John-Paul S. Bellistri, M.A.

Carcinogenesis and Cancer Prevention in Barrett’s Esophagus: A Translational Study   abstract

Advisor: Carol Lin

Jing Chai , M.A.

Inducing Pancreatic Progenitor Cells from Human Embryonic Stem Cells in Vitro   abstract

Advisor: Hsun T. Ku

Michael Francis D’Ecclessis, M.A.

The Evolution of Alzheimer’s Disease Treatment Strategies   abstract

Advisor: Daniel Kalderon

Eléonore Depardon, M.A.

The Immune Microenvironment in Hepatocellular Carcinoma   abstract

Advisor: Chantal Donne

Phi C. Doan, M.A.

Sorting Through the Gene Repertoire of Alzheimer’s Disease: Toward a Comprehensive Genotypic Profile   abstract

Advisor: James Russo

Ivan Georgiev Georgiev, M.A.

Alzheimer’s Disease: Yesterday, Today and Tomorrow   abstract

Advisor: Daniel Kalderon

Samuel Twining Globus, M.A.

Entry to Meiotic S-phase is Controlled by Ime2p Phosphorylation and Subsequent Cdc4p-dependent Ubiquitination of Sic1p.   abstract

Advisor: Liisa Kauppi

Lyn Goldsmith, M.A.

Acetyl-L-Carnitine for Chemotherapy Induced Peripheral Neuropathy   abstract

Advisor: Clifton Gooch

Jeffrey Hui, M.A.

Validation of an Enterovirus Typing Microarray   abstract

Advisor: Gustavo Palacios

Maya Kappil, M.A.

Polymorphisms within Base Excision Repair Genes as Potential Biomarkers for Lung Cancer Risk Determination   abstract

Advisor: Regina Santella

Susan Koujak, M.A.

The Use of Gene Expression Profiling to Diagnose Allograft Rejection   abstract

Advisor: Mario Deng

Angela Ming-Lai Liu, M.A.

The Monogenic Disease APECED: Insights into Immunological Tolerance   abstract

Advisor: Daniel Kalderon

Li Ma, M.A.

Review on Diabetes Mellitus and the Anti-diabetes Drugs   abstract

Advisor: Milan Stojanovic

Lena M. Matthai, M.A.

Type II Diabetes: Current and Emerging Therapies   abstract

Advisor: Paul Harris

Valerie Mattison, M.A.

Angiogenesis and Future Prospects of Anti-Angiogenic Therapy   abstract

Advisor: Jingyue Ju

Gregory Minevich, M.A.

Description of Two New HLA-C Alleles in a Black South African Population   abstract

Advisor: Robert Winchester

Benjamin Samuel Neymotin, M.A.

Bacterial Metagenomics: Searching for the Elusive Microbes   abstract

Advisor: James Russo

Sharon Orenstein, M.A.

Neurogenesis in the Adult Human Brain   abstract

Advisor: James Goldman

Moshe C. Ornstein, M.A.

Application of In Vivo Imaging to Cancer Therapy and the Study of the Immune Response   abstract

Advisor: Carol Lin

Maya Pious Panjikaran, M.A.

Heat Shock Proteins as Emerging Therapeutic Targets as well as Therapeutic Agents   abstract

Advisor: Linda Einbond

Meghavi J. Patel, M.A.

Current Concepts in Autoimmune Hepatitis with Focus on Treatment Options   abstract

Advisor: Jingyue Ju

Phillip C. Penny, M.A.

Amyotrophic Lateral Sclerosis: Past, Present and Future   abstract

Advisor: Derron Bishop

Raju Manga Reddy, M.A.

Dendritic Cells: Its Biology and their Potential Use in Cancer Immunotherapy   abstract

Advisor: Ron Prywes

Michal Silverberg, M.A.

Molecular vs. Cellular Approaches to Treat Coronary Artery Diseases   abstract

Advisor: Carol Lin

David A. Simhaee, M.A.

VEGF Therapy: An Exploration of the Properties, Wound Healing Mechanisms, and Therapeutic Potential of VEGF and a Novel VEGF Analogue in Accelerating Wound Healing in Diabetics   abstract

Advisor: Carol Lin

Archana Solipuram, M.A.

Therapeutic Strategy Targeting BCL6 in Large B Cell Lymphomas   abstract

Advisor: Hua Gu

Clifford Cheng Sung, M.A.

The Future of Drug Discovery: Crucial Disciplines and Future Considerations   abstract

Advisor: Carol Lin

Pei-yi Sung, M.A.

The Future of Cancer Therapy - Cancer Immunotherapy   abstract

Advisor: Howard Kaufman

Dionne E. Swor, M.A.

Mitochondrial Dysfunction and Schizophrenia   abstract

Advisor: Joseph Gogos

Karen Tang, M.A.

Linking Neuroimaging and Genomics: An Approach to Investigate the Influence of Genetics on Brain Function   abstract

Advisor: Vincent Ferrera

Cynthia Tañón-Santos, M.A.

Is the Future of Diabetes and Heart Disease Treatment in Embryonic Stem Cells?   abstract

Advisor: Carol Lin

Jakob von Moltke, M.A.

Taming the Macrophage: Molecular Basis of Phagosomal Maturation Arrest by Mycobacterium Tuberculosis   abstract

Advisor: Elizabeth Miller

Nafeez Zia, M.A.

RNAi : A Diamond in the Rough   abstract

Advisor: Larry Chasin

Carcinogenesis and Cancer Prevention in Barrett’s Esophagus: A Translational Study

John-Paul S. Bellistri, M.A. 2007

The occurrence of Barrett’s Esophagus, the precursor to esophageal adenocarcinoma, is strongly correlated with chronic gastroesophageal reflux disease.  In this study, I report the possible molecular mechanisms by which Barrett’s Esophagus develops in patients with chronic gastroesophageal reflux.  In addition, I report the preliminary in vitro data that examines the effects of Polyphenon E as a potential chemopreventive agent against development of Barrett’s Esophagus.

Inducing Pancreatic Progenitor Cells from Human Embryonic Stem Cells in Vitro

Jing Chai, M.A. 2007

Stem cell research is one of the most fascinating areas of modern biology with huge potential clinical applications in regenerative and reparative therapies. The capacity of self-renewal and differentiation of human embryonic stem (hES) cells in vitro makes them a potential source of pancreatic endocrine cells that function similarly to primary islets to treat type I diabetes mellitus. Previous studies performed in our laboratory described a unique culture method for the generation of early endocrine pancreas from murine embryonic stem (mES) cell-derived embryoid bodies (EBs). Here, we found that this approach can be translated to human ES cells to differentiate to a population of cells that express insulin, glucagon, amylase, pdx-1, Ngn3, and Sox17, suggesting pancreatic lineages may be generated. Serum replacement (SR) and FGF2 may not be -cellbspecific in inducing human EBs into endoderm development. Addition of   nicotinamide, and ,Bbspecification and differentiation factors activin  exendin-4 to later-stage culture can contribute to pancreas lineage development. Human EBs cultured in the presence of high concentration ofmonothioglycerol (MTG) at first two days increased C-peptide-positive cells to 10.8% of the total population, around 2-fold higher when compared with the low concentration of MTG. The increased whole glutathione peroxidase 2 (Gpx2 transcription and total glutathione (GSH) content of day 2 hEBs cultured in the presence of high concentration of thiol compounds may protect endoderm cells from damage by oxidative stress. Together, this study demonstrates that our culture system is an effective approach to induce hES cell differentiation into β-cell progenitors.

Keywords: human embryonic stem (hES) cells, human embryoid bodies (hEBs), pancreatic lineages, monothioglycerol (MTG). 

The Evolution of Alzheimer’s Disease Treatment Strategies

Michael Francis D’Ecclessis, M.A. 2007

Dementia currently affects nearly twenty four million people world wide, and that number is expected to double every twenty years extrapolating from the current epidemiological trends.  The most common form of dementia is Alzheimer’s disease, which accounts for roughly forty to sixty percent of all dementia cases.  Given this pressing circumstance, it comes as no surprise that the development of effective Alzheimer’s disease therapeutic strategies has become a strong priority in recent years.  Early approaches relied upon the observation that the lowered acetylcholine levels associated with the depletion of cholinergic neurons is a major cause of the symptomatic memory loss.  Thus, the cholinesterase inhibitors that were subsequently developed served to ameliorate some of the symptoms of disease progression temporarily by preventing the breakdown of acetylcholine.  Unfortunately, this approach to disease therapy fails to take into account the cause of cholinergic neuronal death, and therefore fails to provide hope for a therapy that is anything more than a temporary fix.  The evolution in the therapeutic approaches that are currently being pursued can be seen in the development of the mindset that the prevention or even cure of Alzheimer’s is possible, if not likely, in the future.  In this regard, current breakthroughs in the development of nascent technologies coupled with a much richer understanding of Alzheimer’s disease pathology is leading to new hope of a definitive and viable solution to the unsettling prevalence of Alzheimer’s disease in the current population.

The Immune Microenvironment in Hepatocellular Carcinoma

Eléonore Depardon, M.A. 2007

Immunotherapy is still not very efficient to cure cancer. A better understanding of the relationships between the tumor and the immune system will help to find new therapies and new approaches to cure cancer. In order to understand these relationships, studies of the immune microenvironment in hepatocellular carcinoma were done and are still made. In this thesis, we tried defined the genes that are characteristic of an etiology, the progression of the cancer or the length of patient survival. The quantification of the infiltration of different immune cell types in the tumors was then studied. Gene expression analysis by quantitative PCR using a set of 64 immune-related genes and ahierarchical clustering showed that a number of genes linked to CD8+ T cells and/or NK cells are significantly more expressed in cancers with a viral origin (HBV or HCV) compared to non viral-related tumors. A neutrophil signature may also be more prevalent in long-survival patients.

Sorting Through the Gene Repertoire of Alzheimer’s Disease: Toward a Comprehensive Genotypic Profile

Phi C. Doan, M.A. 2007

Alzheimer’s Disease (AD), the most common form of dementia, is a heterogeneous, complex neurodegenerative disease characterized by neurofibrillary tangles and senile plaques formed from amyloid-β protein deposits. While the majority of cases are thought to be sporadic, genetics plays a pivotal role in the etiology and pathology of AD. The early-onset and late-onset forms of the disease display distinct manifestations of AD due to age and hereditary factors. The most notable characteristics of early-onset AD differentiating it from the late-onset form include onset of AD-like symptoms before the age of 65 and monogenic defects following an autosomal dominant pattern of inheritance. On the other hand, late-onset AD, more commonly called “sporadic” AD, has symptoms occurring after 65 years of age and is the more common form, accounting for about 95 percent of all AD cases. However, it has a more complex etiology, complicated by the fact that there is not a simple mode of inheritance and polymorphisms in numerous genes can interact with other nongenetic factors.

Through linkage analysis and association studies, mutations in APP, PSEN1, and PSEN2 genes, encoding amyloid precursor protein, presenilin 1, and presenilin 2, respectively, have been implicated in early-onset AD. These genes have gained wide acceptance as being integral to the AD gene repertoire due to the confirmatory evidence supporting and replicating the initial studies and the fact that they exhibit high penetrance in early-onset AD patients. The search for late-onset genes was more arduous, with ApoE- ε4, encoding the e4 variant of apolipoprotein E, the only front runner since 1993 shown to be linked to late-onset AD. Not surprisingly, dozens of other genes have been proposed, but they remain controversial with conflicting reports and/or the need for the initial association to be replicated. However, most recently, the SORL1 gene, encoding a sortilin-related receptor (a sorting protein), has been shown to be linked to late-onset AD. It has already garnered wide acceptance as an integral player in the AD gene repertoire due to the replication built into the initial study. Altogether, these genes could make the idea of generating a comprehensive genetic risk profile used as a basis for diagnosis and treatment a real possibility.

Alzheimer’s Disease: Yesterday, Today and Tomorrow

Ivan Georgiev Georgiev, M.A. 2007

A little over one hundred years ago Alois Alzheimer described novel pathological findings in the brain of a deceased patient who exhibited unusual psychological behavior.  These findings would eventually earn Dr. Alzheimer the name of the most common form of dementia in the geriatric population; Alzheimer’s disease (AD.  Today, the risk of AD is not only increasing with age but is also increasing in the population making it the 8th leading cause of death in the United States.  Research has been working with this disease for over one hundred years; from the first incidence, through the assimilated aging dilemma to the current state of affairs.  In order to present the pathways of and build a knowledge base for AD, this report presents how the research has gone through a long and difficult road.   In the beginning affairs, AD was assimilated as part of aging and was not thought of as a serious and debilitating disease but eventually was separated from the normal aging process and characterized as a separate entity.  During recent years, Alzheimer’s research has gone through a major evolution with discoveries in its pathways, genealogy and pathology having major contributions.  A cure has been elusive as of yet, but with the current research focusing on early detection, prevention, current drug, future multifactor therapy and comprehensive understanding by the community, a cure may not be far away. 

Entry to Meiotic S-phase is Controlled by Ime2p Phosphorylation and Subsequent Cdc4p-Dependent Ubiquitination of Sic1p.

Samuel Twining Globus, 2007

The initiation of DNA replication is an important landmark event controlling the progression of the sporulation program in Saccharomyces cerevisiae. The cyclin dependent kinase inhibitor Sic1 plays a central role in the regulation of this event by binding the Clb/Cdc28 complexes that are responsible for initiating replication. Sic1 must be degraded to release active Clb/Cdc28 and allow DNA replication to commence. The regulation and mechanism of Sic1 degradation has been well characterized in mitotic cells but not in meiotic cells. The meiosis-specific kinase Ime2 is known to play a role in regulating Sic1 stability but it is not known if this is done directly, indirectly, or in cooperation with other kinases. Once phosphorylated, Sic1 is ubiquitinated and subsequently degraded by the 26S proteasome. During mitosis, phospho-Sic1 is recognized and recruited to the ubiquitin ligase machinery by the F-box protein Cdc4. However, Cdc4’s role during meiosis is not well understood. A Cdc4 homolog from Candida albicans is able to complement a cdc4 mutation during mitosis but not meiosis, suggesting the possibility of a different means of recognition of phospho-Sic1. Cdc4 could also be regulated in a meiosis-specific manner or recognize meiotic phospho-Sic1 differently in meiosis than mitosis. An alternative F-box protein or ubiquitin ligase could also be responsible for Sic1 ubiquitination. This proposal will test the hypothesis that Ime2 regulates the phosphorylation of Sic1 to target it for Cdc4-mediated degradation and allow the initiation of meiotic DNA replication in S. cerevisiae by elucidating both the means through which Ime2 controls Sic1 degradation and if and how Cdc4 promotes its ubiquitination in a meiosis-specific manner.

Acetyl-L-Carnitine for Chemotherapy Induced Peripheral Neuropathy

Lyn Goldsmith, M.A. 2007

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting and often permanent complication of cancer therapy.  Platinum-based drugs are an important class of drugs for a broad range of cancers, but peripheral neuropathy is a frequent and sometimes permanent and disabling side effect for which there is no current treatment.  Acetyl-L-carnitine (ALCAR) is an endogenous compound with important mitochondrial and cellular functions. ALCAR is a safe agent with the potential to protect and heal injured nerves, and has shown efficacy for the treatment of a variety of neuropathies.  Previous studies of ALCAR for chemotherapy induced neurotoxicity have been successful but were not designed to provide the level of scientific proof needed to establish ALCAR as a recommended treatment for CIPN.  Therefore its effectiveness for this problem remains in doubt.   We propose a parallel design, placebo-controlled trial to provide the level of scientific evidence to establish ALCAR as an effective treatment for chemotherapy-induced peripheral neuropathy.

Validation of an Enterovirus Typing Microarray

Jeffrey Hui, M.A. 2007

Enteroviruses infect nearly one billion people worldwide on an annual basis causing disease symptoms ranging from mild or asymptomatic to severe or deadly. Described in this study is the design of a DNA microarray that can detect and genotype enteroviruses.  Current detection and typing strategies involve amplifying specific areas of the genome, notably the hyper-variable VP1 region for typing, and the 5’UTR for detection, followed by DNA sequencing.  The typing array introduced here takes advantage of the multiplex capabilities of DNA microarrays by the design of complementary probes to both the VP1 and 5’UTR regions, along with other broadly reactive areas against all known enterovirus serotypes, allowing for the simultaneous interrogation of multiple areas of the enterovirus genome.  Additionally, this approach benefits from the utilization of a universal priming strategy, which allows for unbiased sample amplification, in contrast to the current molecular PCR typing methods, which rely on successful primer hybridizations in highly variable regions.  The validation of this Enterovirus Typing Array was tested and assessed against 99 samples (39 reference strains and 60 clinical isolates)

Polymorphisms within Base Excision Repair Genes as Potential Biomarkers for Lung Cancer Risk Determination

Maya Kappil, M.A. 2007

The lack of adequate methods to screen for lung cancer contributes to its role as one of the leading causes of cancer-related deaths.  Various molecular epidemiology studies have sought to identify biomarkers that can define risk groups, and, thereby, provide a means to detect and possibly prevent cancer at an earlier time point. However, one of the major confounders of the disease is the fact that although most cases of lung cancer can be attributed to smoke exposure, most smokers do not go on to develop the disease.  Hence, identifying risk groups will require biomarkers that take this variation in inter-individual susceptibility into account. Capacity to repair damage generated by tobacco-smoke carcinogens is believed to be one of the contributors of this variation.  While major genetic defects in DNA repair are rare, more subtle alterations, such as single nucleotide polymorphisms (SNPs), may impact on repair capacity. As base excision repair genes participate in the response against tobacco smoke-generated oxidative stress, polymorphisms within these genes are considered potential biomarker candidates.  Indeed, studies have demonstrated that base excision repair activity appears to be reduced among lung cancer cases.  However, linking OGG1 Ser326Cys, APE1 Asp148Glu, and XRCC1 Arg399Gln, some of the most commonly described SNPs of BER genes, to cancer has proven to be an elusive target.   The most significant association has been observed between OGG1 Ser326Cys and lung cancer risk, while contradictory results have been reported regarding APE1 Asp148Glu and XRCC1 Arg399Gln.   Furthermore, while most studies indicate that the OGG1 326Cys allele impacts repair, no such association has been observed for either APE1 Asp248Glu or XRCC1 Arg399Gln.  These inconclusive results may be due to the variations in study parameters used and limitations of case-control studies.  Use of cohorts with standardized parameters in future studies will greatly facilitate the ability to draw meaningful conclusions regarding the pooled data.

The Use of Gene Expression Profiling to Diagnose Allograft Rejection

Susan Koujak, M.A. 2007

Transplantation has become an accepted treatment for end-stage organ failure.  Despite advances in immunosuppressive therapies and surgical technique, limitations remain.  The five year patient survival rate for heart and lung transplant recipients is 70 and 50%, respectively.  As a result, transplant physicians are forced to ‘walk a thin-line’ between over-immunosuppression, risking infection and drug toxicity, and under-immunosuppression, risking allograft rejection.  Currently, invasive biopsies are considered the ‘gold standard’ to diagnose acute rejection in all organ types.  Biopsies are subject to error and further puts transplant recipients at risk for a range of complications. 

Recently, a multi-center study has led to the development of a gene expression classifier to diagnose cardiac allograft rejection without the need for invasive biopsy.  By utilizing gene expression profiling techniques through the use of microarray technology and RT-PCR, the resulting 11 gene classifier has been independently validated and is commercially available as the AlloMap™ molecular test.  The results and methods of this study are now being used to develop gene classifiers to diagnose allograft rejection in other organs.  The application of gene expression profiling in the field of transplant medicine will undoubtedly improve the management of transplant recipients as well as their quality of life in the years to come.

The Monogenic Disease APECED: Insights into Immunological Tolerance

Angela Ming-Lai Liu M.A., 2007

AIRE (autoimmune regulator) is the underlying gene for the monogenic autoimmune disease ‘autoimmune polyendocrinopathy candidiasis ectodermal dystrophy’ (APECED). AIRE upregulates transcription of peripheral tissue-restricted self-antigens in medullary thymic epithelial cells, and it plays a role in negative selection of autoreactive T cells, which is important in maintaining central tolerance. Recent evidence indicates that AIRE also has a role in the selection and generation of regulatory T cells (Tregs). It is widely accepted that Tregs are essential in maintaining peripheral tolerance by suppressing the activity of repertoire autoreactive T cells that escape from clonal deletion in the thymus. Although the molecular mechanisms by which AIRE functions in these processes await further characterization, the studies on AIRE so far have proved to be extremely informative on understanding how immunological tolerance is maintained.

Review on Diabetes Mellitus and the Anti-diabetes Drugs

Li Ma, M.A., 2007

In diabetes the human body loses the ability to produce enough insulin or insulin itself lacks potency to adjust the blood glucose level. The main forms of diabetes are type 1, type 2 diabetes, gestational, and variations caused by genetic defect and endocrinopathies. The mechanisms underlining most common types of diabetes exist at the genetic level such as the mutation in diabetes related genes and at the molecular biology level including autoimmune response and insulin resistance. Also, this review explored the linkage of diabetes with other diseases such as hypertension, dyslipidemia and atherosclerosis. For diabetes a lot of drug targets and effective drugs were discovered such as dipeptidyl peptidase-4 (DPP-4) inhibitors, alpha-glucosidase inhibitors and thazolidinedione in the past few years. However, despite the great progress that was made since 1920’s when insulin was introduced for the treatment of diabetes, there is still a long way to go to fully understand diabetes and to discover more powerful treatments and cures for it.

Key word: Diabetes mellitus, linkage with cardiovascular disease, antidiabetes drugs

Type II Diabetes: Current and Emerging Therapies

Lena M. Matthai, M.A. 2007

Diabetes is one of the most prevalent, costly and debilitating diseases in the world. Type II diabetes mellitus (T2DM) formerly known as adult onset or non-insulin dependent, results from the body’s ineffective use of insulin. This type of diabetes accounts for approximately 90% of the total diagnosed diabetic population worldwide and prevalence of the disease is increasing. The incidence of diabetes in the United States has increased by 61% since 1991. Factors driving this trend include the ageing demographic profile and an increase in obesity, such that diabetes is currently the sixth leading cause of death in the United States. Biguanides (Metformin) and sulphonylureas are two of the oldest classes of oral antidiabetic drugs that are still considered the ‘gold standard’ in T2DM therapy, despite recent advances including the market launch of novel drug classes such as GLP-1 analogues and DPP-IV inhibitors. However there are still several unmet needs in the T2DM therapeutics market that need to be addressed, the key one being to target the underlying cause of the disease rather than the symptoms of hyperglycemia. However, the complexities of the interacting pathways involved in the progression of this condition have not yet been fully elucidated. This has hindered the development of a therapeutic agent that is 100% effective in the treatment of T2DM.

Angiogenesis and Future Prospects of Anti-Angiogenic Therapy

Valerie Mattison, M.A. 2007

Angiogenesis, the formation of new blood vessels, is essential for physiological and pathological conditions.  Angiogenesis is crucial in supplying growing tissues with adequate blood flow and oxygen during embryonic development.  Physiological angiogenesis is involved in the female reproductive cycle.  The angiogenic mechanism occurs primarily by sprouting of blood vessels, but non-sprouting mechanisms has also been observed.  These processes are controlled by several regulatory molecules such as fibroblast growth factor, endostatin, angiostatin and vascular endothelial growth factor and its receptors. An imbalance in the angiogenic process involving positive and negative regulators has contributed to numerous pathological conditions and diseases such as cancer, rheumatoid arthritis, arteriosclerosis, and Crohn’s disease.  Currently, there are many anti-angiogenic agents aiming for therapeutic targets in treatment of certain cancers and age-macular degenerative disease.  This review gives an overview of angiogenesis and discusses novel anti-angiogenic therapeutic approaches.

Description of Two New HLA-C Alleles in a Black South African Population

Gregory Minevich, M.A. 2007

MHC class I molecules present intra-cellularly processed antigen to T cells as part of the adaptive immune response. Polymorphism of these molecules plays an essential role in developing an individual’s distinct T cell repertoire and also in protecting the species as a whole from newly evolving pathogens. Here I describe two new MHC class I molecules, Cw*0333 and Cw*0217, that have been identified in a Black South African population as part of an ongoing study on the role of MHC in maternal to fetal HIV transmission. Cw*0333 differs from Cw*030201 by an A->G substitution at nucleotide 323. This results in a structurally non-conservative missense mutation of Cys for the generally conserved Tyr-84 at the end of the a1-helical margin of the antigen cleft in the MHC molecule. Molecular modeling suggests this substitution alters the predicted interactions of this critical residue with the opposite a2-helix, the peptide carboxy terminus, and KIR2DL2. The second novel allele, Cw*0217, differs from Cw*0205 by an A->T substitution at nucleotide 368, resulting in a Tyr->Phe substitution at residue 99 of the HLA-C heavy chain b-pleated sheet that likely influences peptide side chain binding. Haplotype analysis of limited mother-child pedigrees that share the new alleles, together with analysis of similar haplotypes frequent in the Sub-Saharan population, suggest that both Cw*0333 and Cw*0217 arose through missense mutations respectively from the prevalent HLA-B*5801-Cw*0302 and HLA-B*080101-Cw*0205 haplotypes found in this population.

Bacterial Metagenomics: Searching for the Elusive Microbes

Benjamin Samuel Neymotin, M.A. 2007

The inability to culture most microbial species has hindered the analysis of their populations.  With the improvement of sequencing technology and enhanced computing power of bioinformatic programs, the possibility now exists to study microbes taken directly from their environments without the use of culturing techniques.  Bacterial metagenomics looks to employ bioinformatic methods to analyze data collected through environmental sequencing projects and make conclusions about the relationships between bacteria and their environments, bacteria and each other, and bacteria and larger organisms.  Ultimately, it should also be possible to determine phylogenetic relationships by sequence analysis of conserved regions of the genome, most notably that of the 16S rRNA regions.  The following paper presents a critical analysis of the progress in bacterial metagenomics and the advancements that are likely to occur in the near future

Neurogenesis in the Adult Human Brain

Sharon Orenstein, M.A. 2007

The mammalian brain has been perceived as a quiescent organ incapable of postnatal neurogenesis for many years. The inability to regenerate cells was considered as the main reason why those who have sustained Central Nervous System (CNS) damage have no hope of recovery. In recent years, several studies have demonstrated that the adult mammalian brain, including the human brain, is indeed capable of neurogenesis. This process was found to be primarily confined to the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampus. The objective of this paper is to review the main studies that were done in this field during the last decade, including the history of neurogenesis in the mammalian brain, the technologies that enable the discovery of neurogenic regions, the hypotheses regarding the stem cells niches, migration and, normal and pathological functions in the adult human brain. The potential clinical application of these cells is discussed, and finally, the main questions that should be addressed in order to utilize adult human stem-cells as a clinical tool for the therapy of CNS diseases and disorders are raised.

Application of In Vivo Imaging to Cancer Therapy and the Study of the Immune Response

Moshe C. Ornstein, M.A. 2007

In vivo imaging facilitates the real-time visualization of cells in an accurate physiological setting without necessitating their extraction from host organisms.  It has long been used as a method by which to study tumor growth.  Cancer vaccines and other tumor immunotherapeutics induce the T cell response to tumors and are currently being developed as treatment for patients with solid tumors such as melanoma, lung, and renal cancers.  The further development and improvement of these vaccines is largely dependent on the ability to study the vaccine-induced immune responses.  Therefore, in vivo imaging techniques are being advanced and applied to allow for the study of individual cellular responses and immune cell interactions.  In this report, we attempt to provide a review of in vivo imaging techniques as they are used in the study of tumor growth and treatment.  Further, we will review the current advances in in vivo imaging methods and their applications in studying specific immune cell responses on a single cell level to a variety of stimuli.  The major focus will be on the imaging results of the analyses of T cells, dendritic cells, and their interactions in the manner of real time immune response to cancer vaccination.  This review aims to provide a comprehensive analysis of the modern in vivo imaging technique and how they can be employed to help produce effective cancer vaccines.

Heat Shock Proteins as Emerging Therapeutic Targets as well as Therapeutic Agents

Maya Pious Panjikaran, M.A. 2007

Heat shock proteins, until recently have been regarded as intercellular molecules which mainly aids in protein folding along with other housekeeping functions. They were also believed to be secreted into the extracellular environment under conditions of stress. But recent studies have shown that these heat shock proteins could be constitutively expressed in the cells even in the absence of any stress and they are believed to exhibit a wider range of immunoregulatory functions. Researchers over the years have correlated the enhanced expression of heat shock proteins in various diseases. Extensive studies in the field of cancer biology, vascular diseases as well as other immunological disorders have concluded several mechanisms as to how several heat shock proteins are induced in these diseases and the roles they play. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can down regulate the disease process. It might be because self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. All the above evidences suggest the role of heat shock proteins as possible therapeutic targets.

Current Concepts in Autoimmune Hepatitis with Focus on Treatment Options

Meghavi J. Patel, M.A. 2007

Amyotrophic Lateral Sclerosis: Past, Present and Future

Phillip C. Penny, M.A. 2007

Amyotrophic lateral sclerosis is a degenerative disease affecting motor neurons of the nervous system that leads to muscle weakness, paralysis and eventually death.  ALS is both familial and sporadic, with the sporadic form of the disease occurring in the overwhelming majority.  A gene has been isolated from familial ALS patients, the superoxide dismutase gene (SOD1) and it is likely that research using mutant SOD1 models will translate to sporadic ALS.  SOD1 mutant mice have been analyzed and results have shown that protein misfolding, mitochondrial dysfunction, disrupted axonal transport and oxidative damage are associated with ALS.  The aforementioned disease symptoms do not arise from a loss of function mutation to SOD1, rather the gene is conferred a toxic gain of function that we know little about.  Often researchers will point to a problem such as protein misfolding without looking at the first step of the disease.  This review will attempt to explain current theories on the initiation and progression of ALS and describe future directions for ALS research.

Dendritic Cells: Its Biology and their Potential Use in Cancer Immunotherapy

Raju Manga Reddy, M.A. 2007

The identification of tumor-associated antigens that can be recognized by T lymphocytes has opened new possibilities for immunotherapy protocols in treating various cancers. Dendritic cells are extremely potent antigen presenting cells, which are well suited to sensitizing naïve T cells toward antigens, including tumor-associated antigens. Immature dendritic cells, which reside in various tissues, are specialized to take up wide array of compounds such as proteins, lipids, oligonucleotides and carbohydrates. Upon activation by pathogens or inflammation, dendritic cells migrate to lymphoid tissues where they prime T cells to induce an antigen specific immune response. Accordingly, dendritic cells pulsed with tumor-associated antigens can used to induce tumor specific responses in patients. Several pilot clinical studies that investigated this approach in various cancers have clearly demonstrated the feasibility, safety and in many cases, the efficacy of DC vaccination. Tumors specific cytotoxic T lymphocyte responses were noted in many phase I, II, and III clinical trials and more importantly, this led to tumor regression and prolonged life spans in patients. Nevertheless, much work needs to be done in standardizing clinical trials and optimizing critical parameters before dendritic cell vaccination can be brought to the clinic. This review overviews dendritic cell biology, addresses critical parameters to optimize dendritic cell vaccination and discusses its role in malignant melanoma, prostrate cancer, and renal cell carcinoma.

Molecular vs. Cellular Approaches to Treat Coronary Artery Diseases

Michal Silverberg, M.A. 2007

Cardiovascular diseases are among the leading causes of death among adults in industrialized countries. Current treatment modalities provide solutions for a large range of patient population, but unfortunately, there are patients that can't be treated adequately with current solutions. These patients are referred to as no options patients. Treatments that are available today on the market include procedures that use medical devices, medications and surgeries. A new arena of therapies, which are in research and development, in the recent years, propose a novel approach to treat Coronary Artery Disease ( CAD ). The rational behind the new approach is treating CAD by promoting angiogenesis.

The angiogenesis therapies fall into two main categories -- molecular therapies and cellular therapies. Some implementations of these approaches have been tested in clinical trials, while others have only been tested in experimental models. 

The molecular angiogenesis therapies that have been tested so far have tried to induce angiogenesis by inserting one protein. This mono-molecular approach has failed in clinical trials, due to lack of efficacy. This failure indicates that attempting to use one molecule to try and trigger the complex cascade of angiogenesis might be overly ambitious. A more realistic alternative within the molecular approach might be to insert a combination of two or more molecules, whose synergistic contribution could be expected to produce a more significant effect on the formation of new blood vessels. The use of cells to induce angiogenesis relies on the elucidation of the angiogenesis process at the cellular level, including the different types of cells involved and the nature of the interactions between them. There is a range of cellular therapies which are in different stages of development and potentially could enter the market.

VEGF Therapy: An Exploration of the Properties, Wound Healing Mechanisms, and Therapeutic Potential of VEGF and a Novel VEGF Analogue in Accelerating Wound Healing in Diabetics

David A. Simhaee, M.A. 2007

One of the most common injuries faced in medical care today is that of “chronic” wounds, referring to tissue that does not heal normally. This condition can occur due to many diseases, of which diabetes is one of the most common. To heal properly, wounds require the deposition of granulation tissue, which consists of new blood vessels and collagen. Treatments for wound healing are few and far between. For the treatment of diabetic ulcers, for instance, there is currently only one FDA approved drug indicated for use (Regranex ®) – though the efficacy of this drug has been disputed and its results have not been reproducible in animal studies.

Vascular Endothelial Growth Factor (VEGF) may have the potential to serve as an effective therapy for healing chronic wounds. VEGF is a protein that is released by a variety of cells and plays a role in stimulating multiple components of the angiogenic cascade. It has been  hypothesized by our lab that the addition of a long-acting VEGF protein helps alleviate poor wound healing appearance and improves vascularization in genetically diabetic mice. Results indicate that VEGF-LA indeed improves wound healing rates compared to other treatments.

In considering the study’s results, this paper explores the current research literature on the structure and function of VEGF, including its potential use as a therapeutic agent for angiogenesis. Discussed are the specific role of VEGF in the angiogenic cascade and its relationship to other growth factors and cells in actively healing wounds. Also dealt with is how VEGF can best be clinically administered in supplementing wound healing.

The study and development of drug products based on this molecule may help increase the availability of therapeutic options in accelerating the rate of closure of chronic wounds. Identifying how VEGF-LA protein improves wound healing, can potentially lead to its use as a feasible treatment as a pharmacological therapeutic agent for accelerating wound healing in diabetic patients

Therapeutic Strategy Targeting BCL6 in Large B Cell Lymphomas

Archana Solipuram, M.A. 2007

Lymphoma, cancer of lymphatic system, is the fifth most common cancer in US. The disease incidence rate has increased two folds in the past 30 years. Lymphoma is subdivided into many categories and cancer types depending on the size, shape, lymphocyte developmental stage and clinical features. Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive Non-Hodgkin type of lymphoma accounting to 30-40% of total lymphomas.

Only combinational therapies have been successful treatment for DLBCL to some extent but the patients have to deal with numerous side effects. Hence researchers are working to come up with more efficient ways of treating this disease. Genetic abnormalities such as chromosomal translocations and somatic hypermutations are shown to be involved in DLBCL. These translocations can involve both immunoglobulin and non-immunoglobulin chromosomal loci but are frequently seen in Bcl6, Bcl2 or cMYC genes. Of these genes, Bcl6 has achieved more attention from researchers. 

Bcl6 is a proto-oncogene found on chromosome 3q27 and encodes BTB/POZ zinc finger protein which binds and recruits histone deacetylases (HDAC) through its POZ domain. This leads to the transcriptional repression essential for the formation of germinal center and hence B cell differentiation and maturation. Various protein-POZ interactions can inhibit recruitment of HDAC, leading to acetylation of Bcl6. This is an important factor in regulation of Bcl6 levels and is controlled by HDAC and SIR2 pathways. It is interesting to see how these pathways are being targeted in DLBCL patients. Addition of acetylases or removal/inhibition of deacetylases leads to bcl6 acetylation which in turn causes cell cycle arrest, apoptosis and hence inhibition of lymphomagenesis. Protein aptamer Apt48 has been recently identified to bind the POZ domain of Bcl6 thus inhibiting recruitment of histone deacetylases by Bcl6, there by leading to reduction in proliferation of lymphoma cells. Also histone acetylases like trichostatin A , niacinamide, suberoylanilide hydroxamic acid, depsipeptide and valproic acid, having shown positive results in inhibiting lymphomagenesis in animal models, are currently under investigation in humans. Promising results in these studies are important for enhanced treatment options in DLBCL patients.

The Future of Drug Discovery: Crucial Disciplines and Future Considerations

Clifford Cheng Sung, M.A. 2007

The drug discovery process dates back thousands and thousands of years to ancient civilizations around the world from Egypt to China.  The initial therapeutic agents used consisted of compounds derived from the natural world, typically plant derivatives.  By the early 19th century however, advancements in chemistry and biology allowed scientists to isolate active ingredients and purify or synthesize new ones, leading to a rapid period of growth in drug discovery and development.  The advent of molecular biology dramatically expanded the scope of drug discovery, with the most pertinent success being the completion of the Human Genome Project in 2003.  Since then, the genomic revolution rapidly developed a broader vision of drug targets and molecular understanding through technologies such as microarray.  The parallel field of proteomics ultimately followed suite, leading the way towards major future advancements in personalized medicine.  As subfields everywhere develop, a move towards a global, unified, systems understanding of the human body is certain.  Bioinformatics will play an enormous role in modeling larger gestalt systems.  To complement the developing synergy of information will be important advances necessary to ensure efficient treatments.  The continued push for generic medicine and the necessity for efficient drug delivery mechanisms are two crucial issues that are essential in our continued advancement in science and medicine.  In this thesis, we discuss these important issues and the guidelines necessary to guarantee that the future of medicine is bright.

The Future of Cancer Therapy - Cancer Immunotherapy

Pei-yi Sung, M.A. 2007

Along with the increasing number of cancer patients and lack of effective anti-cancer treatments, there is a substantial demand for this significant unmet medical need.  Both academia and industry invested tremendous amount of effort to fight cancer, but have yet to live up to initial expectations.  After the discovery of tumor-associated antigens, the concept of using the immune system to fight cancers began to bloom.  However, despite the fascinating science behind immunotherapy, clinical trials have not demonstrated satisfying clinical outcomes.   This review has two objectives: 1) lay out the technologies being developed to generate effective cancer immunotherapy, and 2) address the critical parameters and possible factors that are responsible for the disappointing results of anticancer immunotherapy (despite having attracted considerable attention).  Finally, an overview of the current cancer market from a business perspective and the role pharma/biotech companies play in contributing to the cancer battle are discussed.   

Mitochondrial Dysfunction and Schizophrenia

Dionne E. Swor, M.A. 2007

 Mitochondrial dysfunction has been implicated in schizophrenia as well as various other neuropsychiatric disorders. The sensitivity of the brain to mitochondrial dysfunction can be attributed to the high-energy requirement of the brain making proper mitochondrial function pertinent to neurological function. Several lines of evidence implicate mitochondrial dysfunction in schizophrenia, including altered mitochondrial morphology, dysfunction of the oxidation phosphorylation system, and altered mitochondrial related gene expression. In addition, various schizophrenia susceptibility genes have been found to localize to the mitochondria, further supporting a role for mitochondrial impairment in schizophrenia pathogenesis. One such schizophrenia susceptibility gene, G72, is discussed below and evidence is presented implicating G72 in altering mitochondrial morphology and inducing increased dendritogenesis in synaptically immature primary neurons.

Linking Neuroimaging and Genomics: An Approach to Investigate the Influence of Genetics on Brain Function 

Karen Tang, M.A. 2007

Imaging genomics is a new emerging field that integrates brain imaging with genetics to understand brain structure and function. There has been a major effort within the science community to search for susceptibility alleles for complex disorders, and recent advances in molecular genetics and neuroimaging provide researchers important tools for identifying candidate genes that are associated with a particular behavioral phenotype. Recent studies have used neuroimaging to investigate brain regions that are associated with the clinical symptoms of genetic neurobiological disorders such as Alzheimer’s disease, schizophrenia, and Williams syndrome. The integration of genomic information with neuroimaging has the potential to help identify at-risk individuals, monitor disease progression, and tailor treatment to meet individual needs. This thesis provides an overview of the strengths of the imaging genomics approach and highlights recent studies that effectively use this technique to study genetic mechanisms of disease. This review also analyzes the future directions and challenges of this emerging multidisciplinary strategy and offers suggestions for improving future studies.

Is the Future of Diabetes and Heart Disease Treatment in Embryonic Stem Cells?

Cynthia Tañón-Santos, M.A. 2007

Organisms develop from a pluripotent cell type known as embryonic stem cells. These cells are found at early stages of development and have the capacity to differentiate into any cell in the body like cardiomyocytes or insulin-producing beta islet cells of the pancreas1. For almost 10 years scientists have studied the possibility to use these cells in the treatment of health conditions that are caused by loss of function or death of specific cell types in the body. Many heart disease like infarction, arrhythmias and coronary heart disease can cause death of myocardial cells. Diabetes is caused by immune-mediated destruction or loss of function of insulin-producing cells in the pancreas. Both diseases have no cure and their incidence is escalating every year. Additionally deaths caused by these diseases have become more prevalent in the Unites States and worldwide, clearly indicating that alternative treatments for both diseases have to be considered. This paper presents the background of embryonic stem cells and the advances in this field specifically in heart disease and diabetes treatment.

Taming the Macrophage Molecular Basis of Phagosomal Maturation Arrest by Mycobacterium Tuberculosis

Jakob von Moltke, M.A. 2007

Mycobacterium tuberculosis presents an enormous global health burden, infecting an estimated 1/3 of the population and killing 1.7 million individuals every year. The resilience of M. tuberculosis derives from its ability to survive inside the host macrophage, which it achieves largely by blocking maturation of its phagosome. The molecular mechanisms and pathways required for host phagosome maturation and the ways in which M. tuberculosis subverts these pathways to arrest phagolysosomal biogenesis are beginning to emerge. EEA1, Hrs, and actin are key effectors of phagosomal maturation and their activation and recruitment is coordinated by signaling pathways induced during phagocytosis. Both surface-expressed lipids and secreted M. tuberculosis proteins that alter these host signaling pathways to arrest phagosomal maturation have been identified. Ongoing research must validate these bacterial factors in clinically relevant models of M. tuberculosis infection, while at the same time identifying novel pathogenic factors required for phagolysosomal biogenesis arrest. High-throughput screening approaches facilitated by sequencing of the M. tuberculosis genome have already begun to yield interesting candidates. Finally, as increasingly drug-resistant strains of M. tuberculosis emerge and particularly threaten a growing population of HIV-positive patients, these discoveries should be translated into novel chemotherapies and vaccines.

RNAi : A Diamond in the Rough

Nafeez Zia, M.A. 2007

RNA interference (RNAi) is a well-conserved, endogenous mechanism that uses small double-stranded RNAs called small interfering RNAs (siRNAs) to inhibit gene expression with high specificity.  Initially, this natural mechanism of gene silencing was thought to be used solely by plants to protect themselves from viruses.  However, RNAi-mediated gene silencing is now known to take place in almost all eukaryotic organisms, including protozoa, flies, nematodes, insects, parasites, and mouse and human cell lines.  The fact that RNA interference can be applied to mammalian cell lines has revolutionized the way present day scientists approach gene function studies and drug development.

RNAi has immense therapeutic potential in treating human diseases. Initial tests conducted in vitro and in vivo have shown promising results in the treatment of a variety of diseases including cancer, infectious diseases, neurodegenerative diseases and cardiovascular diseases.  Although clinical trials on humans have yet to start still scientists are very optimistic about the future that lies ahead in terms of drug development and disease therapeutics. 

The RNAi phenomenon is still at the infancy stage.  Scientists are making good progress in elucidating the mechanism of action of RNAi-mediated gene silencing event.  However, there are obstacles involving RNAi.  Delivery and stability of RNAi in the cytoplasm of the target cell are major limitations.  Currently, viral and non-viral vectors are used to aid in the delivery of RNAi.  Many more techniques are in the works and with increasing research; we can expect to overcome these obstacles. 

The current state of RNAi is similar to a crude diamond.  Everyone understands the value of a diamond but in order to receive its value, the diamond has to be cut and refined very meticulously.  Similarly, RNAi is a very recent phenomenon.  Ongoing research and dedication is required to unleash the full potential of RNAi in drug development and disease therapeutics.