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Probing Molecular Mechanisms Of The Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators Of Functional Dynamics, Anshuman Dixit, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could …

Role Of Extracytoplasmic Function Sigma Factors In Porphyromonas Gingivalis, Suhasini Yanamandra Sai

Theses and Dissertations

Porphyromonas gingivalis is a major etiological agent that is responsible for the cause and progression of periodontal diseases. The bacterium is exposed to various environmental conditions and oxidative stress conditions while it is in the oral cavity. So, P. gingivalis should have an efficient regulatory system in order to adjust and survive in the oral cavity. But little is known about the regulatory mechanisms that help the bacteria to survive in the oral cavity. So, it is essential to understand and characterize these regulatory mechanisms. The response and adaptation of P. gingivalis to environmental stress conditions occur at the level …

Synthesis And Computational Studies On Hiv-1 Integrase Inhibitors, Horrick Sharma

Theses and Dissertations (ETD)

HIV-1 integrase (IN) is essential for viral replication and offers a promising target for the development of anti-retroviral drugs. Two decades of extensive research has lead to the recent approval of raltegravir as the first IN inhibitor. Advancement of drug candidate elvitegravir, which is currently in Phase III clinical trial, has furthermore accelerated efforts against this potential target for combating HIV. However, the emergence of resistance against raltegravir and elvitegravir demands exploration of novel chemical scaffolds that could circumvent resistance against currently used HIV-1 IN inhibitors. With the goal of discovering new agents targeting HIV, a novel structural class of …

Microarray-Based Cancer Prediction Using Single Genes., Xiaosheng Wang, Richard Simon

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Although numerous methods of using microarray data analysis for cancer classification have been proposed, most utilize many genes to achieve accurate classification. This can hamper interpretability of the models and ease of translation to other assay platforms. We explored the use of single genes to construct classification models. We first identified the genes with the most powerful univariate class discrimination ability and then constructed simple classification rules for class prediction using the single genes.

RESULTS: We applied our model development algorithm to eleven cancer gene expression datasets and compared classification accuracy to that for standard methods including Diagonal Linear …

Hyperbaric Oxygen Therapy For Promoting Osseointegration Around Dental Implants In Heavy Smokers, Fardos N. Rizk, Nasser Shaheen

Dentistry

Objective: The purpose of this study is to evaluate the effect of hyperbaric oxygen (HBO) therapy on osseointegration of implants supporting mandibular overdenture in heavy smokers. Materials and Methods: Following two stage surgical protocol twelve completely edentulous male heavy smokers received implants placed bilaterally in the canine region to support mandibular overdenture. On the second day after the surgery patients were divided randomly into two equal groups. Patients of group I were placed on a protocol of five consecutive sessions of HBO therapy, while patients of group II received no therapy and served as control. Four months following the surgery …

Critical Evaluation Of The Use Of Dogs In Biomedical Research And Testing In Europe, Nina Hasiwa, Jarrod Bailey, Peter Clausing, Mardas Daneshian, Sándor Farkas, István Gyertyán, Robert Hubrecht, Werner Kobel, Goran Krummenacher, Marcel Leist, Hannes Lohi, Adám Miklósi, Frauke Ohl, Klaus Olejniczak, Georg Schmitt, Patrick Sinnett-Smith, David Smith, Kristina Wagner, James D. Yager, Joanne Zurlo, Thomas Hartung

Companion Animals as Laboratory Research Subjects Collection

Dogs are sometimes referred to as “man’s best friend” and with the increase in urbanization and lifestyle changes, dogs are seen by their owners as family members. Society expresses specific concerns about the experimental use of dogs, as they are sometimes perceived to have a special status for humans. This may appear somewhat conflicting with the idea that the intrinsic value of all animals is the same, and that also several other animal species are used in biomedical research and toxicology. This aspect and many others are discussed in an introductory chapter dealing with ethical considerations on the use of …

41st Annual Wku Student Research Conference, Student Research Council, Western Kentucky University

Student Research Conference Select Presentations

No abstract provided.

Combinatorial Effect Of Non-Steroidal Anti-Inflammatory Drugs And Nf-Κb Inhibitors In Ovarian Cancer Therapy, Luiz F. Zerbini, Rodrigo E. Tamura, Ricardo G. Correa, Akos Czibere, Jason Coideiro, Manoj Bhasin, Fernando M. Simabuco, Yihong Wang, Xuesong Gu, Linglin Li, Devanand Sarkar, Jin-Rong Zhou, Paul B. Fisher, Towia A. Libermann

Human and Molecular Genetics Publications

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor …

2011 Cancer Care Annual Report, Children's Mercy Hospital

Cancer Center Annual Reports

Annual report of cancer care and oncology services at the Children's Mercy Hospital, Kansas City MO, a pediatric medical center.

The Role Of The Pediatrican In The Effort To Prevent Congenital Malformations, Robert L. Brent Dr.

The Selected Works of Robert Brent

No

Design, Synthesis, Biological Evaluation And Metabolic Stability Studies Of Sigma Receptor Ligands, Rohit Bhat

Electronic Theses and Dissertations

Sigma receptors represent a unique family of proteins that includes two subtypes: sigma-1 and sigma-2. Sigma-1 receptors have been implicated in the behavioral and motivational effects of psychostimulants as well as in the pathophysiology of depression and Alzheimer's disease. Sigma-2 receptors are widely expressed on many tumor cells and they are believed to play an important role in tumor cell proliferation. Therefore, sigma receptors are attractive targets for developing pharmaceutical agents directed to the treatment of psychostimulant abuse, cancer, Alzheimer's disease as well as diagnostic agents for cancer and brain imaging. A derivatized 2(3H)-benzothiazolone, (3-(2-(azepan-1-yl)ethyl)-6-propylbenzo[ d]thiazol-2(3H)-one) was reported to have …

Mrna Transcript Quantification In Archival Samples Using Multiplexed, Color-Coded Probes, Patricia Reis, Levi Waldron, Rashmi S. Goswami, Wei Xu, Yali Xuan, Bayardo Perez-Ordonez, Patrick Gullane, Jonathan Irish, Igor Jurisica, Suzanne Kamel-Reid

Publications and Research

Background: A recently developed probe-based technology, the NanoString nCounter™ gene expression system, has been shown to allow accurate mRNA transcript quantification using low amounts of total RNA. We assessed the ability of this technology for mRNA expression quantification in archived formalin-fixed, paraffin-embedded (FFPE) oral carcinoma samples.

Results: We measured the mRNA transcript abundance of 20 genes (COL3A1, COL4A1, COL5A1, COL5A2, CTHRC1, CXCL1, CXCL13, MMP1, P4HA2, PDPN, PLOD2, POSTN, SDHA, SERPINE1, SERPINE2, SERPINH1, THBS2, TNC, GAPDH, RPS18) in 38 samples (19 paired fresh-frozen and FFPE oral carcinoma tissues, archived from 1997-2008) by both NanoString and SYBR Green I fluorescent dye-based quantitative …

Egyptian Body Size: A Regional And Worldwide Comparison, Michelle H. Raxter

USF Tampa Graduate Theses and Dissertations

Human body size and limb proportions can provide important information about adaptation, population movements, and health disparities. This study investigated changes in body size and limb proportions of adult Egyptians temporally and geographically in relation to climatological, sociopolitical and economic developments. It was predicted that Egyptian groups that experienced more environmental stress would be shorter and exhibit less sexual dimorphism. It was also predicted that Egyptians would be intermediate between higher and lower latitude populations in body form and limb length ratios. The main skeletal sample consisted of 492 males and 528 females, all adults from the Predynastic and Dynastic …

Paleoepidemiology Of Intestinal Parasites And Lice In Pre-Columbian South America, Adauto Araujo, Karl Reinhard, Daniela Leles, Luciana Sianto, Alena M. Iñiguez, Martin Fugassa, Bernardo Arriaza, Nancy Orellana, Luis Fernando Ferreira

Karl Reinhard Publications

Some human parasites originated in prehominid ancestors in Africa. Nematode species, such as Enterobius vermicularis (pinworm), hookworms and Trichuris trichiura are shared by humans and other close phylogenetic primates (Pan and Gorilla), showing that they infected a common ancestor to this group. When humans migrated from Africa to other continents they carried these parasites wherever climate conditions allowed parasite transmission from host to host. Other parasites, however, were acquired throughout human biological and social evolutive history when new territories were occupied. Paleoparasitology data is a valuable source to recover emergence and disappearance of parasite infections through analysis of …

Activator Protein 1 (Ap-1) Contributes To Epcam-Dependent Breast Cancer Invasion, Narenda V. Sankpal, John D. Mayfield, Mike W. Willman, Timothy P. Fleming, William E. Gillanders

Open Access Publications

No abstract provided.

The Energy Landscape Analysis Of Cancer Mutations In Protein Kinases, Anshuman Dixit, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The growing interest in quantifying the molecular basis of protein kinase activation and allosteric regulation by cancer mutations has fueled computational studies of allosteric signaling in protein kinases. In the present study, we combined computer simulations and the energy landscape analysis of protein kinases to characterize the interplay between oncogenic mutations and locally frustrated sites as important catalysts of allostetric kinase activation. While structurally rigid kinase core constitutes a minimally frustrated hub of the catalytic domain, locally frustrated residue clusters, whose interaction networks are not energetically optimized, are prone to dynamic modulation and could enable allosteric conformational transitions. The results …

A New Hepato-Protective Flavone Glycoside From The Flowers Of Onopordum Alexandrinum Growing In Egypt, Maha Salama, Shahira Mohammed Ezzat

Pharmacy

A bioactivity-guided fractionation of the ethyl acetate fraction of the flowers of Onopordum alexandrinum L. (Asteraceae) yielded a new flavonoidal glycoside designated as acacetin-7-O-galacturonide (9), alongside with nine known flavonoids; 6-methoxy-apigenin (hispidulin) (1), acacetin (2), apigenin (3), luteolin (4), kaempferol (5), eriodictyol (6), apigenin-7-O-glucoside (7), luteolin-7-O-glucoside (8), and kaempferol-3-O-rutinoside (10). The compounds were assayed for their hepatoprotective activity against CCl4-induced hepatic cell damage in rats and free radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 4, 6, 9, and 10 have not been previously reported from flowers of O. alexandrinum L., and this is the first report of acacetin-7-O-galacturonide (9) in …

What Psychiatry, Developmental Psychology, And Neuroscience Can Teach Us About At- Risk Students, Eileen P. Ryan

Washington and Lee Journal of Civil Rights and Social Justice

No abstract provided.

The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B. Jekabsons, Tyler A. Johnson, Koneni V. Sashidhara, Phillip Crews, Dale G. Nagle, Yu-Dong Zhou

Natural Sciences and Mathematics | Faculty Scholarship

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound …

The Role Of Bcl-2 Modifying Factor (Bmf) In Airway Epithelial Cell Death, Amelia H. T. Unione

Biomedical Sciences ETDs

One of the components that obstruct the airway in asthma is the sudden and increased secretion of mucus from metaplastic mucous cells in small airways. Because previous studies have shown that the resolution of mucous cell metaplasia (MCM) during prolonged exposure of mice to allergen is mediated by IFN gamma and the Bcl-2 family of proteins, we investigated the regulation and the role of a pro-apoptotic BH3 domain-only protein, Bmf, in airway epithelial cells (AECs) treated with IFN gamma. We hypothesize that Bmf is crucial for IFN gamma-induced cell death. Our findings show that IFN gamma suppressed Bmf expression in …

Peripheral Taste System In Inbred Mouse Strains, William Wes Shelton

Theses and Dissertations (ETD)

Taster and non-taster mice strains have been used extensively in animal taste research. Inbred mouse strains C57 and FVB have been proposed to be tasters, where as strains 129 and Balb/C are classified as non-tasters. Therefore, evaluating the peripheral taste system in these mice is of great importance to determine if there are morphological differences that might explain the physiological classification. The purpose of the present study was to determine if inbred mice that have been shown to be tasters have a larger number of fungiform papillae, have larger fungiform papillae and have larger taste buds. My work in this …

Tdiscovery And Development Of Novel Therapeutic Agents For Advanced Melanoma, Zhao Wang

Theses and Dissertations (ETD)

Malignant melanoma is the most dangerous form of skin cancer and accounts for about 75% of skin cancer deaths. Once diagnosed at the metastatic stage, it has a very poor prognosis with a median survival rate of 6 months and a 5-year survival rate of less than 5%. In addition, melanoma has become an important public health hazard owing to its rising incidence, which has been well documented over the past 50 years. Currently there is no effective way to treat melanoma. It is highly resistant to existing chemotherapy, radiotherapy, and immunotherapy. Over the past 30 years, only two drugs …

Use Of Virtual Cell In Studies Of Cellular Dynamics, Leslie M. Loew, Boris M. Slepchenko

UCHC Articles - Research

The Virtual Cell (VCell) is a unique computational environment for modeling and simulation of cell biology. It has been specifically designed to be a tool for a wide range of scientists, from experimental cell biologists to theoretical biophysicists. The models created with VCell can range from the simple, to evaluate hypotheses or to interpret experimental data, to complex multi-layered models used to probe the predicted behavior of spatially resolved, highly non-linear systems. In this Chapter, we discuss modeling capabilities of VCell and demonstrate representative examples of the models published by the Virtual Cell users.

Development Of A Syngeneic Mouse Model Of Epithelial Ovarian Cancer, Bridget A. Quinn, Fang Xiao, Laura Bickel, Lainie Martin, Xiang Hua, Andres Klein-Szanto, Denise C. Connolly

Human and Molecular Genetics Publications

Background

Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies.

Methods

Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no …

2009 Cancer Care Annual Report, Children's Mercy Hospital

Cancer Center Annual Reports

Annual report of cancer care and oncology services at the Children's Mercy Hospital, Kansas City MO, a pediatric medical center. This report has a focus on acute lymphoblastic leukemia.

Sexually Transmitted Infections And Risk Of Prostate Cancer: Review Of Historical And Emerging Hypotheses., Siobhan Sutcliffe

Epidemiology Faculty Publications

No abstract provided.

The Role Of Presynaptic Dynamics In Processing Of Natural Spike Trains In Hippocampal Synapses, Umasankar Kandaswamy, Pan-Yue Deng, Charles F. Stevens, Vitaly A. Klyachko

Open Access Publications

No abstract provided.

Activation Of Metabotropic Glutamate Receptor 5 In The Amygdala Modulates Pain-Like Behavior, Benedict J. Kolber, Michael C. Montana, Yarimar Carrasquillo, Jian Xu, Stephen F. Heinemann, Louis J. Muglia, Robert W. Gereau Iv

Open Access Publications

No abstract provided.

A Novel Multifunctional Oligonucleotide Microarray For Toxoplasma Gondii, Amit Bahl, Paul H. Davis, Michael Behnke, Florence Dzierszinski, Manjunatha Jagalur, Feng Chen, Dhanasekaran Shanmugam, Michael W. White, David Kulp, David S. Roos

Open Access Publications

No abstract provided.

Synthesis, Characterization And Biological Activity Of Copper (Ii) And Zinc (Ii) Complexes Of Thiosemicarbazones And Their N(4)-Substituted Derivatives Derived From 2,4-Dihydroxybenzaldehyde., Tan Kong Wai

Student Works (2010-2019)

Four thiosemicarbazones ligands (1-4) have been prepared with good yield by refluxing 2,4-dihydroxybenzaldehyde with thiosemicarbazide or N(4)-substituted thiosemicarbazide in ethanol or methanol. From these four ligands, 16 new ternary metal complexes (5-20) with the general formulation of M(B)L have been prepared from the reactions of metal acetates with 2,4-dihydroxybenzaldehyde N(4)-substituted thiosemicarbazone in the presence of N,N-heterocyclic base (M2+ = Zn2+ or Cu2+; B = 2,2'-bipyridine, (bpy); 1,10-phenanthroline, (phen); L2- = doubly deprotonated thiosemicarbazones = 2,4-dihydroxybenzaldehyde thiosemicarbazonato, (HT); 2,4-dihydroxybenzaldehyde 4-methylthiosemicarbazonato, (HM); 2,4-dihydroxybenzaldehyde 4-ethylthiosemicarbazonato, (HE) and 2,4-dihydroxybenzaldehyde 4-phenylthiosemicarbazonato, (HP)) These compounds have been characterized by elemental analyses, IR, UV-Vis, NMR and magnetic …