer products (potential sources) using a portable x-ray fluorescence analyzer, (b) measuring PBDEs in dust collected from the home, workplace and car (key microenvironments), (c) measuring PBDEs in personal air and hand-wipe samples (personal exposure), (d) measuring PBDEs in human serum (total absorbed dose), and (e) measuring hormone levels (potential early effects). This powerful study design will generate a rich dataset of repeated exposure measures and allow for a longitudinal assessment of PBDE body burden and hormone levels. Accordingly, the proposed research will provide a more complete understanding of how PBDEs enter the indoor environment, how the general population is exposed to PBDEs, which exposure routes contribute most to total absorbed dose, and the extent to which PBDE exposure may be associated with changes in hormone levels in humans. The levels of polybrominated diphenyl ethers (PBDEs) found in the bodies of Americans have increased for decades and are an order of magnitude higher than in other countries where a few studies have found associations with adverse health outcomes. Although the indoor environment is hypothesized to be the major source of these flame retardants, the sources and routes of human exposure are not well understood. The proposed project will provide a more complete understanding of how PBDEs enter the indoor environment, how people are exposed, and the extent to which they may be associated with human hormones levels

Keywords: Address; Adult; Age; Air; air sampling; American; Animals; Area; Asians; base; Birth; Blood; Blood specimen; Body Burden; Boston; Breathing; Bromine; Carpet; Chemicals; Child; cohort; consumer product; Country; Cryptorchidism; Data; Data Set; design; Diet; Dose; Dust; Electronics; Environment; European; exposed human population; Exposure to; Flame Retardants; Fluorescence; Furniture; General Population; Hand; hazard; Health; Home environment; Hormonal; Hormones; Household; Human; Human body; improved; Massachusetts; Measurement; Measures; metropolitan; Modeling; Nervous system structure; Outcome; Participant; Pattern; phenyl ether; physical model; Polychlorinated Biphenyls; polyurethane foam; Population; Questionnaires; Recruitment Activity; Relative (related person); Reporting; Reproductive system; Research; Research Design; response; Risk; Roentgen Rays; Route; Sampling; Serum; Signal Transduction; Source; Statistical Models; Time; United States; United States Environmental Protection Agency; Variant; Venous blood sampling; Workplace

Project start date: 2008-07-09

Project end date: 2012-05-31

Budget start date: 1-JUN-2011

Budget end date: 31-MAY-2012

PFA/PA: PA-07-070

5R01ES015829-04 (2011): $384163

DELIVERY OF NANOENCAPSULATED TGFBETA AND ATRA FOR THE TREATMENT OF IBD

F Thomas, Senior Research Scientist
Therapyx, Inc.city: Buffalo country: United States (us)

Grant 2R44AI080009-02A1 from National Institute Of Allergy And Infectious Diseases

Abstract: Phase I studies established proof-of-principle for the efficacy of oral sustained-release TGF?1 (TPX-6001) and ATRA (TPX-7001) nanoparticles in the treatment of IBD in a murine adoptive T-cell transfer model. Specifically, a two-week regimen of oral TPX-6001 and TPX-7001 achieved a 50-90 % reduction in the severity of multiple disease indicators in mice with advanced IBD. Importantly, co-administration of ATRA with TGF?1 was essential to achieving maximal therapeutic efficacy and disease amelioration was associated with enhanced T-regulatory cell activity in the colon. Phase II work is designed to further optimize therapy protocol in the pre-clinical murine IBD model, establish scale-up manufacturing process and complete toxicology studies leading up to IND filing. In Aim 1, pre-clinical optimization work is completed. To this end, combination TGF?1 and ATRA dosages are optimized first. This combination is then used to identify the optimal therapeutic regimen, determine the ability of treatment to maintain disease remission in the long-term and monitor side-effects. In Aim 2, scale-up process parameters are established to achieve bulk drug production. Batch-to-batch uniformity and shelf-life are determined for the scaled-up product. Aim 3 studies are designed to complete toxicokinetics in 2 mammalian species. These studies are performed in collaboration with the Navigators Toxicology Group at Charles River Laboratories. The data obtained in Aims 1-3 are then utilized in the preparation of an Investigational New Drug (IND) application to the FDA (Aim 4). Successful completion of Phase II studies will facilitate the advancement of TPX-6001/7001 to a Phase I clinical trial in IBD patients. Current therapies for inflammatory bowel diseases (IBD) such as Crohn´s disease and ulcerative colitis fail a considerable percentage of patients due to ineffectiveness or therapy limiting side effects. TherapyX, Inc. is developing a more advanced drug delivery system that targets Transforming Growth Factor ?-1 and Retinoic Acid to the site of inflammation in the gut thereby reducing systemic side effects. This therapy has the potential to significantly improve morbidity and quality of life of those suffering with IBD

Keywords: Adverse effects; base; Biological Assay; CD4 Positive T Lymphocytes; Clinical Trials; Collaborations; Colon; Crohn`s disease; Data; design; Disease; Disease model; Disease remission; dosage; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; drug production; Effectiveness; Effector Cell; Future; improved; Individual; Inflammation; Inflammatory Bowel Diseases; Investigational Drugs; Investigational New Drug Application; Laboratories; Lamina Propria; Life; Macaca fascicularis; manufacturing process; Mesentery; Modeling; Monitor; Morbidity - disease rate; Mus; Myelogenous; nanoparticle; Oral; particle; Patients; Phase; phase 1 study; phase 2 study; Phase I Clinical Trials; Population; pre-clinical; pre-clinical therapy; Preparation; Process; Protocols documentation; public health relevance; Quality of life; Regimen; Regulatory T-Lymphocyte; Research Design; Rivers; scale up; Serum; Severities; Site; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Toxicokinetics; Toxicology; Transforming Growth Factor beta; Transforming Growth Factors; Treatment Efficacy; Treatment Protocols; Tretinoin; Ulcerative Colitis; Work

Relevance: Current therapies for inflammatory bowel diseases (IBD) such as Crohn´s disease and ulcerative colitis fail a considerable percentage of patients due to ineffectiveness or therapy limiting side effects. TherapyX, Inc. is developing a more advanced drug delivery system that targets Transforming Growth Factor -1 and Retinoic Acid to the site of inflammation in the gut thereby reducing systemic side effects. This therapy has the potential to significantly improve morbidity and quality of life of those suffering with IBD

Project start date: 2008-07-20

Project end date: 2014-03-31

Budget start date: 1-APR-2011

Budget end date: 31-MAR-2012

PFA/PA: PA-10-050

2R44AI080009-02A1 (2011): $999998

THE MICROCIRCULATION IN CLAUDICATION AND EXERCISE REHABILITATION

F Thomas
University Of Pennsylvaniacity: Philadelphia country: United States (us)

Grant 2R01HL075649-06A2 from National Heart, Lung, And Blood Institute

Abstract: Peripheral arterial disease (PAD) is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. PAD is largely thought to be a macrovascular disease manifested by atherosclerosis. The contribution of microvascular dysfunction in the end-organ, muscle, to the incidence of symptoms and progression of PAD is uncertain. Similar to vascular disease in the coronary arteries, it is likely that a combination of macrovascular and microvascular dysfunction is involved in the pathophysiology of PAD progression. A more thorough understanding of the pathophysiology of PAD progression and symptom origin is required to provide the basis for new methods of evaluation and novel therapeutic strategies. Aims Aim-1)To determine in a group of patients with moderate PAD, the relationship between claudication limited exercise tolerance (Peak Walking Time-PWT) and microvascular blood flow. Aim-2)To determine if changes in PWT with exercise rehabilitation correlate with changes in microvascular blood flow. Aim-3) To determine if the vascular health profile, as measured with circulating Endothelial Progenitor Cells (EPCs) and endothelially-derived microparticles (MPs), biomarkers of endothelial health, improves following exercise rehabilitation and correlate with microvascular blood flow. Design & Methods Subjects with moderate PAD will undergo measurement of treadmill PWT. Continuous Arterial Spin Labeling-Perfusion MRI will be used to measure skeletal muscle calf microvascular blood flow and flow cytometry will be used to characterize the endothelial vascular health profile described above. We anticipate that a supervised exercise rehabilitation program will improve PWT, microvascular blood flow, and the endothelial vascular health profile. Peripheral arterial disease is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. Early disability derives from claudication or ischemic muscle pain, inhibiting ambulation. The pathophysiology of this disorder is thought to be of macrovascular origin, however the contribution of the microvasculatrue to this disorder is not well understood and may be important. Improved knowledge of the contribution of the microvasculature to this disorder, and improvement in our ability to monitor, via relatively nonivasive imaging and circulating cellular biomarker assays, the impact of rehabilitation or other therpaeutic interventions, may assist in the treatment of this disorder

Keywords: Affect; American; angiogenesis; Ankle; Atherosclerosis; atherothrombosis; Award; base; Biological Assay; biomarker; Blood; Blood flow; Blood Vessels; Cell membrane; Cells; claudication; Coronary artery; design; disability; Disease; Disease Progression; Endothelial Cells; Enrollment; Evaluation; Exercise; Exercise Tolerance; Flow Cytometry; Functional disorder; Gastrocnemius muscle structure; Goals; Grant; Health; Image; Impairment; improved; Incidence; indexing; Intervention; Ischemia; Knowledge; macrovascular disease; Magnetic Resonance; Magnetic Resonance Imaging; Marrow; Measurement; Measures; Methods; Microcirculation; Monitor; Muscle; Myalgia; novel; novel therapeutics; Organ; Patients; Perfusion; Peripheral arterial disease; Persons; Play; programs; Protocols documentation; public health relevance; Quality of life; Recruitment Activity; Rehabilitation therapy; response; Role; Secondary to; Severities; Skeletal muscle structure; Spin Labels; Stem cells; Symptoms; Techniques; Testing; Time; time use; United States; United States National Institutes of Health; Vascular Diseases; Vesicle; Walking

Relevance: Relevance: Peripheral arterial disease is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. Early disability derives from claudication or ischemic muscle pain, inhibiting ambulation. The pathophysiology of this disorder is thought to be of macrovascular origin, however the contribution of the microvasculatrue to this disorder is not well understood and may be important. Improved knowledge of the contribution of the microvasculature to this disorder, and improvement in our ability to monitor, via relatively nonivasive imaging and circulating cellular biomarker assays, the impact of rehabilitation or other therpaeutic interventions, may assist in the treatment of this disorder

Project start date: 2003-09-22

Project end date: 2014-11-30

Budget start date: 1-APR-2011

Budget end date: 30-NOV-2011

PFA/PA: PA-10-067

2R01HL075649-06A2 (2011): $791531

THE PROXIMAL FEMORAL MUSCULATURE: A NEW RISK FACTOR FOR HIP FRACTURE

F Thomas, Professor In Residence
University Of California San Franciscocity: San Francisco country: United States (us)

Grant 5R01AG029571-04 from National Institute On Aging

Abstract: Osteoporotic fracture has a complex etiology involving skeletal fragility, risk of falling, and impaired reaction to a fall once it is initiated. Currently, quantitative bone assessments such as dual x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) act as surrogates for skeletal strength but are of limited value as surrogates of fracture risk because they do not provide information on non-skeletal risk factors such as falls. Studies have shown that fall risk is associated with reduced muscle strength, particularly of the proximal femoral musculature. The QCT image of the hip provides information on the size and composition of the proximal femoral muscles, and studies at various skeletal sites have shown correlations between muscle strength and muscle size and attenuation measured by x-ray CT. In our laboratory, we have recently shown that combination of muscle size and attenuation data with the CT skeletal measures markedly improves the discriminatory power of the CT measurement. Here, we propose to develop computer algorithms to assess muscle size and attenuation from QCT hip images, prospectively validate that these measures improve fracture prediction when used in combination with hip QCT bone variables, and determine the mechanism by which they predict fracture. The study cohort will be selected from 5000 elderly individuals who have had baseline QCT examinations in the prospective Age Gene/Environment -Reykjavik (AGES-R) study and who are now being followed for incident fractures of the hip and other skeletal sites. The ultimate goal of this research program is to develop a quantitative assessment of an important non-skeletal risk factor that can be combined with QCT bone measurements, thus significantly improving diagnostic efficacy without the cost of an additional procedure. PUBLIC HEALTH RELEVENCE Development of a muscle quantification procedure based on clinically available hip QCT skeletal imaging is an important pathway to improving estimation of hip fracture risk. It would potentially modify management of patients at risk for hip fractures by providing an additional non-skeletal measure reflective of fall risk. This quantitative measurement is modifiable and could become a treatment endpoint for specific exercise or drug therapies

Keywords: Accounting; Age; age group; age related; aging gene; Algorithms; Area; attenuation; base; bone; Bone Density; bone imaging; Clinical; cohort; Cohort Studies; Complex; Computational algorithm; cost; Data; Development; Diagnostic; disability; Elderly; Environment; Etiology; fall risk; falls; Fatty acid glycerol esters; Feasibility Studies; Fracture; frailty; functional decline; Gender; Goals; Health; Height; Hip Fractures; Hip region structure; Image; improved; Individual; interest; Intramuscular; Isometric Exercise; Laboratories; Leg; Lower Extremity; Measurement; Measures; Mediating; meter; Methods; Muscle; muscle strength; osteoporosis with pathological fracture; Pathway interactions; Patients; Performance; Pharmacotherapy; Physical Function; Physical therapy exercises; Procedures; programs; prospective; Reaction; Registries; Research; Risk; Risk Factors; Scanning; Site; skeletal; software development; subcutaneous; technology development; Testing; Thigh structure; Time; Visit; Walking; Weight; X-Ray Computed Tomography

Project start date: 2008-09-01

Project end date: 2012-05-31

Budget start date: 1-JUL-2011

Budget end date: 31-MAY-2012

PFA/PA: PA-07-070

5R01AG029571-04 (2011): $246969

INNATE FACTORS IN TUMOR ANTIGEN CROSS-PRESENTATION

F Thomas, Associate Professor
University Of Chicagocity: Chicago country: United States (us)

Abstract: Observations made studying anti-tumor immune responses in patients with metastatic melanoma have reshaped critical questions to be addressed mechanistically in preclinical models. In many melanoma patients, and in several animal studies, the rate limiting step in the anti-tumor immune response appear to be at the level of immune resistance at the effector phase in the tumor microenvironment. In the previous funding period we have made significant advances in understanding these mechanisms of resistance and how to overcome them. However, this new perspective on anti-tumor immunity has generated a critical new question if tumor antigen-specific T cells frequently can be productively activated without any external intervention, then which innate immune factors are facilitating proper T cell differentiation, in the absence of an obvious infectious pathogen? In theory this should occur only with difficulty, as there are no exogenous TLR ligands to costimulate antigen-presenting cell (ARC) populations in the context of a growing tumor. Our preliminary data have indicated a role for host type I interferons (IFNs) and also IL-1 in this innate immune "awareness" that leads to productive tumor antigen cross-presentation to CD8+ T cells in vivo. In the first specific aim of this proposal, we will identify and characterize the ARC populations mediating apontaneous cross-priming of tumor antigen-specific CD8+ T cells in vivo. The rationale is that we need to understand what occurs normally in order to determine where the blocks are in this process in specific mutant mice. In the second specific aim, we will determine the mechanism by which host type I IFNs facilitate tumor antigen cross-presentation in vivo. In the third specific aim, we will elucidate the role of host IL-1 and its relationship to type I IFNs in productive cross-priming in vivo. These studies will take advantage of several unique reagents and model systems, including a TCR tetramer to recognize peptide/class complexes, conditional IFN-a/bR knockout mice, and a genetic tumor model encoding a model tumor antigen. Understanding the factors and processes that mediate successful T cell priming to tumor antigens when it does occur should point toward new strategies to induce better cross-priming when it does not occur spontaneously

Keywords: Address; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attention; Awareness; Back; Biological Assay; Biological Models; Bone Marrow; Categories; CD8B1 gene; Cell physiology; Cells; Chimera organism; Complex; Cross Presentation; Cross-Priming; Data; Development; Funding; Gene Expression Profiling; Gene Targeting; Genetic; Immune; immune resistance; Immune response; in vivo; interest; Interferon Type I; Interferons; Interleukin-1; Intervention; Knockout Mice; Ligands; lymph nodes; Mediating; melanoma; Metastatic Melanoma; Methods; Modeling; Monitor; Mus; Mutant Strains Mice; Natural Immunity; novel; pathogen; Patients; Peptide/MHC Complex; Peptides; Phase; Population; Pre-Clinical Model; Process; Reagent; resistance mechanism; response; Role; Signal Transduction; T cell differentiation; T-Lymphocyte; theories; Time; trafficking; tumor; Tumor Antigens; Tumor Immunity; type I interferon receptor; Work

Budget start date: 1-JUN-2011

Budget end date: 31-MAY-2012

5P01CA097296-09_0005 (2011): $283941

PROTON RADIATION THERAPY RESEARCH

F Thomas
Massachusetts General Hospitalcity: Boston country: United States (us)

Grant 5P01CA021239-32 from National Cancer Institute

Abstract: Objectives and Specific Aims The goal of cancer treatment is cure without morbidity. Radiation can be an effective locoregional cancer treatment. While any tumor can be killed with enough radiation, any normal tissue can also be injured with sufficient dose to a given volume. The challenge is to deliver the appropriate dose to only those tissues containing tumor. Protons, with no exit dose beyond the target, irradiate less normal tissue than comparable photon (X-ray) fields. This can improve the therapeutic ratio of cure probability to complication risk. While many patients have been treated with protons with impressive clinical results in a number of disease sites, we believe that research can enable and enhance the use of protons in other disease sites. The objective of this multi-institutional program project is to apply advanced proton radiation planning and delivery techniques to improve outcome for patients with non-small cell lung cancer, liver tumors, pediatric medulloblastoma and rhabdomyosarcoma, spine/skull base sarcomas, and paranasal sinus malignancies. We hypothesize that through better use and understanding of the proton range in tissue, and study and management of motion and anatomic changes in the tumor and normal tissues, we can deliver higher precision proton therapy to further improve target coverage and/or reduce dose to nearby critical structures. To test this hypothesis, we propose four integrated projects (1) Proton Dose Escalation and Proton vs. Photon Randomized Trials for the Treatment of Nonsmall Cell Lung Cancer, (2)lmproving the Therapeutic Ration of Proton Radiation Therapy in Challenging Clinical Sites, (3) Reducing Range Uncertainties in Proton Radiation Therapy, (4) Achieving What-You-See-ls-What-You-Get in Proton Radiation Therapy. The proton physical interactions sufficient to allow smallerspecific aims are to (1) develop an understanding of safety margins as well as more robust and conformal dose distributions, allowing protons to more nearly meet their full potential, and to verify that these advantages can be reliably achieved; (2) use these advantages in randomized clinical trials of protons vs. photons in lung cancer; and (3) to use these advantages in the proton therapy of a number of tumor sites for which protons are judged to have an increasingly important role and which have proven problematic for clinicians in the past

Relevance: Relevance to Public Health This research aims to improve cancer treatment for patients undergoing radiation therapy by improving our ability to direct the radiation at the tumor and spare adjacent normal tissue by using protons

Project start date: 1997-04-01

Project end date: 2014-07-31

Budget start date: 21-SEP-2011

Budget end date: 31-JUL-2012

5P01CA021239-32 (2011): $316215

NEUROTOXINS FROM MARINE ALGAE AND CYANOBACTERIA

F Thomas, Professor
University Of California San Diegocity: La Jolla country: United States (us)

Grant 3R01NS053398-10A1S1 from Office Of The Director, National Institutes Of Health

Project start date: 2001-07-01

Project end date: 2016-06-30

Budget start date: 1-JUL-2011

Budget end date: 30-JUN-2012

PFA/PA: PA-10-067

3R01NS053398-10A1S1 (2011): $237875

COMPONENT VI: TRANSLATIONAL DISSEMINATION AND EDUCATIONAL ACTIVITIES RELATED TO A

F Thomas, Professor
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)

Abstract: Component VI - Translational, Dissemination and Educational Activities Related to Alcohol Research This component describes a program of translational, dissemination and educational activities that are integrated with the Center´s theme, investigators, and research programs. We propose to consolidate and expand activities initiated within the UCONN ARC in past years to provide greater service to the research community, clinical practitioners, and health service administrators at the state and national levels. The following activities will be conducted over a five-year period 1) Further development of research integrity and professional development activities. In collaboration with the International Society of Addiction Journal Editors; (ISAJE), we will develop an on-line tutorial based on the book, Publishing Addiction Science (Babor et al., 2004). This will build on an existing foundation and will provide a distance learning capacity to teach graduate students, postdoctoral fellows and junior faculty the essential elements of publication practices and publication ethics. 2) Dissemination of alcohol screening and brief intervention technologies at the state and national levels. These activities will be conducted in collaboration with the State of Connecticut and the federal Center for Substance Abuse Treatment, and will include the development of a continuing education workshop, consultation with state agencies, and collaboration with key experts to coordinate dissemination activities through training workshops and strategic planning programs. There has been growing attention to brief interventions, but their dissemination and continued development in practice requires ongoing work. 3) Organizing a consensus conference on the ethical challenges of conducting research on the genetics of alcoholism and disseminating findings to the alcohol research community. The training and dissemination activities described in this component have the potential to facilitate the translation of research into practice and to improve ethical awareness and publication capabilities in the alcohol research community

Keywords: addiction; Administrator; Alcohol dependence; alcohol research; alcohol screening and brief intervention; Alcohols; ARHGEF5 gene; Attention; Awareness; base; Books; brief intervention; Clinical; Collaborations; Communities; Connecticut; Consensus; Consultations; Continuing Education; design; Development; Distance Learning; Educational Activities; Educational process of instructing; Educational workshop; Elements; Ethics; Etiology; Faculty; Foundations; genetics of alcoholism; graduate student; Grant; Health Professional; Health Services; Healthcare; improved; International; Journals; Policies; Postdoctoral Fellow; programs; Publications; Publishing; Research; research and development; Research Personnel; research to practice; Science; Services; Societies; Strategic Planning; Students; Substance Abuse Treatment Centers; symposium; Technology; Training; Translating; Translational Research; Work

Budget start date: 1-DEC-2010

Budget end date: 30-NOV-2011

5P60AA003510-34_0005 (2011): $158322

REGULATORY B10 CELLS IN AUTOIMMUNE ARTHRITIS

F Thomas, Professor
Duke Universitycity: Durham country: United States (us)

Abstract: B lymphocytes are central mediators of humoral immunity. Aberrant B cell function also contributes to multiple autoimmune diseases, including rheumatoid arthritis (RA). In addition, we and others have recently found that B cells also serve critical negative regulatory functions during adaptive CD4+ T cell responses that can dampen both cellular and humoral immune responses, and the development of autoimmunity. This unexpected observation is explained in part by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity in mice. This regulatory B cell subset is uniquely CD1d+CD5+, produces IL-10. and represents 1-2% of total spleen B cells in wild type mice and <1% of circulating human B cells. We call this subset B10 cells to emphasize that they are the predominant, if not exclusive, B cell population that produces IL-10 and to distinguish them from other regulatory subsets that may also exist. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. In this proposal, we hypothesize that antigen-specific regulatory B10 cells influence autoimmune disease in both mice and humans. We will test this hypothesis and examine B10 cell generation, function, and mechanisms of action using the mouse collagen-induced arthritis (CIA) model of RA and B cells from patients with RA. In four specific aims, the proposed studies will identify the extent that the B10 subset modulates immune responses during autoimmunity, determine whether B10 cells can be manipulated for therapeutic benefit, and identify and characterize this unique B cell subset in normal humans and patients with autoimmunity. Specific Aim 1 will identify and characterize the B10 cell subset before, during and after CIA induction; Specific Aim 2 will characterize B10 cell function during CIA; Specific Aim 3 will develop an in vivo preclinical mouse model for B10 cell adoptive therapy; and Specific Aim 4 will identify and characterize the B10 subset during human autoimmune disease. These overlapping studies will significantly expand our knowledge of how B10 cells regulate both normal and abnormal immune responses in both species

Keywords: Adoptive Transfer; Affect; Age; Antibodies; Antibody Affinity; Antigen Receptors; Antigens; Attenuated; autoimmune arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; autoreactive B cell; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Beta Cell; Blood; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cell surface; Cell Survival; Cells; Chronic; Colitis; Collagen Arthritis; Contact hypersensitivity; cytokine; DBA/1 Mouse; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Generations; Goals; Human; Humoral Immunities; Immune response; In Vitro; in vitro Assay; in vivo; Inbred NOD Mice; Individual; Inflammation; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Knowledge; Lymphoid Tissue; Mediator of activation protein; Methods; migration; Modeling; mouse model; Mus; Pathogenesis; Patients; Phenotype; Population; pre-clinical; Pre-Clinical Model; Production; Property; Regulation; Research Proposals; Resolution; response; Rheumatoid Arthritis; rituximab; Role; Specificity; Spleen; Stimulus; Symptoms; Syndrome; Systemic Lupus Erythematosus; T cell response; T-Cell Activation; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Tissues; Wild Type Mouse

Budget start date: 1-MAY-2011

Budget end date: 30-APR-2012

5U19AI056363-08_7521 (2011): $776250

REGULATORY B CELL INHIBITION OF IMMUNE RESPONSES TO PATHOGENS

F Thomas, Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)

Abstract: B cells are the central source of long-term humoral immune responses to viral pathogens, but also serve critical regulatory functions during adaptive CD4+ T cell responses. It is unknown whether B cells contribute significantly to viral immune responses beyond antibody production or whether their manipulation can hasten or enhance immune responses. Important for emerging infections and biodefense, we have recently shown that B cells are essential for optimal CD4+ T cell priming during bacteria challenge. By contrast, monoclonal antibody (mAb)-induced B cell depletion augments Th1-type cellular immune responses in other models. This unexpected observation is explained by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity. We have labeled this phenotypically unique B cell subset that also secretes IL-10 as "B10" cells, which represent ~1% of total spleen B cells in young mice, and <1% of circulating human B cells. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. Thus, humoral and CD4+ T cell immune responses are balanced by both positive and negative B cell regulation. We have also identified a critical signaling pathway that is required For B10 cell survival in vivo. MAbs that inhibit this B cell-restricted survival signal induce rapid and semiselective B10 cell depletion in vivo, which has an adjuvant-like effect that enhances humoral antibody responses to T cell-dependent model antigens and Thl-type CD4+ T cell immune responses. Thus, B10 cells regulate both humoral and Th1 immune responses. We have also developed a humanized mAb to the same survival target and generated transgenic mice expressing the human survival receptor that will facilitate preclinical translation of these basic studies into human studies. The ability to manipulate B cell contributions to humoral and cell-mediated immunity by mAb treatment offers a new strategy for accelerating mmune responses during acute pathogen challenge. The focus of our proposed studies is to identify the extent that B cells and the B10 subset modulate humoral and cellular immune responses to alphaviruses, and to determine how B cells can be manipulated for therapeutic benefit and vaccine development

Keywords: Acute; Adjuvant; Africa; Age; Alpha Virus; Alphavirus; Americas; antibody biosynthesis; Antibody Formation; Antibody Production; Antibody Response; antibody-based immunity; Antigens; Antigens, Viral; Arboviruses, Group A; Arthralgia; arthritic; Arthritis; Arthritis, Infectious; Asia; ATGN; Attenuated; Autoimmune Status; Autoimmunity; B blood cells; B cell repertoire; B-Cell Subsets; B-Cells; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; balance; balance function; base; biodefense; biological signal transduction; Biological Terrorism; Bioterrorism; Body Tissues; Bp35; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; Capsid Proteins; CD20; CD4 lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; cell biology; Cell Communication and Signaling; Cell Count; Cell Function; Cell Mediated Immunology; Cell Number; Cell physiology; Cell Process; Cell Signaling; Cell Survival; Cell Viability; Cell-Mediated Immunity; Cells; Cells, CD4; Cellular biology; Cellular Function; Cellular Immunity; Cellular Physiology; Cellular Process; Chikungunya virus; Coat Proteins; CSIF; CSIF-10; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Cytokine Synthesis Inhibitory Factor; defined contribution; Disease; disease/disorder; Disorder; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; drug/agent; Drugs; Encephalitis; Encephalitis Viruses; Encephalitis, Equine; Encephalomyelitis, Equine; Epidemic; Equilibrium; Equine Encephalomyelitis; Equine Encephalomyelitis Viral Infections; Equine Encephalomyelitis Virus Infections; Future; Goals; heavy metal lead; heavy metal Pb; helper T cell; host response; Human; Human, General; humanized monoclonal antibodies; Humoral Immunities; IL-10; IL10; IL10A; Immune response; Immunities, Humoral; Immunity; Immunity, Cellular; Immunization; immunogen; immunoglobulin biosynthesis; Immunologic Stimulation; Immunological Stimulation; immunopathology; immunoresponse; Immunostimulation; In Vitro; in vivo; Infection; Infectious Arthritis; Infective Arthritis; Inflammation, Brain; Inflammatory; Inflammatory Myopathy; Inflammatory Response; inhibitor; inhibitor/antagonist; Interleukin 10 Precursor; Interleukin-10; Intracellular Communication and Signaling; Joint Pain; Kinetic; Kinetics; Label; Laboratory mice; Lead; Leu-16; LYT3; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medication; Mice; Moab, Clinical Treatment; Modeling; Monoclonal Antibodies; Mouse Strains; MS4A1; MS4A1 gene; MS4A2; Murine; Mus; Muscle Diseases, Inflammatory; Myositis; pathogen; Pathogenesis; Pathology; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; pre-clinical; preclinical; preclinical study; receptor; Receptor Protein; Regulation; Research; Research Resources; Resources; response; Reticuloendothelial System, Spleen; Role; self recognition (immune); Sensitization, Immunologic; Sensitization, Immunological; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; small molecule; social role; Source; Spleen; Subcellular Process; T cell response; T-Cell Activation; T-Cell Proliferation; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; Testing; Therapeutic; Therapy, Vaccine; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Time; Tissues; Transgenic Mice; Translations; treatment strategy; VAC-TX; Vaccination; vaccine development; Vaccine Therapy; Vaccines; Venezuela; Viral; Viral Antigens; Viral Coat Proteins; Viral Diseases; viral infection; Viral Outer Coat Protein; Virus; virus antigen; Virus Diseases; virus infection; Viruses, General

Relevance: Alphaviruses present in the Americas are considered to be potential bioterrorism agents, and an alphavirus Tom Africa has initiated an major ongoing epidemic in Asia. Very little is known about the role of B cells in these and other infections, and their resulting immunopathology, other than antibody production. Thus, basic studies of B cell biology are necessary to understand how to develop optimal therapies and vaccines

Budget start date: 1-MAR-2011

Budget end date: 29-FEB-2012

5U54AI057157-09_5808 (2011): $336270

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DELPHI EVALUATION OF ALCOHOL ADVERTISING CODES

F Thomas, Professor
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)

Grant 5R01AA015383-04 from National Institute On Alcohol Abuse And Alcoholism

Abstract: As part an R21 exploratory and developmental research project supported by NIAAA, we have been developing procedures that can be used by public health professionals and government officials to monitor the content of alcohol advertising on television and in other media. In this R01 application, we propose to conduct two inter-related studies to validate a new rating procedure designed to detect code violations in industry guidelines for responsible advertising. Study 1 will examine the validity of Delphi technique as an enhanced method to evaluate advertising code violations. The Delphi technique consists of a series of sequential questionnaires or ´rounds´, interspersed by controlled feedback, that attempts to obtain the most reliable consensus of opinion from a group of experts or important constituency groups. The research will use a two group repeated measures cross-over design that compares the guideline ratings of a "vulnerability group" and an "expert group" at Time 1 (initial rating) and Time 2 (feedback-assisted rating). The Vulnerability group will consist of 150 research volunteers selected to represent the vulnerability characteristics (e.g., women of childbearing age, underage drinkers, minority ethnic group status) the industry codes were designed to protect. The Expert group will consist of 150 research volunteers selected on the basis of their expertise in five areas (e.g., public health, psychiatry) considered to be highly relevant to the evaluation of industry advertising guidelines from a public health perspective. Following completion of the first round ratings, participants will be randomized to receive feedback either from their own group or from the other group. Study 2 will build on the findings of Study 1 in order to conduct the first systematic evaluation of a nationally representative series of alcohol advertisements. The research will apply the Delphi technique to the ratings of up to 45 TV advertisements that have been broadcast in national markets likely to be viewed by large numbers of young adults and other vulnerable populations. The long-term goals of this research are to develop both methodological tools and empirical findings that will protect vulnerable populations and enhance the ability of regulatory agencies to monitor alcoholic beverage advertising

Keywords: ing; Adoption; Advertisements; Advertising; Agreement; alcohol advertising; Alcohol consumption; alcohol content; Alcoholic Beverages; Alcohols; alertness; Area; authority; Awareness; base; Beer; Beverages; Characteristics; Child; Classification; Code; Conflict of Interest; Consensus; Crossover Design; Delphi Technique; design; Development; distilled alcoholic beverage; drinking; Drunk driving; Ethnic group; Evaluation; Face; Feedback; Female of child bearing age; Future; Goals; Government Officials; Guidelines; Health Professional; Heavy Drinking; Industry; Informal Social Control; Institutes; interest; Intoxication; Journals; Judgment; Malt Grain; Marketing; Measures; Methods; Minority; Monitor; National Institute on Alcohol Abuse and Alcoholism; Participant; Persons; Procedures; Process; Property; Psychiatry; Psychological Tests; Psychometrics; public health medicine (field); Questionnaires; Randomized; Reporting; Research; Research Personnel; Research Project Grants; Sampling; Series; sound; Television; Time; tool; underage drinker; United States Federal Trade Commission; Validation; volunteer; Vulnerable Populations; Wine; young adult

Project start date: 2006-01-01

Project end date: 2011-11-30

Budget start date: 1-DEC-2008

Budget end date: 30-NOV-2011

5R01AA015383-04 (2009): $291009

COMPARATIVE EFFECTIVENESS AND FEASIBILITY OF SBIRT IN A GENERAL DENTAL CLINIC

F Thomas, Professor
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)

Grant 5RC1DE020455-02 from Office Of The Director, National Institutes Of Health

Abstract: "Comparative Effectiveness and Feasibility of SBIRT in a General Dental Clinic" addresses the broad Challenge Area, (05) Comparative Effectiveness Research and specific Challenge Topic, 05-DE-102 Treatment of tobacco and drug dependence in dental settings. This protocol describes a 2-year, randomized controlled trial designed to achieve two primary aims 1) to evaluate the short-term effectiveness of screening, brief intervention and referral services (SBIRT) for tobacco and other psychoactive substance use when delivered separately and in combined forms and 2) to evaluate the feasibility of implementing SBIRT for patients with at-risk substance use in a community general dental setting. This research will provide the basis for a more ambitious clinical trial that would be conducted in multiple dental settings and include a longer follow-up period. To achieve Aim 1, 175 patients who are smokers and at-risk substance users (including at-risk alcohol users) will be recruited from the general dentistry clinic at the University of Connecticut Health Center. Research staff will use the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), developed by the World Health Organization, to identify eligible patients. Participants will be randomized to one of three experimental conditions 1) a smoking-only brief intervention group; 2) a smoking + other substance use brief intervention group; or 3) a wait-list control condition that includes general dental health counseling. Those assigned to the "active" treatment conditions will be given a brief intervention that will link the patient´s screening assessment data with dental risk factors associated with tobacco only or tobacco + other substance use. Participants will be re- interviewed at 12-weeks post randomization to assess outcome and process measures using a combination of quantitative and qualitative interviewing methods. Regarding Aim 2, the timing of this opportunity and implementation of this clinical trial provides a unique opportunity to follow two cohorts of dental residents to examine the impact of SBIRT residency training on subsequent clinical practice. The first cohort will already be on staff when the study begins and will not have received SBIRT training as part of the residency requirements. The second cohort of residents will be exposed to a three-hour SBIRT training session that will supplement the residency requirements for July, 2010. Although residents will not be asked to provide the brief interventions for the randomized study, they will be encouraged to reinforce the information delivered by research staff. Differences between the two cohorts with regard to attitudes, knowledge and willingness to engage in SBIRT program activities will be measured. There has been a remarkable growth in translational research organized around the SBIRT concept, with numerous clinical trials conducted, new screening tests developed, and implementation programs evaluated to determine the feasibility of SBIRT in primary care and other medical settings. Despite the obvious relevance of SBIRT to the prevention of dental pathology, there has been little attention to the determination of its feasibility, effectiveness and implementation in dental settings. We believe there is now a real research opportunity to not only evaluate the effectiveness of SBIRT with dental patients, but also to improve the technology so that oral health practitioners can feel confident conducting screening, brief intervention and referrals for at-risk users of tobacco, alcohol and other substances. The research described in this application could have significant implications on both clinical science and public health dentistry

Keywords: ing; active method; Address; Alcohol consumption; Alcohol or Other Drugs use; alcohol risk; Alcohols; Area; Attention; Attitude; base; Behavior; Behavioral; brief intervention; Chronic; Clinic; clinical practice; Clinical Sciences; Clinical Trials; Clinical Trials Design; cohort; Communities; comparative effectiveness; Conduct Clinical Trials; Connecticut; Counseling; Data; Dental; Dental Care; Dental caries; Dental Clinics; Dentistry; Disadvantaged; drinking; Drug Addiction; Drug usage; Early identification; Educational aspects; Effectiveness; effectiveness research; evidence base; follow-up; Gingival Recession; Goals; Growth; Health; Health Services Accessibility; Hour; Impaired wound healing; improved; Individual; Interview; Knowledge; Leukoplakia; Link; Low income; Malignant neoplasm of pharynx; Measures; Medicaid; Medical; Methods; Mouth Diseases; Oral cavity; Oral health; Oropharyngeal; Outcome; Participant; Pathology; Patients; Periodontal Diseases; Prevention; primary care setting; Primary Health Care; Procedures; Process Measure; programs; Protocols documentation; Public Health Dentistry; Randomized; Randomized Controlled Trials; Recruitment Activity; Research; Residencies; Resources; Risk; Risk Factors; screening and brief intervention; Screening procedure; Secondary Prevention; Services; Smoke; Smoker; Smoking; Substance Use Disorder; success; Technology; Testing; Time; Tobacco; Tobacco use; Tooth Loss; Training; Translational Research; Trauma; Uninsured; Universities; Waiting Lists; willingness; working group; World Health Organization

Relevance: There has been a remarkable growth in translational research organized around the SBIRT concept, with numerous clinical trials conducted, new screening tests developed, and implementation programs evaluated to determine the feasibility of SBIRT in primary care and other medical settings. Despite the obvious relevance of SBIRT to the prevention of dental pathology, there has been little attention to the determination of its feasibility, effectiveness and implementation in dental settings. We believe there is now a real research opportunity to not only evaluate the effectiveness of SBIRT with dental patients, but also to improve the technology so that oral health practitioners can feel confident conducting screening, brief intervention and referrals for at-risk users of tobacco, alcohol and other substances. The research described in this application could have significant implications on both clinical science and public health dentistry

Project start date: 2009-09-21

Project end date: 2011-08-31

Budget start date: 1-SEP-2010

Budget end date: 31-AUG-2011

PFA/PA: RFA-OD-09-003

5RC1DE020455-02 (2010): $483723

THE MICROCIRCULATION IN CLAUDICATION AND EXERCISE REHABILITATION

F Thomas
University Of Pennsylvaniacity: Philadelphia country: United States (us)

Grant 5R01HL075649-07 from National Heart, Lung, And Blood Institute

Project start date: 2003-09-22

Project end date: 2014-11-30

Budget start date: 1-DEC-2011

Budget end date: 30-NOV-2012

5R01HL075649-07 (2012): $729441