Pharmacology, Toxicology and Environmental Health Commons^™

Sensitization Of Human Cancer Cells To Gemcitabine By The Chk1 Inhibitor Mk-8776: Cell Cycle Perturbation And Impact Of Administration Schedule In Vitro And In Vivo, Ryan Montano, Ruth Thompson, Injae Chung, Huagang Hou, Nadeem Khan, Alan Eastman

Dartmouth Scholarship

Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.

Liposomal Fasudil, A Rho-Kinase Inhibitor, For Prolonged Pulmonary Preferential Vasodilation In Pulmonary Arterial Hypertension, Vivek Gupta, Nilesh Gupta, Imam H. Shaik, Reza Mehvar, Ivan F. Mcmurty, Masahiko Osa, Eva Nozik-Grayck, Fakhrul Ahsan

Pharmacy Faculty Articles and Research

Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were …

Androgen Receptor-Target Genes In African American Prostate Cancer Disparities, Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas W. Jarrett, Harold A. Frazier, Steven R. Patierno, Norman H. Lee

Pharmacology and Physiology Faculty Publications

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …

Asbestos Risk Assessment In Pakistan: Current Scenario And Way Forward, Adeel Ahmed Khan, Asaad Ahmed Nafees, Zafar Fatmi

Community Health Sciences

No abstract provided.

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Collected Faculty Scholarship

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

Health Disparities Experienced By People With Disabilities In The Us: A Behavioral Risk Factor Surveillance System Study, Jennifer Renee Pharr, Timothy J. Bungum

Environmental & Global Health Faculty Research

The Americans with Disabilities Act became law in 1990; since then research has shown that people with disabilities continue to experience barriers to health care. The purpose of this study was to compare utilization of preventive services, chronic disease rates, and engagement in health risk behaviors of participants with differing severities of disabilities to those without disabilities. This study was a secondary analysis of 2010 data collected in the Behavioral Risk Factor Surveillance System national survey in the United States. Rao Chi square test and logistic regression were employed. Participants with disabilities had significantly higher adjusted odds ratios for all …

Increased Geranylgeranylated K-Ras Contributes To Antineoplastic Effects Of Farnesyltransferase Inhibitors., Mandy A. Hall

Dissertations and Theses (Open Access)

The Ras family of small GTPases (N-, H-, and K-Ras) is a group of important signaling mediators. Ras is frequently activated in some cancers, while others maintain low level activity to achieve optimal cell growth. In cells with endogenously low levels of active Ras, increasing Ras signaling through the ERK and p38 MAPK pathways can cause growth arrest or cell death. Ras requires prenylation – the addition of a 15-carbon (farnesyl) or 20-carbon (geranylgeranyl) group – to keep the protein anchored into membranes for effective signaling. N- and K-Ras can be alternatively geranylgeranylated (GG’d) if farnesylation is inhibited but are …

Chemosensitization Of Hepatocellular Carcinoma To Gemcitabine By Non-Invasive Radiofrequency Field-Induced Hyperthermia, Mustafa Raoof

Dissertations and Theses (Open Access)

Gemcitabine is a potent nucleoside analogue against solid tumors however drug resistance rapidly emerges. Removal of gemcitabine incorporated in the DNA by repair mechanisms could potentially contribute to resistance in chemo-refractory solid tumors. In this study, we evaluated homologous recombination repair of gemcitabine-stalled replication forks as a potential mechanism contributing to resistance. We also studied the effect of hyperthermia on homologous recombination pathway to explain the previously reported synergy between gemcitabine and hyperthermia. We found that hyperthermia degrades and inhibits localization of Mre11 to gemcitabine-stalled replication forks. Furthermore, gemcitabine-treated cells that were also treated with hyperthermia demonstrate a prolonged passage …

Binding Efficacy Of Different Polyphenolic Phytochemicals With Β-Lactoglobulin And Human Serum Albumin: Implication For Therapeutics Against Neurodegenerative Diseases, Rene Duran^, Andres Ortiz^, Mahesh Narayan*, Vladik Kreinovich*

COURI Symposium Abstracts, Spring 2012

No abstract provided.

Preventing Mother-To-Child Transmission Of Human Immunodeficiency Virus-1 (Hiv-1): Effects Of Intrapartum And Neonatal Single-Dose Nevirapine Prophylaxis And Subsequent Hiv-1 Drug Resistance At Antiretroviral Treatment Initiation, Amanda L. Harmon

CMC Senior Theses

The prevention of mother-to-child transmission is one of the most powerful tools in human immunodeficiency virus type 1 (HIV-1) prevention and has huge potential to improve both maternal and child health. In the absence of any preventative measures, infants born to and breastfed by their HIV-positive mothers have roughly a one-in-three chance of acquiring the infection themselves. HIV can be passed on from mother-to-child during pregnancy, during labor and delivery, and even after during breastfeeding.

Intrapartum and neonatal single-dose nevirapine (sd-NVP) is the foundation of preventing mother-to-child transmission in lower resource settings where it has been used alone or as …

Overuse Of Antibiotics In Children For Upper Respiratory Infections (Uris): A Dilemma, Malika Taufiq, Rukhsana Wamiq Zuberi

Department for Educational Development

No abstract provided.

When Curiosity Kills More Than The Cat: The Perils Of Unchecked Scientific Inquiry, Jamie Shannon

Pomona Senior Theses

This work analyzes the ecological, physical, emotional and health impacts of the US nuclear testing done in the Marshall Islands in the mid-20th century.

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asiaderived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the …

A Comparison Of Fluoroquinolones Versus Other Antibiotics For Treating Enteric Fever: Meta-Analysis, Durrane Thaver, Anita K. M. Zaidi, Julia Critchley, Asma Azmatullah, Syed Ali Madni, Zulfiqar Ahmed Bhutta

Department of Paediatrics and Child Health

Objectives: To review evidence supporting use of fluoroquinolones as first line agents over other antibiotics for treating typhoid and paratyphoid fever (enteric fever).
Design: Meta-analysis of randomised controlled trials. Data sources: Cochrane Infectious Diseases Group specialised register, CENTRAL (issue 4, 2007), Medline (1966-2007), Embase (1974-2007), LILACS (1982-2007), selected conferences, reference lists, and ongoing trial register (November 2007).
Review methods: Trials comparing fluoroquinolones with chloramphenicol, cephalosporins, or azithromycin in culture-proven enteric fever were included. Two reviewers extracted data and assessed methodological quality. Odds ratios with 95% confidence intervals were estimated. Trials recruiting over 60% children were analysed separately from trials on …

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Collected Faculty Scholarship

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

A Watershed Analysis Of Salmon Lake And Mcgrath Pond: Implications For Water Quality And Land Use Management, Colby Environmental Assessment Team, Colby College, Problems In Environmental Science Course (Biology 493), Colby College

Colby College Watershed Study: Salmon Lake and McGrath Pond (2009, 1993)

In the summer and fall of 2009, the Colby Environmental Assessment Team (CEAT) studied the water quality of Salmon Lake and McGrath Pond, located in the Belgrade Lakes Region of Maine. The physical, chemical and biological characteristics of water quality were measured and analyzed to evaluate the current health of these lakes. Water quality data collected during the summer and fall of 2009 were compared with data from previous years to study the historic water quality trends. Land use patterns in the Salmon/McGrath watershed were also examined to investigate their impact on the lake water quality. The water quality trends …

Ecological Niche Of The 2003 West Nile Virus Epidemic In The Northern Great Plains Of The United States, Michael Wimberly, Michael B. Hildreth, Stephen P. Boyte, Erik Lindquist, Lon Kightlinger

United States Public Health Resources

Background: The incidence of West Nile virus (WNv) has remained high in the northern Great Plains compared to the rest of the United States. However, the reasons for the sustained high risk of WNv transmission in this region have not been determined. To assess the environmental drivers of WNv in the northern Great Plains, we analyzed the county-level spatial pattern of human cases during the 2003 epidemic across a seven-state region.
Methodology/Principal Findings: County-level data on WNv cases were examined using spatial cluster analysis, and were used to fit statistical models with weather, climate, and land use variables as predictors. …

Genome-Wide Compensatory Changes Accompany Drug Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Collected Faculty Scholarship

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …

Biodosepr-2006 Consensus Committee Report On Biodosimetric Methods To Evaluate Radiation Doses At Long Times After Exposure, Steven L. Simon, Ian Bailiff, André Bouville, Paola Fattibene, Ruth A. Kleinerman, David C. Lloyd, Stephen W.S. Mckeever, Alexander Romanyukha, Alexander V, Sevan’Kaev, James D. Tucker, Albrecht Wieser

Uniformed Services University of the Health Sciences

The requirements for biodosimetric techniques used at long times after exposure, i.e., 6 months to more than 50 years, are unique compared to the requirements for methods used for immediate dose estimation. In addition to the fundamental requirement that the assay measures a physical or biologic change that is proportional to the energy absorbed, the signal must be highly stable over time to enable reasonably precise determinations of the absorbed dose decades later. The primary uses of these biodosimetric methods have been to support long-term health risk (epidemiologic) studies or to support compensation (damage) claims. For these reasons, the methods …

Accumulation Of Phycotoxins In The Mussel Mytilus Galloprovincialis From The Central Adriatic Sea, Maja Pavela-Vrančić, Ivana Ujević, Živana Ninčević Gladan, Ambrose Furey

Physical Sciences Publications

Surveys of DSP (Diarrheic Shellfish Poisoning) toxin profiles in the mussel Mytilus galloprovincialis from coastal waters of the central Adriatic Sea, over the years 1995 to 2001, demonstrate that incidents of shellfish toxicity in this area are dominated by the occurrence of okadaic acid (OA) and a PTX derivative, 7-epi-pectenotoxin-2-seco acid (7-epi-PTX-2SA). Toxin composition and the relative ratio of toxic components in shellfish is in correlation with the occurrence of DSP producing organisms from the Dinophysis species along with Prorocentrum micans and Lingulodinium polyedrum. The occurrence of D. sacculus shortly before the appearance of OA in shellfish implicates its possible …

Historical Development Of The Linear Nonthreshold Dose-Response Model As Applied To Radiation, Ronald L. Kathren

The University of New Hampshire Law Review

[Excerpt] "Despite the nearly universal adoption of the linear nonthreshold dose response model (LNT) as the primary basis for radiation protection standards for the past half century, the LNT remains highly controversial and a contentious topic of discussion among health physicists, radiation biologists, and other radiological scientists. Indeed, it has been pointed out that the LNT has assumed the status of a paradigm, synonymous with an ideal, standard, or paragon or perhaps to some, a sacred cow. Reduced to its very basics, the LNT postulates that every increment of ionizing radiation dose, however small, carries with it a commensurate increase …

Workplace Pollution: Nuclear Safety, Ethics, And The Exploitation--Avoidance Argument, Kristin Shrader-Frechette

RISK: Health, Safety & Environment (1990-2002)

The author reviews evidence of poor worker health and safety practices in United States Department of Energy nuclear facilities in contending that less protective standards for workplace hazards constitute an environmental injustice not rectified by a hazard pay premium.

Over A Decade Of Comparative Risk Analysis: A Review Of The Human Health Rankings, David M. Konisky

RISK: Health, Safety & Environment (1990-2002)

The author reviews a method for undertaking a cross-project comparison of comparative risk analyses to understand which environmental problem areas have been cited most as often posing the severest risks.

Escherichia Coli O157:H7 In Free-Ranging Deer In Nebraska, David G. Renter, Jan M. Sargeant, Scott E. Hygnstrom, Jeff D. Hoffmann, Jerry R. Gillespie

School of Natural Resources: Faculty Publications

In order to determine the prevalence and distribution of the human pathogen, Escherichia coli O157:H7, in free-ranging deer, hunters were asked to collect and submit fecal samples from deer harvested during a regular firearm season (14–22 November 1998). Prior to the season, 47% of the hunters with permits in the southeastern Nebraska (USA) study area indicated a willingness to participate in the study. Approximately 25% of successful hunters in the area submitted deer fecal samples. Escherichia coli O157:H7 was cultured from four (0.25%) of 1,608 total samples submitted. All of the fecal samples that were properly identified (1,426) and all …

Media Coverage Of Epa's Draft Dioxin Reassessment Report, Sharon M. Friedman, Megan A. Fitzpatrick, Brenda P. Egolf

RISK: Health, Safety & Environment (1990-2002)

Using content analysis, the authors examine the utility of news media in democratic decision making.

Review Of: National Research Council, Issues In Risk Assessment, Diane M. Albert

RISK: Health, Safety & Environment (1990-2002)

Review of: National Research Council, Issues in Risk Assessment (National Academy Press). Appendices, executive summary, figures, preface, references, tables. LC 92-61838; ISBN 0-309-04786-2. [374 pp. Paper $37.50 - S&H, $4 for first and $0.50 for each additional copy. 2101 Constitution Avenue, NW, Washington DC 20418.]

Review Of: M. Stuart Madden, Toxic Torts Deskbook, Laura Marron

RISK: Health, Safety & Environment (1990-2002)

M. Stuart Madden, Toxic Torts Deskbook (Lewis Publishers 1992). Acknowledgements, case index, general index, notes, preface. LC 91-48238; ISBN 0- 87371-508-X. [230 pp. Cloth $69.95 domestic, $84.00 elsewhere. 2000 Corporate Boulevard, NW, Boca Raton FL 33431.]Review of:

Policy For Identifying And Assessing The Health Risks Of Toxic Substances, Maine Bureau Of Health

Maine Collection

Policy for Identifying and Assessing the Health Risks of Toxic Substances

by Norman T. Anderson, Environmental Toxicology Program, Division of Disease Control, Bureau of Health (February, 1988).

Contents: Section I: Introduction / Section II: Methods / Section III: Exposure Assessment / Section IV: Hazard Identification / Section V: Hazard Assessment / Section VI: Risk Characterization / List of Figures / List of Tables

The Great Potato Debate, James D. Hudson

Honors Theses

Anencephaly and spina bifida cystica are two of the most common severe congenital malformations consistently observed in human populations. Both represent defects in the neural tube and share a significant number of similar epidemiological associations among them, occupational class, geography, sex ratio, maternal age, year and season of the year. In anencephaly most of the brain and upper skull never form usually resulting in death within a few hours of birth. Spina bifida cystica is a malformation of the spinal cord often causing paralysis, vulnerability to infection, and early death. In 1972, Dr. J.H. Renwick presented a controversial hypothesis which …