Attached below are:
Assessing access to prenatal HIV screening in Salvador, Brazil
Sabrina Tom, student (HSPR!)
Corinna Haberland, mentor (Health Research & Policy)
Vertical transmission of HIV is the main source of HIV infection in children. In Brazil, vertical transmission was responsible for approximately 85% of AIDS cases in children over the past decade and reduction of vertical transmission has been among the priorities of the Brazilian Ministry of Health’s National STD/AIDS Program. The introduction of antiretroviral therapy for HIV positive pregnant women has been an enormously effective intervention. However, the earlier the antiretrovirals are initiated, the greater their efficacy in preventing infection in infants. This study will obtain information about the perceived availability of prenatal care and the quality of prenatal screening for human immunodeficiency virus (HIV) in Salvador, Brazil through the presentation of a questionnaire to women who have just delivered at the main public hospital in Salvador. By identifying potential gaps in prenatal care and screening, this data may help guide local clinicians and policy-makers to establish more effective approaches to educating women, and improving access to care, thereby improving maternal health, and aiding in the prevention of vertical transmission of HIV.
A whole-cell lymphoma vaccine to boost anti-tumor immunity induced by adoptive cell transfer immunotherapy
James Torchia, student (MBM)
Ronald Levy, mentor (Medicine…Oncology)
Adoptive cell transfer immunotherapy for lymphoma involves the transfer of T-cells to a patient with the intention of using cell based immunity to specifically target cancerous cells for destruction. Our group previously described a vaccination maneuver that efficiently generates T-cells reactive against the murine A20 B-cell lymphoma. Recent studies have demonstrated that lymphocytes derived from mice inoculated with this anti-tumor vaccine cure large murine lymphomas when adoptively transferred to lymphopenic tumor-bearing recipients. The lymphopenic environment appears to provide transferred T-cells with a signal to proliferate and the number of anti-tumor CD8 T-cells significantly increases resulting in enhanced anti-tumor immunity.
I propose to investigate whether such anti-tumor immunity can be further enhanced by the transfer of a whole cell lymphoma vaccine in conjunction with the transferred anti-tumor lymphocytes – a maneuver we have termed a “vaccine boost”. Such a maneuver could provide transferred tumor-specific T-cells with additional activating signals through T-cell receptor (TCR) engagement and co-stimulation, conferring a selective proliferative advantage on the tumor-reactive population. Thus a vaccine boost may increase the potency and duration of the anti-cancer immune response in the recipient animal and may allow adoptive transfer therapy to be performed in less lymphopenic recipients.
Immunologic Response to Human Embryonic Stem Cell-Derived Cardiomyocytes in the Humanized Mouse
Jeremy Pearl, student (MBM/CVP)
Joseph Wu, mentor (Medicine…Cardiovascular Medicine)
The purpose of this medical scholar’s proposal is to define the immunogenicity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and identify the molecular basis of the immune response. In contrast to undifferentiated hESCs which produce teratomas, the more differentiated hESC-CMs do not. Furthermore, recent investigations have demonstrated hESC-CM's efficacy for myocardial regenerative therapy. However, allogeneic transplantation of hESC- CMs may produce an immune response and be rejected. Previous studies have been limited because they used either xenogeneic transplantation of human cells or allogeneic transplantation of mouse cells. The current proposal avoids these limitations by focusing on allogeneic transplantation of human cells, using a novel “humanized” mouse model as the graft recipient. Non-invasive bioluminescent imaging will be used to track transplanted cell survival and identify the timing of rejection. Since hESC-CMs may become immunogenic due to changes in the cells after transplantation, these changes will be analyzed by recovering the cells after transplantation and using FACS and microarrays to assess cell surface expression of inflammatory molecules and expression of genes related to the immune response. Finally, the SEREX technique will be used to identify the exact molecular sequence of the antigens which produce the immune response. Defining the immunologic profile of hESC-CMs before and after transplantation and identifying the molecular sequence of hESC-CM antigens will provide a platform to design novel interventions for managing the immune response during cell transplantation.
Media Treatment of the Ethical, Legal, and Social Implications of Personal Genomics
Hugh Keegan, student (BEMH)
Mildred Cho, mentor (Pediatrics…Genetics)
The completion of the first several individual human genomic sequences by multiple groups over the last year portends the beginning of the “personal genomics” era. Individuals will increasingly be able gain access to their personal genome. Though other forms of genetic testing have been available for decades, new technological breakthroughs have made sequencing large percentages of individual genetic variation, and even complete genomes, economically feasible. In a harbinger of things to come, over the last several months a variety of commercial entities have begun to offer personal genomic services directly to consumers. Though many of the ethical, legal, and social implications (ELSIs) likely to arise in the personal genomics area have been thoroughly discussed in professional circles, it is largely unknown how mass media has covered the potential implications of personal genomics in their recent reporting. To the extent that the public learns about genomics through mass media, it is important to examine how ELSIs and technological limitations have been covered. We seek to analyze how ELSIs of personal genomic technologies have been represented in the US print media from 2006-2008 through a focused content analysis, and to use this information to develop conclusions about current trends in media communications. With this data we aim to identify potential ELSI issues surrounding personal genomics that are under-represented in current mass media, and comment on possible explanations for the findings.
Hematopoietic Stem Cell Transplantation in Pediatric Leukemia Patients: A Study on the Prognostic Value of Regimen-Related Toxicity
Meera Sridhar, student (CR)
Joshua Schiffman, mentor (Pediatrics…Hematology/Oncology)
Acute leukemia is the most common pediatric malignancy, accounting for nearly 30% of all new cancer in children. Survival for children with leukemia has markedly improved since the early 1970s, mostly due to improvements in treatment regimens and randomized clinical trials. Yet further improvements are needed, as relapsed leukemia remains the leading cause of death in children with cancer. The use of hematopoetic stem cells transplant (HSCT) remains the recommended treatment for patients considered to be at high risk and provides the highest cure rates. Current prognostic determinants for HSCT recipients are limited to the type of transplant received (allogeneic vs. autologous) and severity of graft vs. host disease (GVHD). One parameter whose prognostic significance has yet to be investigated is regimen related toxicity (RRT). For reasons not yet completely clear, patients receiving the same preparative regimens respond with varying degrees of toxicity, suggesting that individual variations in genetic composition may play a role in these differences. HSCT-related toxicities may consequently determine how patients respond to their preparative treatment regimen, and therefore to what extent the regimen eradicates the leukemia during the treatment phase. The purpose of this study is to establish whether RRT can be used to predict the outcome of pediatric HSCT patients. To accomplish this, a systematic chart review will be conducted on 100 pediatric allogeneic HSCT recipients with acute leukemia. A previously validated toxicity grading scale designed to distinguish RRT from other toxicities (ie GVHD) will be used to assess stomatotoxicity, hepatoxicity, nephrotoxicity, and time to hematological recovery as indicators of RRT. An independent sample, two-tailed t-test will be used to compare RRT scores between children in different transplantation outcome groups (relapse and death vs. complete remission) to determine if a statistically and clinically significant difference exists between the two groups. Kaplan-Meier analysis will also be used to compare overall survival rates between patient groups stratified based on cumulative RRT. A correlation between RRT and outcome would have important clinical implications and could lead to the introduction of RRT as part of the prognostic scoring system for pediatric HSCT patients.
The Use of Manganese-Enhanced Magnetic Resonance Imaging to Visualize Nociception-related Spatiotemporal Changes in the Peripheral Nervous Sytem
Harpreet Dhatt, student (CH/NBC)
Sandip Biswal, mentor (Radiology…Diagnostic Radiology)
Chronic pain sufferers, including individuals with arthritis, back pain, inflammatory pain and neuropathic pain, not only face limited therapeutic options but also face tremendous diagnostic challenges. The lack of diagnostic accuracy can be partly explained by our inability to accurately localize hypersensitive pain-sensing (a.k.a. ‘nociceptive’) neural pathways that are acting as pain generators. In the past several years, manganese-enhanced magnetic resonance imaging (MEMRI) has emerged as a powerful surrogate marker for imaging calcium flux into tissues. Since activated, firing pain-sensing neurons rely upon calcium fluxes for propagation of the pain signal, MEMRI has the potential to image heightened nociceptive activity in the spinal cord, DRG, and peripheral nerve. We hypothesize that MEMRI can be used not only to localize a ‘fired-up’ pain pathway but also objectify nociceptive activity in the central and peripheral nervous system in living, longitudinal models of peripheral pain. Specifically, I will ask 2 questions: 1.) Is there spatiotemporal distribution of MnCl2 (manganese) in the spinal cord, dorsal root ganglion, and peripheral nerve in the context of increased nociceptive activity? 2.) What is the difference in MEMRI between neuropathic, inflammatory and acute injury pain as well as in sham and analgesic models?
Monitoring Anti-VEGF Therapy Using [18F]-5-Fluorouracil PET/CT Imaging
Maurice Zissen, student (BENG/CBIO)
Andrew Quon, mentor (Radiology…Nuclear Medicine)
It has recently been shown that the addition of anti-angiogenic agents such as bevacizumab to standard chemotherapy increases treatment response rate and prolongs overall survival [1,2]. However, long-term or high-dose anti-angiogenic therapy may lead to a vasculature that is inefficient for drug delivery and resistant to current treatment standards. Bevacizumab, commercially known as Avastin, is known to bind and inactivate circulating vascular endothelial growth factor. However, the mechanism and the in-vivo physiologic effects of this inactivation have been the subject of intense debate and investigation. The Jain hypothesis suggests that treatment with bevacizumab improves chemotherapy efficacy by normalizing tumor vasculature leading to more efficient oxygen and drug delivery [4,5]. Furthermore, this theory implicates the timing and dosage of bevacizumab with respect to chemotherapy as an important consideration in treatment regimen design. However, no studies have yet been conducted in humans to determine the most effective time to administer bevacizumab to maximize its effects. This study is designed to determine whether using a radiolabelled analog of 5-FU, [18F]-5-fluorouracil, for PET/CT imaging can directly demonstrate differential chemotherapy delivery to known tumor sites before and after administration of bevacizumab. Furthermore, we hope to determine the optimal timing of bevacizumab administration to maximize the chemotherapy delivery. PET/CT scans will be acquired dynamically for 120 minutes to determine the maximum concentration of [18F]-5FU in the tumor (C_max) and area under the time activity curve (AUC) for each metastatic lesion. Differences between pre- and post-bevacizumab C_max and AUC will be calculated as the primary outcome measures. Quantifying differential chemotherapy delivery to known tumor sites will allow us to determine the optimal timing of bevacizumab infusion in order to improve therapy monitoring and treatment success.
Testing the Importance of Surrounding Residues in Positioning Hydrogen Bond Donors in the Oxyanion Hole of Ketosteroid Isomerase
Sarah Nelson, student (MBM)
Daniel Herschlag, mentor (Biochemistry…Operations)
Enzymes are central to all biological processes and attractive targets for pharmaceutical intervention in health and disease. Deep understanding of the chemical and physical principles that govern enzymatic catalysis is a requirement for the design of enzymes with desired properties and may aid in designing highly specific and effective medicines. Although the chemical steps of many enzymatic reactions are known, understanding the physical basis of enzyme rate enhancement remains a significant challenge. A longstanding hypothesis in biochemistry is that enzymes are electrostatically and geometrically complementary to the transition states of the reactions they catalyze and that the resulting preferential stabilization of the transition state relative to the ground state contributes significantly to rate enhancement. The bacterial enzyme ketosteroid isomerase (KSI) provides a powerful model system in which to test this hypothesis and probe the contributions of electrostatic and structural complementarity to catalysis. Previous work with this enzyme suggests that charge complementarity makes only a modest contribution (Kraut et al., 2006). To test whether shape complementarity contributes significantly to KSI catalysis, I will continue to mutate residues that contact and appear to help position active site hydrogen bond donors Tyr16 and Asp103, both of which appear exquisitely pre-positioned to preferentially stabilize the tetrahedral transition state relative to the planar ground state. As these mutations are expected to alter the positioning of Tyr16 and Asp103, determining the magnitude to which these mutations are able to reduce KSI catalysis will suggest whether geometric complementarity plays a significant catalytic role and thus test a long-standing theory regarding the physical origin of enzyme catalysis.
Building the Human Disease "Etiome"
Yueyi “Irene” Liu, student (BMI)
Atul Butte, mentor (Medicine...Stanford Medical Informatics)
It has long been known that both genetic and environmental factors contribute to human diseases. Though genetic contributions are relatively well characterized for some monogenetic diseases, there has been no effort at curating the extensive list of environmental factors. In this project, I plan to first identify all genes associated with complex diseases from a database of genetic association studies. A human disease network based on genetic contributions can then be built. I also plan to build another disease network based on environmental etiological factors, which can be identified from a comprehensive search of MEDLINE articles. Combining the two networks will result in a human disease “etiome”, a first-step towards a comprehensive compendium of both genetic and environmental etiological factors associated with diseases. I hope to identify hubs of genes or environmental factors, i.e. genes/environmental factors that are associated with many diseases.