Michael Cook - US grants

ABSTRACT CTS-9410994 University of Massachusetts Amhers Peter Monson The Department of Chemical Engineering at the University of Massachusetts, Amherst, will purchase computer graphics workstations which will be dedicated to support research in engineering. The equipment will be used for several research projects on molecular and materials modeling, including in particular: 1. Modeling absorption equilibrium in porous and heterogeneous solids; 2. Theoretical studies of solid-phase thermodynamics and solid-fluid equilibrium for non-spherical molecules and mixtures; 3. Analysis of transition-state structures and reaction theory in gas kinetics; 4. Mechanistic modeling of plasma-enhanced chemical vapor deposition; 5. Coupling agents at the adhesive interface; and 6. Molecular simulations of nanophase materials. Visualization of molecular, surface, and bulk atomic structures is central to the analysis of these systems. The four co-PI's bring together an unusual combination of expertise in molecular and materials modeling for chemical engineering, exploiting statistical mechanics, molecular simulation and ad initio quantum chemistry. The graphics workstations will help them create new insights, foster synergistic collaborations, and educate chemical engineering students in the use of computational chemistry and molecular structure.

This project covers a broad range of studies which focus on elucidating risk factors for, and the natural history of, esophageal adenocarcinoma (esophageal cancer) and the precursor lesion Barretts esophagus (aka Barrett esophagus). Barretts esophagus is a metaplastic change in the lower esophagus which is characterized by the replacement of the native squamous cell epithelium with a glandular-type of epithelium. This metaplastic change is thought to be primarily the result of genotoxic damage induced by gastroesophageal refluxacid and bile salts reflux up into the esophagus, exposing cells not equipped to deal with these reactive chemicals. Re-epithelization with the metaplastic Barretts epithelium provides for a tissue which is better able to withstand the exposure to such compounds. However, it also increases the risk of esophageal adenocarcinoma approximately 10-50 fold that of the general population. The incidence of esophageal adenocarcinoma has increased over 650% in the United States over the last 35 years and most individuals present with late stage malignancies, resulting in a 5-year survival rate of less than 20%. This indicates that researchers need to be able to better identify those at high risk and Barretts esophagus is a good starting point. However, although this metaplasia greatly increases the risk of esophageal adenocarcinoma relative to the general population, the absolute risk remains low at around 0.5% or 1 in 200 patient years of follow-up. This is because approximately 90% of individuals who develop esophageal adenocarcinoma are diagnosed at their first (index) endoscopy. Thus, not only do we need to be able to better identify those with high risk (Barretts esophagus) in the general population, we also need to be able to triage these individuals into high and low risk groups so that surveillance resources can be focused on those who most need them, which would make the cost-benefit equation of surveillance endoscopy more attractive. Therefore, the ultimate goals of all the studies within this project seek to better understand the natural history of this disease, risk factors for progression, diagnostic markers and modalities with high sensitivity, and prognostic biomarkers for efficient triaging of risk.The Barrett's Breath Test Pilot (CAS ID:10592) is assessing the utility of quantifying volatile organic compounds (VOCs) in the breath for a future epidemiologic study. Specially, it is assessing what the intraclass correlation coefficients are for VOCs over a 98 day period, with three time points with biological duplicates taken from each of five volunteers. The Barrett's Esophagus Consortium project (CAS ID:10593) is a pooling project that brings together and harmonizes data from five case-control studies of Barrett's esophagus. We have already assessed the exposures tobacco smoking (published in Gastroenterology), body mass index and waist circumference (published in Gut), alcohol (published in American Journal of Gastroenterology). We are currently working on analyses of GERD and NSAID use; adiponectin; and insulin-like growth factors (IGFs) in relation to this precursor metaplasia for publication. The Esophageal Cancer in SEER-Medicare project (CAS ID:10633) is assessing metabolic syndrome in relation to Barrett's esophagus (published in Journal of Clinical gastroenterology) and esophageal adenocarcinoma (manuscript in progress), as well as the comparative utility of staging modalities in relation to survival following diagnosis of esophageal adenocarcinoma (published in Cancer). We are also assessing whether there is are demographic, medical history, and survival differences in esophageal adenocarcinoma by whether there was a prior diagnosis of the precursor condition Barrett's esophagus (submitted for publication). A new project will assess whether we can develop an algorithm to accurately identify diagnoses of esophageal adenocarcinoma using Medicare billing data alone.The CPRD EAC Progression Study is an analysis in collaboration with our colleagues at Boston University and will enable us to assess whether metabolic syndrome is a risk factor for progression from Barretts esophagus to esophageal adenocarcinoma. This analysis is based in the Clinical Practice Research Datalink (CPRD) which was formerly called the General Practice Research Database (GPRD). The manuscript is currently being drafted. In the Hormones in Barrett's Esophagus project (CAS ID:10638) we have assessed circulating androgens and estrogens in Barrett's esophagus patients compared with gastroeosphageal reflux disease controls in the BEEDS study based at the Walter Reed (published in Clinical Gastroenterology and Hepatology). We are currently assessing similar exposures in a second Barrett's esophagus population for external replication (manuscript being drafted) as well as expansion to esophageal cancer (adenocarcinoma).The Kaiser BE Cohort project will enable us to assess different risk factors for progression from Barretts esophagus to esophageal adenocarcinoma. Currently, a majority of evidence for Barretts esophagus patients comes from studies of risk factors for esophageal adenocarcinoma but a majority of such patients are never previously diagnosed with Barretts esophagus. Thus a disconnect may exist in the population for study and the population under surveillance. These analyses will provide evidence that is directly applicable for a Barretts esophagus population undergoing surveillance. All of these projects are closely aligned to the aims of elucidating the etiology of Barrett's esophagus and esophageal adenocarcinoma as well as providing potential utility for diagnostics and prognostics.

Center for Excellence in Logistics and Distribution (CELDi)
Proposal #1127937

This proposal seeks funding for the Center for Excellence in Logistics and Distribution (CELDi) located at the University of Missouri-Columbia.Funding Requests for Fundamental Research are authorized by an NSF approved solicitation, NSF 10-601. The solicitation invites I/UCRCs to submit proposals for support of industry-defined fundamental research.

Sustainable energy sources are a critical component of our nations future and security. One critical aspect of realizing the potential of biomass energy is the logistics component. To date biomass energy is not being realized due to the high costs of biomass logistics systems. This proposal will address this problem and allow for the development of a multi-stage biomass supply chain and logistics model that addresses uncertainties, such as those in the biomass availability, process performance, and final product demand / price to name a few. The model will also support dynamic decision making and address a broad mix of inherent problems in biomass logistics. Using the results of the research, alternative scenarios will be evaluated and decision support tools will be developed.

If this project is successful then biomass based sources would become viable and biomass based energy sources would reduce carbon emissions, lead to rural economic development, reduce dependence on foreign sources of energy, increase energy security, increase the likelihood for cost effective energy, and influence policy. Participation by students, including continued recruitment of students from underrepresented groups, will be emphasized by the PI. The project provides benefits for CELDi by positioning both the university members and industry partners in a leadership position for biomass based energy. In addition, the industry partners stand to benefit from an early view of the results that will allow them to develop and implement biomass based energy sources and develop possible market strategies and products.

In Ghana, Africa, we have conducted a population-based survey of men to assess the population prevalence of prostatic disease (CAS ID:01130). We have also collected consented into the study a clinical series of men diagnosed with prostate cancer. This dynamic epidemiologic design of a population survey combined with a larger case series, is enabling us to assess the burden of prostate cancer in African men as well as assess risk factors associated with prostate cancer in an important and understudied population. Biological samples collected from the 1,038 healthy men in the population survey component will allow us to establish the nutritional, hormonal, and genetic profiles of African men. In addition, linking interview data from these 1,038 healthy subjects with biomarkers will produce insights into whether westernization in African men is associated with an adverse metabolic profile (obesity; abdominal obesity; higher levels of insulin, low-density lipoprotein, and insulin-like growth factor I), which has been associated with excess prostate cancer risk. The additional 677 prostate cancer cases that we recruited through the clinical component has enabled us to conduct a genome wide association study (GWAS) of prostate cancer in this unique population. In addition, we have sequenced the 8q24 region and identified several novel variants as well contributed to a recent effort of imputation and subset based meta-analysis (ASSET) of chr5p15.33 across mutliple cancer types. Lastly, we are also using the population component to assess the prevalence of malaria-resistance genes with a view to uncovering the genetic risk factors of Burkitt lymphoma in Africa.We have conducted a multidisciplinary study in China to assess risk factors for prostate cancer in a low-risk population in order to understand more clearly the reasons for the large racial differences in prostate cancer risk (CAS ID:01140). That study involved the collection of multiple biologic samples, with a primary aim of assessing risk factors and how westernization influences the risk of prostate cancer. The study also involved the collection of tissue samples from prostate cancer tumors to permit precise tumor classification as well as assays of tumor biomarkers, in some cases using newly developed tissue microarray techniques. In addition to specific dietary factors, dietary patterns will be identified and compared with those of controls to evaluate whether a western-style diet in China is related to excess prostate cancer risk. The study is also assessing biological correlates of westernization to look for potential biological links between westernization and excess prostate cancer risk. Data on genotypes and circulating levels of hormones provide a unique opportunity to investigate the interrelationships between serum hormones and genetic variants to gain insights into the functional significance of these genetic markers. In another study of prostate cancer in 15 cities in China, we are assessing the role of soy in prostate cancer by developing a dietary isoflavone index. In addition, several nested case-control studies in large cohorts, including Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and the Prostate Cancer Prevention Trial (PCPT), and the American Cancer Society Nutrition Cohort (CPS-II), we are assessing the relationships of obesity, dietary patterns, insulin resistance, and chronic inflammation with subsequent risk of prostate cancer. Together, these cohorts provide over 3,000 prostate cancer cases for the investigation of prostate cancer etiology. They are unique in having collected pre-morbid blood and multiple biologic samples over time, permitting an assessment of how hormone and other biomarker levels change as patients approach diagnosis. A methodologic study is currently underway to evaluate whether circulating levels of androgens reflect intraprostatic androgenicity, a key issue in hormonal carcinogenesis of the prostate (CAS ID:01072). This methodologic study has collected samples of fasting blood and snap-frozen fresh tissue (over 3,000 pieces) from 600 study subjects in three racial/ethnic groups. Data from this study will provide a unique opportunity to investigate the interrelationships among serum and tissue hormones and variants in genes involved in the androgen metabolism pathways to provide critical data for determining the functional significance of these genetic markers. The collection of tissue samples also will provide a unique opportunity for gene expression studies. In continuing the theme of hormonal perturbations in relation to prostate cancer, we are also using a large health database to assess whether testosterone replacement medications are associated with prostate cancer risk (CAS ID: 10667). Prostate development is reliant upon androgens while anti-mullerian hormone (AMH) is also a key (peptide) hormone helping confer a male phenotype during early development. In addition circumstantial and indirect (in vitro and animal models) evidence links AMH to prostate cancer. Therefore, we are assessing the relationship between AMH levels and future risk of prostate cancer in the PLCO Trial (CAS ID: 10675). Sarcosine (a methylated derivative of the amino acid glycine) measured ion the urine has been shown to be a correlate of sarcosine levels in tissue. Combined with putative evidence that sarcosine may be a predictive marker of future prostate cancer risk, we are assessing such using both the PLCO Trial as well as the ATBC Diet and Health Study (CAS ID: 10603). For more accurate and detailed follow up in PLCO to enable prostate recurrence analyses and analyses of outcomes post-diagnosis in this resource, we are currently extending the follow-up time beyond the first year post-diagnosis to capture all clinically relevant data (CAS ID: 10515). We are collaborating with investigators from the American Cancer Society (ACS) to investigate the role of insulin resistance and chronic inflammation in prostate cancer in a nested case-control study of 1,209 prostate cancer cases and an equal number of controls selected from the ACSs Cancer Prevention Study (CPS)-II LifeLink Cohort (CAS ID: 10028).Lastly, we are using data from AARP to investigate the association of NSAID use and subsequent risk of cancer, including prostate cancer (CAS ID: 10547).

The goal of this project is to identify a practical blood-based biomarker(s) that can be used as a screening test to determine who has Barrett's esophagus (BE) and who does not. Secondary goals of the project are to characterize germ line and tissue biomarkers associated with BE, and compare biomarkers in non-BE patients with and without GERD. Tertiary goals are to explore associations between biomarkers in blood or tissue and progression from BE to dysplasia or EAC, and to assess the stability of proteomic patterns over time. This study will be conducted among patients in the Barrett's Esophagus Registry (currently with 206 registrants) established at the National Naval Medical Center (NNMC) in Bethesda beginning in 1992 as well as a comparison group of approximately 600 matched non-BE patients endoscoped in the GI clinic at NNMC for other conditions. Blood and tissue samples will be collected as well as questionnaire data on risk factors and medications as well as GERD. Data analyses will be based primarily on laboratory testing of newly collected esophageal biopsies, brush samples, and blood samples, but secondarily will also include use of archival tissue biopsy samples. Follow-up of BE Registry patients will include standard periodic surveillance endoscopies, additional blood samples, and ascertainment of disease status (i.e., progression). To distinguish BE versus non-BE patients, we will: (i) assess predictability of BE status from serum proteomic patterns; (ii) characterize esophageal biopsies and brush samples for selected DNA alterations, RNA expression, and proteomic profiles; (iii) genotype patients for selected polymorphisms potentially associated with BE; (iv) compare blood and tissue biomarkers in non-BE patients with and without GERD; (v) explore the association of biomarkers with progression from BE to dysplasia or EAC; and (vi) assess proteomic pattern stability over time in BE patients. Recent studies in this project have (i) profiled and compared tissue RNA expression differences among BE, cardia, and normal squamous tissues in BE cases; (ii) compared serum hormones in BE cases versus noncases; and (ii) conducted a pilot study of serum proteomics in BE cases and noncases.

Project Summary. The Akwesasne Research Center for Health (ARCH) project is submitted by the St. Regis Mohawk Tribe (SRMT) of Akwesasne, NY in partnership with the Roswell Park Comprehensive Cancer Center (RP) led by the RP Center for Indigenous Cancer Research (RP- CICR) in Buffalo, NY. Establishing the ARCH will support the development of two research projects and one student enhancement project, all co-developed and co-led by SRMT and RP. The proposed Administrative Core will establish key personnel, supplies, and in-person or virtual meetings to coordinate project timelines, deliverables, evaluation efforts, and community engagement. The Environmental Health Research Project will engage RP environmental scientists and state-of-the-art equipment to measure environmental health concerns in Akwesasne landscapes and their relationships to the human condition. The liver wellness project titled, LIVE (Live, Indigenous, Virtual, Enhancement), includes a culturally tailored liver health promotion program to encourage traditional and healthy life ways through community-based education and lifestyle modification. To support research interest amongst the younger generation in Akwesasne, the ARCH proposal includes the St. Regis Mohawk Research Scholars Program. This program engages high school and college students in a three-prong approach, 1.) Community Engagement Conferences to create research and science career awareness and recruit students to participate in afterschool and summer research opportunities; 2.) An After School Health Science Club to provide students with working knowledge of public health, data collection methods, statistical analysis approaches, health behavior and epidemiology principles; and 3.) a Summer Program to provide high school and college students with immersive research experiences integrated with core research projects of ARCH, and to apply principles and skill sets to addressing cancer health disparities and environmental health issues specific to the SRMT. Each project in the ARCH would be directed by the Principal Investigator from the SRMT Health Division and coordinated by key personnel identified both at SRMT and RP's Center for Indigenous Cancer Research. This direct partnership with the SRMT Health Division supports RP's existing Memorandum of Understanding with the Indian Health Service that agrees to collaborate in the areas of cancer research; research; consultation/technical assistance focused on cancer prevention; capacity building; and direct services in partnership with American Indian and Alaska Native communities. The SRMT will activate this MoU to further guide the development of the ARCH.