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Clinical and Translational Science Center

Clinical and Translational Science Center

K12 Program - Scholars

2011 Scholars

LORIEN DALRYMPLE, M.D., M.P.H.
Assistant Professor, Department of Internal Medicine

Mentors:
• George Kaysen, M.D., Ph.D., Chief, Professor and Acting Chair, Department of Biochemistry and Molecular Medicine
• Ellen Gold, Ph.D., Professor and Chair, Department of Public Health Sciences
 
Research Study: 
As of 2005, approximately 340,000 persons with end-stage renal disease (ESRD) were on dialysis in the United States. Among persons with ESRD, the overall one-year mortality rate is 20% and the five-year mortality rate exceeds 60%.1 Infections are the second leading single cause of mortality in persons with ESRD.1 The majority of studies examining the epidemiology of infections among patients on dialysis have focused on bacteremia, sepsis, or peritonitis whereas few studies have examined the full range of infections (e.g. pulmonary, soft tissue, genitourinary, etc.) observed in dialysis patients. Further study of the types, rates, and risk factors for infection is needed in order to better understand infection-related morbidity and mortality in this population. Additionally, research examining the potential consequences of infection, in particular, whether infections increase the risk of cardiovascular events is needed. The primary goals of this project are to 1) determine the rates of and risk factors for infections in patients with ESRD, 2) determine whether infections are a risk factor for cardiovascular events among persons with ESRD on hemodialysis, and 3) compare how different biomarkers of inflammation predict the risk of cardiovascular death in patients on dialysis.

The primary goals of this proposal are to 1) determine the rates of and risk factors for infections in patients with ESRD, 2) determine whether infections are a risk factor for cardiovascular events among persons with ESRD on hemodialysis, and 3) compare how different biomarkers of inflammation predict the risk of cardiovascular death in patients on dialysis.


ANUURAD ERDEMBILEG, M.D., Ph.D., M.A.S.
Assistant Researcher, Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition and Vascular Medicine

Mentors:
• Lars Berglund, M.D., Ph.D., Professor of Medicine, Associate Dean for Research
• Laurel Beckett, Ph.D., Vice Chair, Department of Public Health Sciences

Research Study:
Despite four decades of declining mortality, cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the United States. The metabolic syndrome (MS), a cluster of metabolic abnormalities including hypertriglyceridemia, low HDL-cholesterol, hypertension, abdominal obesity, and increased fasting glucose levels, has been associated with subsequent development of diabetes mellitus and CVD. Increases in the prevalence of some of these CVD risk factors, such as diabetes, obesity, and the MS, may reverse present downward trends in CVD mortality. Although the concept of the MS has been somewhat controversial. the syndrome captures the presence of a high risk metabolic environment. Inflammation has also become well recognized in the pathogenesis of CVD, and contributes to all phases of atherosclerosis, from fatty streak initiation to CVD events. Further, inflammation may be a common phenomenon underlying many chronic diseases. We hypothesize that presence of a disadvantageous risk factor constellation together with pro-inflammatory conditions will potentiate long-term risk for CVD. This might be further modulated by family history, which to some extent reflects genetic risk factors. Here we focus on how the combination of genetic factors and the metabolic environment promote a high-risk phenotype, accelerated by the presence of inflammation. Further, based on our results to date, we hypothesize that the degree of cardiovascular risk might differ across African American and Caucasian ethnicity, reflecting differences in metabolic risk factors, genetics and/or inflammatory burden. To test this hypothesis, we will investigate risk factor constellations across ethnicity.


ESTELLA GERAGHTY, M.D., M.S., M.P.H./C.P.H., F.A.C.P.
Assistant Professor, Department of Internal Medicine

Mentors:
• Richard Kravitz, M.D., M.S.P.H., Professor, Division of General Medicine, Co-Vice Chair (Research), Department of Internal Medicine
• Peter Franks, M.D., Professor of Family Medicine, Family and Community Medicine
• James Case, M.S., D.V.M., Ph.D., Professor of Clinical Diagnostic Informatics, California Animal Health and Food Safety Laboratory
• Anne Kjemtrup, D.V.M., M.P.V.M., Ph.D., Research Scientist III, California Department of Public Health, Vector-Borne Disease Section

Research Study: 
Pesticides play an important role in public health as part of a sustainable mosquito control system. In fact, chemical control with pesticides is still the most important element in the integrated approach to vector management. The safety of public health pesticide use has long been a concern among international (World Health Organization), national (Centers for Disease Control and Prevention, Environmental Protection Agency), and local agencies (Departments of Public Health). However, since the arrival of West Nile virus (WNV) in the United States, the issue of pesticide safety has also gained sway with the public, inciting heated debates about the risk-to-benefit ratio for aerial pesticide applications. This K12 research plan addresses the question of ‘risk’ to human health when pyrethrin pesticides are sprayed aerially for WNV mosquito control, through the use of rigorous and innovative methods.

WNV is a mosquito-borne disease, causing human infections ranging in severity from asymptomatic to fatal. Since there is no specific treatment for WNV, prevention of infected mosquito bites remains the only viable option. So when WNV surveillance established the presence of epidemic conditions in California in 2005, many of the state’s vector control agencies chose adulticiding (killing adult mosquitoes) as the best pest management option to break the WNV transmission cycle and to reduce WNV associated morbidity and mortality. Pyrethrin-based pesticides were sprayed aerially to cover the large geographic regions showing this epidemic activity. However, the pyrethrin-based pesticides can cause acute human health effects including respiratory problems, skin and eye irritation, and nervous system disorders. The potential for aerial pesticide spraying to cause these health effects spurred widespread public fear and led to significant opposition to the spraying program.

This research focuses on the relationship of aerial pesticide spraying to the incidence of acute physiologic complaints in the California population during the summer of 2005. Previous studies conducted in New York City, showed that ground spraying activities, using pyrethrin pesticides, did not increase emergency room visits for asthma exacerbations.


TIANHONG (TINA) L.I., M.D., Ph.D.
Assistant Professor of Medicine, Department of Internal Medicine, Division of Hematology and Oncology

Mentors:
• David Gandara, M.D., Professor of Medicine, Associate Director for Clinical Research, Director of Thoracic Oncology, Department of Internal Medicine
• Primo N. Lara, Jr., M.D., Professor of Medicine, Associate Director of Translational Research, Director of Clinical Trial Support Unit, Department of Internal Medicine

Research Study:
The development of anti-epidermal growth factor receptor (EGFR) therapy represents a significant advance in treating patients with advanced non-small cell lung cancer (NSCLC). Small molecule EGFR tyrosine kinase inhibitors (TKIs) have modest single agent activity with mild toxicities in unselected patients with advanced NSCLC. Our long-term goal is to improve the therapeutic index of EGFR inhibitors by selecting the subgroups of patients who are more likely to respond to EGFR inhibitors and/or by a rational combination of an EGFR inhibitor with cytotoxic or other molecularly targeted agents to overcome the primary or acquired resistance. This subject has been one of the common research interests of the applicant and UC Davis thoracic oncology team for several years.

We previously reported that the drug administration schedule that pharcodynamically separates the cellular effect of erlotinib from pemetrexed avoids their antagonistic interactions in preclinical NSCLC models. To test this hypothesis, the applicant developed an investigator-initiated, multi-center, randomized phase II study comparing the progression-free survival between the rational combination of erlotinib and pemetrexed and pemetrexed alone in patients with progressive or relapsing NSCLC. The boundary to move to the second-state accrual to a total of 82 patients has been met in the pre-specified first-stage analysis. In parallel to the clinical trial, blood and archival tumor specimens from the study patients have been collected for the proposed correlative studies. The overall objective of this proposal is to identify the predictive biomarkers for clinical benefit of EGFR inhibitors and explore the resistant mechanisms using two of the most clinically accessible tumor specimens (i.e., archival tumor specimen and serum tumor DNA) in NSCLC patients and our repertoire of in vitro and in vivo human NSCLC models.

Two specific aims are proposed to test the following hypothesis:
1. Pretreatment tumor dependency on the activity of EGFR signaling pathway, as characterized by a high pEGFR:pAKT ratio, the presence of high EGFR gene copy number and/or EGFR-activating somatic mutations, predicts clinical benefit of erlotinib in combination with pemetrexed.
2. The molecular alterations in serum tumor DNA identified by the genome-wide array-based assay for single nucleotide polymorphism (SNP) and copy number variant analysis (CNV) at progression of treatment compared to pretreatment can be used to determine the resistant mechanisms of treatment and to select individualized further treatment in NSCLC patients.


STEVE MARTINEZ, M.D.
Assistant Professor, Department of Surgery

Mentors:
• John Boone, Ph.D., Professor and Vice Chair (Research) of Radiology
• Primo N. Lara, Jr., M.D., Professor of Medicine, Associate Director of Translational Research, Director of Clinical Trial Support Unit, Department of Internal Medicine
 
Research Study: 
The chemotherapy regimens used to treat breast cancer (BCa) are not uniformly effective. Only 8% of breast cancer (BCa) patients who receive chemotherapy obtain an absolute overall survival benefit, leaving 92% exposed to potentially toxic, ineffective therapy.1 The administration of chemotherapy before surgery, termed neoadjuvant chemotherapy (NAC), is used as a surrogate for chemotherapy sensitivity in the adjuvant setting. Unfortunately, patients must receive 12-24 weeks of NAC before a response can be assessed by physical examination or imaging techniques such as mammography, ultrasonography, or MRI, which can be inaccurate. An accurate assessment of response early in the course of NAC would allow responders to continue therapy, while nonresponders could discontinue toxic, ineffective treatment.

Current NAC trials indicate that approximately 20% of patients achieve a pathologic complete response (pCR) and therefore may not necessarily benefit from surgery. Although these patients have superior disease-free and overall survival compared to their counterparts achieving less significant responses2-4, there are currently no methods to identify them beyond performing surgery to verify a pCR. By better identifying the size and extent of residual disease, an accurate assessment of response after NAC completion would allow clinicians to stratify patients to receive breast conservation therapy (BCT), mastectomy, or possibly no surgery if the assessment correctly predicted a pCR. With NAC as a platform to estimate BCa response to chemotherapy, we will use novel functional imaging techniques and serum circulating glycomic biomarkers as surrogate predictors of early response (i.e., after one cycle of NAC) and final response (i.e., after completion of NAC).

We hypothesize that a functional tumor assessment utilizing high-definition positron emission tomography/computed tomography (HD PET/CT) and real-time serum glycomic profiling will predict NAC response in BCa patients.


CHRISTOPHER POLAGE, M.D.
Assistant Professor, Department of Pathology and Laboratory Medicine

Mentors:
• Jay V. Solnick, M.D., Ph.D., Professor of Medicine and Microbiology & Immunology
• Stuart Cohen, M.D., Professor of Medicine, Clinical Director, Department of Epidemiology and Infection Control

Research Study: 
Clostridium difficile is a spore forming Gram positive bacterium that can cause diarrhea, colitis and death. Since 2001, the frequency and severity of C. difficile infection (CDI) has increased ~5-fold in association with a hypervirulent strain, NAP1/BI/027. Currently, CDI is one of favor major healthcare associated infections and 178,000 to 500,000 U.S. patients develop CDI in the hospital each year. CDI increases hospital lengths of stay, has a 6 month all cause mortality of 30-34%, and adds 1.1 to 3.2 billion dollars annually to the healthcare budget. Typically, 20% of antibiotic treated patients become colonized with C. difficile in the hospital and 4-12% develop CDI. For 1 in 5 patients with CDI, illness recurs 1 to 8 times despite treatment. Host susceptibility, C. difficile virulence and disruption of the “normal” intestinal microbiota (e.g., by antibiotics) are risk factors for the development of CDI but the bacterial changes that precede C. difficile colonization and infection are incompletely characterized. In vitro and animal studies suggest that C. difficile germination, survival and growth may be altered by nutrient, bile and bacterial interactions (e.g., Bacteroidales, Lachnospiraceae, Ruminococcaceae, Bifidobacteriales) but the applicability of these data to human pathogenesis is not known. We have promising preliminary data that bacteria in the Gram negative order, Bacteroidales and Gram positive family, Lachnospiraceae are preferentially decreased in patients with CDI.


ELISA TONG, M.D., M.A.
Assistant Professor of Medicine, Department of Internal Medicine

Mentors:
• Moon S. Chen, Jr., Ph.D., M.P.H., Professor, Department of Internal Medicine
• Debora A. Paterniti, Ph.D., Associate Adjunct Professor, Department of Internal Medicine and Department of Sociology
• Janice Tsoh, Ph.D., Associate Adjunct Professor, Department of Psychiatry, University of California, San Francisco

Research Study: 
Tobacco is the leading preventable cause of morbidity and mortality, yet declines in smoking prevalence are slow and new strategies are needed to address utilization of cessation assistance and prevention of relapse. Smokefree policies, based on the fact that secondhand smoke harms others, have been important public health measures that foster public social norm changes to encourage smokers to quit and protect nonsmokers from exposure.  However, these public health policies have not yet been fully translated into clinical interventions to promote adult cessation.  Secondhand smoke interventions have been conducted on behalf of the pediatric population, but success has mostly involved reducing the child’s exposure and not parental cessation. Social relationships between adults have been demonstrated in epidemiologic studies to be associated with cessation, but the heterogeneous interventions which involve adult nonsmokers supporting smokers to quit have led to mixed results.  Nevertheless, the belief that secondhand smoke harms others, along with provider advice, is associated with wanting to quit among adult smokers.  Smokefree home rules are associated with being a former or lighter smoker in California, particularly amongst recent immigrants from countries that do not have smokefree social norms.  To date, no one has used the idea that secondhand smoke is harmful to others as a basis for fostering bidirectional social support for a smokefree social norm between adult smokers and nonsmokers.

We propose to adapt a secondhand smoke counseling intervention for adults, using dyads of smokers and household nonsmokers, that can be implemented in the outpatient setting.  The theoretical basis for this intervention is grounded in the Population Health Promotion Model and social support theory.  Preliminary results from our National Cancer Institute-funded pilot study developed the basis for this study: California Chinese-speaking adult smokers and nonsmokers (who have experienced a recent smokefree social norm change as immigrants) want health professionals, communication strategies, and lab tests to help navigate discussions about quitting smoking and eliminating smoke exposure.  The UC Davis Medical Center is an ideal setting for empirical investigation, given its clinical outpatient and Clinical Translational Science Center resources, and Sacramento provides an ideal population with its ethnic and socioeconomic diversity and higher smoking prevalence (16%) than the rest of the state (14%). 

The intervention will be assessed and analyzed in a pilot randomized trial, designed to evaluate efficacy with a control condition of minimal intervention and no personal contact.  The proposed intervention will consist of:  1) group education for dyads of smokers and household nonsmokers about being smokefree together, followed by 2) motivational interviewing with each dyad that incorporates biomarker feedback for their smoke exposure.  The control condition will have dyads of smokers and household nonsmokers receiving the state’s free quitline contact information in the mail with assessment only. 


AMIR ZEKI, M.D., M.A.S.
Assistant Professor of Medicine, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine 

Mentors:
• Nicholas Kenyon, M.D., Associate Professor of Medicine, Department of Internal Medicine
• Reen Wu, Ph.D., Professor of Medicine, Department of Internal Medicine

Research Study: 
Asthma continues to progress in many patients despite our best current therapies. Multiple observational studies have demonstrated improvements in asthma and COPD lung function and health outcomes associated with statin use. However, small clinical trials in asthma using statins have yielded mixed or negative results. Based on results from our asthma mouse model and cell culture work, we have uncovered a critical role for the enzyme HMG-CoA reductase (HMGR), the central target of the statin drugs in the mevalonate pathway. Given that asthma is an airway disease with aberrant and progressive airway structural changes (aka ‘remodeling’), and given the involvement of HMGR in inflammatory and proliferative responses, it remains unknown whether orally ingested statins penetrate into the human airway and inhibit HMGR. Therefore, I hypothesize that the statin drugs ingested at cholesterol-lowering doses penetrate into the airway and inhibit the target enzyme HMG-CoA reductase.

The hypothesis will be tested with the following specific aims:
1. Test the hypothesis that systematically administered simvastatin a) inhibits HMG-CoA reductase enzyme activity in mouse airways in vivo, and b) is measurable in mouse airways.
2. Test the hypothesis that simvastatin treatment of primary human airway epithelial cells at concentrations found in human serum will inhibit HMG-CoA reductase enzyme activity.
3. Pilot Study: to determine if airway epithelial cells derived from normal controls, statin-treated asthmatic patients, and asthmatics not treated with statins a) have different levels of HMG-CoA reductase enzyme activity, and b) whether the statin of interest is measurable in human airways.
 

Former Scholars

APRIL ARMSTRONG, M.D.
Assistant Professor of Dermatology, Department of Dermatology
Mentors:
• Richard Kravitz, M.D., M.S.P.H., Professor, Division of General Medicine, Co-Vice Chair (Research),
Department of Internal Medicine
• Fu-Tong Liu, M.D., Ph.D., Professor and Chair, Department of Dermatology
• Thomas S. Nesbitt, M.D., M.P.H., Professor of Family & Community Medicine

MARK AVDALOVIC, M.D.
Assistant Professor, Department of Pulmonary and Critical Care
Mentors:
• Dallas M. Hyde, Ph.D., Professor and Director, California National Primate Research Center
• John Robbins, M.D., M.S., Professor of Medicine, Department of Internal Medicine

ANDREW BREMER, M.D.
Assistant Professor, Department of Pediatrics
Mentors:
• Lars Berglund, M.D., Ph.D., Professor of Medicine, Associate Dean for Research
• Peter J. Havel, D.V.M., Ph.D., Professor, Molecular Biosciences and Nutrition

JENNIFER LEE, M.D.
Assistant Professor, Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine
Mentors:
• Lars Berglund, M.D., Ph.D., Professor of Medicine, Associate Dean for Research
• Ellen Gold, Ph.D., Professor and Chief, Division of Epidemiology, Department of Public Health Sciences

MICHAEL MINZENBERG, M.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences
Mentors:
• Cameron Carter, M.D., Professor, Department of Psychiatry and Behavioral Sciences
• Charan Ranganath, Ph.D., Associate Professor, Department of Psychology

CHONG-XIAN PAN, M.D., Ph.D.
Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology
Mentors:
• Kit S. Lam, M.D., Ph.D., Professor and Chief, Division of Hematology/Oncology
• Ralph de Vere White, M.D., Professor, Department of Urology, and Director, UC Davis Cancer Center

ULFAT SHAIKH, M.D., M.P.H.
Assistant Professor, Department of Pediatrics
Mentors:
• Patrick S. Romano, M.D., M.P.H., Professor of Medicine & Pediatrics
• Thomas S. Nesbitt, M.D., M.P.H., Professor of Family & Community Medicine
• Dennis M. Styne, M.D., Professor of Pediatrics & Division Director, Pediatric Endocrinology

MARK UNDERWOOD, M.D.
Assistant Professor, Department of Pediatrics
Mentors:
• Charles L. Bevins, M.D., Ph.D., Professor, Department of Microbiology and Immunology
• David A. Mills, Ph.D., Associate Professor, Department of Viticulture and Enology