Kathryn Abele, M.A.
Voltage Gated Calcium Channels: Potential Drug Targets for Blockbuster Indications abstract
Advisor: Jian Yang
Aseem Anand, M.A.
Molecular Profiling of Circulating Tumor Cells in Patients with Castrate Resistant Metastasizing Prostate Cancer abstract
Advisor: Daniel Danila
Claudia B. Assor, M.A.
The Immunological Challenges of Bacterial Biofilms abstract
Advisor: John Loike
Theodor M. Borgovan, M.A.
Barrett’s Esophagus Associated Adenocarcinoma Cell(Seg-1) Resistance to the Green Tea Cathecin Polyphenon E May Be Due To Increased BCL2 Expression abstract
Advisor: Andrew Joe
Neli Brod, M.A.
RNAi: From Laboratory to the Clinic abstract
Advisor: Carol Lin
Dane O. Campbell, M.A.
Looking to RNAi to Treat Cancer abstract
Advisor: Larry Chasin
Mei-Ki Chan, M.A.
Novel Approaches to Micrometastasis Detection abstract
Advisor: Solomon Mowshowitz
Ku-yu Chang, M.A.
Medicinal Plants in Drug Discovery and Development of Pharmaceutical and Biotech Industry, From a Taiwanese Perspective abstract
Advisor: Ron Guido
Ning-En Chang, M.A.
Review on Cancer Stem Cells abstract
Advisor: Cristina Antonescu
Sean Wei Chung Chen, M.A.
Human Heat Shock Protein 27 Overexpressing Mice Demonstrate Increased Renal Ischemia Reperfusion Injury in vivo abstract
Advisor: HT Lee
Tuan Li Chuang, M.A.
Inteins: Protein Splicing and Biotechnology Applications abstract
Advisor: Henry Colecraft
Jorida Çoku, M.A.
Investigation of the Mitochondrial DNA Depletion Syndrome (MDS) due to Thymidine Kinase (Tk2) Deficiency abstract
Advisor: Michio Hirano
Earl J. DeSouza, M.A.
Diabetes Mellitus Type 1: Where has Research Taken us in Prevention, Diagnosis, and Treatment? abstract
Advisor: John Manavalan
Travis Gorenc, M.A.
Analysis of Drosophila Reaper Peptide as an IAP Antagonist in Human Tumor Cell Cultures abstract
Advisor: Hermann Steller
Wan-Ying Hsieh, M.A.
The Molecular Rationale for Inhibiting Histone Deacetylase in the Treatment of Lymphoma abstract
Advisor: Owen A. O'Connor
Arun Marcel Jaganathan, M.A.
Optimization of HIV/AIDS Cocktail Regimens: A Case Study for Maraviroc, a Novel Co-receptor Antagonist abstract
Advisor: Robert Pollack
Jamie Kim, M.A.
Adult Neurogenesis and its Effect on Depression and Antidepressant Treatment abstract
Advisor: Alex Dranovsky
Jelena Kling, M.A.
The STAT5 Pathway and Its Role in Hematopoiesis abstract
Advisor: Christian Schindler
Xiayin Liang, M.A.
Application of SNPs in the HapMap-based Genome-wide Association Studies abstract
Advisor: Daniel Kalderon
Shichong Liu, M.A.
BRCA1/BRCA2 Associated Hereditary Breast Cancer: Searching for Optimal Detection Methods and Potential Treatments abstract
Advisor: James Russo
Philip Magli, M.A.
Memantine: an Innovative Class of Moderate Affinity NMDA-Receptor Antagonist used to Treat Moderate to Severe Alzheimer's Disease abstract
Advisor: Carol Lin
Aishwarya Movva, M.A.
Stem Cell Transplantation for Age Related Macular Degeneration, and Peripheral Retinal Degenerations abstract
Advisor: Lucian Del Priore
Lauren A. Peters, M.A.
The Characterization of Insect Olfactory Receptors and Novel Vector Control Strategies abstract
Advisor: Richard Axel
Brittany Potz, M.A.
The Role of SGZ Neurogenesis in Hippocampal Dependent Learning and Memory abstract
Advisor: David Leonardo
Nadia Propp, M.A.
Alzheimer’s Disease: Current Therapies and Future Drug Development abstract
Advisor: James M. Noble
Presha Rajbhandari, M.A.
A Systems Biology Perspective on Cellular Networks: Cell Signaling and Gene Regulation abstract
Advisor: Andrea Califano
Miriam Segura, M.A.
The Nesprin-2G Protein in Polarity and Migration abstract
Advisor: Gregg Gundersen
Anjali A. Shah, M.A.
Next Generation DNA Sequencing: How we Arrived at Current Technologies and what is Next abstract
Advisor: James Russo
SungWon Song, M.A.
A Requirement for the p85 PI3K Adaptor Protein BCAP in the Protection of Macrophages From Apoptosis Induced by ER Stress abstract
Advisor: Steven Greenberg
Patricia Tamburi, M.A.
Neurotoxicity in Alzheimer’s Disease abstract
Advisor: Daniel Kalderon
Te-Yang Tsai, M.A.
Specialized Beads-on-a-String abstract
Advisor: Carol Lin
Ziwei Wang, M.A.
TDNA Sequencing Technologies –Development: Past, Current and Future abstract
Advisor: Jingyue Ju
David Brandin Weir, M.A.
The MicroRNA Revolution abstract
Advisor: Jingyue Ju
Dennis Widjaja, M.A.
The Need for a Second Green Revolution: Can Incorporating Rice Domestication Genes be a Feasible Approach in Solving the Current Global Food Security Crisis? abstract
Advisor: Michael Purugganan
Liang-Ta Wu, M.A.
Natural Anti-cancer Products: Why is Broccoli Good for You? abstract
Advisor: Alexander Tzagoloff
Hao Xu, M.A.
Stem Cells—an Old Term with Brand New Implications in Clinical Research abstract
Advisor: Alexander Tzagoloff
Ching Tary Yu, M.A.
The Risks of Inducing Regeneration in Medicine abstract
Advisor: Alice Heicklen
Tiantian Zhang, M.A.
Reprogramming Somatic Cells towards Pluripotency: From Nuclear Transfer and Cell Fusion to Induced Pluripotent Stem (iPS) Cells abstract
Advisor: James Russo
Maggie Xiaoling Zhong, M.A.
Adoptive-Cell-Transfer Therapy for Patients with Melanoma: The Promise and Challenges abstract
Advisor: Eric Pamer
Voltage Gated Calcium Channels: Potential Drug Targets for Blockbuster Indications
Kathryn Abele, M.A. 2008
Voltage gated calcium channels (VGCCs) are involved in many important physiological processes, such as cardiac muscle contraction, neurotransmitter release, and hormone secretion. Many diseases are associated with VGCC channelopathies, whether due to genetic mutations or a disruption in channel properties. VGCCs are multisubunit complexes that associate with many cellular proteins that act in a regulatory or modulatory fashion. Currently, VGCC-specific antagonists are on the market for indications such as hypertension, pain, and epilepsy, however many of these drugs were developed based off outdated mechanistic approaches and many elicit adverse side effects. Recent research has provided a better understanding of VGCCs function in disease states, as well as uncovering many proteins integral in VGCC activity. This knowledge has provided many new opportunities for drug development, whether by targeting specific channel isoforms with iRNA, antagonizing the channel subtype directly, or interfering with trafficking and regulatory proteins. New evidence linking VGCCs to autism, as well as their known involvement in pain signaling and fertility, will aid in the development of new pharmaceutical agents with blockbuster market potential.
Molecular Profiling of Circulating Tumor Cells in Patients with Castrate Resistant Metastasizing Prostate Cancer
Aseem Anand, M.A. 2008
Clinically validated techniques of enumerating circulating tumor cells (CTC) have been FDA approved to aid in assessing and monitoring advanced breast and colorectal cancer patients. CTC holds a similar promise to advanced prostate cancer patients. However, the isolation of CTCs from a simple blood based assay with minimum patient discomfort also necessitates the development of sensitive and specific assays for characterizing the prostate cancer.
Profiling CTC with biological assays will allow the detection of biological abnormalities in real time, therefore, helping the physicians to decide the best course of treatment for patient with advanced prostate cancer. Here we will analyze hormone therapy and propose molecular assays to characterize androgen receptor and intracrine androgen synthesis pathway in CTCs of castrate resistant metastasizing prostate cancer (CRPC) patients.
The Immunological Challenges of Bacterial Biofilms
Claudia B. Assor, M.A. 2008
Although a lot of progress has been made in the healthcare sector, hospital-acquired infections are still common, lead to a high mortality rate, and cost millions of dollars to the health care system in the United States. Indwelling medical devices, such as catheters, cause most of these infections. Indeed, these devices serve as opportunistic sites for bacteria to grow and form more organized structures called biofilms. Bacteria within a biofilm differ considerably from bacteria that grown in suspension, commonly referred to as planktonic bacteria. A biofilm is formed when planktonic bacteria adhere to a surface and sends chemical signals to other adjacent bacteria to aggregate on the surface. Neutrophils migrate into infected sites in response to chemoattractants that the bacteria release or, that other white blood cells in contact with the bacteria release. When neutrophils migrate to an infected site, they phagocyte the bacteria and release cytotoxic substances such as hydrogen peroxide that kill the bacteria by mechanism. Biofilms differ from normal infections and are very difficult to eradicate because they are resistant to both antibiotics and the effectors cells from the innate immune system such as neutrophils. While there are many hypotheses to explain the resistance of biofilms to the immune system or to antibiotic treatment, there are no solid scientific evidences to support any of these hypotheses.
Biofilms are known to generate an exopolysaccharide matrix, which allows the intercellular adhesion and gives the biofilm a slimy appearance. This matrix has been found to be mostly responsible for the resistance of biofilms to both the immune system and antibiotics. Indeed, it confers a protection, and may prevent cells or drugs to pass through it. Bacteria most often isolated from biofilm are part of coagulase negative group, such as Staphylococcus epidermidis.
Nowadays, there are many ongoing researches that aim to overcome to the biofilm resistance in a variety of ways. Either the development of new antibiotics, or vaccination against certain gene products responsible for the biofilm matrix formation, or enzymes might disrupt the bacterial matrix and render the biofilms more susceptible to eradication by the immune system or to the activity of antibiotics. Another approach is to treat biofilms with low frequency ultrasound or surface acoustic waves (SAW). The use of Surface Acoustic Waves directly on catheters seems to have an influence on the immune system to help disrupting the biofilm.
Barrett’s Esophagus Associated Adenocarcinoma Cell(Seg-1) Resistance to the Green Tea Cathecin Polyphenon E May Be Due To Increased BCL2 Expression
Theodor M. Borgovan, M.A. 2008
Barrett’s esophagus is a premalignant lesion that is characterized by replacement of the normal squamous mucosa of the lower esophagus with metaplastic (early changing) columnar epithelium. Metaplasitc cells are those in which cells of one mature, differentiated type are replaced by cells of another type. This is contrasted to dysplasia, in which cells are delayed in differentiation and maturation. Early changing meataplastic cells have an increased potential to progress towards low, or high grade dysplasia, and ultimately cancer. Chronic gastroesophageal reflux disease appears to be the most important risk factor for the development of Barrett’s esophagus, and patients with Barrett’s esophagus have an increased risk of developing esophageal cancer. It has been previously reported that the Barrett’s esophagus-associated adenocarcinoma (BAA) cell line Seg-1 is relatively resistant to the growth inhibitory effects of the green tea extract Polyphenon E (Poly E) (IC50 = 50 ug/ml), compared with two other BAA cell lines Bic-1 and Flo-1 (IC50 = 25 ug/ml).
We investigated the mechanisms of Seg-1 resistance to Poly E by comparing gene expression profiles of Poly E sensitive (Bic-1, Flo-1) and Poly E resistant (Seg-1) BAA cells using the Affymetrix Human Genome U133 Plus 2.0 Array. Cells were treated in duplicate with Poly E (25 ug/ml) or media (“untreated”), and gene expression signal intensities were normalized using the Affymetrix MAS software. Unsupervised hierarchical clustering using a sampling of 2000 genes (i.e. 500 genes with the highest variability within each of the 4 quantiles of the expression distribution) revealed that Poly E treated and untreated samples clustered according to cell line and that sensitive cells (Bic-1 and Flo-1) clustered separately from the resistant (Seg-1) cells. After applying a two-sample t-test to all 54,613 genes and controlling the type I error rate of each test at the 0.0001 level, we identified 616 genes that were differentially expressed between untreated Poly E-sensitive (Bic-1 and Flo-1) and untreated Poly E-resistant (Seg-1) cells, including BCL2. The log2 mean signal intensity was significantly higher in Seg-1 cells (6.534) compared with Bic-1 (3.081) and Flo-1 (3.176) cells.
We confirmed this finding by demonstrating increased BCL2 protein expression in Seg-1 cells, compared with Bic-1 and Flo-1 cells, by western blotting. Seg-1 cells were then treated with HA 14-1 (5 mM), a small molecular inhibitor of BCL2, and increasing doses of Poly E. After 72 hours, the Poly E IC50 value was 25 ug/ml, which is similar to the IC50 values of the Poly E sensitive Bic-1 and Flo-1 cells. Thus, co-treatment with HA14-1 increased the sensitivity of Seg-1 cells to Poly E. Our results suggest that increased BCL2 expression may explain Seg-1 resistance to the antiproliferative activity of Poly E. BCL2 expression could be used to select patients for clinical treatment with Poly E.
RNAi: From Laboratory to the Clinic
Neli Brod, M.A. 2008
Soon after the inception of RNA interference (RNAi) by Fire and colleagues in the worm, RNAi became a successful laboratory technique for silencing gene expression post-transcriptionally in order to elucidate molecular pathways and gene functions. Not long after that, researchers wanted to move their success in the lab to the clinic, and RNAi started being explored as new class of therapeutics. The effecter molecule of RNAi is small interfering RNA (siRNA) which is a 19-21 nt RNA molecule that binds to complementary targets, resulting in a potent downregulation of gene expression. The advantage of RNAi over other methods lies in the specificity, potency, and the ability to target an unlimited number of genes, silencing coding and non-coding molecules, therefore ameliorating almost any genetically based medical condition. Currently, there are 12 early and late-stage clinical trials in progress, with more expected to emerge. The appearance of RNAi therapeutics appears closer than ever. However, there are several obstacles to be addressed before RNAi may become a mainstream therapy including off-target effects, immune system stimulation, saturation of the endogenous RNAi pathway, and most importantly, efficient delivery to target cells. This review summarizes the challenges and advancements in the field of RNAi-based therapeutics.
Looking to RNAi to Treat Cancer
Dane O. Campbell, M.A. 2008
Andrew Fire and Craig Mello published their landmark paper in 1998 which reported that double stranded RNAs are capable of silencing targeted genes in C. elegans. This novel mode of gene regulation was surprising to many and it quickly garnered immense interest in the scientific community. The implications of Fire and Mello’s work meant that any desired gene could be turned off at will including “diseased genes”. Sure enough many looked to this new RNA interference technology to silence oncogenes which are known to be involved in cancer progression and survival. Several research projects now use RNA interference to treat several types of cancers such colon, breast, lung and a host of others. The main objective in these studies is to target single important genes that are involved in tumor maintenance such as ras and b- catenin. While current cancer drugs offer some opposition to cancer progression and survival, many are associated with severe side effects and resistance. It is possible that if RNAi is properly refined we could harness a remedy to cure diseases such as cancer. However, before the full potential of RNAi is realized, several hurdles must be surmounted. Systemic delivery of small interfering RNAs remains a challenge. Enzymatic activity reduces their half-life and the fact that they are negatively charged makes it difficult for them to enter cells. Ongoing research studies continue to address these issues but an effective general delivery method is yet to be developed. Still the quest to package RNAi as an effective anti-cancer therapy provides innovative ways to fully refine the technology. Promising results continue to emerge from this area of research suggesting that it is possible to move RNAi from the bench to the bedside.
Novel Approaches to Micrometastasis Detection
Mei-Ki Chan, M.A. 2008
Micrometastasis occurs when a single cancer cell detaches from a primary tumor location and travels through blood vessels or lymphatic vessels to a distant location. The presence of circulating cancer cells in blood or micrometastasis in lymph node is predictive of a poorer prognosis with decreased survival rates and disease-free intervals. Micrometastasis detection, therefore, is important to guide post-operative adjuvant therapy and to monitor treatment response. In this review, we discuss the current methods in wide clinical use, methods used in research establishments connected to clinical centers, as well as novel approaches under development that are more accurate and easy to adapt in clinical settings. New methods for detecting circulating cancer cells in blood are CellSearch system, MAINTRAC analysis, and circulating cancer cell microarray detection. CellSearch system is an FDA-approved semi-automated system for detecting individual circulating cancer cells. MAINTRAC and circulating cancer cell microarray are new research methods designed to detect and capture circulating cancer cell in blood with minimal sample preparation, and which also allow cell characterization by maintaining viability of the captured circulating cancer cells. New approaches in detecting micrometastasis in lymph node are using fluorescently labeled oncolytic viruses and nanotechnology-enhanced imaging. Fluorescently labeled oncolytic viruses, such as specially modified herpes simplex virus-1 and adenovirus, originally designed for therapy, can detect micrometastasis in lymph node in real time when used intra-operatively. Both viruses are safe and offer detection precision, in some cases, superior to current research techniques. Biodegradable nanoparticles can enhance the ability of current imaging techniques such as MRI to detect micrometastasis in lymph node with increased accuracy and sensitivity. As these novel techniques mature, they may be used alone or in combination with current clinical methods to help manage therapy in cancer.
Medicinal Plants in Drug Discovery and Development of Pharmaceutical and Biotech Industry, From a Taiwanese Perspective
Ku-yu Chang, M.A. 2008
Life Science is one of the most important industries in the 21st century. With drug discovery by biotechnology and pharmaceutical companies being the most invested and attention grabbing sector. It is estimated that 25% of prescriptions in the United States containing plant extract or active principles prepared from higher plants. Yet of the estimated 250,000 higher plants species reported on our planet, only less than 6% have been screened for bioactivity. Medicinal plants as source for drug discovery and development is becoming a popular trend in the biotech and pharmaceutical industry. As a multidisciplinary student born and raised in Taiwan, I believe that Taiwan has a very promising future in the global biotech and pharmaceutical industry. Taiwan has many advantages using medicinal plants in drug discovery, such as biodiversity within the island, knowledge of plants from aboriginal people, well documented historical use of traditional Chinese medicine, good agricultural practice and meeting international good clinical practice as well as good manufacturing practice implementation. This thesis papers not only discusses the niche of using medicinal plants in drug discovery in Taiwan, but also provide a successful case study of DCB-WH1, a multi-component diabetic wound healing drug derived from Chinese herbal medicine recently approved by FDA for phase II clinical trials. Base on literature reviews and collected data, this thesis suggest how Taiwan’s pharmaceutical and biotech industry might be improved to increase successful drug discovery, development and increase return of investments from drug candidates, at the same time contributing to the worldwide biotech pharmaceutical industry as an upstream pipeline innovator.
Ning-En Chang, M.A. 2008
The role of stem cells in cancer development, progression and drug resistance has been recently put forward in a number of tumors. Identification of small subsets of cells within a tumor, carrying the phenotype of stem cells has been reported first in leukemia in 1997, subsequently, cancer stem cells (CSCs) have been isolated from brain tumor, and some epithelial malignancies, such as breast, colon, etc. One of the main characteristics of stem cells is their ability for self-renewing cell division. Secondly, they are resistant to apoptosis. CSCs maintain this characteristic, which accounts for the ineffectiveness of current therapy to destroy them. It also points out the need for a different strategy for developing anticancer drugs, that should be selected for lethality against CSCs and not, as at present, for their ability to kill any cellular tumor subset. Therapies aimed at CSCs have shown some promise, but their further development will require a more thorough understanding of the biology of CSCs and methods for identifying and isolating this cell subpopulation
Sean Wei Chung Chen, M.A. 2008
A1 adenosine receptor activation is known to protect the kidney against renal ischemia-reperfusion injury via the phosphorylation and upregulation of heat shock protein 27. In this study, transgenic mice overexpressing human heat shock protein 27 were used to determine if systemic expression of the protein was protective against renal ischemia-reperfusion injury. In vitro experiments with proximal tubule cells cultured from transgenic mice showed an increased resistance against hydrogen peroxide-induced necrosis compared to the proximal tubule cells cultured from wild-type mice. However, in vivo assays suggest that transgenic mice have decreased renal function after renal ischemia-reperfusion injury. This reduction in renal function was correlated with increased expression of proinflammatory cytokines and earlier neutrophil infiltration in the kidneys of transgenic mice. Analysis of lymphocyte trafficking to the kidney by flow cytometry demonstrated that the transgenic mice had increased influx of CD3+, CD4+, CD8+, and NK1.1+ lymphocytes 3 hours after renal ischemia. Wild-type mice also showed increased renal injury after adoptive transfer of splenocytes or NK1.1+ cells from transgenic mice. Furthermore, the depletion of lymphocytes by splenectomy or the neutralization of NK1.1+ cells resulted in improved renal function in transgenic mice after renal ischemia-reperfusion injury. Therefore, although the increased production of human heat shock protein 27 in renal tubules makes the cells resistant to necrosis, the systemic expression of the protein likely negates this protection by exacerbating renal inflammation and leukocyte-mediated injury.
Inteins: Protein Splicing and Biotechnology Applications
Tuan Li Chuang, M.A. 2008
Inteins are self splicing proteins inserted into foreign protein hosts. With remarkable precision, they can catalyze self removal from the host protein and splice together the N and C terminal fragments of the host protein. Many inteins contain homing endonuclease functionality, allowing for the horizontal transfer of the intein gene. The discovery of their existence has led to development of biotechnology applications for inteins. Affinity purification of proteins, protein splicing and cyclic peptides are just three of the applications that make use of intein technology. The development of protein trans-splicing and cyclic peptide backbones has led to novel methods in disease research and treatment. The future promises many more exciting new developments using inteins for their ability to splice proteins together and catalyze peptide bond cleavage.
Investigation of the Mitochondrial DNA Depletion Syndrome (MDS) due to Thymidine Kinase (Tk2) Deficiency
Jorida Çoku, M.A. 2008
Mitochondrial DNA Depletion Syndrome (MDS) is an autosomal recessive disorder characterized by paucity of mitochondrial DNA (mtDNA). Unlike many mitochondrial disorders, which result from defects in the mitochondrial genome, MDS is due to primary pathogenic mutations in the nuclear genome. So far, mutations in nine nuclear genes have been identified in MDS. Not surprisingly, all of their gene products are involved in mitochondrial DNA replication, transcription, repair or stability. Among these genes, two are essential for the mitochondrial pyrimidine and purine salvage pathway, thymidine kinase 2 (TK2), which, when mutated primarily causes myopathy and deoxyguanosine kinase (DGUOK), when defective causes a hepatocerebral variant of MDS. dGK and TK2 proteins are crucial for mitochondrial dNTP pool maintenance because they phosphorylate the four nucleosides required for DNA synthesis. When this nucleotide balance is perturbed, MDS develops.
To elucidate the role of Tk2 in mice, we have generated a knock-in H126N Tk2 murine model, which is homologous to the human H121N Tk2 mutation. The murine Tk2 deficient model exhibits a tissue specific phenotype, which contrary to our expectations, affects the brain and spinal cord rather than the muscle. In his application we propose to test the following hypotheses: 1) Tk2-deficiency causes mitochondrial deoxynucleotide pool alterations, which, in turn, cause pathogenic depletion of mitochondrial DNA (mtDNA); 2) Tk2-deficiency can be offset by decreased levels of thymidine substrate; and 3) decreasing the conversion of dTMP to dT will counterbalance the effects of defective Tk2. To investigate these questions, we propose three specific aims: 1) characterization of the Tk2-deficient mouse; 2) crossing of the Tk2 H126N mouse with thymidine phosphorylase/ uridine phosphorylase) double-knockout (TP-/-/UP-/-) mice to assess whether the phenotype of Tk2 H126N knockin mouse can be ameliorated; and 3) inhibiton of deoxynucleotidase 2 (dNT2) expression by RNAi in order to counterbalance the Tk2-deficiency.
Diabetes Mellitus Type 1: Where has Research Taken us in Prevention, Diagnosis, and Treatment?
Earl J. DeSouza, M.A. 2008
Diabetes Mellitus Type 1, the second most common chronic illness among children in the United States is on the rise. Type 1 diabetes is an autoimmune disease where the body’s immune system attacks its own beta cells which produce insulin within the pancreas. The only known treatment for diabetes type 1 is insulin treatment. Research in the past decade, has led scientists to the belief that approximately 50% of genetic contributions to this autoimmune illness is attributed to the HLA regions. With over 20 regions in the HLA system that play an important role in determining type 1 diabetes onset, medical researchers are able to help determine type 1 diabetes earlier than expected. Other non-HLA genes, such as INS and CTLA-4 have also been proven to contribute in early onset of Diabetes Mellitus Type 1. Although, genetic factors are a major contributor to the onset of early diabetes, there are environmental factors that also play a key role as well. Current research in this field of study is built upon previous research and has made a presence in preventing and treating Diabetes Mellitus Type 1 patients.
Analysis of Drosophila Reaper Peptide as an IAP Antagonist in Human Tumor Cell Cultures
Travis Gorenc, M.A. 2008
Apoptosis is a morphologically distinct form of programmed cell death that performs an important role during development and homeostasis in metazoans. The core machinery that is used to execute apoptosis is evolutionarily conserved and is essentially present in all cells at all times. Abnormalities in apoptosis are associated with a variety of human diseases, including cancer, autoimmune diseases and neurodegenerative disorders. The potential to re-instruct the apoptotic pathway through an understanding of its mechanisms is of major interest to cancer therapeutics. One promising therapeutic strategy involves the antagonism of the Inhibitor of Apoptosis Protein (IAP) family and ensuing activation of the cell-intrinsic suicide program. Indeed, a number of firms from industry and academic institutions have employed the use of small-molecule IAP-antagonist peptides and mimetics in drug development. In this study, a Drosophila Reaper-IBM domain containing peptide is analyzed for its ability to activate Caspases-3 and -7 in a human tumor cell line panel via a luminescence assay for caspase cleavage. After initiation of apoptosis by staurosporine, those lines found to be sensitive to Reaper are the breast BT-549, melanoma MALME-3M and melanoma SK-MEL-5 cell lines. The quantitative and qualitative assessment of cell death induced by Reaper is measured by morphological changes that are characteristic of apoptotic cells. Here, Reaper is able to induce cell death in MALME-3M and SK-MEL-5 cells, however the cell death phenotype was not clearly evident in the BT-549 cell line. Additional experiments will afford a greater understanding of the molecular differences between these three cell lines and provide further insight into the mechanisms of cell death in human tumor cells more generally. Since protein expression levels of key regulators of the apoptotic pathway are known to be altered during malignancy, a selection of these regulators are surveyed in the human tumor cell line panel via western blot analysis. While the levels of some proteins are mostly similar, a few cell death factors, including XIAP, ARTS and Bcl-2, vary considerably between different cell lines and correlate with experimental results in this work. The summation of this study emphasizes the complexities that arise as Reaper utilizes additional domains besides its IBM for cell killing and where untold cross-talk occurs between the intrinsic and extrinsic pathways. Overall, a greater comprehension into the precise mechanism for which Reaper-family proteins inactivate IAPs may lead to more opportunities to target IAPs for cancer therapeutics.
The Molecular Rationale for Inhibiting Histone Deacetylase in the Treatment of Lymphoma
Wan-Ying Hsieh, M.A. 2008
Epigenetic events such as histone acetylation and DNA methylation have been widely demonstrated to be involved in normal cell signaling. Aberrant histone deacetylation by recruiting histone deacetylases (HDACs) have been found in several types of lymphoma, including diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma and peripheral T-cell lymphoma. Therefore, inhibiting HDACs may be an important therapeutic target in the treatment of lymphoid malignancies. Several HDAC inhibitors have been shown to induce cell cycle arrest, differentiation, and/or apoptosis both in vitro and in vivo. Recently, a number of new HDAC inhibitors have entered phase I/II clinical trials in different types of hematological malignancies or epithelial tumors. These studies suggest that as a class, these drugs can produce meaningful remissions in a host of cancers including Hodgkin’s Disease, T-cell lymphomas, and in combination may be effective for a variety of solid tumor malignancies. Although the exact mechanism of how HDAC inhibitors induce cell death or cell cycle arrest is unclear, increasing evidence is now suggesting that the post-translational modification of key regulatory proteins may be central to their activity, especially in lymphoma. As a result, increasing interests are now focusing on how HDACs alter non-histone proteins, recruited leading to alterations in protein function and possibly even global gene expression. Additionally, studies have shown that targeting two or more nonhistone proteins by using different classes of HDAC inhibitors may have synergistic effects with DNA damage agent. While the basic molecular mechanisms of HDAC inhibitors are not fully uncovered, it is still believed that HDAC inhibitors have a significant impact on treating certain types of lymphomas, and possibly even other types of cancer.
Optimization of HIV/AIDS Cocktail Regimens: A Case Study for Maraviroc, a Vovel Co-receptor Antagonist
Arun Marcel Jaganathan, M.A. 2008
The development of small-molecule inhibitors against HIV/AIDS drug targets has been effective in treating the infection. Historically, monotherapy administration quickly results in the emergence of resistant HIV-1 isolates. Although the implementation of combination therapy has been successful, it has been met with shortcomings due to accumulated point mutations. In this paper, I discuss a potential framework to delay the emergence of resistant strains with respect to a new class of viral entry inhibitors. Targeting HIV co-receptors, CCR5 and CXCR4, these inhibitors most notably include maraviroc (Selzentry) and a range of mono/bicyclam preclinical compounds in development. I will frame this evaluation in a context that considers the viral mutation rate, pre-existing mutations and drug-drug interactions. Through a survey of recent literature, it is evident that cocktail regimens, when implemented correctly, can curb the onset of drug resistance. However, this also requires the incorporation of a hedging mechanism such as small interfering RNA biologics that afford a second line of defense. In clinical practice, this can potentially limit the emergence of resistant quasi-species, boosting the potential for a patient to mount a strong, if only transient, immune response. This appears to be highly dependent on a limited time ‘window’ during which optimal therapeutic indices are attained in order for CD4+ T-cell counts to be replenished. Furthermore, it requires sustained efforts to characterize viral isolates through genotype assays, phenotype assays and structural binding analyses. These recommended guidelines should influence the way clinical researchers and physicians approach novel regimens.
Adult Neurogenesis and its Effect on Depression and Antidepressant Treatment
Jamie Kim, M.A. 2008
Depression is a devastating disease that affects over 20% of the world population. Despite the vast amount of study that has been done, the etiology and pathophysiology of depression are yet to be determined. The discovery of adult neurogenesis in the hippocampus has opened doors to a new approach to treating depression and improving currently available antidepressant drugs. It has been repeatedly reported that depression leads to a volumetric reduction in the hippocampus. However, whether this reduction is related to a decreased rate of adult hippocampal neurogenesis is yet to be determined. In contrast, numerous studies have shown a strong correlation between adult neurogenesis and antidepressant response. Further investigation of the contribution of neurogenesis to antidepressants and vice versa may lead us to novel drug targets, and thus the development of improved treatment for depression. Discussed are the major studies that demonstrated the role of adult neurogenesis in depression and treatment response, as well as the history and future direction of depression treatment.
The STAT5 Pathway and Its Role in Hematopoiesis
Jelena Kling, M.A. 2008
Stat5 proteins modulate gene transcription upon cytokine and growth factor activation. IL-2, IL-3 and IL-5 are among the cytokines that stimulate the JAK dependent phosphorylation of STAT5. Activated STAT5 enters the nucleus to regulate the transcription of several genes, such as cyclins, and other genes that direct the development and maturation of hematopoietic lineages. This thesis will discuss STAT5 pathways and explain the roles of pathway members upstream and downstream of STAT5.
The focus of this thesis will be the role of the STAT5 pathway in hematopoietic development. It will also explore the biological consequences of mutations that lead to aberrant STAT5 activation, the impact of those changes on target gene transcription, and the many phenotypes associated with deleting the STAT5a and STAT5b gene. Lastly, the thesis will propose future areas of study to further test the effects of STAT5 pathways on hematopoiesis.
Application of SNPs in the HapMap-based Genome-wide Association Studies
Xiayin Liang, M.A. 2008
Common complex diseases are affected by both genetic and environmental factors. Genome-wide association (GWA) studies, which use a dense map of single nucleotide polymorphisms (SNPs) as genetic markers, have been considered as a powerful and efficient tool to identify the relationship between genetic variants and complex diseases. The HapMap project provides a map of these genetic variants. This review explores how to use the information provided by The HapMap project to construct haplotype blocks, identify haplotypes, and study the association between SNPs and diseases. However, with the current technologies and information available, there are limitations and challenges in association studies. It is still a big task to make these studies more efficient and discover more powerful applications of SNPs in both pharmacogenomics and personalized medicine.
BRCA1/BRCA2 Associated Hereditary Breast Cancer: Searching for Optimal Detection Methods and Potential Treatments
Shichong Liu, M.A. 2008
About 10% of breast cancer cases diagnosed yearly have a hereditary origin; most of these are due to an alteration in the BRCA1 or BRCA2 gene. The population carrying these hereditary mutations has a five-fold increase in lifetime risk for and early onset of breast cancer. Thus, they should be identified as soon as possible so that certain precautions and surveillance can be undertaken to improve their chance of survival. In order to fully understand and accurately detect hereditary breast cancer, scientists have studied BRCA1/BRCA2 genes at the molecular level since their discovery. This work has suggested that these two proteins are specialized for repairing double-strand breaks by homologous recombination, controlling cell cycle arrest and maintaining chromosome stability. Future studies will concentrate on the characterization of BRCA1 targets and their association with cancer predisposition, the effect of post-translational modification of BRCA1 on its role in transcriptional regulation, as well as further investigation on the details of how BRCA2 protein responds to DNA damage. The findings on the functions of these two proteins provide a way to construct useful functional assays to properly assess the role of particular genetic alterations on cancer causality. Nevertheless, the ultimate solution for BRCA1/BRCA2 hereditary breast cancer rests on figuring out an effective treatment for this group of carriers. Current study has shown that the PARP inhibitor, in particular, is a very promising drug as it is not only demonstrated to be safe and highly effective, but it also specifically targets BRCA1 and BRCA2 mutations.
Memantine: an Innovative Class of Moderate Affinity NMDA-Receptor Antagonist used to Treat Moderate to Severe Alzheimer's Disease
Philip Magli, M.A. 2008
Alzheimer’s disease (AD) is responsible for the gradual loss of neurons impairing both cognitive and functional capabilities. Risk and deterministic genes increase the likelihood of developing AD. Common stages of symptom progression have been documented and referenced to understand how the disease may unfold. Under pathologic conditions, excess glutamate can lead to excitotoxicity which can lead to lesions in the brain. There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at N-methyl-D-aspartate (NMDA) receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia. Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction. Signal-to-noise studies have shown that AD occurs due to overactive glutamatergic system which impairs the detection of relevant signal in learning under normal conditions. Electrophysiological data show that memantine is able to serve as a filter and allow the detection of the relevant signal thereby restoring synaptic plasticity. Memantine has produced symptomatic improvements in learning under conditions of tonic NMDA receptor activation in AD. In contrast to first generation therapies such as donepezil, galantamine, rivastigmine or tacrine, memantine provides in vivo protection from a variety of toxic conditions such as β-amyloid, inflammation, or inhibition of mitochondrial function at concentrations used in the treatment of AD to slow down disease progression. Memantine also provides other benefits to AD patients by increasing their cognitive and psychomotor functioning, thereby allowing patients to benefit from activities of daily living.
Stem Cell Transplantation for Age Related Macular Degeneration, and Peripheral Retinal Degenerations
Aishwarya Movva, M.A. 2008
A variety of ocular diseases, including age –related macular degeneration (AMD) and retinitis pigmentosa (RP) are characterized by the loss of photoreceptors, retinal pigment epithelium (RPE) and/or choriocapillaris, resulting in visual loss. In this group of diseases, the inner retinal layers are relatively well-preserved despite profound loss of outer retinal layers, retinal pigment epithelium and choriocapillaries. Recently there have been significant advances in the management of exudative AMD with the use of anti-VEGF drugs to control neovascularization but many patients still suffer severe visual loss and there is no effective therapy for peripheral retinal degenerations. Replacement of retinal tissue by transplantation has been proposed as a potential method of restoring vision in these patients. Fetal, adult retinal pigment epithelial transplantation, photoreceptor transplantation and iris pigment epithelial transplantation have been studied by various groups. However, transplantation of mature retinal cells is hindered by the limited availability of donor cells, immunological rejection and ethical issues. At this juncture, there is interest in stem cell therapy because of their properties of self renewal and ability to differentiate into any type of cell in the body. Given the right environment and growth factors, stem cells differentiate into numerous mature cell types including neurons, beta cells and cardiomyocytes. In the eye, induction of human stem cells along retinal neuronal RPE cell lines offer hope in restoring the vision for patients with ocular diseases.
The Characterization of Insect Olfactory Receptors and Novel Vector Control Strategies
Lauren A. Peters, M.A. 2008
Insects are vectors for transmission of a variety of animal and plant pathogens which can lead to the spread of disease and significant crop destruction. Efforts to control insect vectors are focused on blocking behaviors such as feeding, mating and host seeking in order to prevent pathogen transmission to plants and insect bite transmitted disease to humans. The most viable molecular targets for controlling insect behavior are receptors found on the olfactory sensory neurons. Olfactory receptors are the interface between the environment and the insect and thus are central to driving the insect’s behavior in response to external chemosensory cues.
The main advantage in targeting olfactory receptors for vector control is their specificity. Although related in structure and function, olfactory receptors differ between species, allowing discrimination between insect and mammalian receptors, as well as between receptor repertoires from different insect species. Olfactory receptors can be linked to particular behaviors and are divergent enough, even within a given insect species, to allow for selective targeting to alter behavior. Knowledge of the peripheral olfactory landscape and characterization of odorous ligands has contributed to olfactory receptor target identification and corresponding assay development for analog discovery employed in strategic vector control.
This paper reviews the olfactory circuit and its main mechanisms in the fly, Drosophila. Furthermore, it contextualizes the receptor point of intervention on the olfactory pathway substrate, and explores opportunities to target individual receptors that are directly linked to behavioral outcomes. Olfaction, longevity, and immunity in relation to vector competence are discussed and various vector control strategies are evaluated for the mosquito, Anopheles. Finally, this paper proposes an insect vaccine approach intended to compromise the vector transmission of malaria.
The Role of SGZ Neurogenesis in Hippocampal Dependent Learning and Memory
Brittany Potz, M.A. 2008
Advances in technology have allowed for the discovery of adult neurogenesis in the human brain. Adult neurogenesis is found only in the subventricular zone (SVZ) and subgranular zone (SGZ) in the dentate gyrus region of the hippocampal formation. There are two types of progenitors found in the SGZ and their growth is thought to be influenced by their immediate environment called the neurogenic niche. Research suggests that new neurons generated in the brain are integrated into existing brain circuitry. This paper will focus on neurogenesis in the SGZ and provide evidence supporting its influence on the hippocampal functions of learning and memory.
It appears that some forms of hippocampal dependent learning influence levels of neurogenesis and that the number of adult born neurons influences learning and memory. SGZ neurogenesis is thought to be regulated by factors such as genetics, environment, and age. These factors regulate some forms of hippocampal dependent tasks in a correlative manner. Research on the function of SGZ neurogenesis in hippocampal dependent learning and memory comes to varying conclusions that are caused by differences in procedures. Research indicates that the relationship between adult neurogenesis in the SGZ and hippocampal dependent learning and memory may be dependent on: the age of the neurons, the age of the subjects and the type of learning that is occurring. More work needs to be done before a comprehensive understanding of the functionality of adult neurogenesis can be made.
Alzheimer’s Disease: Current Therapies and Future Drug Development
Nadia Propp, M.A. 2008
Dementia, a progressive cognitive decline, leads to memory loss and increasing restriction of daily activities. In the Western world, Alzheimer’s disease is the leading cause of dementia in aging adults over 65 years of age. The increasing incidence of the occurrence of the disease requires the development of treatment strategies that will aim at improving the cognitive deficits and slowing the neurodegenerative progression. The disease is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles and extensive gray matter loss. Current treatments are neurotransmitter-based approaches of cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) blockers. These therapies have been shown to have moderate symptomatic effects without the disease-modifying consequences. With increasing knowledge of pathology and mechanisms involved in the disease new targets and therapies emerge. Secretase inhibitors, the dual action drug with cholinesterase inhibition as well as NMDA blocker, active immunization with amyloid peptides and passive immunization with Ab antibodies, are the emerging and perhaps disease-modifying therapies for treatment of Alzheimer’s. This paper will focus on a short overview of the disease and its current therapies and the future of the disease-modifying therapies that are based on clearing of the amyloid deposits and/or decreasing its production.
A Systems Biology Perspective on Cellular Networks: Cell Signaling and Gene Regulation
Presha Rajbhandari, M.A. 2008
The emerging studies in the field of systems biology have helped us understand the dynamics of complex cellular environment by revealing its novel molecular interactions. This includes crosstalk between different signaling pathways and coordination of transcription by multiple transcription factors and chromatin remodeling, feedback and feedforward genetic networks. The phenotype of a cell resulting from these interactions comes from transcriptional as well as post-transcriptional regulation through protein-DNA interactions, protein-protein interactions as well as action of non-coding RNA such as miRNA and siRNA.
The study of these large set of molecular interactions occurring inside the cell is made possible by technologies such as whole genome sequencing, microarray, ChIP-chip, and high-throughput biochemical and cell-based assays. The vast amount of data generated is analyzed by various computational approaches to derive regulatory networks. The knowledge of the dynamics of these networks would allow us to exploit the cellular system to develop drugs of high therapeutic value for complex diseases like cancer. While challenges remain in the field, systems biology has helped us bridge the gap produced by studying a molecule in isolation; and allows us to better understand the cellular processes at an organismal level.
The Nesprin-2G Protein in Polarity and Migration
Miriam Segura, M.A. 2008
Directed cell migration is critical to normal biological processes such as development, wound healing, and immune system function. Improperly regulated cell migration underlies many disease states such as cancer metastasis. Understanding directed cell migration is essential to elucidating these processes as well may provide key therapeutic approaches to these disease states. Polarization of cells is critical for directed cell migration. Polarization in migrating fibroblast begins with positioning the nucleus towards the rear of the cell. Previous work has indicated that this movement depends on the actin cytoskeleton. A mechanism of actin-mediated nuclear movement has been proposed but requires the validation of a nuclear-cytoskeletal link. Nesprin-2G proteins have been proposed as a link between the nucleoskeleton and the cytoskeleton in migrating cells. While previous work has been done on the role of Nesprin-2G proteins in migration, it was not complete and did not provide a mechanistic interpretation of this link and its role in migration and in the initiation of cell polarization. We propose a study to examine the role of Nesprin-2G proteins in migration and in the initiation of cell polarity that will combine cell morphological, biochemical, and live-imaging approaches.
Next Generation DNA Sequencing: How we Arrived at Current Technologies and what is Next
Anjali A. Shah, M.A. 2008
The modern study of the Human Genome began in 1953 with publication of the double helix structure in Nature. In the fifty-five years since Watson and Crick’s groundbreaking findings, scientists have made significant strides to decipher the human genome. These developments have provided insight into evolutionary divergence and disease pathways, with research benefiting many areas including personalized medicine. The road thus traveled has been directed predominantly by the Human Genome Project and included numerous international collaborations coupled with strong competitive spirit. Up until recent years, sequencing technologies were focused mainly on enhancements to dideoxynucleotide sequencing by increasing throughput while decreasing costs. Over the last five years, the international genomic community has targeted efforts in engineering new resequencing and gene expression technologies, with significant developments in sequencing by synthesis platforms, as well as ChIP-based technologies. With these new techniques, it is possible that we will reach the ultimate goal of sequencing the human genome for less than $1,000 while maintaining the stringent accuracy standards developed through the Human Genome Project. However, we still cannot say with certainty which technology will provide the best massively parallel sequencing technology soonest or which company will win the race to mass commercialize their technology.
A Requirement for the p85 PI3K Adaptor Protein BCAP in the Protection of Macro phages From Apoptosis Induced by ER Stress
SungWon Song, M.A. 2008
Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of ER stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified BCAP, a p85 PI3K-binding adaptor protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among 9 PI3K adaptor proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a SERCA inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP-/- mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK under these conditions and unlike BCAP-deficient B cells, expressed normal amounts of the NF-kB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with WT BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the pro-apoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is an important PI3K adaptor protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that BCAP is a novel downstream target of innate immune receptors that is required maximal survival under conditions of enhanced susceptibility to apoptosis, such as exposure to Gram negative bacteria
Neurotoxicity in Alzheimer’s Disease
Patricia Tamburi, M.A. 2008
Alzheimer’s disease, one of the most studied and common neurodegenerative diseases, is characterized by early cognitive and memory deficits. Originally, it was thought that fibrils made up of amyloid beta protein were the neurotoxic entity responsible for the synaptic dysfunction and neuron death seen in the brains of patients afflicted with the disease. It is now becoming increasingly evident, however, that the apparent toxic species are not the plaques themselves but rather the soluble amyloid beta proteins that have the ability to form oligomers of varying sizes. These oligomers have been shown to directly and potently cause both functional and structural deficits in neurons ultimately causing transient synaptic dysfunction. Due to the reversibility of these processes, it has been postulated that these soluble oligomers play a role very early on in the disease even before cell death and plaque formation take place.
Te-Yang Tsai, M.A. 2008
Not only a monotonously repeating structure purposing to package DNA sequence, chromatin had been found as an important platform displaying tremendous possibility and flexibility for regulation of many DNA-templated cellular processes during the past decade. Based on the epigenetic findings, cells can mediate the dynamics of such structure to dominate transcription through a variety of complex processes, including histone posttranslational modifications, chromatin remodeling, and the substitution of histone variants. As the most evolutionarily conserved histone protein, H2A.Z, a variant of H2A, has been substantiated its significance and essential biological functions in many species. Therefore, when, where, and how it replace the canonical H2A is a rising issue for investigating a novel approach of gene regulation and even the early diagnosis of cancer in epigenetic field. Intriguingly, H2A.Z has positive influence in activating genes not only in euchromatin but also in heterochromatin. In fact, H2A.Z-containing nucleosomes have been indicated as heterochromatin boundary in current articles. However, past studies on the characterization of this histone variant still remains somewhat controversial, even contrary. As the progression of molecular techniques, new methodology, so-called GWLA, has provided researchers plenty of clues to reveal enigmatic questions of H2A.Z. This reviews is an attempt to organize the published results relevant to biophysical properties and biological functions of H2A.Z and H2A.Z-containing nucleosomes for understanding the basis of H2A.Z substitution mechanism and its effects. Otherwise, it also purposes to digest the recent avalanche of genome-wide studies for further suggesting hypothetical models, which facilitate us to further illustrate the role played by H2A.Z in cellular machinery.
TDNA Sequencing Technologies –Development: Past, Current and Future
Ziwei Wang, M.A. 2008
The invention of Sanger sequencing technology thirty years ago started a new era in genome sequencing, which led to the completion of the megaproject known as the Human Genome Project in 2006. The HGP provided a blueprint and a huge database, which have had great impact on human genomic, biomedical and evolutionary studies. During this thirty year period, many sequencing technologies with distinct principles have been developed and continue to be developed, including Sanger sequencing, Pyrosequencing, Sequencing by Hybridization, Sequencing by Ligation, Nanopore sequencing, Mass Spectrometric detection, and so on. In the most recent decade, Applied Bioscience, Illumina, and several other biotechnology companies have investigated next-generation sequencing machines capable of decoding DNA faster than ever before. The price of sequencing DNA has also fallen rapidly with the advent of these machines from $25-50 million in the HGP to approximately $1 million. This essay will discuss several major sequencing technologies in detail, focusing on some of the most recently developed methods and instruments.
David Brandin Weir, M.A. 2008
MicroRNAs (miRNAs) are small (~22nt) noncoding RNA gene products that are processed by Dicer from precursors with a characteristic stem-loop secondary structure. miRNAs are capable of post-transcriptional regulation of protein coding mRNAs. This class of regulatory molecules is extremely widespread, found in almost all cell types of both plants and animals. MicroRNAs have been shown to play numerous biological functions in development and disease, and thus they have the potential to be a novel class of therapeutic targets.
The Need for a Second Green Revolution: Can Incorporating Rice Domestication Genes be a Feasible Approach in Solving the Current Global Food Security Crisis?
Dennis Widjaja, M.A. 2008
Due to a rise in global population and declining global rice production, the world is facing a potential food security crisis, resulting in more hunger and malnutrition to the world’s poorest. This situation is even more serious for people in the developing countries, where such a problem first occurred in the 60s, culminating in the Green Revolution which managed to increase crop production by almost two-folds. Hence, a new, second Green Revolution might be required to solve this crisis. The recent discoveries of rice domestication genes, genes which contribute to key traits of the rice plants such as plant architecture and grain size, can possibly offer us a way to jump-start another Green Revolution. The incorporation of these domestication genes in creating new rice varieties can give us rice plants with better yield and vigor, varieties highly beneficial to farmers in the Third World. In applying our knowledge to real life application, creating transgenic plants, despite it being highly controversial, might be the most effective way to incorporate these genes. While strong social and political opposition exist against this approach, it seems that the benefit of creating transgenic plants outweighs its risk, especially in light of the current food security crisis. In order to realize this potential, a strong partnership between the public and private sector is required.
Natural Anti-cancer Products: Why is Broccoli Good for You?
Liang-Ta Wu, M.A. 2008
Regular dietary consumption of fruits and vegetables has been well established as the primary preventive measure against several chronic diseases including cancer, diabetes, cardiovascular diseases, etc. Cruciferous vegetables, of Brassicaceae family, are of particular research interest owing to their composition of chemoprotective phytochemicals. In particular, glucosinolates are sulfur-containing compounds that produce an array of degradation metabolites upon hydrolysis by endo- or exogenous myrosinase. These glucosinolate derivatives are the bioactive compounds naturally responsible for plant’s defense against microbial pathogens and general herbivores. In terms of chemoprotective properties, glucosinolates have been reported to impede the progression of carcinogenesis through several molecular and cellular mechanisms. For instance, glucosinolate derivatives are capable of inducing phase 2 detoxification enzymes and inhibiting expression of phase 1 enzymes as well as modulating cell cycle arrest, cyclin, apoptosis, oxidative stress and histone deacetylase activity, etc. Moreover, recent discovery of anti-bacterial, anti-viral and anti-inflammatory properties of glucosinolates have further established them as potential therapeutic agents for a wide range of plaguing medical conditions. However, the disparity between in vitro and in vivo efficacy of glucosinolates has yet to be reconciled. Nonetheless, amidst the controversies, the health benefits of glucosinolate-rich vegetables are irrefutable. In this article, the mechanisms whereby chemoprotection against pathogenesis by glucosinolate is rendered will be discussed in detail.
Stem Cells—an Old Term with Brand New Implications in Clinical Research
Hao Xu, M.A. 2008
Stem cells are cells found in most of multicellular organisms. They are defined as the cells that have the ability to renew themselves by mitotic cell division and differentiating into a diverse range of specialized cell types. Depending on their potency to differentiate, stem cells are divided into four groups, they are totipotent, pluripotent, multipotent, and unipotent cells. Embryonic stem cells are usually derived from the embryos five or six days after fertilization. Since Dr. Thomson derived the first human embryonic stem cell line, scientists have made great effort to try to use embryonic stem cells in therapy of human diseases such as acute myocardial infarction. Adult stem cells, which are also called somatic stem cells in contrast to embryonic stem cells derived from the fertilized zygote, are a group of undifferentiated cells among differentiated cells in tissues or organs. Recent research on adult stem cells light up the future of stem cell therapy. Current controversy against the stem cell research is from the ethical field, mainly because the production of hES (human embryonic stem cells) cells requires the destruction of human embryos. There are many similarities between normal stem cells and tumorigenic cells. Like stem cells, cancer cells are also thought to have the ability of self-renewal and differentiation. Therefore, the identification of cancer stem cells leads to important implications in the therapy of cancers.
The Risks of Inducing Regeneration in Medicine
Ching Tary Yu, M.A. 2008
Regeneration is a process of reforming tissues and organs that were damaged or lost. It is a great interest to medicine because most of our tissues and organs do not possess the ability to regenerate. Instead, they would heal by wound healing with collagen-rich connective scar tissue resulting in less-organized and less functional tissues. There are many approaches currently being studied for regeneration in human. However, due to the similarities between tumor formation and the regeneration process as well as the intrinsic properties of the stem cells, the approaches may theoretically have the potential to become tumorigenic. In this paper, we shall examine these risks of cancer.
Reprogramming Somatic Cells towards Pluripotency: From Nuclear Transfer and Cell Fusion to Induced Pluripotent Stem (iPS) Cells
Tiantian Zhang, M.A. 2008
Stem cell research is at the forefront of research impinging on science and society, and advances in stem cell research can lead to the development of numerous clinical applications with huge potential in regenerative medicine and cell-based drug discovery. Among a variety of research directions, reprogramming differentiated somatic cells towards pluripotency has become a particularly popular research interest of many scientists in this field. This area may provide possible means to generate reliable stem cell sources for research purposes and also for cell transplantation therapy in clinical practices. Currently, most of the human embryonic stem (hES) cells used in research laboratories were generated from embryos produced in excess of clinical demands in in-vitro fertilization (IVF) facilities with informed consent of the parents. However, there exists an intense controversy over human stem cell research since generation of hES cell lines requires the destruction of a human embryo. Thus, reprogramming differentiated cells back towards pluripotency has become an important research interest of many scientists. Somatic cell nuclear transfer (SCNT, a.k.a. therapeutic cloning) and cell fusion with embryonic stem (ES) cells are two reprogramming strategies that have been studied extensively, but each has its own drawbacks including the serious ethical issue alluded to above. In 2006, a group of Japanese scientists successfully demonstrated that pluripotent stem cells can be generated by introducing four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) into mouse somatic cells; this technique has tremendous potential in the generation of patient and disease-specific pluripotent cells in clinical applications and it does not involve any substantial ethical complications. In this review, we will briefly introduce the basics of stem cells and discuss two reprogramming strategies, nuclear transfer and cell fusion with embryonic stem cells; then we will move on to a thorough discussion of the latest strategy in nuclear reprogramming: induced pluripotent stem (iPS) cells.
Adoptive-Cell-Transfer Therapy for Patients with Melanoma: The Promise and Challenges
Maggie Xiaoling Zhong, M.A. 2008
The concept of harnessing the body’s own immune response system to target malignant cancer cells for destruction has led to the development of innovative cancer immunotherapies, such as cytokine treatments, antibody-based approaches, and gene therapy. In particular, adoptive-cell-transfer therapy, also referred to as adoptive T-cell therapy, has emerged as a promising immunotherapeutic approach for the treatment of patients with melanoma. It is a therapeutic strategy to circumvent normal immune regulatory mechanisms that suppress endogenous tumor-specific T-cell responses. Adoptive-cell-transfer therapy involves the recovery of effector T cells from a patient’s tumor, their expansion and activation ex vivo, and subsequent re-administration into the patient where they can specifically target antigen-expressing tumor cells for immune destruction.
In this review, I provide a description of the mechanisms of adoptive-cell-transfer therapy and its clinical application, specifically for the treatment of melanoma. Then I discuss the main factors that determine the therapeutic efficacy of adoptive-cell-transfer therapy, including (i) identification and characterization of potential tumor antigens, (ii) generation and ex vivo expansion of tumor-specific T cells, (iii) in vivo activities of the adoptively transferred T cells: persistence, trafficking to tumor sites, and maintenance of effector functions. These factors represent the elements that limit the therapeutic efficacy of adoptive therapy. But they also suggest opportunities for improvement since they represent parameters that can be manipulated to improve the current treatment protocol. Approaches such as lymphodepletion, vaccination, and cytokine treatment are employed to improve the clinical outcome of adoptive therapy, and are often associated with challenges. Moreover, objective clinical response to adoptive T-cell therapy can be coupled with the onset of autoimmunity. These hurdles must be overcome to render T-cell-based antitumor therapy effective. Despite the challenges and limitations, the encouraging results from clinical studies show the real promise of adoptive T-cell therapy, and provide renewed optimism for cancer patients.