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O-Linked Beta-N-Acetylglucosamine (O-Glcnac) And The Mitochondrion, Christopher Calderon Jan 2013

O-Linked Beta-N-Acetylglucosamine (O-Glcnac) And The Mitochondrion, Christopher Calderon

All ETDs from UAB

O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic and ubiquitous posttranslational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc has emerged as an important regulator of cellular processes such as cell signaling, transcription, translation, apoptosis, and cell cycle regulation, among others. O-GlcNAc is thought to be a contributor to pathologies such as hyperglycemia and insulin resistance. O-GlcNAc has been viewed as an indicator of cellular energy levels and is associated with diabetic complications under nutrient excess. Other studies have shown that a variety of stress stimuli increase the levels of protein O-GlcNAc in mammalian cells, and this increase …

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Adapter Based Strategies For Adenovirus Vector Retargeting To T Lymphocytes, Matthew S. Beatty Jan 2013

Adapter Based Strategies For Adenovirus Vector Retargeting To T Lymphocytes, Matthew S. Beatty

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Adenoviruses are the most commonly used gene therapy vector for cancer therapy clinical trials. While adenovirus has shown a great track record in a variety of cancer therapeutics it has not progressed as a vector system for the modification of T lymphocytes. One of the major roadblocks towards utilizing adenovirus for T cell therapy is the lack of coxsackie virus and adenovirus receptor on the cell surface of T cell lineages. Exploitation of alternative receptors has allowed adenovirus vectors to be utilized in a variety of cell types that native adenovirus type 5 cannot infect. Thus, retargeting adenovirus to an …

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Epigenetic Regulation Of Kir4.1 In Normal And Pathological States: A Focus On Spinal Cord Injury, Sinifunanya Elvee Nwaobi Jan 2013

Epigenetic Regulation Of Kir4.1 In Normal And Pathological States: A Focus On Spinal Cord Injury, Sinifunanya Elvee Nwaobi

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Astrocytes are the most numerous cells in the brain and play a critical role in maintaining homeostatic extracellular potassium ([K+]e). This process is mediated, in part, by a glial-specific, inwardly rectifying potassium channel, Kir4.1. Pharmacological inhibition, knock down, or complete knock out of this channel results in astrocytes with increased membrane resistance, depolarized resting membrane potential, and altered extracellular potassium dynamics. Subsequent to the dysregulation of [K+]e, Kir4.1 knockout (KO) animals suffer from ataxia, seizures, and early postnatal death. Interestingly, Kir4.1 has long been characterized as a seizure susceptibility gene. The importance of Kir4.1 is further underscored by recent studies …

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New Mouse Models To Aid Studies Of The Role Of Primary Cilia In Limb Patterning And Bone Development, Amber Kathleen O'Connor Jan 2013

New Mouse Models To Aid Studies Of The Role Of Primary Cilia In Limb Patterning And Bone Development, Amber Kathleen O'Connor

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Hedgehog (Hh) signaling is required for many developmental processes, and causes several diseases and cancers. Described in chapter one below, vertebrate Hh sig-naling is dependent on the primary cilium (PC), a small organelle that extends from the surface of most mammalian cell types. A better understanding of how the PC modulates Hh signaling is important, as defects in the structure or function of PC result in severe human disorders termed the ciliopathies. For example, patients with Meckel-Gruber Syndrome have extra digits and neural tube defects, which are Hh both related pheno-types. In chapter two we sought to further understand the …

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Phospho-Erk And Amyloid Beta: Targets Of Estrogen In The Brain, Thomas Reed Peavy Jan 2013

Phospho-Erk And Amyloid Beta: Targets Of Estrogen In The Brain, Thomas Reed Peavy

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Estrogen replacement therapy (ERT) has been shown to improve memory function in menopausal women, but increases hormone sensitive cancers, prompting a more targeted investigation of estrogen's action in learning and memory to develop more targeted therapeutics. Estrogen improves performance on the novel object recognition task by increasing phosphorylation of extracellular signal-regulated kinase (pERK) within minutes in the hippocampus. Dr. Lori McMahon's lab showed that the improvement in novel object recognition can be seen 24 hours after subcutaneous injection of proestrous levels of estrogen (referred to as E24). Whether a corresponding increase in pERK occurs at the E24 time point had …

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The Origin, Regulation, And Function Of Tbet In Effector Cd4 T Cells During Chronic Autoimmune Disease, Wen-I Yeh Jan 2013

The Origin, Regulation, And Function Of Tbet In Effector Cd4 T Cells During Chronic Autoimmune Disease, Wen-I Yeh

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Multiple Sclerosis (MS) is an autoimmune disease resulting from aberrant immune cells causing demyelination. We utilize the well-studied mouse model, experimental autoimmune encephalomyelitis (EAE), to decipher the underlying pathogenesis of MS. Effector CD4 T-cells play a critical role during EAE because the disease is induced by adoptively transferring myelin-specific CD4 T-cells into naïve mice. Classically, effector CD4 T-cells have been divided into distinct subsets based on their functional properties: Th1 cells produce IFNγ, Th2 cells secrete IL-4, IL-5, and IL-13, Th17 cells make IL-17A, IL-17F, IL-21, and IL-22, and regulatory T cells produce IL-10. Th1 cells were originally identified as …

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Regulation Of Stim1 By O-Glcnacylation In Cardiomyocytes, Xiaoyuan Zhu-Mauldin Jan 2013

Regulation Of Stim1 By O-Glcnacylation In Cardiomyocytes, Xiaoyuan Zhu-Mauldin

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In non-excitable cells, STIM1 and Orai1 are the primary mediators of store-operated Ca2+ entry (SOCE); however little is known about their roles in cardiomyocyte Ca2+ handling. We have previously shown that acute increases in the levels of O-GlcNAcylation (the attachment of O-linked N- acetylglucosamine (O-GlcNAc) to target proteins) are cardioprotective through attenuating Ca2+-mediated injury and increased O-GlcNAcylation blunts SOCE in cardiomyocytes. Therefore, the goals here were to determine the regulation of STIM1 and STIM1-mediated SOCE by O-GlcNAcylation in cardiomyocytes. Immunohistochemical analysis demonstrated the co-localization of STIM1 with SERCA and RyR in adult cardiomyocytes. NRVMs were transfected with the eYFP-tagged STIM1 …

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The Role Of Nr4a3 And Its Agonists In Skeletal Muscle Glucose Transport And Insulin Sensitivity, Qinglan Liu Jan 2013

The Role Of Nr4a3 And Its Agonists In Skeletal Muscle Glucose Transport And Insulin Sensitivity, Qinglan Liu

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Insulin resistance plays a central role in the pathogenesis of Type 2 Diabetes (T2DM) and involves diminished stimulation of glucose transport in skeletal muscle. Improvements in insulin sensitivity are essential for both prevention and treatment of T2DM. However, the limitation of current medications highlights the need for alternative molecular regulators of insulin action and developing new insulin sensitizers. Our laboratory has initially identified roles for the orphan nuclear receptor NR4A3 in insulin-sensitization and stimulation of glucose transport. However, the cellular effect and downstream mechanisms of NR4A3 and its agonists (e.g. 6-mercaptopurine/6-MP) on insulin effector system in skeletal muscle remain unknown. …

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Investigation Of Death Receptor-5 Mediated Apoptosis And Inhibition Of Wnt/Ss-Catenin Signaling In Basal-Like Breast Cancer Stem Cells, Angelina Ix-Ik' Londono-Joshi Jan 2013

Investigation Of Death Receptor-5 Mediated Apoptosis And Inhibition Of Wnt/Ss-Catenin Signaling In Basal-Like Breast Cancer Stem Cells, Angelina Ix-Ik' Londono-Joshi

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Basal-like breast cancers (BLBC) display aggressive clinical behavior attributed to the presence of cancer stem cells (CSCs). TRA-8, a monoclonal antibody that binds specifically to TRAIL death receptor 5, preferentially induces apoptosis in BLBC subtype cells; however it is unknown if TRA-8 is also cytotoxic to the CSC population. Moreover, some BLBC cell lines are resistant to TRA-8, and overcoming resistance is critical for clinical translation of this therapy. One potential approach to overcome TRA- 8 resistance is to target the Wnt/ß-catenin pathway. LRP6 is a cell surface receptor that is an indispensable element of the Wnt/ß-catenin signaling pathway that …

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Intracellular Quantitation And Pharmacokinetic Modeling Of Nucleoside Analogs In The Female Genital Tract, Amanda Marie James Jan 2013

Intracellular Quantitation And Pharmacokinetic Modeling Of Nucleoside Analogs In The Female Genital Tract, Amanda Marie James

All ETDs from UAB

Human Immunodeficiency Virus (HIV) is one of the leading infectious diseases in the world. In spite of substantial progress in the advancement of antiretroviral therapy for HIV treatment, new infections outpace the number of infected persons initiating ART. Therefore, the prevention of HIV remains a crucial health issue. Pre-Exposure Prophylaxis, (PrEP), which involves using one or more antiretroviral agents to reduce the risk of HIV infection prior to potential exposure, has shown effectiveness at reducing HIV transmission in study volunteers with different sexual orientation around the world. The clinical pharmacology of antiretroviral drugs, specifically tenofovir (TFV) and emtricitabine (FTC), in …

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Rhob Controls Coordination Of Adult Angiogenesis And Lymphangiogenesis Following Injury By Regulating Vezf1-Mediated Transcription., Damien Gerald, Irit Adini, Sharon Shechter, Carole Perruzzi, Joseph Varnau, Benjamin Hopkins, Shiva Kazerounian, Peter Kurschat, Stephanie Blachon, Santosh Khedkar, Mandrita Bagchi, David Sherris, George C Prendergast, Michael Klagsbrun, Heidi Stuhlmann, Alan C Rigby, Janice A Nagy, Laura E Benjamin Jan 2013

Rhob Controls Coordination Of Adult Angiogenesis And Lymphangiogenesis Following Injury By Regulating Vezf1-Mediated Transcription., Damien Gerald, Irit Adini, Sharon Shechter, Carole Perruzzi, Joseph Varnau, Benjamin Hopkins, Shiva Kazerounian, Peter Kurschat, Stephanie Blachon, Santosh Khedkar, Mandrita Bagchi, David Sherris, George C Prendergast, Michael Klagsbrun, Heidi Stuhlmann, Alan C Rigby, Janice A Nagy, Laura E Benjamin

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mechanisms governing the distinct temporal dynamics that characterize post-natal angiogenesis and lymphangiogenesis elicited by cutaneous wounds and inflammation remain unclear. RhoB, a stress-induced small GTPase, modulates cellular responses to growth factors, genotoxic stress and neoplastic transformation. Here we show, using RhoB null mice, that loss of RhoB decreases pathological angiogenesis in the ischaemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to the RhoB-mediated differential regulation of sprouting and proliferation in primary human blood versus …

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The Role Of Il-21 And Il-17 In Regulating Follicular T Helper Cells In Germinal Center Response Of Autoimmunity, Yanna Ding Jan 2013

The Role Of Il-21 And Il-17 In Regulating Follicular T Helper Cells In Germinal Center Response Of Autoimmunity, Yanna Ding

All ETDs from UAB

Overreactivity of the germinal center (GC) is a central feature of autoantibody-mediated autoimmune diseases. Follicular T helper (Tfh) cells are the primary T helper subset that migrates to the incipient GC and forms close contacts with GC-B cells to promote GC formation and help GC-B cell differentiation, resulting in high-affinity antibody production. Increased levels of interleukin (IL)-21 and aberrant accumulation or function of Tfh cells have been associated with autoimmune disease severity in humans and lupus-prone mice. Follicular regulatory T (Tfr) cells are the regulatory T cell subset that also localizes in the GC and inhibits GC B cell differentiation. …

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Role Of Kca3.1, A Calcium-Activated Potassium Channel, In Cell Migration In The Adult Brain, Kathryn L. Turner Jan 2013

Role Of Kca3.1, A Calcium-Activated Potassium Channel, In Cell Migration In The Adult Brain, Kathryn L. Turner

All ETDs from UAB

A limited amount of migration occurs in the adult brain, including migration of neuroblasts during adult neurogenesis and pathological migration of primary brain tumors. Ion channels are commonly utilized during migration to allow shape and volume changes required for cell movement, and we specifically examine the role of KCa3.1 in the adult brain. These channels are well-suited to facilitate movement because they respond to common migration signals, i.e. intracellular Ca2+ changes, and efflux K+, allowing the outflow of water and cell volume regulation. Our findings suggest that KCa3.1 is highly expressed in migratory cells, adult neuroblasts and glioma cells, but …

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The Role Of Pneumococcal Choline-Binding Protein A (Pcpa) In The Mechanism Of Virulence And Protective Immunity, Melissa Marie Walker Jan 2013

The Role Of Pneumococcal Choline-Binding Protein A (Pcpa) In The Mechanism Of Virulence And Protective Immunity, Melissa Marie Walker

All ETDs from UAB

pcpA is under control of the Mn 2-dependent repressor PsaR. In the high manganese environment of mucosal sites pcpA gene expression is repressed and at the low manganese environment of the lung and blood derepression of pcpA gene expressionis observed. Previous data has shown that immunization of mice with rPcpA elicits protection against pneumonia and sepsis but had no effect on nasal colonization. We and others have shown that pcpA expression significantly enhances adherence of pneumococci to lung epithelial cell lines and although it is a virulence factor for pneumonia in mice there is no biologically relevant role for PcpA …

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Anti-Group B Streptococci Monoclonal Antibodies Protect Against Invasive Aspergillosis, Rebekah Wharton Jan 2013

Anti-Group B Streptococci Monoclonal Antibodies Protect Against Invasive Aspergillosis, Rebekah Wharton

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Aspergillus fumigatus is a ubiquitous saprophytic fungus which can potentially cause life-threatening infections in immunocompromised individuals. Although a serious threat, current treatments are largely ineffective at reducing morbidity and mortality. To this end, we have characterized a monoclonal antibody generated against Group B Streptococci, type Ib, which also recognizes Aspergillus fumigatus conidia and hyphae. We show that this antibody appears to bind a similar epitope on both pathogens and provides a significant degree of protection in a murine model of invasive aspergillosis via a mechanism that appears to be dependent on complement. The studies we performed using this antibody should …

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Genetic And Biochemical Characterizations Of The Capsular Glycosyltransferases In Streptococcus Pneumoniae Serotype 2, David Boyd Anthony James Jan 2013

Genetic And Biochemical Characterizations Of The Capsular Glycosyltransferases In Streptococcus Pneumoniae Serotype 2, David Boyd Anthony James

All ETDs from UAB

The principle objective of this dissertation is to develop a thorough understanding of the genetics and biochemistry of capsule synthesis. Specifically, it involves the identification and characterization of the capsular glycosyltransferases in Streptococcus pneumoniae serotype 2, with investigations into their regulation. S. pneumoniae (the pneumococcus) is a significant human pathogen that has the ability to persist as a commensal and then transition to a virulent state, the latter of which is a major contributor to global morbidity and mortality. The capsular polysaccharide (CPS) of S. pneumoniae is a protective surface structure that plays an integral role in this disease process. …

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Marcks Is A Regulator Of Growth, Radiation Sensitivity And Is A Novel Prognostic Factor For Glioblastoma Multiforme, John Jarboe Jan 2013

Marcks Is A Regulator Of Growth, Radiation Sensitivity And Is A Novel Prognostic Factor For Glioblastoma Multiforme, John Jarboe

All ETDs from UAB

Glioblastoma multiforme (GBM) is the most common and deadly primary brain malignancy necessitating improved understanding of GBM biology. In this study, we explore the role of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) in the context of GBM. We have discovered that the MARCKS protein regulates GBM growth as well as response to radiation therapy through its effects on proliferation, senescence, and DNA repair based on our studies in cell culture and in patient-derived xenograft tumors implanted in mice. Importantly, our analysis of clinical patient data demonstrates that MARCKS is an independent predictor for outcome in GBM patients. Indeed, high MARCKS …

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Usp49 And H2b Deubiquitination In Chromatin And Cellular Function, Amanda E. Jones Jan 2013

Usp49 And H2b Deubiquitination In Chromatin And Cellular Function, Amanda E. Jones

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Histones are globular proteins which help package and organize DNA in the eukaryotic nucleus. The four core histones, H2A, H2B, H3 and H4, combine with approximately 146 base pairs of DNA to form a nucleosome, the fundamental unit of chromatin. Post-translational modifications to the C-terminal and N-terminal histone tails regulate chromatin structure and function, and play important roles in transcriptional regulation, replication, DNA damage response, and mRNA processing. Histone H2B ubiquitination is an evolutionarily conserved modification with roles in gene expression and DNA damage repair. In addition, H2B ubiquitination may also regulate mRNA splicing. Here, we identify USP49, a cysteine …

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The Role Of Histone Deacetylase Inhibitors In Ameliorating Memory Dysfunction Of An Alzheimer's Disease Mouse Model, Mark Kilgore Jan 2013

The Role Of Histone Deacetylase Inhibitors In Ameliorating Memory Dysfunction Of An Alzheimer's Disease Mouse Model, Mark Kilgore

All ETDs from UAB

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid beta plaques and neurofibrillary tangles, along with cognitive impairments that progress to dementia and eventually death. The development of drug treatments that rescue memory deficits could be a promising therapy given in the early stages of AD. In the following studies, we tested the potential for systemic treatment with histone deacetylase (HDAC) inhibitors to ameliorate cognitive deficits in a mouse model of AD. Using the APPSwe/PS1dE9 mouse model of AD, we showed that giving HDAC inhibitors systemically for 3 weeks reversed contextual memory deficits, stably maintained memories over a 2-week …

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Cyclic Gmp Phosphodiesterase As A Novel Target For Colorectal Cancer Chemoprevention, Nan Li Jan 2013

Cyclic Gmp Phosphodiesterase As A Novel Target For Colorectal Cancer Chemoprevention, Nan Li

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Nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. However, many investigators have concluded that COX-independent mechanisms are responsible for their antineoplastic activity. We previously reported that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) is a non-COX target of sulindac sulfide (SS). However, the specific isozyme families involved have not been well studied. Here we demonstrate that SS inhibits the growth of colon tumor cells through a novel mechanism involving inhibition of two cGMP degrading isozymes, PDE5 and PDE10, to activate cGMP-dependent protein kinase (PKG). …

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Surveying The Serum Proteome For Biomarkers Of Early-Stage Pancreatic Cancer, Michael Robert Ludwig Jan 2013

Surveying The Serum Proteome For Biomarkers Of Early-Stage Pancreatic Cancer, Michael Robert Ludwig

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SURVEYING THE SERUM PROTEOME FOR BIOMARKERS OF EARLY STAGE PANCREATIC CANCER MICHAEL ROBERT LUDWIG MICROBIOLOGY ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a uniformly fatal disease due to its refractory nature to conventional therapies at the time of initial diagnosis. In order to in-crease the curative potential of surgical resection, early detection of organ-confined neoplasia is needed. Currently, no effective diagnostic tools are available to detect early-stage pancreatic ductal lesions termed pancreatic intraepithelial neoplasia (PanIN) or lo-cally invasive, organ-confined disease. One way to identify biomarkers that may be use-ful for the early detection of PDAC is through the study of the …

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The Role Of Palmitoylation And Other Post-Translational Modifications In Cftr Biogenesis, Michelle Mcclure Jan 2013

The Role Of Palmitoylation And Other Post-Translational Modifications In Cftr Biogenesis, Michelle Mcclure

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Post-translational modifications (PTMs) are important contributors to protein bio-genesis and function. CFTR in particular is known to be regulated by multiple PTMs, in-cluding glycosylation, phosphorylation, and ubiquitination. The functional significance and specific CFTR residues responsible for the majority of PTMs within CFTR are not known. The goal of this dissertation was to identify and characterize novel PTMs that influence wild-type and F508del CFTR. The study employed a combination of tandem and multiple reaction ion monitoring mass spectrometry to identify covalent side chain attachments. Analysis revealed the specific locations of numerous phosphorylated resi-dues, several sites of methylation, and more than twenty-five …

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Characterizing The Roles Of Il-11 And Cd68 In Breast Cancer Bone Metastasis, Erin Mills Mccoy Jan 2013

Characterizing The Roles Of Il-11 And Cd68 In Breast Cancer Bone Metastasis, Erin Mills Mccoy

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The molecular mechanisms regulating the preferential metastasis of breast cancer to bone have not been fully elucidated, but it is hypothesized that local conditions in the bone create an environment conducive to colonization by breast cancer cells and that the breast cancer cells interact directly with cells in the bone. In this dissertation, two goals were pursued: (1) to explore breast cancer secreted interleukin (IL)-11's role on osteoclast function and (2) investigate the expression and potential role of CD68 in breast cancer adhesion to bone. Higher rates of bone metastasis occur in human breast cancer tumors expressing IL-11, a cytokine …

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Microevolution Of Capsule Synthesis Genes Contributes To Pneumococcal Capsule Diversity, Melissa Beth Oliver Jan 2013

Microevolution Of Capsule Synthesis Genes Contributes To Pneumococcal Capsule Diversity, Melissa Beth Oliver

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Streptococcus pneumoniae (pneumococcus) is an important human pathogen that expresses a capsular polysaccharide (PS) to shield underlying antigenic structures from complement-mediated opsonophagocytosis. Thus, capsular PS is the major virulence factor, the target of primary immune responses to pneumococcal infections, and the antigenic component of pneumococcal vaccines. Pneumococci have diverse capsular PS synthesis (cps) loci and express over 90 different capsule types. Such diversity helps pneumococci escape immune detection and adapt to changing environments. Recombination of cps genes has been recognized as the main driver of capsule diversity. However, we show point mutations in cps genes encoding glycosyltransferases can broaden enzymes' …

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The Role Of Complement In Experimental Cerebral Malaria, Theresa N. Ramos Jan 2013

The Role Of Complement In Experimental Cerebral Malaria, Theresa N. Ramos

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Cerebral malaria (CM) is one of the most severe clinical complications of P. falciparum malaria with a fatality rate of 15-30%, and 10% of CM survivors have permanent neurological sequelae. Since inflammation is a central pathophysiological tenet of CM, we began examining the role of the complement system in pathogenesis of experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA) model. Previous studies using this model indicated that mice naturally deficient in complement component C5 were protected from cerebral complications, and wild type mice treated with anti-C5aR antibody were also protected. To determine the protective mechanism of naturally-C5 deficient mice, …

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Commensal Microbiota And Its Impact On Health And Autoimmune Diabetets, Kyle James Wolf Jan 2013

Commensal Microbiota And Its Impact On Health And Autoimmune Diabetets, Kyle James Wolf

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Environmental exposures such as diet, use of antibiotics, and lifestyle have significant impact on the health of an individual. One mechanism that acts as a major pathway in these environmental exposures is the role intestinal commensal microbiota play in both metabolic and immunological responses. Metabolic pathways are altered through changes in metabolites provided by commensal microbiota; alterations in microbial make-up can have drastic impacts on metabolic function. Similarly, the development and maturation of the immune system is dependent on the intestinal microbes to induce tolerance and act as both an immune modulator as well as a barrier against pathogens. We …

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Characterization Of The Mumps Virus Replicase, Robert Marsden Cox Jan 2013

Characterization Of The Mumps Virus Replicase, Robert Marsden Cox

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Negative strand RNA viruses (NSV) are unique because their nucleocapsids are used directly as the template for both transcription and replication. The viral genomic RNA is coated by the nucleoprotein (N) for the entirety of the NSV replication cycle. The viral polymerase, which is composed of the L and P proteins, can only recognize encapsidated RNA as the template for RNA synthesis. Our previous studies have solved the EM structure of the MuV N-RNA complex at 25Ņ. This structure revealed how the nucleocapsid is assembled and provides an initial model for examining how the viral polymerase may recognize the …

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Sulindac Sulfide Amide As A Novel Agent For The Prevention And Treatment Of Lung Cancer, Evrim Gurpinar Jan 2013

Sulindac Sulfide Amide As A Novel Agent For The Prevention And Treatment Of Lung Cancer, Evrim Gurpinar

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Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their use in cancer prevention. We recently described a N,N-dimethylethyl amine derivative of SS, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines and evaluated its preclinical pharmacology. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2-5 μ compared with 44-52 …

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Clinical Consequences Of Micrornas In Colorectal Cancer, Liselle C. Bovell Jan 2013

Clinical Consequences Of Micrornas In Colorectal Cancer, Liselle C. Bovell

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Colorectal cancer (CRC) is a heterogeneous disease, and factors such as tumor location, the environment, genetics, and ethnic differences, can influence its development and progression. Over the last few decades, overall CRC mortality rates have declined; however, racial disparities in mortality rates have increased. The discovery of biomarkers that focus on identifying individual differences based on confounders such as tumor stage and patient race/ethnicity is needed, for such biomarkers can lead to development of personalized therapeutic approaches to target these molecules. MicroRNAs (miRNAs) are a class of small molecules that regulate genes at the post-transcriptional level. Altered miRNA expression levels …

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Therapeutic Potential Of Genetically-Engineered Mesenchymal Stem Cells In Multiple Myeloma, Jerome T. Higgs Jan 2013

Therapeutic Potential Of Genetically-Engineered Mesenchymal Stem Cells In Multiple Myeloma, Jerome T. Higgs

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ABSTRACT Multiple Myeloma (MM) remains the second most common hematologic malig-nancy occurring in adults, which primarily affects the skeletal system causing severe bone destruction, spinal cord compression and hypercalcemia. Current therapies, which include chemotherapy, radiotherapy, autologouos stem cell transplantation and in some cases surgery, have extended the median survival between 3 and 10 years. However, MM is still incurable and therefore improving current therapies or developing newer ones to reduce the burden of osteolytic damage and extend survival rate will be highly beneficial for patient management. The long-term goal of this study is to develop a novel therapeutic approach to …

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