Prior Pilot Studies Awardees
2015 Faculty Awardees
Emily Carmody, MD
Assistant Professor of Orthopaedic
Co-Investigators: Michael Zuscik and Christopher Ritchlin
Project: Assessment of Forteo as a Therapeutic to Treat Knee Osteoarthritis
Traditional treatment strategies for Osteoarthritis are palliative, with the focus on pain management and joint replacement. Development of disease-modifying agents that can rejuvenate cartilage is a great unmet need. Thus, development of an effective remittive treatment for Osteoarthritis is a vital public health initiative with potential for tremendous impact. Data mined from the NIH-sponsored OA Initiative revealed improved WOMAC knee function scores in arthritic subjects coincidentally prescribed Forteo to treat osteoporosis. These preclinical and human data provide compelling rationale to study Forteo as a novel OA therapy directed at improving joint structure and function. The central Aim of this research program is to challenge the paradigm that cartilage loss in Osteoarthrtitis is irreversible.
David Herrmann, MD
Professor of Neurology
Project: A Pilot Study of Mexiletine for Muscle Cramps in Charcot Marie tooth Disease
Charcot Marie Tooth Disease (CMT) is a family of inherited peripheral neuropathies which affects 1/ 2500 individuals. CMT Type 1A (CMT1A) is an autosomal dominant disorder that accounts for 50% of CMT and manifests in childhood or early adulthood with progressive muscle weakness and atrophy, sensory loss, impaired ambulation, pain and disability. Muscle cramps affect about 85% of adults with CMT1A and impact quality of life and have been identified as an important therapeutic target in CMT1A. Mexiletine is an oral sodium channel blocker that in low doses has shown promise for prevention of muscle cramps, but data is lacking on its effectiveness in CMT1A. The overall goal of this pilot, double-blind randomized placebo controlled crossover study, is to obtain preliminary data on the efficacy and tolerability of low dose mexiletine for muscle cramps in adults with CMT1A.
Eva Pressman, MD
Chair and Professor of Obstetrics and Gynecology
Co-Investigator: Kimberly O'Brien
Project: Vitamin D Kinetics During Pregnancy
Nearly 30% of US women are either vitamin D insufficient or deficient. Vitamin D inadequacy during gestation is increasingly linked to adverse birth outcomes including preterm birth, risk of cesarean section and placental and pregnancy associated infections. At this time the IOM has not advocated any increase in vitamin D intake across gestation but this remains controversial in large part due to insufficient information on the basic physiology of vitamin D. Recent mass spectrometric instrumentation advances have provided opportunities to use deuterated vitamin D analogs as tracers to gain novel data on in vivo vitamin D metabolism at key life stages. In this pilot study, the overall objective is to take advantage of UHPLC-MS/MS instrumentation and deuterated vitamin D to obtain information on the absorption and half-life of vitamin D3 in non-pregnant and pregnant women.
Xingping Zhang, MD, PhD
Associate Professor of Orthopaedics
Co-Investigator: Stephen Kates
Project: Identification of the Effective Vascular Progenitors for Bone Repair and Regeneration
Stem/progenitor cell-based therapy has taken the center stage of regenerative medicine in the past two decades. A new cell-based therapy is emerging that aims to utilize endothelial progenitor cells (EPCs) alone or in combination with mesenchymal stem cells (MSCs) to enhance revascularization of the implant and thereby the survival and differentiation of the osteoprogenitors. Studies from several laboratories have demonstrated that delivery of EPCs alone or in combination enhances the vascularization of the implant and even contributes to the formation of bone in repair and reconstruction. However, despite the accumulating reports, the mechanisms by which EPCs participate in repair and the effective sources/populations of the EPCs that synergize with skeletal progenitors to enhance repair in vivo remain controversial and poorly defined. The goal of this pilot project is to devise a translational strategy to enhance bone repair and reconstruction.
2015 Clinical Trials Methods and Technologies
Martin Zand, MD, PhD
Professor of Medicine (Nephrology)
Co-Investigators: Jiong Wang, PhD, and John Treanor, MD
Project: Assessing Heterosubtypic Antibody Responses in Influenza Vaccine Clinical Trials
Pandemic influenza from emerging or mutated influenza strains is a large public health threat, and each year multiple clinical trials are done to assess vaccine efficacy. Current flu vaccination strategies confer strain specific immunity by inducing antibodies directed at the viral hemagglutinin protein, thus preventing virus binding to target cells and infection. Unfortunately, current methods of assessing vaccine efficacy are based on the hemagglutinin inhibition assay (HAI), which is 80 years old, time and labor intensive, and does not provide a continuous quantitative readout. Thus, there is a great need for an easy, rapid, sensitive and accurate assay to evaluate influenza vaccine efficacy, especially the induction cross-reactive immunity to multiple influenza strain subtypes (heterosubtypic immunity). The long-term goal of this project is to use this validation data to examine and track population heterosubtypic immunity, and to seek involvement in clinical trails of new H5 and H7 avian influenza vaccines..
2015 Trainee Awardees
Graduate Student in the Department of Medicine (Allergy, Immunology, and Rheumatology)
Mentors: Jennifer Anolik, Minsoo Kim, and Jane Liesveld
Project: Neutrophils as a driver of inflammation in lupus bone marrow
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease with a complex pathogenesis that presents a challenge for development of specific and effective therapeutic targets. This pilot project examines the role of one central mediator of SLE pathogenesis: chronically elevated type I interferon (IFN), examining both the mechanisms underlying its generation as well as its contribution to pathology in SLE marrow. The results of this pilot grant will lay the groundwork for development of specific therapeutic targets needed to treat pathology in lupus bone marrow.
2014 Faculty Awardees
Roman Eliseev, MD
Assistant Professor, Center for Musculoskeletal Research
Improving Mitochondrial Function in Mesenchymal Stem Cells to Accelerate Fracture Repair in Aging
The goal of this project is to test whether improving mitochondrial function in mesenchymal stem cells (MSC) will accelerate fracture healing during aging. In aging, MSC function and osteogenicity are compromised which is suggested to be a reason for delayed fracture healing. Our data and the literature indicate that MSC ability to differentiate into osteogenic lineage depends on their ability to activate mitochondria which are initially inactive in undifferentiated MSCs. Mitochondria in aged MSCs are less active due possibly to the MPT, a non-specific mitochondrial pore regulated by cyclophilin D and frequently observed in aged mitochondria. Thus, inhibition of the MPT is hypothesized to improve MSC mitochondrial function, osteogenicity, and, as a consequence, outcomes of fracture repair in aged mice.
Elizabaeth Guancial, MD
Assistant Professor of Medicine (Hematology and Oncology)
Chemoprevention of bladder cancer through estrogen receptor modulation
While bladder cancer (BC) has not historically been viewed as a hormone-sensitive cancer, differences in rates of development and prognosis between men and women with BC suggest that estrogens or the estrogen receptor (ER) may be involved in BC carcinogenesis. In vitro studies in BC cell lines demonstrate ER-dependent growth inhibition by antiestrogen agents. Most patients with muscle-invasive BC are unable to receive recommended neoadjuvant or adjuvant chemotherapy due to medical comorbidities and toxicity, despite a high risk of relapse after radical cystectomy alone. Therefore, new treatments are urgently needed to reduce the risk of BC relapse after surgery and for the treatment of advanced BC in patients with other comorbidities. Antiestrogens are commonly used to treat breast cancer and have an acceptable safety profile for most patients. The objective of this project is to investigate the therapeutic role of antiestrogens in the chemoprevention and treatment of BC in order to identify novel therapies that are effective and tolerable and to establish a mechanism of action for these agents through the study of the relative contribution of the two ER subtypes, ERalpha (ERa) and ERbeta (ERb), to BC carcinogenesis in order to identify predictive biomarkers of response to antiestrogens.
R. John Looney. MD
Professor of Medicine (Allergy, Immunology and Rheumatology)
Role of the Gut Microbiome in Preventing Allergic Disease
The epidemic of allergic and autoimmune diseases in developing countries is one of the greatest medical challenges of the 21st century. Although we have greatly improved treatment for many of these diseases, our goal should also be prevention. As discussed above there is considerable data suggesting that the key to this epidemic his how the environment influences immune system development. Finding a population at low risk and comparing immune system development in that population to immune system development in a high risk population is a critical need for this entire area of investigation. The Old Order Mennonite's (OOMs) population of upstate New York provides and an ideal low risk population. The OOMs have a lifestyle incorporating all the various environmental factors that have been associated with a low risk of asthma and allergic diseases including growing up on a farm, having large families, exposure to numerous pets in farm animals, exposure to raw milk, low rate of smoking, and low rate of antibiotic utilization. Our preliminary studies have confirmed at the OOMs did have a markedly lower risk of asthma in the general population in upstate New York. Central Hypothesis – The low rate of atopic disease in children who grow up on farms with numerous siblings is related to accelerated maturation of the immune system due to stimulation of the mucosal immune system early in life by the a diverse microbiome that stimulates innate immune receptors.
Edward Messing, MD
Professor of Urology
Exosomes from bladder cancer patients can serve as biomarkers of disease progression
Bladder cancer is the 5th most commonly diagnosed cancer, the most expensive to treat over the lifetime of the patient, and utilizes the most Medicare dollars. Much of the cost associated with bladder cancer is related to the surgical interventions necessary to diagnose and treat the disease. Moreover, treatment of high-grade bladder cancer is marked with elevated rates of morbidity and mortality (i.e. 36% 5 year survival for pT2 disease). Over the last thirty years there has been very little advancement in chemotherapeutic options for bladder cancer. Identifying markers of tumor progression through less invasive means could expedite treatment, prevent progression, identify novel therapeutic targets and contain cost. Recently an interest in small membrane bound vesicles called exosomes has emerged. Exosomes have been shown to be important mediators of tumor progression and contain biologically active proteins, messenger (m)RNA, long non coding (lnc)RNA, and micro (mi)RNA. Importantly, exosomes can be readily isolated from blood and urine. We have identified lncRNA and mRNA associated with tumor progression in the exosomes of patients with pT2 bladder cancer suggesting the feasibility of this project. The fundamental goals of this project are to identify stage-specific biomarkers of bladder cancer progression by RNA-sequencing of primary tumors as well as exosomes purified from the urine and blood of patients, and ultimately in downstream experiments identify which of these RNA are important in tumor progression and therefore may serve as targets for anti-sense therapeutics.
Craig Morrell, DVM, PhD
Associate Professor of Medicine
Novel microRNA Based Therapy to Improve CD4+ T-cell Responses to Vaccination
This project will explore how miR-451 regulates T-cell responses to malaria infection and the use of antagomirs to increase responses to malaria vaccination or infection, representing an important conceptual and therapeutic advancement. These studies will be catalytic in generating new programs and funding for our clinically applicable research. An additional goal of our program is the stimulation of continued crossdisciplinary collaborations between members of the CVRI and Microbiology and Immunology. We will use the combined expertise and knowledge of the Morrell lab, who have extensive experience in animal models of malaria infection), the Lowenstein lab who have published many studies related to miRNA, and the Fowell lab who have great expertise in mechanisms of CD4+ T cell responses.
Sherry Spinelli, PhD
Research Associate Professor of Pathology and Laboratory Medicine
The Role of Microparticle-Derived Thy-1 (CD90) in Type 2 Diabetes Mellitus
Thy1 (CD90) is a glycophosphatidylinositol-anchored protein that was discovered decades ago, and recognized simply as a surface marker of unknown function. Recently, our laboratory pioneered studies demonstrating that Thy1 is a key signaling protein that inhibits adipogenesis (fat formation). Thy1 expression down regulates crucial pro-adipogenic factors, such as peroxisome proliferator activated receptor gamma (PPARgamma). While Thy1 was originally identified on the surface of nucleated cells, we have discovered it is present on anucleate platelets and on the platelet progenitor cell, the megakaryocyte. Importantly, Thy1 is also released in platelet microparticles (MPs), thus Thy1 could control adipogenic potential via transcellular regulation in recipient cells. Given the importance of Thy1 in the regulation of adipogenesis and attenuation of proinflammatory adipokines, Thy1 may be an integral player in the pathophysiology of type 2 diabetes mellitus (T2DM), an emerging global epidemic characterized by obesity and a proinflammatory profile. Our group recently detected and measured Thy1 expression in megakaryocytes, platelets and MPs in type 2 diabetics (T2D) versus healthy individuals. Levels of Thy1 were much lower in T2Ds, and importantly, the lack of Thy1 in T2D MPs could be a crucial mediator in upregulating inflammation and adipogenesis in recipient cells.
2014 Trainee Awardees
Specialized proresolving mediators act as novel therapeutics against infection
Nontypeable Haemophilus influenzae (NTHi) is a gram-negative, opportunistic pathogen that commonly causes respiratory diseases, including bronchitis and pneumonia. People with a preexisting inflammatory condition, such as chronic obstructive pulmonary disease (COPD) or an additional infection, are particularly susceptible to NTHi. These infections are increasing in incidence and are often persistent, resulting in bacteria propagating in the airways. Recently, endogenously produced, specialized proresolving lipid mediators (SPMs) were discovered. SPMs play a critical role in the active resolution of inflammation through both anti-inflammatory and pro-resolving actions and are thus strong candidates for use in treating infections. They have been shown to be efficacious in reducing mortality and in decreasing bacteria blood levels through enhanced phagocytosis in mice infected with E. coli. The efficacy of SPMs in promoting resolution of pulmonary infections, however, has not been investigated. My unpublished data shows that SPMs can dampen lung inflammation caused by cigarette smoke or LPS in preclinical mouse models. In human macrophages SPMs increase phagocytosis of bacteria and apoptotic neutrophils.. This research is the first to assess SPMs in pulmonary infections and will provide the groundwork for further investigation and eventual translation of SPMs into a clinical setting.
Comparative effectiveness of screening methods for type 2 diabetes: a pilot study
The ultimate goal of this project is to compare, in a large-scale randomized clinical trial, the effectiveness of three screening strategies to detect type 2 diabetes: fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and point of care testing (POCT) HbA1c, as they are performed in real clinical settings. Currently, more than one quarter of adult diabetics in the US are undiagnosed and thus at risk of developing diabetes complications by the time of their delayed diagnosis. The panel of approved tests for screening and diagnosis of type 2 diabetes includes only tests performed at central laboratories, such as FPG and HbA1c. Although not approved for this purpose, POCT HbA1c, which is performed at the practice’s site and provides the results within minutes of testing, is used to screen for type 2 diabetes in some clinical settings. Previous studies have focused on the laboratory performance of the screening tests for diabetes, but have not compared their effectiveness when used in real clinical settings.
2014 NBEM Awardees
Associate Professor of Biostatistics and Computational Biology
Cure Model in Recurrent Event Data
Although cure model has been studied in traditional survival analysis, for recurrent event data, the case is much more complicated. Unlike the survival data with at most a single event, the observations are censored for study subjects. Some subjects may be cured from the very beginning of the study while some subjects are cured after a few relapses. In this study we will (1) develop a method to test whether the follow-up is long enough to declare some individuals cured; (2) develop nonparametric method to estimate the cure fraction; (3) develop semiparametric method to study the effects of come covariates on the cure probability; and (4) develop a method to make prediction of cure based on some prognostic factors.
Assistant Professor of Biostatistics and Computational Biology
Causal Inference with Zero-inflated Predictors: Alcohol, HIV Risk, and Depression
To make causal inference, we have to compare outcomes between the at- and non-risk groups
separately derived from the theoretical concept of structural zeros. The challenge is that the membership of the two risk groups is unknown for subjects without observed drinking (e.g., 0 in the days of drinking); they may or may not be at-risk, depending on whether they have structural or random zeros. Some recent studies modeled the zero-inflated nature of the count response when they appear as the dependent (or response) variable, but no statistical methodology is available to infer the causal relationships when such variable appears as independent variable. Our goals in this proposal are (1) develop new statistical methods to model the latent membership of the at and non-risk group to enable causal inference of the risk (i.e., an independent variable) on health outcomes; (2) create software for implementing the new statistical methods; (3) test the hypotheses about the role of alcohol on causing (a) depression, and (b) greater frequency of HIV risk behaviors using HANES 2009-2010 data; (4) document the findings as pilot results for our R01 resubmission.
Research Assistant Professor of Biostatistics and Computational Biology
Modeling Human Interactions in Social Networks
The proposed research addresses the lack of methods for modeling and assessing the effect of human interaction on behavioral and health outcomes of socially connected individuals. A main premise of this pilot study draws upon recent innovations and methods in the evolving field of data science, a new and burgeoning field that integrates both qualitative and quantitative data analytics to draw and capitalize upon Big Data possibilities stemming from mobile and web technologies and social media. We stand on the cusp of a new opportunity due to: improvements in computing, the rapidly growing ubiquity of smart environments, and a resulting duality in contemporary society, that is, the norm of living simultaneously within virtual as well as geophysical proximal interactions and community contexts. Massive amounts of diverse unstructured and structured data about interactions and interventions can now be culled from online sources such as social media, emails, and websites. Mobile devices and online social media such as Smart phones and Twitters generate new potentials over the traditional research paradigm for virtually all disciplines including statistics and its applications to clinical research and practice. Traditional statistical paradigms premised upon individual, within-subject attributes are fundamentally at odds with dependent human interconnections in such data. Well-developed theories of U-statistics and Functional Response Models, along with our experience with leading these theories and applications, positions the proposed proof of concept study to pilot test a new paradigm to model the effect of human interaction on changes of behavioral and health outcomes of socially connected individuals. Further, the software and associated documentation, to be made available via a number of venues including "CTSpedia.org" (a new NIH-funded reference and resource website with a repository of statistical functions to promote multidisciplinary interactions and collaborations), will catalyze the use of such interpersonal, participatory and interactive information from online and mobile sources in disease prevention and health promotion.
2013 Faculty Awardees
W. Richard Burack, MD, PhD
Associate Professor, Pathology and Laboratory Medicine
Quantifying Tumor Diversity to predict and target Cancer progression
Biomarkers that predict chemotherapy resistance, relapse and/or transformation risk are critically needed. Because intratumoral genetic diversity is the basis for the evolution of chemotherapy
resistance, relapse, and aggressive transformations of cancers, a metric of genetic diversity has the potential to be a transformative biomarker. Genetic diversity has long been recognized in Follicular lymphoma (FL), a B cell non-Hodgkin Lymphoma that is generally indolent but has a propensity to suddenly transform into a highly malignant form. Follicular B cells normally express an intrinsic genome-damaging enzyme, the APOBEC family member Activation-Induced (Cytidine) Deaminase (AID), an activity required for immunoglobulin diversification. While mutations associated with cancer frequently have the signature sequence of APOBEC/AID targeted loci, data directly implicating AID-induced damage in the generation of intra-tumoral diversification are lacking. Demonstrating this association would suggest a powerful biomarker for risk of progression: greater diversity predicting a greater risk of progression. Making this link requires a quantitative assay that measures AID-dependent intra-tumoral genetic diversity in a high throughput fashion from patients’ specimens, and such an assay has not been reported. Dr. Burack has developed a novel, DNA sequencing based method and analytical approaches to quantify intra-tumoral genetic diversity attributable
to AID. Dr. Burack’s group will apply this method to typical human tumor specimens to directly test if diversity predicts cancer progression.
Laura Calvi, MD
Associate Professor, Medicine (Endocrinology)
Osteoblastic Function in Human Leukemia
The mechanisms by which a leukemic clone suppresses normal hematopoiesis are poorly understood, and yet this phenomenon likely contributes to disease progression, disease morbidity and response to therapy. A recent analysis of the bone marrow microenvironment (BME) in a syngeneic mouse model of acute myeloid leukemia demonstrated dramatic osteoblastic defects. Dr. Calvi's laboratory has demonstrated the central role of osteoblastic lineage cells in hematopoietic stem cell (HSC) regulation, these data identify osteoblastic cells as a potential clinical target to stimulate normal HSC recovery in leukemia and decrease BME support of leukemic stem cells (LSCs). Moreover, they discovered leukemic production of the chemokine CCL3, which inhibits osteoblastic function in multiple myeloma. The goal of this pilot project is improving normal hematopoiesis and decreasing microenvironmental support for Leukemic Stem Cells, efficiently, effectively and safely apply pharmacologic tools currently approved for bone anabolic
treatment to leukemia. Data from this project would represent a paradigm shift in the therapy for patients with AML, where targeting of the BME improves our ability to treat the leukemia and more readily restore normal hematopoiesis.
Alan Smrcka, PhD
Professor, Pharmacology and Physiology
Inhibition of G protein beta/gamma signaling as a therapeutic approach to treatment of lupus
In complex autoimmune diseases such as Systemic lupus erythematosus (SLE) or rheumatoid arthritis the pathologies are driven in part by alterations of many circulating factors and responsiveness of cells to these factors. Inhibition of a shared signaling mechanism downstream from these receptors, that operates both in the adaptive and innate immune system, will likely result in higher efficacy than specific pathway or factor targeting. One such pathway is the G protein beta/gamma subunit signaling pathway downstream of the chemokines receptors that control the migration activation and survival of all types of immune cells. Dr. Smrcka has identified a compound that inhibits G protein beta/gamma subunit-dependent signaling in isolated human neutrophils, inhibits neutrophil migration in vitro, and inhibits acute inflammation in mice by preventing neutrophil migration and activation at sites of inflammation. Dr. Smrcka plans to test the viability of Gbeta/gamma inhibition as a treatment paradigm for lupus and to test a novel hypothesis that Gbeta/gamma inhibition ameliorates disease by acting at both the innate and adaptive immune system. Dr. Smrcka will collaborate with Jennifer Anolik, MD, PhD, Associate Professor of Medicine (Allergy/Immunology and Rheumatology) on this project.
2013 Trainee Awardees
Hsi-min (Jim) Hsiao, BS, MS
Pathology and Laboratory Medicine
Novel pro-resolving lipid mediators reduce cigarette smoke-induced emphysema
Chronic obstructive pulmonary disease (COPD, emphysema and chronic bronchitis) is the fourth leading cause of death in the United States. Importantly, the disease continues to worsen even after smoking cessation. Current therapies for COPD attempt to relieve the symptoms but do not alter the course of the disease; therefore, new therapies for COPD are desperately needed. This study will provide critical pre-clinical data needed to prepare for human clinical trials of resolvins in lung disease. A multidisciplinary collaboration has also been established to analyze the effects of resolvins on lung function, inflammatory response, cell death and signaling cascades, including clinically relevant measures such as pulmonary function testing, to increase the translational potential.
Jonathan Stone, BA, MD
Intraparenchymal Stent for Obstructive Hydrocephalus (IPSOH): a Novel Technology
Hydrocephalus is a common debilitating neurologic disease affecting a significant portion of the pediatric and adult population. The current surgical treatment options are fraught with complications and excessive costs heralding the need for new technology. Furthermore, the pathophysiological effects of hydrocephalus and fluid shunting on brain interstial fluid are unknown and need further investigation to improve patient care. This project will not only test the efficacy of this new shunt system in an animal model, but will also evaluate the movement of interstial fluid in hydrocephlaus and after both interventions.
2013 UNYTE Awardees
Steven Bernstein, MD
Professor of Medicine (Hematology and Oncology)
Lymphoma and its microenvironment; a novel in vivo model to study its interplay
Follicular lymphoma is an incurable disease with conventional therapy and thus new approaches for treatment are needed. As the lymphoma cells require signals from the other non-malignant cells in the tumor (the tumor microenvironment) to survive, targeting such interactions represents a novel approach for treatment. Recent data shows that the FL immune microenvironment, particularly the distinct T-cell populations infiltrating the tumor, play a critical role in modulating the biology and clinical behavior of this disease; however an understanding of how these populations modulate FL B-cell growth, viability and sensitivity to immune-chemotherapy (IC) is lacking. The investigators are now poised for the first time to test the central hypothesis that the interplay of FL Tregs and Tfh either directly or indirectly modulate FL B-cell growth, viability and sensitivity to IC in vivo.
Ankur Chandra, MD
Assistant Professor of Surgery (Vascular Surgery)
Regional Ultrasound Wall Strain Measurements to Predict Risk of AAA Rupture
Two-hundred thousand new Abdominal Aortic Aneurysm (AAA) cases are diagnosed each year in the United States; fifteen thousand people die from AAA rupture each year, making it the 13th leading cause of death in this country and affecting 1 in 250 individuals over 50 years of age. The exact cause of AAA formation is still unknown, although many theories base their pathogenesis as a multifactorial cause. Creating a “strain fingerprint” to determine the probability of a rupture is a viable new option that could significantly decrease AAA deaths. The project goal is to develop a novel application of existing ultrasound strain algorithms as a transcutaneous imaging modality to predict the risk of AAA rupture, regardless of size.
2013 NBEM Awardees
Anthony Almudevar, Bsc, Msc, PhD
Associate Professor of Biostatistics and Computational Biology
Predictive Models for Longitudinal Technological Home Monitoring Data
The aim of this proposal is to develop preliminary data and a proof-of-concept demonstration to leverage future research. The CB assessment application is particularly suitable for a number of reasons. The number of alternative assessment tools is limited to self-reporting, psychometric testing, or direct interview. We note also the availability of processed data from two parallel monitoring systems for caregiver/patient dyads, which is a highly specialized and uncommon scenario.
Changyong Feng, PhD
Associate Professor of Biostatistics and Computational Biology
Allowance for center effects in the analysis of randomized clinical trial with time-to-event outcomes
Many randomized clinical trials (RCT) have time-to-event outcomes. The log-rank test is widely used to analyze such event-time data as it is the most efficient nonparametric test under the hypothesis of proportional hazards. However the log-rank test assumes that individuals in the same treatment group are all homogeneous. Heterogeneity among individuals in a randomized study does not invalidate the log-rank tests, but it may make it less efficient. It is common to control heterogeneity using a stratified log-rank test (SLRT). It is known that if there is substantial heterogeneity among centers, the SLRT will be more sensitive to treatment differences than the unstratified test (here denoted ULRT). On the other hand, unnecessary stratification can lead to a loss of efficiency. However the trade-off between these two situations is still not well understood. In some practical situations the ULRT appears to be more sensitive than the SLRT even when there is quite substantial heterogeneity between Centers. In this proposal we will compare the relative efficiency of SLRT and ULRT under two different scenarios and obtain an optimal linear combination of these test statistics which maximize the power.
Xing Qiu, PhD
Assistant Professor of Biostatistics and Computational Biology
A Unified Method for Differential Expression and Differential Association Analyses
Thousands of basic research projects use the microarray technology, yet very few of them have been successfully translated into clinical applications. This proposal responds to this challenge by integrating normalization, DE analysis, and DA analysis, in such a way that not only the computational cost is reduced, but also the false positives/negatives are reduced by using one MTP for both analyses simultaneously.
2012 Faculty Awardees
Neil Blumberg, MD
Professor, Pathology and Laboratory Medicine
Improving Platelet Storage and Transfusion Outcomes with PPARγ Ligands
Platelet transfusion is the most commonly used therapy for patients with trauma, hematologic diseases or cancer who are experiencing bleeding and low platelet counts. Our proposed investigations are vitally important, since in the USA alone, almost two million platelet transfusions are given each year. Poorly understood mechanisms that occur during platelet storage, termed the “platelet storage lesion”, reduce platelet transfusion efficacy and safety. Consequently, patients are transfused not only with partially or abnormally activated platelets that reduce transfusion efficacy, but also with storage supernatants containing many potentially harmful bioactive mediators that can elicit adverse responses to transfusion. For example, platelet transfusion can cause alloimmunization, fever, rigors, and allergic reactions. A critical barrier to the prevention of adverse post-platelet transfusion events is the absence of approaches to modify storage conditions that ameliorate the platelet storage lesion. Hence, there is an urgent need to investigate new targets to attenuate platelet activation mechanisms, thus improving the efficacy and safety of platelet storage.
Our objective is to focus on novel aspects of platelet biology to better understand the mechanisms that drive unwanted platelet activation during storage, leading to the development of new technologies of platelet storage that will maintain normal platelet quality and function.
Lisa DeLouise, PhD, MPD
Associate Professor, Dermatology
High throughput sorting of rare cells from blood using Microbubble Arrays
Development of monoclonal antibodies (mAbs) for therapeutic use is a rapidly growing $50 billion/year market. Hybridoma technology is a time tested technique used to generate antibodies; but it is costly to screen all clones generated and therefore quality antibodies
maybe missed. Non-animal techniques that can identify and characterize ASC in peripheral human blood that exhibit high binding specificity and affinity are in high demand. Microbubbles are novel compartments formed in an optically clear elastomeric material. MBs exhibit unique properties for cell culture which are leveraged in this screening application that provides many advantages over existing techniques.
Our project seeks to advance development of a new high throughput cell screening technology based on microbubble (MB) arrays. Based on preliminary studies we will investigate the development of MB arrays to enrich, identify, characterize, and recover rare antigen specific antibody secreting (ASC) from peripheral blood. This project will investigate the limits of this assay and to automate the data acquisition and analysis.
Ajit Kulkarni, PhD
Research Assistant Professor, Medicine (Pulmonary/Critical Care Division)
Characterization of antifibrotic effects of CDDO, a small electrophilic compound
Pulmonary Fibrosis compromises normal lung function and structure due to scarring of lung tissues. Scarring is caused by proliferation of fibroblasts and myofibroblasts, and excess deposition of extracellular matrix proteins in fibrotic foci. There is an urgent unmet need to develop new therapies for pulmonary fibrosis since effective treatments are often lacking.
We have reported that a small electrophilic compound, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) inhibited the transforming growth factor (TGF)-β induced differentiation of human lung fibroblasts to myofibroblasts (scar forming cells) in vitro. We hypothesize that by inhibiting myofibroblast differentiation and proliferation, and by inhibiting expression of pro-fibrotic genes by fibroblasts and myofibroblasts, we will be able to slow or arrest the progress of the disease in patients with lung fibrosis. Here, we will investigate the efficacy of CDDO in vivo using models of pulmonary fibrosis. We hope these studies will rapidly lead to a new therapy for patients with suffer from pulmonary fibrosis.
Yang Liu, BM, PhD
Research Assistant Professor, Neurosurgery
Therapeutic targeting of CXCR7 in malignant glioma by small molecule antagonist
Malignant gliomas represent a uniformly fatal form of cancer. Despite advances in neurosurgical techniques, chemotherapeutic regimens and radiotherapy protocols, little improvement has been made in the 5-year relative survival rates of brain tumor patients during the past several decades. Glioblastomas, the most common and highest grade of malignant glioma, are highly vascular, highlighting a potential therapeutic target. Chemokines and their receptors play critical roles in many physiological and pathological processes, including brain cancer. Chemokine receptor 7 (CXCR7) was recently identified as second receptor for stromal cell derived factor 1 (SDF1) and exerts an important role in tumor growth and vascularization.
Previously, we found that CXCR7 mRNA was expressed at levels 9 times higher in brain tumors than normal brain samples and was localized to vascular regions within glioma samples. We also found that inhibition of CXCR7 expression by targeted siRNA significantly impeded glioma cell proliferation and motility in vitro and limited intracranial xenograft growth and improved mouse survival, validating CXCR7 as a potential therapeutic target for glioma. Furthermore, recent studies have shown that SDF1 can recruit bone marrow derived endothelial progenitor cells to tumor neovessels and attract haematopoietic progenitor cells to intracerebral glioma. Therefore, we propose that SDF1/CXCR7 play an important role in brain tumor growth and maintenance of the vascular niche between brain tumor stem cells and the neurovasculature.
2012 Trainee Awardee
PhD Candidate (Epidemiology), Public Health Sciences
Developing an age-specific decision scheme for prehospital triage of injured older adult
Injury is among the leading causes of death and disability for older adults. Treatment at advanced care hospitals specializing in injury, also known as trauma centers, has been shown to significantly improve patient outcomes. However, the selection of a receiving hospital is dependent upon emergency medical services (EMS) providers making appropriate clinical judgments in the prehospital setting – a process referred to as trauma triage. It is known that older adults are less likely to receive trauma center care than younger adults, but reasons for this age-based disparity are not well understood. Evidence suggests two mechanisms are involved: 1) EMS providers' decision-making process differs for older adults compared to younger adults; and 2) the current guidelines to aid EMS providers in their trauma triage decisions are inadequate to identify older adults who require trauma center care. This proposal aims to assess both of these potential reasons by using a combination of analytic methods. As the number of older adults in the US is projected to increase dramatically in future years, injury will continue to be a major burden on the public's health. Identifying and addressing reasons for the age-based disparity in trauma center care is vital to improving patient outcomes for this population.
2012 UNYTE Awardee
Katia Noyes, PhD, MPH
Professor, Public Health Sciences
Validity of Self-Reported Data for Studying Cognitive Problems and Depression
MS is the most common neurologic disease affecting young adults, striking nearly 500,000 people in the US. MS-related symptoms include physical disability, fatigue, cognitive impairment, and affective disorders. MS is different from most of other chronic conditions: its financial impact associated with person's productivity, social functioning, and employment is nearly as significant as the economic burden of medical treatment. The prevalence of major depression in patients with MS (16%) is over twice that among chronically ill population without MS (9%), and nearly four times higher than in general population (4%). Hence, it is critical that the research community takes concrete steps toward resolving the uncertainty surrounding the optimal treatment of individuals suffering from MS, particularly those with affective and cognitive dysfunction.
The main goal of this study is to assess validity of self-reported information about cognitive and mental health status in patients with multiple sclerosis (MS) and to understand feasibility of using these data for quality of care assessment and program evaluation. This study aims to stimulate and enhance our cross-disciplinary collaboration between the Departments of Public Health Sciences and Neurology, University of Rochester and Baird MS Center in Buffalo, NY. The study will involve two sites (University of Rochester and University of Buffalo/Jacobs Neurologic Institute in Buffalo, NY) of the New York State Multiple Sclerosis Consortium, one of the largest databases of MS patients.
2012 Novel Biostatistical Epidemiological Methods (NBEM) Awardees
Hua He, PhD
Assistant Professor, Biostatistics and Computational Biology
Novel models for analyzing drinking outcomes: A pilot study comparing competing approaches
The COMBINE Study was conducted from 2001 to 2004, with 1,383 individuals of alcohol dependence assigned to one of nine pharmacological and/or psychosocial treatment conditions. The only other alcohol treatment study in the U.S. on this scale was Project MATCH, conducted in the early 1990’s. COMBINE compared two promising pharmacological treatments for alcoholism, naltrexone and acamprosate, alone and in combination with an combined behavioral intervention (CBI). Although the primary outcome papers of COMBINE have been published, researchers are at an early stage in exploiting the potential of this dataset to address questions beyond a comparison of its treatment conditions.
This application addresses an important statistical issue in alcohol research: the analysis of a bounded count response with structural zeros and overdispersion within a longitudinal data setting. This issue is highly relevant to the analysis of treatment effectiveness of drinking interventions for various risk populations. We will develop a new approach for such zero-inflated binomial-based (ZIB) count response for cross-sectional and longitudinal studies, and use it as a benchmark to evaluate the performance of the approaches that either have been used for analyzing such count responses in the alcohol research literature or existing alternatives in the statistical literature, such as zero-inflated Poisson (ZIP) model, general regression model for transformed count response and Hall & Zhang's marginal models for ZIB, by conducting intensive simulation studies and applying them to drinking outcomes in COMBINE.
Rui Hu, PhD
Research Assistant Professor, Biostatistics and Computational Biology
Detecting Intergene Association Changes in Microarray Data
Microarray technology has become a routine gene expression analysis tool in recent years. Biomedical researchers rely on this technology to identify potentially “interesting” genes. Typically, individual genes are tested for their differential expressions between phenotypes by the two-sample Student’s t-test or its nonparametric counterpart. The resulting p-values are adjusted by a chosen multiple testing procedure (MTP) in order to control certain group-wise Type I errors.
We plan to develop a novel gene selection procedure based on intergene association structure changes across different phenotypes. Gene differential association analysis which was explored in our preliminary study utilized the gene association vector in the gene selection, which provided quite conservative testing power. In this study, we will focus on gene pairs and search for most powerful statistical tests to detect differential associated genes.
Yinglin Xia, PhD, MS
Research Assistant Professor, Biostatistics and Computational Biology
Integrative Analysis of Pathways to SA and PPD in High Risk Families
This proposal is to develop a new class of statistical models to facilitate integrative analysis of multi-faceted data and to illustrate the new methodology by applying it to examine pathways to suicide attempts (SA) in high risk families using the GenRED database. The feature-rich GenRED database provides a rare and unique opportunity to explore the types of risk factors and what roles they play in the pathways to SA. Significant advances have been made over the past few decades in the theory and applications as well as software development for fitting structural equation models (SEM). However, our recent work shows that there are several limitations in existing methods.
Our goals in this proposal are to (1) test hypotheses of SA using existing standard SEM, (2) develop a class of distribution-free SEM, (3) test hypotheses using the new methods. Specifically, we will create a dataset using GenRED to examine the following set of hypotheses concerning pathways to SA using existing SEM.
2011 Faculty Awardees
Nancy Bennett, MD, MS
Director of the Center for Community Health
Co-Investigators: Jennifer Carroll, MD, MPH, Linda Clark, MD, MS, Michael Nazar, MD, and James Sutton, PA.
Project: Comparative Effectiveness of practice-based diabetes prevention programs
The Healthy Living Program, a community-developed program, adapted from the evidence-based Stanford program, and conducted in community settings has been ongoing in the Rochester community since 2001 and has had over 1,700 participants in both the original program targeting African Americans and the revised program, Vida en Salud, for the Latino community. We propose to compare the effectiveness and costs of the two programs through a randomized trial conducted at primary care practices. In addition, we will study the feasibility of collecting data regarding the behavioral/motivational mechanisms through which these programs are successful. This pilot will enable the team to design the optimal study, refine endpoints and measurement instruments, explore the feasibility of randomization in a community health center clinical setting, and collect pilot data to determine effect sizes.
John Frelinger, PhD
Professor of Microbiology and Immunology
Co-Investigator: Mark Sullivan, PhD
Project: Protease activated cytokines: a novel methodology for the delivery and activation of cytokines
Cytokines play critical roles in cellular immune responses. The immunotherapy of cancers with cytokines has had some dramatic clinical successes, but side effects limit their use when delivered systemically. We are developing a novel approach that employs a fusion protein (FP) in which a cytokine is joined to its specific binding moiety; an antibody fragment (scFv) identified using phage display, separated by a protease site. The strategy is that before cleavage, the cytokine is largely inactive, but that after cleavage by a protease expressed at the tumor site, the cytokine can become available to interact with high affinity receptors on immune cells.
Sherry Spinelli, PhD
Research Associate Professor of Pathology and Laboratory Medicine
Co-Investigators: Richard Phipps, PhD, Charles Francis, MD, and Stephen Hammes, MD, PhD
Project: Microparticle miRNAs as transcellular messengers in diabetes and vascular disease
Microparticles (MPs) are submicron-sized membrane vesicles that are released into the blood by platelets and vascular cells. MPs contain cellular information in the form of bioactive proteins, lipids and molecules that influence cells, not only in the region of their release, but are carried in the circulation to elicit broad-reaching transcellular effects. A major knowledge gap is in understanding the mechanisms that govern MP transcellular communication. This research plan will investigate MPs derived from healthy and type-2 diabetic individuals. The hypothesis is that altered packaging of miRNAs in platelet MPs is a key element in vascular cell communication that may promote inflammation. We predict that differences in miRNA levels and types could serve as biomarkers of disease progression and lead to therapeutic strategies to modulate cellular dysregulation.
2011 Trainee Awardee
Roni Kobrosly, MPH
PhD Candidate in the Department of Public Health Sciences (Epidemiology)
Co-Investigators: Edwin van Wijngaarden, PhD, (primary mentor), Jan Moynihan, PhD, Deborah Cory-Slechta, PhD, Christopher Seplaki, PhD
Project: Examining the link between allostatic load and depressive symptoms among the elderly
Allostatic load is a developing epidemiologic concept that has been used to quantify the physiologic costs of cumulative life stress, whether psychological or physical. Although various forms of life stress have been linked with late-life depressive symptoms, the association between allostatic load and depressive symptoms has never been assessed. This proposal entails a cross-sectional study of approximately 200 community dwelling older adults examining the complex relationship of life stress, allostatic load, and psychosocial factors with the severity of late-life depressive symptoms. One specific aim and one exploratory aim are detailed: (1) to examine the relationship between allostatic load and the severity of depressive symptoms, and, as an exploratory aim, (2) to conduct a path analysis to examine the complex causal web of biological, psychological, and social factors underlying late-life depressive symptoms.
2011 UNYTE Awardees
Richard Burack, MD, PhD
Associate Professor of Pathology and Laboratory Medicine
Co-Investigator: Robert Hutchison, MD (SUNY Upstate Medical University)
Project: Regional stat tumor procurement to support studies of lymphoma
A major barrier to studying cancer and its treatment is the limited availability of human tumors. To address this problem, the NCI funds biorepositories such as the lymphoma-specific biorepository at URMC, a component of the NCI-funded SPORE in lymphoma at URMC. While tumor “banks” are common, the focus of the URMC biorepository on viable specimens is perhaps unique in the country, and has been critical to obtaining NCI-funding for projects at URMC. The availability of this resource has spurred interest in studying lymphoma, all with important technologies and/or hypotheses that could be reasonably tested given sufficient materials. However, current NCI-funded programs are using essentially all the specimens obtained at Strong Memorial Hospital/URMC. Demonstrating a regional lymphoma biorepository focused on stat distribution of living lymphomas to researchers will be critical to several proposals under development for submission to the NCI and NIH.
Janet Dehoff-Sparks, PhD
Professor of Pathology and Laboratory Medicine
Co-Investigator: Michael Greene, PhD (Bassett Research Institute)
Project: Protein kinase C (PKC) activation and inhibition of VLDL triglyceride (TG) export
Obesity is associated with non-alcoholic fatty liver disease (NAFLD) which can progress to the more serious condition of non-alcoholic steatohepatitis (NASH), a known precursor to cirrhosis and hepatocellular carcinoma in humans. In this proposal we examine the extent to which specific hepatic PKC isoforms regulate hepatic TG balance. Results will provide evidence to support a pharmacologic approach to reduce hepatic steatosis by blocking PKC signaling specifically in the liver thereby reducing lipogenesis and enhancing VLDL TG export.
2011 Novel Biostatistical Epidemiological Methods (NBEM) Awardees
Rui Hu, PhD
Research Assistant Professor of Biostatistics and Computational Biology
Co-Investgators: Sandhya Dwarkadas, PhD, Galina Glazko, PhD, Xing Qiu, PhD
Project: Clustering Differentially Associated Genes
We plan to develop a novel gene clustering procedure based on gene differential association analysis which was explored in our preliminary study. By applying this procedure to microarray gene expression data, we can search for differentially associated gene groups such that genes belonging to the same group do not change their association structure across different phenotypes while the association structure of genes from different groups are differentiated across phenotypes. This novel procedure has the ability to uncover biologically meaningful gene groups which contain differentially associated genes. Consequently, it can complement and enhance the existing clustering algorithms based on differentially expressed genes. It will also help us understand how the phenotypic differences of gene dependence structure can be used to cluster genes into biologically meaningful units.
Hongqi Xue, PhD
Research Assistant Professor of Biostatistics and Computational Biology
Project: Parameter estimation for nonlinear stochastic differential equation models from noisy longitudinal data in HIV dynamic research
In AIDS research, one major area is to model the interaction between HIV virus and the immune cellular responses. It is very useful for understanding the pathogenesis of HIV infection and assessing the potency of antiviral therapies. The investigator is focusing on the following four aims: (1) To develop multidimensional nonlinear SDE models for modeling the interaction between HIV virus and the CD4+ T cells for HIV-infected patients under treatment; (2) To develop parameter identifiability methods for such models with noisy longitudinal data; (3) To develop novel parameter estimation methods with sound theoretical justifications and computational efficiency for such models; and 4) To develop novel model selection methods between SDE models and ODE models.