Yu Wei Chang, M.A.
A Review of Cellular Apoptosis Pathways abstract
Advisor: Ava Brent
ChunMing Chen, M.A.
microRNAs and Cancer abstract
Advisor: Alla Grishok
Jingkang Chen, M.A.
Therapeutic Strategies for Nerve Agent Exposure abstract
Advisor: V Cornish
Jessica DeLalio, M.A.
The Complex Role of Mast Cells in Multiple Sclerosis abstract
Advisor: Katherine Nautiyal and Solomon Mowshowitz
Meaghan Dendy, M.A.
Identifying Novel Roles of BAF180 as a Tumor Suppressor abstract
Advisor: Ramon Parsons
Subbhalakshmi Dhalladoo, M.A.
Biotech Bridge: Business Proposal for SBIR Application to the National Center for Advancing Translational Sciences (NIH) abstract
Advisor: David Sable
Pedro Herrera, M.A.
The FDA 505(b)(2) pathway: A Review of Approved Drugs abstract
Advisor: Robert MacArthur
Salvin Jacob, M.A.
The Enigma that is HIV abstract
Advisor: David Sable
Rajbir Kaur, M.A.
Development Challenges in the Field of Antibiotics- Impact on Current Unmet Needs abstract
Advisor: Ron Guido
Natalia Kruchevsky, M.A.
The Role of Magnetic Resonance in Prostate Cancer Diagnosis, Characterization and Treatment abstract
Advisor: Ellen Ackerstaff
Jeremy Lieberman, M.A.
A framework for systematic promoter motif discovery and expression profiling from high dimensional brain transcriptome data abstract
Advisor: Saeed Tavazoie
Edwin Lin, M.A.
Methodology and Application of High-Throughput Sequencing of T-cell and B-cell Repertoires abstract
Advisor: Shen Yufeng
Yang Lu, M.A.
The Application of Nanotechnology to Genomic Sequencing in the New Century abstract
Advisor: James Russo
Vincent Macri, M.A.
Glioblastoma Multiforme: Review and Immunotherapeutic Strategies abstract
Advisor: Ron Guido
Yufei Mou, M.A.
Halophiles as a Source of Novel Genes and Application in Biotechnology abstract
Advisor, Guixian Xia
Jessica Neufeld, M.A.
Nosology, Genetics and Epigenetics in Schizophrenia Research: a Shift in Paradigm abstract
Advisor: Ragy Girgis
Arturo Olguin, M.A.
A Review of Genetic Transfer Therapy Trials from a Regulatory Perspective for the Scientific Understanding abstract
Advisor: Ron Guido
Vimala Punsammy, M. A.
Human Heart Regeneration-the future of regenerative therapy and modern medicine abstract
Advisor: Ron Guido
Brian C. Wang, M.A.
Oncolytic Virus Therapy Usinh HSV-1 for the Treatment of Gliomas abstract
Advisor: Joanna Shisler
Chen-Lin Wang, M.A.
The MFRP, which encodes a Frizzled-related protein, plays an important role in eye growth regulation abstract
Advisor: Stephen Tsang
Yasemin Yozgat, M.A.
Age-dependent changes in oncogenic KIT signaling and imatinib response in a mouse model of gastrointestinal stromal tumor abstract
Advisor: Peter Besmer
Shui Yu, M.A.
The Role of Stem Cells in Inflammatory Bowel Disease abstract
Advisor: Samuel Asfaha
Biao Zhang, M.A.
The Evolution of Pharmaceutical Regulation towards Global Harmonization: An Emphasis on International Collaboration with Developing Countries abstract
Advisor: Ron Guido
A Review of Cellular Apoptosis Pathways
Yu Wei Chang, M.A. 2013
Cancer is one of the leading causes of death worldwide1. A malfunctioned apoptosis is one of the hallmarks of cancer. The balance between cell life and death is needed in order to maintain cellular homeostasis. Therefore, programmed cell death is a necessary process for eliminate of damaged or unneeded cells. Generally, apoptosis can trigger two different signaling pathways: extrinsic and intrinsic apoptosis. Extrinsic apoptosis pathways occur when the extrinsic cellular stress activates pro-apoptotic receptor and initiates caspase mechanism. Bcl 2 gene family regulates cell life/death by the interaction between anti-apoptotic and pro-apoptotic proteins3, 5. Imbalance between anti-apoptotic and pro-apoptotic protein ratio is one hallmark of cancer cells. For example, when overexpressed anti-apoptotic proteins appear inside the cell, apoptosis is inhibited and instead the cell starts to proliferate. On the other hand, intrinsic apoptosis pathway is initiated from within the cell when a cell is mutated or damaged. Mitochondria release pro-apoptotic proteins and activate caspase cascade2. Bcl 2 family membranes also regulate the mitochondrial permeability and trigger downstream apoptosis pathway53. In addition, p53 tumor suppressor is highly correlated with apoptosis and cell cycle arrest34, 35. Understanding of normal apoptosis and its mechanism at the cellular level is a promising approach for novel chemotherapeutic treatment for current cancer. The insight transduction pathways can target cancerous cells without affecting normal cells. Further characterization and understanding of different cascades is necessary to reveal novel strategies controlling the cell cycle process. Many studies only focus on specific parts of apoptosis pathways but neglect the big picture of how complex interaction between extrinsic and intrinsic pathways. In addition, even in the same pathway, there are many factors can affect apoptosis. This paper presents an overall review of the factors of apoptosis and the interactions between extrinsic and intrinsic pathways. In addition, many studies have applied the apoptosis methodology for cancer treatment and prevention. Therefore, understanding apoptosis can be very useful for therapeutic interventions.
ChunMing Chen, M.A. 2013
microRNAs, a class of non -coding, small, endogenous RNA molecules, have recently emerged to be essential for gene regulation in multicellular eukaryotes, including humans. microRNAs control gene expression post-transcriptionally and affect many cellular processes, such as growth, cell differentiation, cell cycle and apoptosis. Hence, abnormal expression of microRNAs has been implicated in several human diseases, including cancer. In this review, the discovery of microRNAs, microRNA biogenesis and their function in gene regulation are briefly described. Next, both in vitro and in vivo evidence, illustrating the roles of four prominent microRNAs as oncogenes or tumor suppressor genes in different cancers is presented. Also, the targets of these microRNAs and their biological functions are discussed. Finally, this review ends with a discussion of microRNAs as potential cancer biomarkers, the origins of circulating microRNAs, and the current microRNA biomarkers identified for various cancers.
Therapeutic Strategies for Nerve Agent Exposure
Jingkang Chen, M.A. 2013
The recent turmoil in Syria has renewed concerns amongst nations, both neighboring and worldwide, that a desperate Syrian government may deploy chemical weapons against rebel forces. As recent as August 2013, chemical weapons had been allegedly deployed by the Syrian government according to US intelligence and local media sources. The situation is further exacerbated by the potential proliferation of such Weapons of Mass Destruction (WMD) should they fall into the hands of rebel groups with ties to terrorist organizations such as the Al-Qaeda. Arguably, the most lethal and devastating of chemical agents are the nerve agents. Despite these real threats, the toxicity of current antidotes against nerve agents, such as atropine, precludes their distribution to the general public. Furthermore, the need for immediate administration of such toxic antidotes upon exposure to the nerve agent limits its effectiveness in preserving the lives of military responders and civilian casualties. Therefore, it is timely and an imperative to review and consider alternative therapeutic strategies for treatment of nerve agent exposure. This paper aims to address the shortcomings of current treatments and explore how alternative strategies can serve to overcome these limitations.
The Complex Role of Mast Cells in Multiple Sclerosis
Jessica DeLalio, M.A. 2013
Mast cells are key immunocytes in immune surveillance and known mediators of Type I hypersensitivity reactions. However, their role in central nervous disease, specifically multiple sclerosis, is less well defined. Mast cells are commonly located in and around sclerotic plaques in the multiple sclerosis brain. Their release of potent vascular mediators, proteases, cytokines, and chemokines exacerbate debilitating neuroinflammatory symptoms. Mast cells also release anti-inflammatory and neuroprotective mediators, which raises questions as to whether mast cells’ role in multiple sclerosis is harmful or helpful. Mast cell deficient murine lines and the experimental autoimmune encephalomyelitis model are helping to answer these questions and elucidate mast cells’ complex role in disease. In hindsight, select current multiple sclerosis therapeutics indirectly target mast cells. This helps establish mast cells’ role as detrimental disease mediators and suggests there is therapeutic value in their exploitation.
Identifying Novel Roles of BAF180 as a Tumor Suppressor
Meaghan Dendy, M.A. 2013
Chromatin remodelers are molecules that modify chromatin to allow transcription factors access to the DNA strand. It has been determined that SWI/SNF chromatin remodeling complexes can regulate gene activation/repression. Individual subunits of these complexes have been recently identified as tumor suppressors in various cancer subtypes. BAF180 is a member of the PBAF complex and has been identified as a tumor suppressor that is mutated in human breast, pancreatic and clear cell renal cell carcinoma. The mechanistic role of BAF180 as a tumor suppressor is still unknown and the lack of an existing mouse model has inhibited its identification as a bona fide tumor suppressor gene. Findings show that p21 is directly regulated by BAF180 in human breast cancer. As a result, it has been hypothesized that the role of BAF180 may be to regulate tissue- specific genes at the transcription level. This grant proposal aims to identify the role of BAF180 in human cancers via techniques in cell biology, biochemistry, cancer biology and mouse genetics. In vitro experiments will define where BAF180 binds in the genome in breast and renal cancer models. The generation of a conditional BAF180 mouse knockout model will outline the mechanism and timeline for tumorigenesis. This mouse model will also provide a comparable model for clear cell renal cell carcinoma which is thus far absent in the field. Assessment of the proliferative difference, genome targeting and modifications at the histone level will allow us to assess the actions of BAF180 at the cellular level. The identification of novel BAF180 protein binding partners will further contribute to the understanding of BAF180’s tumor suppression mechanisms and lead to future research in the field.
Biotech Bridge: Business Proposal for SBIR Application to the National Center for Advancing Translational Sciences (NIH)
Subbhalakshmi Dhalladoo, M.A. 2013
A symbiotic relationship exists between basic research done in an academic setting and applied research performed in industry, yet transfer of knowledge from one place to the other is not highly efficient. This makes the drug discovery and development process longer and more expensive. My proposed entity, Biotech Bridge, seeks to bridge these fields using a dynamic, two-way flow of information. Using crowdsourcing, knowledge brokering, and product development partnership principles, Biotech Bridge seeks to create an online information sharing as well as social network.
To test the feasibility of Biotech Bridge, a small-scale trial run, studies, and surveys, are planned. Potential for commercial applications and governmental use will be assessed. $385,375 is requested from this SBIR application to the National Center for Advancing Translational Sciences of the NIH.
The FDA 505(b)(2) pathway: A Review of Approved Drugs
Pedro Herrera, M.A. 2013
The FDA 505(b)(2) pathway was developed to foster innovation in drug development and bring new products to the market that would address unmet medical needs. It allows applicants to rely completely or partially upon previously submitted clinical data to bring a new drug to market, reducing the cost of drug development dramatically. Drug products approved through this pathway are eligible for different periods of extended market exclusivity. The objective of this study was to review the characteristics of drugs approved via the 505(b)(2) pathway from a regulatory affairs and financial standpoint. We reviewed and obtained information from Summary Basis of Approval (SBA) and approval letters since 2002. 505(b)(2) products account today for almost half of total FDA annual approvals. Most of these receive standard review, with few priority reviews and orphan designations. A list of common indications for 505(b)(2) products obtaining priority review is included. The most common changes introduced by 505(b)(2) products were changes in dosage (39.4%) and formulation (28%). Only a few new chemical entities (4.9%) and new indications (0.8%) were approved, limiting the number of products that get larger periods of market exclusivity. More than half of all 505(b)(2) approved drugs were developed by public companies with a market capitalization higher than $2 billion (51%). Novartis and Sandoz were the most common developers with 24 drug products, followed by Teva with 11 and, Pfizer, GSK and Mylan with 10 products each. Products approved via this pathway offer little innovation for unmet public health needs, and allow companies to maintain higher drug prices for longer periods of time.
Salvin Jacob, M.A. 2013
Human Immunodeficiency Virus (HIV) is a disease that has been studied extensively for many years without a tangible cure. This is mainly due to the ability of this retrovirus to adapt, avoid, and weaken the host immune system. The extended asymptomatic phase (clinical latency) in the viral infection which can last from months to years also helps promote the spread of the virus through unsuspecting hosts. In the past, the major problem that occurred in the treatment of HIV was resistance because of the virus’ ability to quickly adapt. Though this resistance is not highly prevalent today, current treatments do not aim to cure the patient. These treatments are geared towards treating the disease as chronic infection. These current drug therapies are based on combination of drugs that must be taken daily. Though it has greatly prolonged the life of infected individuals, the ultimate goal is to eradicate the disease from the genome of all humans. Though it may seem like a daunting task, future treatments look very promising to prevent infection and finally eliminate the disease. These more novel treatments include a focus on new drug targets, gene therapy, and a genetic approach with human model systems. As the scientific knowledge base of this infectious virus is expanded, even more treatment possibilities can be explored.
Development Challenges in the Field of Antibiotics- Impact on Current Unmet Needs
Rajbir Kaur, M.A. 2013
After the discovery of first antibiotic, the field of science and medicine was completely revolutionized. The once incurable infections were now curable and large numbers of untimely deaths were avoided. However, soon after the introduction of antibiotics into the health care, microbial species started to become resistant to these antibiotics. Most of the microbial strains like Staphylococcus and gram negative Bacilli became multi drug resistant and evolved significantly to evade every possible treatment. This has stalled further growth in the field of antibiotics, which has hindered our ability to address the unmet needs in the field of infectious diseases. Both research and development field have almost hit the wall, as the number of new drugs reaching the market is continuously receding. Therefore, there is a need for more efficient approach to look for effective antimicrobial drug candidates, so that the global community can overcome this paramount crisis situation of antimicrobial resistance.
The Role of Magnetic Resonance in Prostate Cancer Diagnosis, Characterization and Treatment
Natalia Kruchevsky, M.A. 2013
One in six men will be affected by prostate cancer in their life time. Prostate cancer can be slow or fast growing and it affects mainly men over fifty. Current options for treatments are surgery, radiation, hormone therapy, immunotherapy, chemotherapy and active surveillance. Magnetic resonance imaging and spectroscopy is a non-invasive, sensitive, and non-radioactive way to detect, characterize and understand the anatomy, physiology and metabolism of a tumor. MRI provides high image resolution that depicts the zonal anatomy of the prostate and cancer in areas that may have been missed by a biopsy. The field of MRI/MRS is constantly evolving toward new emerging techniques that can provide higher accuracy and sensitivity for cancer detection as well as treatment planning.
A framework for systematic promoter motif discovery and expression profiling from high dimensional brain transcriptome data
Jeremy Lieberman, M.A. 2013
Understanding the regulatory logic of genes across discrete brain substructures can elucidate the basis for neural function and the cause of disease. Promoter motifs, in particular, that govern high or low expression gene networks present an important fulcrum for phenotypic behavior. Using the Allen Institute Brain Atlas we took various clustering methods to find closely regulated genes, and generated substructure specific expression profiles to run through FIRE, a motif discovery algorithm and iPAGE, a functional ontology algorithm. Notably, we found a single large cluster of genes that had tightly coordinated behavior across hundreds of brain substructures, as well as a unique upstream promoter signature, yet highly diverse ontological characteristics. We also present a BRain EXpression Profile ASSembly script (BEXPASS) whose output is customized for FIRE and iPAGE input. Lastly we look at language processing and speech control areas of the brain and put forward recommendations for promoters that can serve as part of DNA constructs for optogenetic research an emerging neuroscientific research method that uses bacterial light-gated ion channel protein, channelrhodopsin (ChR1 or ChR2), as an activity control tool to activate neural pathway signaling.
Methodology and Application of High-Throughput Sequencing of T-cell and B-cell Repertoires
Edwin Lin, M.A. 2013
The adaptive immune system is capable of producing highly specific responses tailored to particular antigens. This specificity comes from selection of semi-stochastically generated T cell receptor (TCR) combinations that have high affinity towards a particular antigen, resulting in huge genetic diversity in the immune system. TCR-antigen recognition underlies many important biological processes, including pathogen detection and autoimmunity. Recent advance of high throughput sequencing makes it feasible to study the entire TCR repertoires. Here I describe the quantitative problems and solutions in analyzing TCR repertoire sequencing. This approach will have broad applications in the immunology, cancer biology, and virology. The field and applications of immune repertoire sequencing will continue to expand rapidly due to exponential increases in sequencing and computational power.
The Application of Nanotechnology to Genomic Sequencing in the New Century
Yang Lu, M.A. 2013
Genomic sequencing technology has developed tremendously in the last decades. Among the many sequencing methods that have been studied, the application of nanopores as biosensors in genomic sequencing has received special emphasis lately. Since nanopores have the potential to sequence the DNA strand at single-molecule level with base-specific resolution, nanopore sequencing technology has a high likelihood of reaching the $1000, or even lower, genome goal. This review will focus on three directions of nanopore sequencing research: nanopore technology in DNA strand sequencing, nanopore technology using exonuclease, and nanopore technology using released tags.
Glioblastoma Multiforme: Review and Immunotherapeutic Strategies
Vincent Macri, M.A. 2013
Glioblastoma multiforme is the most common and aggressive type of high-grade glioma, the most common subset of central nervous system tumors. Patients with glioblastoma multiforme suffer from one of the worst prognoses of all cancers, with median survival of 14.6 months. Standard treatment for glioblastoma currently consists of maximal surgical resection followed by radiation and chemotherapy. In addition, only one immunological therapeutic agent, the monoclonal antibody bevacizumab, is currently approved by the FDA for treatment of the disease. There are complex hurdles associated with treating the disease, which include a growing, yet incomplete, understanding of glioblastoma immunity, as well as the complex microbiology of the disease and its interface with vast, overlapping cytokine networks. Gliomas utilize both molecular and cellular methods for creating both intratumoral and systemic immune response reduction. For this reason, immunological therapies for glioblastoma multiforme, while still in the early stages of development, may provide targeted therapy that complements or replaces existing treatment regimens and improves patient outcomes. This paper reviews some of the relevant molecular biology and immunology associated with the progression of glioblastoma multiforme, provides information about current immunotherapeutic efforts, and proposes directions that future treatment strategies might take. Particular attention is paid to immune system responses, conventional glioblastoma immunosuppression, and immunotherapeutic strategies involving monoclonal antibodies and dendritic cells.
Halophiles as a Source of Novel Genes and Application in Biotechnology
Yufei Mou, M.A. 2013
Halophiles refer to salt-loving microorganisms that thrive under hypersaline environments such as salt lakes, saltpans and seawater. They are mainly classified into two categories according to the salt concentration in their habitat: moderate halophiles and extreme halophiles. The capability of halophiles to resist the denaturing effects of salts and the increasing number of hypersaline environments all over the world, have contributed to the development of biological resource applications for extreme environments. In recent years, many studies have focused on the biological characteristics of halophiles, especially its genetic features and the application of halophilic genes, in an effort to generate salt-tolerant transgenic plants and bacteria. This review will cover the genetic and biological characterization of halophiles, along with the current successes and prospects with using applications derived from halophilic bacteria.
Nosology, Genetics and Epigenetics in Schizophrenia Research: a Shift in Paradigm abstract
Jessica Neufeld, M.A. 2013
Schizophrenia is a morbid psychiatric disorder that affects more than 24 million people worldwide. Evidence suggests that both genetic and epigenetic factors contribute to this heterogeneous pathology; yet, etiology of the illness remains evasive, giving rise to nonspecific therapeutics and suboptimal patient outcomes. An inspection of nosologic evolution and diagnostic parameters unveils inherent obstacles to scientific progress and provides a refined filter through which to interpret the armament of etiological data. This thesis will overview the evolution of schizophrenic nosology, discuss the putative polymorphic and epigenetic influence of nine proposed susceptibility genes (DISC1, DISC2, 5-HTR2A, Nrg1, Nrg3, DRD2, DRD3, DRD1, and COMT), and propose future strategies to elucidate the origins of this diverse and devastating illness.
A Review of Genetic Transfer Therapy Trials from a Regulatory Perspective for the Scientific Understanding
Arturo Olguin, M.A. 2013
The present work reviews the safety and efficacy concerns of the Recombinant DNA Advisory Committee (RAC) regarding Gene Transfer Therapy (GTT) clinical trials. The RAC, an advisory board established by the National Institutes of Health (NIH) is charged with reviewing and discussing GTT clinical trials and give regulatory guidance to the NIH for further proceedings. Considering the infamous past of GTT clinical trials, where malignancies have been found as a serious adverse event, one of the main concerns among regulators is the possible insertional mutagenesis (IM) caused by the viral vector used in this kind of trials. Many controls have been suggested to decrease this risk like fully characterizing the insertion sites (IS) of the vector used. The rest of the regulatory concerns are related to efficacy and safety of the whole therapy. This is no different from any other type of therapy or drug that is subject to FDA approval, however, there are some specific points for GTT clinical trials that must not be ignored. Based on these concerns, I include two case studies to exemplify how their findings would be reviewed from a regulatory perspective The first is a trial that uses an Adenovirus-associated virus vector to treat adult patients suffering from Hemophilia B. The trial is successful but they did not covered key efficacy and safety aspects that would fully convince a regulator to approve this kind of therapy. The second trial uses a lentiviral vector to transduce ex-vivo hematopoietic cells to correct the condition known as X-linked adrenoleukodystrophy (X-ALD), which affects children from 5-12 years of age and results in mental retardation and if not treated can cause death. The researchers on this trial took a lot of measures and controls to ensure the safety of the therapy however they failed to include a statistically significant population that would describe the efficacy of the therapy over the standard of care. I hope this can serve as a guide to harmonize the understanding of regulatory requirements from the science community and work together for a better drug development process.
Human Heart Regeneration-the future of regenerative therapy and modern medicine
Vimala Punsammy, M. A. 2013
With the discovery of mammalian heart regeneration observed as possible within few days of birth, associated stem cell research and cardiac muscle cell regeneration, new cardiac therapeutic solutions may address cardiac infarction, the leading cause of death. Heart disease is the number cause of death in the United States in both men and women, killing more and more people each day. It usually results from a lack of blood and oxygen to the heart killing specialize cells known as cardiomyocytes. These cardiomyocytes unlike those of lower organisms such as zebrafish and salamander are unable to proliferate in adult mammals and thus unable to heal the heart when sick. The advancement on regenerative therapy for heart attack is proving to be a success and unlocking the secret of why mammals are unable to regenerate may soon be understood.
Oncolytic Virus Therapy Using HSV-1 for the Treatment of Gliomas
Brian C. Wang, M.A. 2013
Gliomas are the most common form of primary brain tumors and are characterized by highly aggressive growth and poor patient prognosis. Recent development of novel therapeutics for the treatment of malignant gliomas has involved the use of oncolytic viruses. These viruses are genetically-engineered to selectively infect and lyse tumor cells. In particular, oncolytic viruses derived from herpes simplex virus-1 have several prominent safety advantages, along with larger capacities for incorporating therapeutic foreign genes. As a result, several herpes simplex virus-1 oncolytic mutants have been developed for clinical use in glioma patients and have already achieved early success in preclinical and early clinical studies. These oncolytic mutants utilize a wide range of combination and “arming” strategies, offering a broad spectrum of potential treatments for complex tumors like gliomas.
Chen-Lin Wang, M.A. 2013
Myopia is a common refractive error that affects vision health around the world. The increasing high prevalence of myopia, coupled with the pathologic complications of high myopia, has led to more intensified research efforts towards discovering the causes of myopia and how refractive errors can be regulated. This review summarizes the evidence suggesting that the membrane-type frizzled-related protein (MFRP) plays a critical role in ocular growth regulation.
MFRP is a gene selectively expressed in the retinal pigment epithelium (RPE) and the ciliary body. Patients with recessive mutation of MFRP display a cluster of phenotypes, including short axial length, photoreceptor degeneration, and rod-cone photoreceptor death. Understanding the role of MFRP gene will not only show the regulation of ocular growth, but also provide new insights for therapeutic applications for myopia control.
Age-dependent changes in oncogenic KIT signaling and imatinib response in a mouse model of gastrointestinal stromal tumor
Yasemin Yozgat, M.A. 2013
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the human gastro intestinal tract. GISTs express KIT and they are thought to derive from a KIT+ or KITlow interstitial cell of Cajal (ICC) progenitor or ICCs themselves. 69-89% of GIST lesions have a KIT activating mutation and 5%-13% of GIST lesions have a PDGFR α mutation. The most common activating mutations in GIST are found in KIT exon 11 which encodes the juxta-membrane domain of the KIT protein. A germline mutation of exon 11 found in a case of familial GIST had been introduced into the mouse Kit gene by a knock-in strategy in our lab before. The resulting KitV558Δ/+ mice develop cecal GIST with full penetrance. Imatinib mesylate is a tyrosine kinase inhibitor that inhibits KIT activity, and is used as a frontline treatment for advanced GIST patients. However, while imatinib treatment in GIST patients delays tumor progression, it does not cure the disease. We recently observed better histological response of GIST tumors to imatinib treatment in old KitV558Δ/+ mice compared to young mice. This is a surprising result since in general tumors are thought to become more aggressive over time. In this study we investigated whether key differences exist in signal transduction pathways in gastrointestinal stromal tumors from young mice versus old mice. We found that activation of ERK was diminished in old tumors and also activation of SRC and FAK was not further stimulated in old tumors upon imatinib treatment. These results highlight the importance of changes in ERK and SFK signaling during GIST progression.
The Role of Stem Cells in Inflammatory Bowel Disease
Shui Yu, M.A. 2013
Inflammatory bowel disease (IBD) which consists of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder with rising incidence and prevalence in North America. Even though current treatments can ameliorate the IBD symptoms to some extent, none of them can show a long-term efficacy and free side effects. Stem cell-based therapies have been applied in some clinical conditions and the potential for stem cell-based therapies continues to expand exponentially due to advances in stem cell researches. In this review, hematopoietic (HSC), mesenchymal (MSC), tissue specific (TSC) and embryonic stem cells (ESCs) are reviewed as emerging and effective approaches for IBD treatment.
The Evolution of Pharmaceutical Regulation towards Global Harmonization: An Emphasis on International Collaboration with Developing Countries
Biao Zhang, M.A. 2013
To counter fast-evolving diseases of the 21st century, the world is facing unprecedented challenges. Inherent issues such as the growing population, high percentage of aging and the shift towards unhealthy lifestyle further aggravate the burden of pharmaceutical industry in advancing quality of life. While promising innovations are consistently being brought out of the laboratory, mature product is still lacking on the market leaving human beings behind the steps of diseases. Effort to improve the so called “innovation gap” has mainly been put into boosting basic research and fueling pharmaceutical development. Recently however, attention has been focused on regulatory policy which lengthens the approval cycle and caused numerous life-saving projects to terminate and promising ideas to be shelved. If this issue is looked at from a world-wide perspective, the inefficient spreading of first-line product or technology from developed countries to those that are not raises major concerns. The crux lies in the inconsistency of policies among countries and the problem is worsened especially in developing countries. As the developing world gradually take lead in both the market size and R&D capabilities and with the global shift of R&D activities to these countries, the lack of standardized international regulation that facilitates the global shift of R&D activities to these countries has manifested to be a central issue. China as the mostly populated country relies heavily on advanced pharmaceutical products in order to release domestic healthcare stress. The revolution and modernization of China’s healthcare systemtogether with international organizations’ effort to formulate unified procedures marked an important step in the global harmonization of pharmaceutical regulation standards. Under the current trend of globalization, spreading the whole drug R&D process across multiple countries has also become an inevitable path towards the successful marketing of the world population. The collaboration has already started taking place, but is still facing difficulties that can be solved by a better policy framework.