Medicine and Health Sciences Commons^™

Profile Of Veliparib And Its Potential In The Treatment Of Solid Tumors, Lars M. Wagner

Pediatrics Faculty Publications

Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small-molecule inhibitors of PARP appear most effective when used to treat tumors with underlying defects in DNA repair, or when combined with DNA-damaging agents. Veliparib is one of several recently developed oral inhibitors of PARP currently in clinical trials. This review summarizes the pharmacology, mechanisms of action, toxicity, and activity of veliparib seen in clinical trials to date. Also discussed are proposed mechanisms of resistance, potential biomarkers of activity, and issues regarding patient selection and combination therapies that may …

Hybrid Nanocrystals For Treatment And Bioimaging Of Disease, Tonglei Li

Pharmaceutical Sciences Faculty Patents

Hybrid nanocrystals able to reach specific targets in the body for treatment and biological imaging are provided, as well as methods of making and administering same for treatment of disease conditions and for bioimaging and radiotherapy. The hybrid nanocrystals and methods can be used alone or in combination with other treatment and imaging modalities.

Veraflo Negative Pressure Wound Therapy With Household Bleach For Refractory Driveline Infection In A Patient With Left Ventricular Assist Device., Amr Idris, Amanda Hart, Sarah Branam, Maya Guglin

The VAD Journal

Driveline infections and sepsis are amongst the most common causes of morbidity and mortality in a patient with a left ventricular assist device. In this case, we present a patient with a multi drug resistant pseudomonas aeruginosa driveline exit site infection. Initially, it was treated with dual antibiotics, followed by surgical debridement utilizing Dakin’s solution irrigation and standard negative pressure wound therapy. Wound healing was minimal determined by poor granulation appearance, unchanged size from surgical debridement, purulent drainage, and the wound base remained colonized with multi drug resistant pseudomonas aeruginosa. A novel treatment of VeraFlo negative pressure wound therapy in …

Targeted Dna Damage At Individual Telomeres Disrupts Their Integrity And Triggers Cell Death, Luxi Sun, Rong Tan, Jianquan Xu, Justin Laface, Ying Gao, Yanchun Xiao, Myriam Attar, Carola Neumann, Guo-Min Li, Bing Su, Yang Liu, Satoshi Nakajima, Arthur S. Levine, Li Lan

Markey Cancer Center Faculty Publications

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.

Smoking Duration, Respiratory Symptoms, And Copd In Adults Aged ≥45 Years With A Smoking History, Yong Liu, Roy A. Pleasants, Janet B. Croft, Anne G. Wheaton, Khosrow Heidari, Ann M. Malarcher, Jill A. Ohar, Monica Kraft, David M. Mannino, Charlie Strange

Preventive Medicine and Environmental Health Faculty Publications

BACKGROUND: The purpose of this study was to assess the relationship of smoking duration with respiratory symptoms and history of chronic obstructive pulmonary disease (COPD) in the South Carolina Behavioral Risk Factor Surveillance System survey in 2012.

METHODS: Data from 4,135 adults aged ≥45 years with a smoking history were analyzed using multivariable logistic regression that accounted for sex, age, race/ethnicity, education, and current smoking status, as well as the complex sampling design.

RESULTS:The distribution of smoking duration ranged from 19.2% (1-9 years) to 36.2% (≥30 years). Among 1,454 respondents who had smoked for ≥30 years, 58.3% were current …

Advances In The Management Of Gastrointestinal Cancers—An Upcoming Role Of Immune Checkpoint Blockade, Gaurav Goel, Weijing Sun

Internal Medicine Faculty Publications

Gastrointestinal cancers are a group of highly aggressive malignancies, and novel therapeutic strategies with higher clinical efficacy are being actively sought. 'Immunotherapy' is now emerging as one such promising strategy for the treatment of these tumors. This article briefly reviews the recent advances that utilize targeting of immune checkpoint pathways, in the management of gastrointestinal malignancies.

Crystal Structure Of O-Methyltransferase Calo6 From The Calicheamicin Biosynthetic Pathway: A Case Of Challenging Structure Determination At Low Resolution, Oleg V. Tsodikov, Caixia Hou, Christopher T. Walsh, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Calicheamicins (CAL) are enedyine natural products with potent antibiotic and cytotoxic activity, used in anticancer therapy. The O-methyltransferase CalO6 is proposed to catalyze methylation of the hydroxyl moiety at the C2 position of the orsellinic acid group of CAL.

RESULTS: Crystals of CalO6 diffracted non-isotropically, with the usable data extending to 3.4 Å. While no single method of crystal structure determination yielded a structure of CalO6, we were able to determine its structure by using molecular replacement-guided single wavelength anomalous dispersion by using diffraction data from native crystals of CalO6 and a highly non-isomorphous mercury derivative. The structure …

Zbtb20 Is A Sequence-Specific Transcriptional Repressor Of Alpha-Fetoprotein Gene, Hai Zhang, Dongmei Cao, Luting Zhou, Ye Zhang, Xiaoqin Guo, Hui Li, Yuxia Chen, Brett T. Spear, Jia-Wei Wu, Zhifang Xie, Weiping J Zhang

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Alpha-fetoprotein (AFP) represents a classical model system to study developmental gene regulation in mammalian cells. We previously reported that liver ZBTB20 is developmentally regulated and plays a central role in AFP postnatal repression. Here we show that ZBTB20 is a sequence-specific transcriptional repressor of AFP. By ELISA-based DNA-protein binding assay and conventional gel shift assay, we successfully identified a ZBTB20-binding site at -104/-86 of mouse AFP gene, flanked by two HNF1 sites and two C/EBP sites in the proximal promoter. Importantly, mutation of the core sequence in this site fully abolished its binding to ZBTB20 in vitro, as well …

B Lymphocytes Are Required During The Early Priming Of Cd4+ T Cells For Clearance Of Pneumocystis Infection In Mice, Michael M. Opata, Melissa L. Hollifield, Frances E. Lund, Troy D. Randall, Robert Dunn, Beth A. Garvy, David J. Feola

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B cells play a critical role in the clearance of Pneumocystis. In addition to production of Pneumocystis-specific Abs, B cells are required during the priming phase for CD4⁺ T cells to expand normally and generate memory. Clearance of Pneumocystis was found to be dependent on Ag specific B cells and on the ability of B cells to secrete Pneumocystis-specific Ab, as mice with B cells defective in these functions or with a restricted BCR were unable to control Pneumocystis infection. Because Pneumocystis-specific antiserum was only able to partially protect B cell–deficient mice from infection, we …

Modeling Of Mpges-1 Three-Dimensional Structures: Applications In Drug Design And Discovery, Chang-Guo Zhan, Xiaoqin Huang, Adel Hamza

Pharmaceutical Sciences Faculty Patents

This invention relates to representations of prostaglandin synthase three-dimensional structures. Such representations are suitable for designing agents that modulate the activity of the enzyme by binding to the substrate binding domain.

Medicaid Crowd-Out Of Other Public Health Spending: Modeling Economic & Health Effects, Glen P. Mays

Health Management and Policy Presentations

MOTIVATION: Thirty states are expanding Medicaid eligibility under the Affordable Care Act (ACA) as of 2015, and while federal funds cover most costs for newly eligible recipients, states must share the additional costs of covering previously-eligible state residents who enroll in Medicaid. States, together with their local government counterparts, also provide the vast majority (87%) of public sector funds for public health programs designed to promote health and prevent disease and injury on a population-wide basis. Fiscal constraints and generous federal matching funds create strong budgetary incentives for states to channel their health-related spending to Medicaid rather than to other …

Sex Differences In Clinical Features Of Early, Treated Parkinson's Disease, Erika F. Augustine, Adriana Pérez, Rohit Dhall, Chizoba C. Umeh, Aleksandar Videnovic, Franca Cambi, Anne-Marie A. Wills, Jordan J. Elm, Richard M. Zweig, Lisa M. Shulman, Martha A. Nance, Jacquelyn Bainbridge, Oksana Suchowersky

Neurology Faculty Publications

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial.

METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between …

Full-Range Public Health Leadership, Part 2: Qualitative Analysis And Synthesis, Erik L. Carlton, James W. Holsinger Jr., Martha C. Riddell, Heather Bush

Preventive Medicine and Environmental Health Faculty Publications

Public health leadership is an important topic in the era of U.S. health reform, population health innovation, and health system transformation. This study utilized the full-range leadership model in order to examine the public health leadership. We sought to understand local public health leadership from the perspective of local health department leaders and those who work with and for them. Public health leadership was explored through interviews and focus groups with directors (n = 4) and staff (n = 33) from local health departments. Qualitative analytic methods included reflexive journals, code-recode procedures, and member checking, with analysis facilitated …

Toll-Like Receptors And Dectin-1, A C-Type Lectin Receptor, Trigger Divergent Functions In Cns Macrophages, John C. Gensel, Yan Wang, Zhen Guan, Kyle A. Beckwith, Kaitlyn J. Braun, Ping Wei, Dana M. Mctigue, Phillip G. Popovich

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid …

Altered Lysosomal Proteins In Neural-Derived Plasma Exosomes In Preclinical Alzheimer Disease, Edward J. Goetzl, Adam Boxer, Janice B. Schwartz, Erin L. Abner, Ronald C. Petersen, Bruce L. Miller, Dimitrios Kapogiannis

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.

METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.

RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane …

Arm Dominance Does Not Influence Measures Of Scapular Muscle Strength And Endurance In Healthy Individuals, Joseph M. Day, Heather M. Bush, Arthur J. Nitz, Tim L. Uhl

Physical Therapy Faculty Publications

BACKGROUND PURPOSE: Scapular muscle performance is potentially influenced by arm dominance. The purpose of this study was to investigate the effect of arm dominance on clinical measures of scapulohumeral muscle strength and endurance.
METHODS: Thirty-two healthy individuals between the ages of 30 and 65 years were recruited to participate. Scapular muscle strength of the upper trapezius (UT), middle trapezius (MT), lower trapezius (LT), and serratus anterior (SA) were recorded with a hand held dynamometer. One scapulohumeral isometric muscle endurance task was performed in prone. The order of testing (strength and endurance) was randomized for each individual. Dominant to …

Regression Of Gastric Cancer By Systemic Injection Of Rna Nanoparticles Carrying Both Ligand And Sirna, Daxiang Cui, Chunlei Zhang, Bing Liu, Yi Shu, Tong Du, Dan Shu, Kan Wang, Fangping Dai, Yanlei Liu, Chao Li, Fei Pan, Yuming Yang, Jian Ni, Hui Li, Beate Brand-Saberi, Peixuan Guo

Markey Cancer Center Faculty Publications

Gastric cancer is the second leading cause of cancer-related death worldwide. RNA nanotechnology has recently emerged as an important field due to recent finding of its high thermodynamic stability, favorable and distinctive in vivo attributes. Here we reported the use of the thermostable three-way junction (3WJ) of bacteriophage phi29 motor pRNA to escort folic acid, a fluorescent image marker and BRCAA1 siRNA for targeting, imaging, delivery, gene silencing and regression of gastric cancer in animal models. In vitro assay revealed that the RNA nanoparticles specifically bind to gastric cancer cells, and knock-down the BRCAA1 gene. Apoptosis of gastric cancer cells …

Radiobiological Evaluation Of Intensity Modulated Radiation Therapy Treatments Of Patients With Head And Neck Cancer: A Dual-Institutional Study, G. Narayanasamy, A. P. Pyakuryal, S. Pandit, J. Vincent, C. Lee, P. Mavroidis, N. Papanikolaou, Mahesh Kudrimoti, T. T. Sio

Radiation Medicine Faculty Publications

In clinical practice, evaluation of clinical efficacy of treatment planning stems from the radiation oncologist's experience in accurately targeting tumors, while keeping minimal toxicity to various organs at risk (OAR) involved. A more objective, quantitative method may be raised by using radiobiological models. The purpose of this work is to evaluate the potential correlation of OAR-related toxicities to its radiobiologically estimated parameters in simultaneously integrated boost (SIB) intensity modulated radiation therapy (IMRT) plans of patients with head and neck tumors at two institutions. Lyman model for normal tissue complication probability (NTCP) and the Poisson model for tumor control probability (TCP) …

Can Dentistry Have Two Contracts With The Public?, David A. Nash

Oral Health Science Faculty Publications

The social contract is an implicit agreement between parts of society and society as a whole. Since the Middle Ages, the learned professions, recently including dentistry, have had a covenantal relationship with the public based on trust, exchanging monopoly privileges for benefiting the public good. Unlike commercial trade in commodities, professional relationships are grounded in ensuring an adequate level of oral health to all. A second contract is emerging where dentists relate to society as business operators, exchanging commodity services for a price. Recent actions by the Federal Trade Commission and the U.S. Supreme Court make it unlikely that dentistry …

Changes In Serum Strongylus Vulgaris-Specific Antibody Concentrations In Response To Anthelmintic Treatment Of Experimentally Infected Foals, Martin Krarup Nielsen, Jessica Scare, Holli Sullivan Gravatte, Jennifer Lynn Bellaw, Julio C. Prado, Craig Robert Reinemeyer

Maxwell H. Gluck Equine Research Center Faculty Publications

Strongylus vulgaris is the most pathogenic nematode parasite of horses. Its extensive migration in the mesenteric blood vessels can lead to life-threatening intestinal infarctions. Recent work has shown that this parasite is still identified among managed horse populations. A serum enzyme-linked immunosorbent assay (ELISA) has been developed for the detection of migrating larvae of S. vulgaris. Previous work has documented an increase in ELISA values following larvicidal treatment with ivermectin and suggested that the target parasite antigen is primarily produced by the later larval stages. The aim of this study was to experimentally inoculate cohorts of foals with S. …

The Effects Of Antiepileptic Inducers In Neuropsychopharmacology, A Neglected Issue. Part Ii: Pharmacological Issues And Further Understanding, Jose De Leon

Psychiatry Faculty Publications

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions.

The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic …

Role Of Mitochondria In Regulating Microrna Activity And Its Relevance To The Central Nervous System, Wang-Xia Wang, Joe E. Springer

Physical Medicine and Rehabilitation Faculty Publications

No abstract provided.

New Approach To Develop Ultra-High Inhibitory Drug Using The Power Function Of The Stoichiometry Of The Targeted Nanomachine Or Biocomplex, Dan Shu, Fengmei Pi, Chi Wang, Peng Zhang, Peixuan Guo

Pharmaceutical Sciences Faculty Publications

AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number.

METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui's Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population.

RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with …

Influence Of Linker Length And Composition On Enzymatic Activity And Ribosomal Binding Of Neomycin Dimers, Derrick Watkins, Sunil Kumar, Keith D. Green, Dev P. Arya, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The human and bacterial A site rRNA binding as well as the aminoglycoside-modifying enzyme (AME) activity against a series of neomycin B (NEO) dimers is presented. The data indicate that by simple modifications of linker length and composition, substantial differences in rRNA selectivity and AME activity can be obtained. We tested five different AMEs with dimeric NEO dimers that were tethered via triazole, urea, and thiourea linkages. We show that triazole-linked dimers were the worst substrates for most AMEs, with those containing the longer linkers showing the largest decrease in activity. Thiourea-linked dimers that showed a decrease in activity by …

Inhibition Of Aminoglycoside Acetyltransferase Resistance Enzymes By Metal Salts, Yijia Li, Keith D. Green, Brooke R. Johnson, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

Aminoglycosides (AGs) are clinically relevant antibiotics used to treat infections caused by both Gram-negative and Gram-positive bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn²⁺ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6')-Ib in Acinetobacter baumannii and Escherichia coli. In this study, we explore a wide array of metal salts (Mg²⁺, …

A Genetic Porcine Model Of Cancer, Lawrence B. Schook, Tiago V. Collares, Wenping Hu, Ying Liang, Fernanda M. Rodrigues, Laurie A. Rund, Kyle M. Schachtschneider, Fabiana K. Seixas, Kuldeep Singh, Kevin D. Wells, Eric M. Walters, Randall S. Prather, Christopher M. Counter

Toxicology and Cancer Biology Faculty Publications

The large size of the pig and its similarity in anatomy, physiology, metabolism, and genetics to humans make it an ideal platform to develop a genetically defined, large animal model of cancer. To this end, we created a transgenic "oncopig" line encoding Cre recombinase inducible porcine transgenes encoding KRAS^G12D and TP^53R167H, which represent a commonly mutated oncogene and tumor suppressor in human cancers, respectively. Treatment of cells derived from these oncopigs with the adenovirus encoding Cre (AdCre) led to KRAS^G12D and TP^53R167H expression, which rendered the cells transformed in culture and tumorigenic when engrafted into …

Low Neural Exosomal Levels Of Cellular Survival Factors In Alzheimer's Disease, Edward J. Goetzl, Adam Boxer, Janice B. Schwartz, Erin Abner, Ronald C. Petersen, Bruce L. Miller, Olga D. Carlson, Maja Mustapic, Dimitrios Kapogiannis

Sanders-Brown Center on Aging Faculty Publications

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer's disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer's disease neurotoxic proteins.

Liver-Fibrostard Checklist And Glossary: Tools For Standardized Design And Reporting Of Diagnostic Accuracy Studies Of Liver Fibrosis Tests, Jérôme Guéchot, Jérôme Boursier, Victor De Ledinghen, Thierry Poynard, Fabrice Carrat, Vincent Leroy, Grace Lai-Hung Wong, Mireen Friedrich-Rust, Mirella Fraquelli, Mario Plebani, Giada Sebastiani, Robert Myers, Paul Angulo, Sandrine Bertrais, Dominique Wendum, Ivan Bricault, Paul Calès

Internal Medicine Faculty Publications

No abstract provided.

Clinical Spectrum And Radiographic Features Of The Syndrome Of The Trephined, Cara L. Sedney, William Dillen, Terrence Julien

Neurosurgery Faculty Publications

OBJECT: Craniectomy is a common neurosurgical procedure. Syndrome of the trephined (ST) occurring after craniectomy results in neurologic symptoms that are reversible with cranioplasty. While well-documented, previous literature consisted of case reports, symptom spectrum and risk factors have not been well characterized.

MATERIALS AND METHODS: A retrospective review of 29 consecutive cases who underwent decompressive craniectomy within a 30-month period was performed. Patients were considered affected by ST if a previously stable neurological deficit improved within 3 weeks after cranioplasty. Prevalence of ST was measured and association with demographic information, clinical symptoms patterns, indication for and size of craniectomy, as …

Quality Of Life Of Parents Of Children With Asthma, Anna Trzcieniecka-Green, Kamilla Bargiel-Matusiewicz, Agnieszka Wilczyńska, Hatim A. Omar

Pediatrics Faculty Publications

An increased frequency of asthma in children has been lately observed. The course of asthma depends not only on treatment, but also on the actions taken by the parents of a sick child. Design: A non-experimental cross-sectional design. Methods: In this study the Pediatric Asthma Quality of Life Questionnaire (PACQLQ) and Satisfaction with Life Scale (SWLS) were administered to 60 parents of children with asthma. Two groups of parents were compared. The first group consisted of parents of children who had been diagnosed with asthma less than three months before the beginning of the study. The second group consisted of …