David C. Smith - US grants

Liarozole is a benzimidazole compound that is currently under development for the treatment of malignant disease. Liarozole has been shown to raise endogenous levels of retinoic acid in animal models, probably by binding to the cytochrome P450 moiety of the 4-hydroxylase responsible for retinoic acid catabolism. This study will assess the effect of liarozole on the P450 system and markers of retinoid metabolism and effect in humans.

Calcitriol is the active form of vitamin D. Calcitriol plays a role in normal and neoplastic cell growth and can modulate growth through specific receptors resulting in differentiation and growth inhibition. This study will evaluate the ability to administer calcitriol via a parenteral route in cancer patients alone and in combination with prednisone which has been shown to reduce hypercalcemia and potentiate the antitumor effects.

This pilot study will assess the safety/tolerance and length of time that plasma levels of unchanged paclitaxel exceed 0.07 uM after oral administration of paclitaxel. 18 adult patients with stable metastatic prostate, breast or lung cancer will be enrolled. After an overnight fast, the patients will receive 5 mg/kg cyclosporin oral solution dose (Sandimmune) 1 hour prior to and concomitantly with oral paclitaxel at one of three planned doses.

Prostate Cancer is the most common malignancy and the second leading cause of cancer death in males in the United States (1). Despite advances in localized therapy of prostate cancer, a significant fraction of men develop metastatic disease at some point in the course of the illness. We have previously studied treatment approaches for this disease which focus on the nuclear matrix and the DNA replication complex. This protocol will continue those studies using the topoisomerase I inhibitor irinotecan (CPT-11) in combination with estramustine.

DESCRIPTION (Provided by applicant): Angiogenesis is a critical factor in the progression of malignant disease. Malignant cells overexpress several factors that stimulate the process of vascularization including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Copper plays a critical role in the process of angiogenesis, acting as a cofactor for the function of several of the key mediators of angiogenesis. The copper-depleting agent tetrathiomolybdate (TM) has been shown to modulate the process of angiogenesis by inhibiting the production of these proangiogenic agents. Both benign and malignant prostate cells express VEGF and bFGF. Recent evidence shows that these molecules are differentially expressed with disease progression in prostate cancer. Urinary VEGF levels correlate with survival in patients with advanced disease indicating the importance of angiogenesis in the progression of this disease. This phase II clinical trial will evaluate the activity of an antiangiogenesis strategy using tetrathiomolybdate to deplete copper in patients with prostate cancer. Assessment of the efficacy of therapy in prostate cancer is difficult due to the predominance of bone metastases in this disease. Prostate specific antigen (PSA) has been shown to be a marker of response following hormonal and cytotoxic therapy for prostate cancer. In a laboratory model, PSA has been shown to inhibit angiogenesis, complicating its use as a response indicator to monitor the effect of therapies aimed at inhibiting angiogenesis. This study will evaluate PSA as an indicator of response to antiangiogenic therapy by correlating levels with evidence of response and progression on computed tomography and bone scan and with the degree of copper depletion measured by serum ceruloplasmin level. The antiangiogenic effects of therapy will also be evaluated by measurement of serum VEGF, bFGF, and interleukins 6 and 8 which are associated with cell proliferation and bone metabolism. The levels of these growth factors/cytokines will then be correlated with the degree of copper depletion, PSA level and response to therapy.

A grant has been awarded to the University of Rhode Island to acquire an automated DNA sequencer and supporting equipment. The Environmental Biotechnology Initiative (EBI) at the University of Rhode Island was developed to promote biotechnology at the institution through research, teaching, and outreach. Four central facilities are envisioned for the EBI - Imaging, Genomics and Proteomics, Transgenics, and Bioinformatics. This grant award will establish the URI Genomics Facility by providing funds for the acquisition of a DNA sequencer and ancillary equipment dedicated for sample preparation. Additionally, funds to support the hire of a Research Associate to manage and operate the facility are provided by this award and matching funds from the University of Rhode Island.

The instrumentation and Research Associate will support the currently funded research activities of the three Principal Investigators (PIs) and eight other major users in five separate departments in three different colleges at the university. The funded research projects of the PIs include: studies of gene regulation in the causative agent of Lyme disease (Borrelia burgdorferi), studies of gene regulation in Vibrio anguillarum (a major bacterial pathogen of farmed salmon and other fish), determination of the bacterial species succession of Narragansett Bay, identification of the microbes that inhabit the deep ocean biosphere, determination of the regulation of the molecular mechanisms of osmoregulation in fish, identification of the microbes that inhabit the gastrointestinal tract of salmon, and population genetics of selected marine finfish (e.g., haddock and tautog). The establishment of the Genomics Facility will allow user directed DNA sequencing with more rapid turnaround and lower costs then is presently available to URI-based investigators, who are forced to contract with other academic or commercial sequencing facilities. It also is anticipated that numerous other investigators at URI will make use of the facility.

The ability to study life at the DNA level has fundamentally changed almost every aspect of research in the life sciences. The high sample throughput afforded by automated DNA sequencers allows researchers to address questions concerning genetic diversity and gene regulation that were unapproachable only a few years ago. The Genomics Facility also will play an integral role in training our students in state-of-the-art research methodologies and the art of scientific investigation. The Research Associate will work with interested faculty to develop and refine laboratory exercises in molecular biology that include the theory and practice of the DNA sequencer purchased with these funds. Additionally, it is anticipated that the acquisition of Genomics Facility will enhance the ability to attract new graduate students. URI has actively engaged in the recruitment of students from under-represented groups for some years to enhance the number and quality of such students in our graduate programs in the biological sciences. The availability of this core facility to support the research training of all students is expected to enhance recruitment and retention of students from under-represented groups. The combination of improved research infrastructure and training opportunities will enable URI faculty to better compete for research funds, new faculty, and students.

DESCRIPTION (provided by applicant): This proposal aims to evaluate the efficacy of Native American ethnobotanical treatments for tuberculosis for the purpose of making available acceptable, affordable alternatives to current TB drugs, especially in developing countries with massive TB case loads such as the People's Republic of China. No new drugs have been introduced for the treatment of tuberculosis for the past 30 years. Today the world faces a resurgence of tuberculosis, the number one bacterial killer and an intensive search has been launched to find new drugs, primarily in the public, academic and biotech sectors. One of the confounding factors is the high cost of any new drug development (and thus cost of the drugs to the public) together with the relatively low profit potential for TB drugs, thus discouraging big pharmaceuticals from investing in TB. Native Americans relied entirely upon botanical treatments for tuberculosis following the epidemics that occurred with the introduction of this disease by the European colonialists. Some of these treatments continued to be used ethnomedically throughout the 20th century. Preliminary phytochemical and bacteriological studies confirmed the anti-TB activity of 2 such plants but studies were discontinued prematurely due to lack of funds (and perceived lack of urgency at the time). This study will evaluate the activity of ethobotanical and organic solvent preparations of 2 plants in mice infected by aerosol with low doses of Mycobacterium tuberculosis. Both acute and chronically infected mice will be treated for 2-3 weeks and the treatment evaluated by determining the number of bacteria in lungs and comparing to untreated controls. Concurrent with this evaluation will be a bioassay-guided fractionation of the plants in order to identify the active principle(s) for the purpose of standardization of botanical preparations. At every step of the fractionation, both cytotoxicity and anti-TB activity will be assessed in an attempt to identify a preparation requiring minimal processing that possesses maximum selectivity for the tubercle bacillus. Such a preparation would be the subject of further development for use in clinical TB.

A critical problem for the study of the biosphere in deep marine sediments is the pervasively low level of microbial metabolic activity that renders conventional techniques relatively ineffective for detecting microbes. Based on the recognition that H2 is a ubiquitous intermediate product of anaerobic microbial processes, this research program will develop a new hydrogenase(H2ase)-based technique to measure the activity of this enzyme in marine sediments and will calibrate the technique for application to measuring microbial metabolic rates in anoxic sediments like those often encountered during deep ocean drilling. If successful, the methods devised by the researchers will find immediate and wide-ranging application in IODP studies of the deep biosphere and in studies of conventional cores from anoxic marine sediments. The goals of the program directly address the biosphere component of the IODP long-range science plan. The research also has the potential for expanding understanding of the minimum energy required to sustain life and the environmental limits of life in the deep biosphere. The program supports education and human resource development through training of a postdoctoral researcher and involvement of undergraduate research fellows.

0421167
D'Hondt
This Major Research Instrumentation award to University of Rhode Island provides funds to build and instrument a portable field laboratory for research and research training focused on subseafloor life. The laboratory will be designed to be carried on research vessels or used on land to study estuarine regimes. It will be fully outfitted for 1) microbiological and biogeochemical sampling of diverse subsurface environments, 2) on-site analyses of biologically significant transient properties, and 3) on-site analyses of chemical and physical properties that will be used to guide microbiological and biogeochemical sampling strategies. It will be used to sample subsurface life from diverse marine environments, including estuaries and coastal sediments, shallow sediments of the deep ocean, and ocean crustal aquifers. Samples and analyses taken with the proposed field laboratory will allow URI scientists and the broader scientific community to document the nature of life in diverse subseafloor environments. The broader impact of the acquisition includes a strong education and outreach development at URI, and it should lead to a better understanding of subsurface biota, and possibly help understand the origin of life on earth. URI is providing 30% of the project cost from non-federal funds. This proposal is supported by the Division of Ocean Sciences at NSF.
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CLINICAL TRIALS OFFICE The Clinical Trials Office (CTO) provides infrastructure support for the conduct of clinical trials at the University of Michigan Comprehensive Cancer Center. CTO services are grouped into three major categories; regulatory services, data management services, and information technologies services. Major areas of responsibility include support for regulatory submissions to the IRB, two Protocol Review Committees (therapeutic and prevention), GCRC and other institutional review committees, FDA, and NCI. The CTO provides data management services for PRC-approved clinical trials as well as serving as a centralized data repository for research data generated on clinical trials. These services include study implementation, data collection and entry, and submission to investigators and outside sponsors. The information technology services include Case Report Form (CRF) development and database implementation and maintenance. The primary mission of the CTO is to assist the Cancer Center investigators in the development, conduct, and reporting of innovative clinical research in an efficient, regulatory compliant, and scientifically sound manner.

Recent studies of subseafloor life, that is microbes living deep below the ocean?s seafloor, have produced astonishing results that challenge fundamental ideas about the limits and distributions of life. These include; (1) that the microbial biomass of subseafloor sediments is spatially much more variable and possibly much smaller than previously believed; (2) that rates of subseafloor sedimentary microbial activity are far below the rate required for cell maintenance, implying that either most subseafloor cells are inactive or that the energy required for their cellular maintenance is lower than anticipated; and (3) the global distributions of subseafloor sedimentary microbes and their activities are significantly affected by the oceanographic properties of the overlying water column. This proposal will conduct fieldwork to test these ideas at a range of sites in the equatorial Pacific. To do this the principal investigators will conduct a transect study where the following samples and measurements will be taken; (1) coring the sediment to ~18 meter or more below seafloor (mbsf) at 12 sites in the Pacific Ocean, (2) conducting extensive microbiological and biogeochemical analyses of these cores, (3) surveying the oceanographic and geologic characteristics of each site, and (4) using the results to test and refine models for the global distribution of subseafloor microbial abundances and their metabolic activities. With this data the investigators will then address four important questions: What are the principal controls on the magnitude and geographic distribution of subseafloor sedimentary cell abundance and steady-state rates of microbial activities? Can we accurately estimate the magnitude and global distribution of subseafloor sedimentary cell abundance? Can we accurately estimate the global distribution of organic carbon-fueled microbial activity in subseafloor sediment? Do different subseafloor sediments with very different cell abundances and rates of metabolic activity characterized by different groups of organisms? This study will significantly advance our understanding of life in the subseafloor ocean and will provide samples for diverse independent studies, including the International Census of Marine Microbes. This project will also have a strong research and training impact at both the graduate and undergraduate levels as the inherently multidisciplinary nature of subsurface life provides an ideal entry into collaborative modern science. The project will also support a Subsurface Life website at the University of Rhode Island which can be accessed by the public and that will be expanded to include a strong focus on this project and its results. Additional outreach activities include enhancing K-12 education and teacher professional development, in part by integrating a high school science classroom into the at-sea component of the project.

This Research Experience for Undergraduates (REU) program is located at the University of Rhode Island's Graduate School of Oceanography (GSO) in Narragansett, RI. Named the "Summer Undergraduate Research Fellowships in Oceanography" (SURFO) program, the REU Site is a 10-week research/educational program designed to expose 12 undergraduates per year to cutting-edge, authentic, oceanographic research. Each student will work with a research advisor and graduate student to develop/conduct a research project in an area of oceanography appropriate to each student's background and interests. The research or educational niche filled by the SURFO program deals with the more quantitative aspects of oceanography, which closely parallels the strengths of GSO. The research projects undertaken by participants are typically part of a separately funded research program, but the student project focuses on an interesting aspect of the research that was not anticipated. Many of the student projects result in important initial findings for subsequent research proposals or publications. Numerous research seminars and professional development workshops are conducted specifically for the SURFOs. At the end of the summer, students present their results during a student research symposium and they write a research paper. Students and advisors are strongly encouraged to continue the projects for presentation at national/regional meetings or submission to refereed journals.

The site is supported by the Department of Defense in partnership with the NSF REU program.

The University of Rhode Island will host the Summer Undergraduate Research Fellowships in Oceanography (SURFO) program at the Graduate School of Oceanography (GSO)in Narragansett, RI for 10 weeks each summer. SURFO will engage 12 undergraduates in a cutting-edge, authentic oceanographic research and educational experience primarily focused on quantitative aspects of oceanography (e.g., physical oceanography, geophysical fluid dynamics, marine geophysics, population genetics and biodiversity, biogeochemical cycling, and quantitative ecology). Each student works with a research advisor and a graduate student to develop/conduct a hands-on research project in an area of oceanography appropriate to each student's background and interests. The program recruits undergraduates with a strong background in mathematics, physics, biology, chemistry, computer science, or engineering. The intended outcome is to develop interest in ocean science research, and prepare students for careers and/or graduate studies in the field. Students also benefit from a SURFO-tailored seminar series and workshops chosen to help them better integrate into research environments, critically analyze and develop science knowledge, safely maneuver in the laboratory and field, improve their writing and oral communication skills, and nurture ethical behavior.