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Title: Induction of apoptosis in mouse thymocytes by Microcolin A and its synthetic analog.
Creator: Zhang, L.-H., Longley, Ross E., Harbor Branch Oceanographic Institute
Date Issued: 1999
PURL: http://purl.flvc.org/FCLA/DT/3331937
Subject Headings: Apoptosis, Thymocytes
Format: Document (PDF)

Title: An analysis of the effectiveness of dichloroacetate as an anti-cancer agent.
Creator: Flint, Valerie., Harriet L. Wilkes Honors College
Abstract/Description: Dichloroacetate (DCA) is a chemical with potential to be a cancer therapy due to its ability to treat mitochondrial metabolic disorders. Previous studies have affirmed DCA's ability to target cancer cells, leaving healthy cells unharmed (Bonnet et al., 2007). Javonia Washington continued research that Bonnet et al. began by testing DCA's effectson a greater number of cell types (Washington, 2008). This project collects and analyzes the data generated by Washington's research using the...
Show moreDichloroacetate (DCA) is a chemical with potential to be a cancer therapy due to its ability to treat mitochondrial metabolic disorders. Previous studies have affirmed DCA's ability to target cancer cells, leaving healthy cells unharmed (Bonnet et al., 2007). Javonia Washington continued research that Bonnet et al. began by testing DCA's effectson a greater number of cell types (Washington, 2008). This project collects and analyzes the data generated by Washington's research using the computer programs Excel and SPSS. The analysis shows that DCA concentration is vital when considering the chemical as an anti-cancer drug ; it had a significant effect on the cancerous cells from 0.5mM and higher, but both cancerous and non-cancerous cells died at similar rates when the concentration reached 10mM. Further, DCA affects some cancer cells more quickly than others, which could increase the risk of harming surrounding healthy cells if used improperly as a cancer treatment.
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Date Issued: 2010
PURL: http://purl.flvc.org/FAU/3335018
Subject Headings: Chloroacetic acids, Therapeutic use, Antineoplastic agents, Apoptosis
Format: Document (PDF)

Title: Characterization of the spinster gene ortholog C13C4.5 in Caenorhabditis elegans.
Creator: Zahornacky, Darrin., Harriet L. Wilkes Honors College
Abstract/Description: The dauer larva is an alternate larval stage which allows the nematode C. elegans to survive environmestress during development. Dauer formation requires autophagy, a cellular process responsible for degrading and recycling cytoplasmic components. I investigated the role of a spinster orthiolog, C13C4.5, by examining the effects of C13C4.5 loss-of-function and by generating a transgenic strain which expressed a C13C4.5::GFP fusion protein. Under normal conditions C13C4.5::GFP is expressed...
Show moreThe dauer larva is an alternate larval stage which allows the nematode C. elegans to survive environmestress during development. Dauer formation requires autophagy, a cellular process responsible for degrading and recycling cytoplasmic components. I investigated the role of a spinster orthiolog, C13C4.5, by examining the effects of C13C4.5 loss-of-function and by generating a transgenic strain which expressed a C13C4.5::GFP fusion protein. Under normal conditions C13C4.5::GFP is expressed diffusely in the intestine, but under autophagy-promoting conditions the expression pattern becomes more punctate. This is consistent with localization of C13C4.5 to autophagolysomoes during autophagy, as has been shown for spinster in D. melanogaster. Loss of C13C4.5 function in a dauer-constitutive mutant resulted in a reduction in the proportion of animals entering into the dauer stage. Together these data suggest that C13C4.5 is involved in dauer formation and the autophagy pathway.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3359320
Subject Headings: Gene expression, Apoptosis, Caenorhabditis elegans, Proteins, Analysis
Format: Document (PDF)

Title: Effects of Target Neuron Loss on Olfactory Receptor Neurons in the Adult Rat.
Creator: Sultan, Krista K., Guthrie, Kathleen M., Florida Atlantic University
Abstract/Description: Unlike most neurons in the adult nervous system, olfactory receptor neurons (ORN), found in the olfactory epithelium (OE), continually turnover in the adult rat. These neurons project their axons to the olfactory bulb which is their central target. The present study eliminated target neurons in the bulb using N-methyl-D-aspartate (NMDA) to examine the effects of target loss on ORN survival and maturation. We compared the effects of the NMDA lesion to bulbectomy, a permanent surgical removal...
Show moreUnlike most neurons in the adult nervous system, olfactory receptor neurons (ORN), found in the olfactory epithelium (OE), continually turnover in the adult rat. These neurons project their axons to the olfactory bulb which is their central target. The present study eliminated target neurons in the bulb using N-methyl-D-aspartate (NMDA) to examine the effects of target loss on ORN survival and maturation. We compared the effects of the NMDA lesion to bulbectomy, a permanent surgical removal of the bulb, which simultaneously causes damage to ORN axons. We found that unlike bulbectomy, large numbers of dying OE cells were not observed at any time after the lesion. The number of immature neurons increased relative to the control side, and the number of mature neurons also slightly increased with time following NMDA lesion. Survival of ORNs does not seem to be significantly altered in the absence of its target.
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Date Issued: 2007
PURL: http://purl.flvc.org/fau/fd/FA00000838
Subject Headings: Rats--Physiology, Neurophysiology, Apoptosis, Regeneration (Biology)
Format: Document (PDF)

Title: Expression of autophagy transcripts and proteins in the ocular lens suggests a role for autophagy in lens cell and cellular differentiation.
Creator: Mattucci, Lyndzie., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: The lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The...
Show moreThe lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The process responsible for orchestrating lens cell differentiation has yet to be elucidated. In recent years, data has emerged that led our lab to hypothesize that autophagy is likely involved in lens cell maintenance, cell differentiation, and maintenance of lens transparency. As a first step towards testing this hypothesis, we used RT-PCR, western blot analysis, immunohistochemistry, confocal microscopy, and next generation RNA-Sequencing (RNA-Seq) to examine autophagy genes expressed by the lens to begin mapping their lens function.
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Date Issued: 2013
PURL: http://purl.flvc.org/fcla/dt/3360958
Subject Headings: Cell differentiation, Protein binding, Research, Cellular control mechanisms, Apoptosis
Format: Document (PDF)

Title: In search of MMP specific inhibitors: protein engineering of TIMPs.
Creator: Bahudhanapati, Harinathachari., Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description: The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs). Since unregulated MMP activities are linked to arthritis, cancer, and atherosclerosis, TIMP variants that are selective inhibitors of disease-related MMPs have potential therapeutic value. The structures of TIMP/MMP complexes reveal that most interactions with the MMP involve the N-terminal region of TIMP and the C-D B-strand connector which occupy the primed (right side of...
Show moreThe tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs). Since unregulated MMP activities are linked to arthritis, cancer, and atherosclerosis, TIMP variants that are selective inhibitors of disease-related MMPs have potential therapeutic value. The structures of TIMP/MMP complexes reveal that most interactions with the MMP involve the N-terminal region of TIMP and the C-D B-strand connector which occupy the primed (right side of the active site) and unprimed (left side) regions of the active site. Substitutions for Thr2 of N-TIMP- 1 strongly influence MMP selectivity. In this study we found that Arg and Gly, which generally reduce MMP affinity, have less effect on binding to MMP-9. When the Arg mutation is added to the NTIMP-1 mutant with AB loop of TIMP-2, it produced a gelatinase-specific inhibitor with Ki values of 2.8 and 0.4 nM for MMP-2 and MMP-9, respectively. The Gly mutant has a Ki of 2.1 nM for MMP-9 and > 40 uM for MMP-2, indicating that engineered TIMPs can discriminate between MMPs in the same subfamily. In collaboration with Dr. Yingnan Zhang at Genentech, we have developed a protocol for the phage display of full-length human TIMP-2 to identify high-affinity selective inhibitors of human MMP-1, a protease that plays a role in cleaving extracellular matrix (ECM) components, connective tissue remodeling during development, angiogenesis, and apoptosis. We have generated a library containing 2x1010 variants of TIMP-2 randomized at residues 2-6 (L1), at residues 34-40 (L2) and 67-70 (L3)., The L1 library yielded a positive signal for MMP-1 binding. Clones from the L1 library, designated TM1, TM8, TM13, and TM14, were isolated after 5 rounds of selection on immobilized MMP-1 and MMP-3 and found to show a greater selectivity for MMP-1 relative to MMP-3. TM8, which has Ser2 to Asp and Ser4 to Ala substitutions, showed the greatest apparent selectivity of 10-fold toward MMP-1 compared to MMP-3. The various mutations identified by phage display were introduced into recombinant Nterminal TIMP-2 and the variants characterized as inhibitors of an array of MMP catalytic domains. The TM8-based mutant showed pronounced selectivity (> 1000-fold for MMP-1 vs. MMP-3) and may be a step towards the generation of MMP-1-specific inhibitors. Molecular modeling was used to rationalize the structural basis of MMP selectivity in the mutants.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/221942
Subject Headings: Metalloproteinases, Inhibitors, Apoptosis, Extracellular matrix proteins, Proteolytic enzymes
Format: Document (PDF)

Title: Thermodynamic Origins of Selectivity in the Interactions of N- TIMP Variants and Metalloproteinases Catalytic Domains.
Creator: Zou, Haiyin, Brew, Keith, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Matrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue...
Show moreMatrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) which are avid broad-spectrum inhibitors of numerous human matrixins (MMPs and ADAMs). Uncontrolled matrix degradation occurs when the balance between TIMPs and MMPs is disrupted, resulting in serious diseases such as cancer, arthritis and chronic tissue ulcers. Thus, the engineering of TIMPs to produce highly selective and efficacious inhibitors of individual MMPs may be utilized for future treatment of diseases. Such engineering requires detailed analysis for the structural and biophysical information of MMP-TIMP interaction. Changes in the dynamics of proteins and solvent that accompany their associations with different binding partners, influence the specificity of binding through entropic effects. From the current studies it appears that the interactions of the inhibitory domains of TIMPs-1 and -2 (N-TIMPs) with MT1-MMP are driven by entropy increases that are partitioned between solvent and conformational entropy (ΔSsolv and ΔSconf), and a large conformational entropy penalty is responsible for the weak inhibition of MT1-MMP by NT1.We investigated how mutations that modify N-TIMP selectivity affect the thermodynamics of interactions with MMP1, MMP3 and MT1-MMP. The weak inhibition of MT1-MMP by N-TIMP-1 is enhanced by mutation of threonine 98, on the edge of the binding ridge, to leucine. This mutation increases the large ΔSconf cost for binding to MT1-MMP but this is offset by a greater increase in ΔSsolv. In contrast, this mutation enhances binding to MMP3 by increasing ΔSconf for the interaction. ΔSsolv and ΔSconf show mutual compensation for all interactions, with characteristic ranges for each MMP. Distinct electrostatic and dynamic features of MMPs are key factors in their selective inhibition.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00004643
Subject Headings: Metalloproteinases -- Inhibitors., Proteolytic enzymes., Extracellular matrix proteins., Apoptosis.
Format: Document (PDF)

Title: Thermodynamics-structure correlations of interactions between metalloproteinases and tissue inhibitors of metalloproteinase variants.
Creator: Wu, Ying., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description: The 23 matrix metalloproteinases (MMPs) in humans catalyze the turnover of all protein components of the extracellular matrix (ECM) and have important roles in tissue remodeling, wound healing, embryo implantation, cell migration and shedding of cell surface proteins. Excess MMP activities are associated with many diseases including arthritis, heart disease and cancer. The activities of MMPs are regulated by a family of four protein inhibitors, the tissue inhibitors of metalloproteinases ...
Show moreThe 23 matrix metalloproteinases (MMPs) in humans catalyze the turnover of all protein components of the extracellular matrix (ECM) and have important roles in tissue remodeling, wound healing, embryo implantation, cell migration and shedding of cell surface proteins. Excess MMP activities are associated with many diseases including arthritis, heart disease and cancer. The activities of MMPs are regulated by a family of four protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), that are endogenous inhibitors of matrix metalloproteinases (MMPs), ADAMs (A Disintegrin And Metalloproteinase) and ADAMTS (disintegrin-metalloproteinase with thrombospmdin motifs) .... The balance between TIMPs and active metzinicins is very important and imbalances are linked to human diseases such as arthritis, cancer, and atherosclerosis. The engineering of TIMPs to produce specific inhibitors of individual MPs could provide new therapeutic principles for disease treatment, but this requires a detailed understanding of the biophysical and structural basis of the interactions of TIMPs and MMPs and ADAMs.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3356904
Subject Headings: Proteolytic enzymes, Metalloproteinase, Inhibitors, Apoptosis, Extracellular matrix proteins
Format: Document (PDF)

Title: Potential mechanism of phytochemical-induced apoptosis in human prostate cancer cells: Genistein and beta-lapachone.
Creator: Saddler, Shawnette Simone, Florida Atlantic University, Kumi-Diaka, James
Abstract/Description: The present study was undertaken to determine the chemotherapeutic potential of genistein and beta-lapachone and possible mechanisms of action in prostate cancer in vitro. The bioassays used included: MTT and LDH chemosensitivity-cytotoxicity assays, NQO1 detection, annexin V-FITC, TUNEL and the caspase protease (CPP32) apoptotic detection assays. The results showed that: (i) PC3 cells are sensitive to single and combination treatments in a dose and time dependent manner; (ii) there was...
Show moreThe present study was undertaken to determine the chemotherapeutic potential of genistein and beta-lapachone and possible mechanisms of action in prostate cancer in vitro. The bioassays used included: MTT and LDH chemosensitivity-cytotoxicity assays, NQO1 detection, annexin V-FITC, TUNEL and the caspase protease (CPP32) apoptotic detection assays. The results showed that: (i) PC3 cells are sensitive to single and combination treatments in a dose and time dependent manner; (ii) there was treatment-induced dual death pathways (apoptosis and necrosis) with increasing toxicity (necrosis) at higher concentrations in single and combination treatments; (iii) combination treatment was more growth inhibitory than single treatments; (iv) the NQO1 enzyme substantially enhances the toxicity of beta-lapachone but not genistein, while genistein exerted its apoptotic inducing effects via the caspase 3 pathway. The overall results indicate that combination treatments with beta-lapachone and genistein are more efficacious in killing PC3 human prostate cancer cells than treatment with either agent alone.
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Date Issued: 2003
PURL: http://purl.flvc.org/fcla/dt/13042
Subject Headings: Prostate--Cancer--Cytopathology, Apoptosis, Prostate--Cancer--Molecular aspects
Format: Document (PDF)

Title: Tissue Protection and Cell Death Pathways in Myocardial Ischemia.
Creator: Rickaway, Zach T., Prentice, Howard, Florida Atlantic University
Abstract/Description: The excess generation of Reactive oxygen species (ROS) can damage cell components and disrupt cellular functions. Methionine in proteins is easily oxidized by ROS and converted to methionine sulfoxide. The enzyme peptide Methionine Sulfoxide Reductase reduces methionine sulfoxide back to methionine. We report here that MsrA over expression in rat cardiac myocytes prevents damage from ROS and increases cell viability after hypoxic/reoxygenation events. The nonsteroidal anti-inflamatory drug ...
Show moreThe excess generation of Reactive oxygen species (ROS) can damage cell components and disrupt cellular functions. Methionine in proteins is easily oxidized by ROS and converted to methionine sulfoxide. The enzyme peptide Methionine Sulfoxide Reductase reduces methionine sulfoxide back to methionine. We report here that MsrA over expression in rat cardiac myocytes prevents damage from ROS and increases cell viability after hypoxic/reoxygenation events. The nonsteroidal anti-inflamatory drug (NSAID) sulindac contains a methyl sulfoxide moiety that can scavenge ROS. Sulindac can be reduced by MsrA and contribute as an antioxidant in the cell. Our results demonstrate that 1 OOuM sulindac can reduce cell death in rat cardiac myocytes during hypoxia/reoxygenation, and ischemia/reperfusion in Langendorf[ perfusions. The BNIP proteins are pro-apoptotic members of the Bcl-2 family of apoptosis regulating proteins. Hypoxia/acidosis stabilizes BNIP-3 and increases its association with the mitochondria, causing the release of cytochrome C and cell death. We report the retrograde perfusion Langendorffmodel is inconclusive in mouse hearts.
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Date Issued: 2006
PURL: http://purl.flvc.org/fau/fd/FA00000820
Subject Headings: Mitochondrial pathology, Heart--Pathophysiology, Apoptosis, Cell differentiation
Format: Document (PDF)

Title: A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis.
Creator: Guzman, Esther A., Johnson, J. D., Linley, P. A., Wright, Amy E., Gunasekera, Sarath P.
Date Issued: 2010
PURL: http://purl.flvc.org/FCLA/DT/3318907
Subject Headings: Pancreas--Cancer, Apoptosis, Sponges--Research, Marine natural products, Drug Discovery
Format: Document (PDF)

Title: Correlation between specific carcinogenic chemicals and specific mitotic defects and the restorative role of antioxidants.
Creator: Yates, Travis., Harriet L. Wilkes Honors College
Abstract/Description: The progression of cancerous cells towards a more aggressive tumor can be linked to external elements called carcinogens. The goal of this project is to examine the correlation between exposure to specific carcinogens and an increase of mitotic defects. These defects can manifest as lagging chromosomes, multipolar spindles, and anaphase bridges. Some of these instabilities are associated with the formation of reactive oxygen species (ROS), which are known to damage DNA. The potential for...
Show moreThe progression of cancerous cells towards a more aggressive tumor can be linked to external elements called carcinogens. The goal of this project is to examine the correlation between exposure to specific carcinogens and an increase of mitotic defects. These defects can manifest as lagging chromosomes, multipolar spindles, and anaphase bridges. Some of these instabilities are associated with the formation of reactive oxygen species (ROS), which are known to damage DNA. The potential for damage to the genome can be averted via antioxidants. Using the oral cancer cell line UPCI:SCC103, we established a baseline for the mitotic defects in the absence and presence of various ROS-inducing carcinogens using DAPI-stained fixed cells examined by immunofluorescent microscopy, The cells were treated with varying concentrations of the antioxidants, Vitamin C, (Sb(B-Carotene, and Vitamin E. The reactive oxygen scavengers significantly reduced the number of mitotic defects. A possible link between the carcinogens and lagging chromosomes was established.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/210007
Subject Headings: Cellular signal transduction, Genetic regulation, Antioxidants, Therapeutic use, Apoptosis, Molecular aspects, Cancer, Chemoprevention
Format: Document (PDF)

Title: Engineered and natural TIMP mutations.
Creator: Hamze, Asmaa Bilal., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description: Tissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP ...
Show moreTissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP (MT1-MMP) as a model, since it is inefficiently inhibited by TIMP-1 in contrast with the other TIMPs. We designed and engineered mutations in the N-domain of TIMP-1, based on current knowledge of TIMP interactions. By measuring inhibition levels of each mutant against several MMPs, including MT1-MMP, we were able to obtain a triple mutant with an vii improved affinity for MT1-MMP., Our results, along with previous data, confirm that multiple residues in the critical interface segments between TIMPs and MMPs, namely at positions 2, 4, 5, 6, and 98, are key in determining the basic interaction between the two molecules. The second part of this work focused on naturally occurring mutations in TIMP-3 which cause an early form of macular degeneration called Sorsby's Fundus Dystrophy (SFD). The TIMP-3 mutants identified so far share certain features but the mechanism by which they result in macular disease is not yet understood. As an initial step, we expressed recombinant TIMP-3 carrying a truncation mutation, glutamic acid 139 to a stop codon (E139X), and assessed its activity towards representative MMPs and tumor necrosis factor-(Sa (Bconverting enzyme, another metalloproteinase normally inhibited by TIMP-3. Our results indicate that this mutation does not impair the inhibitory activity of TIMP-3., Expression of this mutant in mammalian retinal cells revealed a difference in localization between wild-type and E139X mutant TIMP-3. Therefore, we concluded that the SFD mutations may actually influence the processing and/or binding properties of TIMP-3 in the retina.
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Date Issued: 2008
PURL: http://purl.flvc.org/FAU/186296
Subject Headings: Proteolytic enzymes, Extracellular matrix proteins, Metalloproteinases, Inhibitors, Apoptosis, Retinal degeneration, Research
Format: Document (PDF)

Title: Gene selection for sample sets with biased distribution.
Creator: Kamal, Abu Hena Mustafa., College of Engineering and Computer Science, Department of Computer and Electrical Engineering and Computer Science
Abstract/Description: Microarray expression data which contains the expression levels of a large number of simultaneously observed genes have been used in many scientific research and clinical studies. Due to its high dimensionalities, selecting a small number of genes has shown to be beneficial for many tasks such as building prediction models from the microarray expression data or gene regulatory network discovery. Traditional gene selection methods, however, fail to take the class distribution into the...
Show moreMicroarray expression data which contains the expression levels of a large number of simultaneously observed genes have been used in many scientific research and clinical studies. Due to its high dimensionalities, selecting a small number of genes has shown to be beneficial for many tasks such as building prediction models from the microarray expression data or gene regulatory network discovery. Traditional gene selection methods, however, fail to take the class distribution into the selection process. In biomedical science, it is very common to have microarray expression data which is severely biased with one class of examples (e.g., diseased samples) significantly less than other classes (e.g., normal samples). These sample sets with biased distributions require special attention from researchers for identification of genes responsible for a particular disease. In this thesis, we propose three filtering techniques, Higher Weight ReliefF, ReliefF with Differential Minority Repeat and ReliefF with Balanced Minority Repeat to identify genes responsible for fatal diseases from biased microarray expression data. Our solutions are evaluated on five well-known microarray datasets, Colon, Central Nervous System, DLBCL Tumor, Lymphoma and ECML Pancreas. Experimental comparisons with the traditional ReliefF filtering method demonstrate the effectiveness of the proposed methods in selecting informative genes from microarray expression data with biased sample distributions.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/186330
Subject Headings: Gene expression, Research, Methodology, Medical informatics, Apoptosis, Molecular aspects, DNA microarrays, Research
Format: Document (PDF)

Title: Potential therapies and neuroprotective cascades in anoxia tolerant freshwater turtle Trachemys scripta ellegans.
Creator: Nayak, Gauri., Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description: Mammalian neurons exhibit extreme sensitivity to oxygen deprivation and undergo rapid and irreversible degeneration when oxygen supply is curtailed. Though several neuroprotective pathways are activated during oxygen deprivation, their analyses are masked by the complex series of pathological events which are triggered simultaneously. Such events can be analyzed in the anoxia tolerant fresh water turtle, which can inherently survive the conditions of oxygen deprivation and post-anoxic...
Show moreMammalian neurons exhibit extreme sensitivity to oxygen deprivation and undergo rapid and irreversible degeneration when oxygen supply is curtailed. Though several neuroprotective pathways are activated during oxygen deprivation, their analyses are masked by the complex series of pathological events which are triggered simultaneously. Such events can be analyzed in the anoxia tolerant fresh water turtle, which can inherently survive the conditions of oxygen deprivation and post-anoxic reoxygenation without brain damage. It is likely in such a model that modulation of a particular molecular pathway is adaptive rather than pathological. The major objective behind this study was to analyze the intracellular signaling pathways mediating the protective effects of adenosine, a potential neuromodulator, and its effect on cell survival by influencing the key prosurvival proteins that prevent apoptosis. In vivo and in vitro studies have shown that adenosine acts as a neuroprotective metabolite and its action can be duplicated or abrogated using specific agonist and antagonists. Stimulating the adenosine receptors using selective A1 receptor agonist N6-cyclopentyladenosine (CPA) activated the presumed prosurvival ERK and P13-K/AKT cascade promoting cell survival, and suppression of the receptor using the selective antagonist DPCPX (8- cyclopentyl-1,3-dipropylxanthine) activated the prodeath JNK and P38 pathways. The complex regulation of the MAPK's/AKT signaling cascades was also analyzed using their specific inhibitors. The inhibiton of the ERK and AKT pathway increased cell death, indicating a prosurvival role, whereas inhibiton of the JNK and p38 pathway increased cell survival in this model. In vitro studies have also shown a high Bcl-2/BAX ratio during anoxia and reoxygenation, indicating a strong resistance to cell death via apoptosis., Silencing of the anti-apoptotic Bcl-2 gene using specific siRNA upregulated levels of prodeath BAX, thus altering the Bcl-2/BAX ratio and elevating cleaved Caspase-3 levels leading to increased cell death. Another promising neuroprotective target which we analyzed was Neuroglobin, which was induced during oxygen crisis and silencing this gene indicated that its plays a major role in modulation of ROS. This study strongly emphasizes the advantages of an alternate animal model in elucidating neuroprotective mechanisms and revealing novel therapeutic targets which could eventually help clinicians to design new stroke therapies based on naturally tolerant organisms.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/186762
Subject Headings: Turtles, Physiology, Adenosine, Receptors, Cellular signal transduction, Molecular neurobiology, Apoptosis, Research, Cellular control mechanisms
Format: Document (PDF)

Title: An investigation of the role of PAK6 tumorigenesis.
Creator: Roberts, JoAnn, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: The function and role of PAK6, serine/threonone kinase, in cancer progressionhas not yet been clearly identified. Several studies reveal that PAK6 may participate in key changes contributing to cancer progression such as cell survival, cell motility, and invasiveness. Basedon the membrane localization of PAK6 in prostate and breast cancer cells,we speculated that PAK6 plays a rolein cancer progression cells by localizing on the membrane and modifying proteins linked to motility and...
Show moreThe function and role of PAK6, serine/threonone kinase, in cancer progressionhas not yet been clearly identified. Several studies reveal that PAK6 may participate in key changes contributing to cancer progression such as cell survival, cell motility, and invasiveness. Basedon the membrane localization of PAK6 in prostate and breast cancer cells,we speculated that PAK6 plays a rolein cancer progression cells by localizing on the membrane and modifying proteins linked to motility and proliferation. We isolated the raft domain of breast cancer cells expressing either wild type (WT), constitutively active (SN), or kinase dead PAK6 (KM) and found that PAK6 is a membrane associated kinase which translocates from the plasma membrane to the cytosol when activated. The downstream effects of PAK6 are unknown ; however, results from cell proliferation assays suggest a growth regulatory mechanism.
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Date Issued: 2012
PURL: http://purl.flvc.org/FAU/3356888
Subject Headings: Apoptosis, Cancer, Etiology, Cancer cells, Proliferation, Cellular signal transduction, Cellular control mechanisms, Cell cycle, Regulation
Format: Document (PDF)

Title: Integrin αVβ5-mediated Removal Of Apoptotic Cell Debris By The Eye Lens And Its Inhibition By UV-light Exposure.
Creator: Bakina, Olga, Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: The lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris...
Show moreThe lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris from the lens. In the set of experiments it was proven that integrin αvβ5-mediated pathway is involved in phagocytosis of apoptotic cell debris in the ocular lens, thus contributing to its homeostasis. Additionally, it was shown that exposure to UV-light plays role in cataract formation by influencing integrin αvβ5-mediated phagocytosis function.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00004568
Subject Headings: Eye x Diseases--Research., Retinal degeneration., Cellular control mechanisms., Apoptosis
Format: Document (PDF)

Title: Synthesis, structural characterization and biological studies of organotin polyethers (Sn-O).
Creator: Barot, Girish Vallabhbhai., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description: Cancer is the second leading cause of death in the western world. In order to treat various types of cancer, platinum-based drugs are most widely employed as metal-containing chemotherapeutic agents. However, their clinical usage is hindered by toxic side effects, and by the emergence of drug resistance. Our focus was to replace platinum with less toxic metal like tin which can give better alternatives for cancer treatment. The major aim of our study was to synthesize novel organotin...
Show moreCancer is the second leading cause of death in the western world. In order to treat various types of cancer, platinum-based drugs are most widely employed as metal-containing chemotherapeutic agents. However, their clinical usage is hindered by toxic side effects, and by the emergence of drug resistance. Our focus was to replace platinum with less toxic metal like tin which can give better alternatives for cancer treatment. The major aim of our study was to synthesize novel organotin polyethers (Sn-O) which can be used to combat cancer. Preliminary results from our laboratory using organotin polyethers, that were synthesized by varying the structure of diols showed growth inhibition in Balb-3T3 cells. This study directly led us to hypothesize the two structural windows, first by changing the distance between diol and second, by presence of unsaturation in diols, the biological activity of organotin polyethers (Sn-O) can be enhanced significantly. Different series of polymeric compounds were synthesized based upon these two structural windows and the formation of products was validated using standard techniques like infrared spectroscopy (IR), light scattering photometer, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and nuclear magnetic resonance (NMR). The synthesized polymers arrested the growth of cancer cell lines including bone, prostate, colon, breast, pancreas and lung cancer derived cell lines in vitro. In number of instances where chemotherapeutic index values of two and greater were found that these polymers are significantly more active against cancer cells than non-cancerous cells in culture., These results support the starting premise that the polymers may exhibit cancer cell selectivity. In general, it was found that the presence of unsaturation increased the probability that the polyether would inhibit the growth of various cancer cell lines. Further, in some cases, polyethers with short distances between the oxygen atoms showed a superior ability to inhibit the growth of various cancer cell lines in comparison to those with longer distances between the oxygen atoms. These results provide a framework for the discovery of novel cancer therapeutics.
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Date Issued: 2009
PURL: http://purl.flvc.org/FAU/186672
Subject Headings: Organometallic polymers, Cancer, Molecular aspects, Apoptosis, Molecular aspects, Antineoplastic agents, Testing, Polymers in medicine
Format: Document (PDF)

Title: Protective Mechanisms of Granulocyte-Colony Stimulating Factor Against Experimental Models of Stroke.
Creator: Menzie-Suderam, Janet, Wu, Jang-Yen, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description: Ischemic stroke has a multiplicity of pathophysiological mechanisms. Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exerts a diverse range of neuroprotection against ischemic stroke. Several lines of evidence demonstrated the contribution of endoplasmic reticulum (ER) in apoptotic cell death involving ischemia. Cell culture of undifferentiated PC12 cells were subjected to 10mM glutamate and selected doses of G-CSF (25ng/ml, 50ng/ml, 100ng/ml and 250ng/ml)...
Show moreIschemic stroke has a multiplicity of pathophysiological mechanisms. Granulocyte-colony stimulating factor (G-CSF) is an endogenous growth factor that exerts a diverse range of neuroprotection against ischemic stroke. Several lines of evidence demonstrated the contribution of endoplasmic reticulum (ER) in apoptotic cell death involving ischemia. Cell culture of undifferentiated PC12 cells were subjected to 10mM glutamate and selected doses of G-CSF (25ng/ml, 50ng/ml, 100ng/ml and 250ng/ml) for 24 hours. Cell viability, expression of the G-CSF receptor and expression level of CHOP were assessed in vitro. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Rats were subcutaneously injected with G-CSF (n= 15; 50ug/kg body weight) 24 hours post-MCAO for 4 days. Vehicle treated rats were administered 5% dextrose for 1 day (n=4) or 4 days (n=16). Sham-operated rats (n=9) were not subjected to MCAO. Neurological deficit and infarct volume were measured while expression levels of pAKT, Bcl2, Bax, Bak, cleaved caspase-3, GRP78, ATF4, ATF6, p-p38MAPK, pJNK, CHOP and HSP27 were analyzed by western blotting. In vitro G-CSF receptor was expressed on undifferentiated PC12 cell, and an optimal dose of 50 ng/ml G-CSF significantly protected these cells against glutamate-induced cytotoxicity (P < 0.05). G-CSF significantly down-regulated (P < 0.01) the ER stressinduced pro-apoptotic marker CHOP in vitro. In vivo, G-CSF reduced infarct volume to 50% while significantly improved neurological deficit compared to vehicle rats. G-CSF significantly (P < 0.05) up-regulated pro-survival proteins pAKT and Bcl2 while downregulating pro-apoptotic proteins Bax, Bak and cleaved caspase 3 in the ischemic brain. It also significantly (P < 0.05) downregulated the ER intraluminal stress sensor GRP78, proteins of ER stress induced intracellular pathway; ATF4, ATF6, p-p38MAPK, pJNK and the ER stress induced apoptotic marker CHOP, which suggests that ER stress is being ameliorated by G-CSF treatment. G-CSF also reduced the level of HSP27, providing additional evidence of cellular stress reduction. G-CSF treatment increased cell survival by attenuating both general pro-apoptotic proteins and specific effector proteins in the ER stress induced apoptotic pathways. Our data has provided new insight into the anti-apoptotic mechanism of G-CSF, especially as it relates to ER stress induced apoptosis in ischemia.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00004795, http://purl.flvc.org/fau/fd/FA00004795
Subject Headings: Cerebral ischemia--Protection., Apoptosis., Rats as laboratory animals., Cellular signal transduction., Oxidation-reduction reaction.
Format: Document (PDF)

Title: Protective mechanism of Sulindac against animal model of ischemic stroke.
Creator: Modi, Jigar P., Charles E. Schmidt College of Medicine, Department of Biological Sciences
Abstract/Description: The Effect of Sulindac was studied on an animal model of ischemic stroke. Sulindac, a non steroid anti inflammatory drug (NSAID) could protect cell death due to hypoxia/reoxygenation. This drug was given 2 days before and 24 hrs after ischemia until animals were sacrificed on 3rd or 11th day. Infarct size was measured for these animals. Sulindac induced Hsp 27 in ischemic penumbra and core on Day 3 & 11 with uncoated nylon suture which shows its cell-survival and anti-apoptotic activity. Also...
Show moreThe Effect of Sulindac was studied on an animal model of ischemic stroke. Sulindac, a non steroid anti inflammatory drug (NSAID) could protect cell death due to hypoxia/reoxygenation. This drug was given 2 days before and 24 hrs after ischemia until animals were sacrificed on 3rd or 11th day. Infarct size was measured for these animals. Sulindac induced Hsp 27 in ischemic penumbra and core on Day 3 & 11 with uncoated nylon suture which shows its cell-survival and anti-apoptotic activity. Also, it increased expression of cell survival markers such as Akt, Bcl2 & Grp 78 in ischemic penumbra and core. With silicon suture it reduced expression of Hsp 27 in ischemic penumbra and core, alleviating cell stress and having pro-survival and anti-stress effects. In conclusion sulindac may have excellent potential as neuro protective agent against oxidative stress in cerebral ischemia.
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Date Issued: 2011
PURL: http://purl.flvc.org/FAU/3333056
Subject Headings: Apoptosis, Biochemical markers, Diagnostic use, Oxidation reduction reaction, Cerebral ischemia, Prevention
Format: Document (PDF)

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