Pharmacology, Toxicology and Environmental Health Commons^™

Lead Identification Of Β-Lactam And Related Imine Inhibitors Of The Molecular Caperone Heat Shock Protein 90, Niamh O'Boyle, Andrew Js Knox, Trevor P. Price, D. Clive Williams, Daniela M. Zisterer, David G. Lloyd, Mary J. Meegan

Articles

Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the identification of inhibitors based on β-lactam and imine templates. β-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC₅₀ values of 5.6 μM, 14.5 μM and 22.1 μM respectively. The binding affinity displayed …

Synthesis, Biochemical And Molecular Modelling Studies Of Antiproliferative Azetidinones Causing Microtubule Disruption And Mitotic Catastrophe, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Niall O. Keely, Andrew Js Knox, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC₅₀ value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for …

Adding Value To Ecological Risk Assessment With Population Modeling, Valery E. Forbes, Peter Calow, Volker Grimm, Takehiko I, Hayashi, Tjalling Jager, Agnete Katholm, Annemette Palmqvist, Rob Pastorok, Dan Salvito, Richard Sibly, Julann Spromberg, John Stark, Richard A. Stillman

Valery Forbes Publications

Current measures used to estimate the risks of toxic chemicals are not relevant to the goals of the environmental protection process, and thus ecological risk assessment (ERA) is not used as extensively as it should be as a basis for cost-effective management of environmental resources. Appropriate population models can provide a powerful basis for expressing ecological risks that better inform the environmental management process and thus that are more likely to be used by managers. Here we provide at least five reasons why population modeling should play an important role in bridging the gap between what we measure and what …

Genotoxin-Induced Acetylation Of The Werner Syndrome Protein (Wrn) And Effect On Its Dna Metabolic Function, Enerlyn Meliza Lozada Santiago

University of Kentucky Doctoral Dissertations

Loss of function of the WRN protein causes the genetic disorder Werner Syndrome that is characterized by increased cancer and premature aging. WRN belongs to the RecQ helicase family that plays key roles in preventing genome instability. In response to treatment with genotoxins, WRN is subject to post-translational modification. The relationship of post-translational modification of WRN with its function in DNA metabolism is unknown. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA replication. Consistent with this notion, WS cells are sensitive to DNA replication inhibitors and DNA damaging agents …

Anaplasmataceae As Human Pathogens : Biology, Ecology And Epidemiology, Marina E. Eremeeva, Gregory A. Dasch

Environmental Health Sciences: Faculty Publications

This review describes the biology, ecology, and epidemiology of known human pathogens in the family Anaplasmataceae that are transmitted by ticks and belong to the genus Anaplasma and genus Ehrlichia. We discuss the current status of diagnosis and surveillance of the diseases they cause, and address the challenges and new perspectives raised due to continuous recognition of new emerging human pathogens in the family Anaplasmataceae.

Identification Of Activities Involved In Cag/Ctg Repeat Instability, Nelson Lap Shun Chan

University of Kentucky Doctoral Dissertations

CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction.

Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged …

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.

Mycotoxins In Grains – Causes, Prevention And Control, Hester F. Vismer

INTSORMIL Presentations

Discusses mycotoxins, their effect on grain, mitigation considerations, and resulting human toxicology.

Pharmacokinetic Evaluation Of The Blood: Tissue Relationship In Poultry: Screening For Antibiotic Residues In Chicken Muscle, Ixchel Reyes Herrera

Graduate Theses and Dissertations

During their life, humans are exposed to numerous substances that are naturally present in the environment or that are the result of man made processes, including heavy metals, persistent organic pollutants, pesticides and veterinary drugs. Some of these substances can leave residues in food products and possibly expose consumers to their potential toxic effects. To address these problems extensive regulatory efforts are devoted to prevent, detect and control these substances from reaching the food supply. However, given the vast diversity of food products that requires monitoring and the immense diversity of potential chemical contaminants, the need for an efficient and …

Exhausted Or Unlicensed: Can Field-Of-Use Restrictions In Biotech License Agreements Still Prevent Off-Label Use Promotion After Quanta Computer?, Kristal M. Wicks

The University of New Hampshire Law Review

[Excerpt] “In the biotechnology (biotech) industry, companies must be increasingly aware of their intellectual property and how their licensing strategies can impact their rights. When licensing patented technology, it is common practice for biotech companies to include restricted field-of-use provisions in their license agreements. Such provisions permit a licensee to only use licensed technology in a defined field and restrict use or development in another field. This licensing strategy plays an important role within the biotech industry because it allows companies to more effectively control their intellectual property and to more efficiently research and develop pharmaceutical products.

A problem that …

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 …

Anticancer And Antifungal Activity Of Copper(Ii) Complexes Of Quinolin-2(1h)-One-Derived Schiff Bases, Bernadette S. Creaven, Brian Duff, Denise A. Egan, Kevin Kavanagh, Georgina Rosair, Venkat Reddy Thangella, Maureen Walsh

Articles

The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2–14). The copper(II) complexes (2a–14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, ¹H and ¹³C NMR, AAS, UV–Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate …

Comparison Of Bacteroides Human Markers For Pollution Diagnostics In Recreational Waters, Asli Aslan, Joan B. Rose

Environmental Health Sciences: Faculty Presentations (2010-2017)

This presentation was given during the Great Lakes Beach Association Annual Conference.

Invernaderos: La Búsqueda Por El Trabajo Estable Y Seguro Y Un Medioambiente En Peligro, Elli Matkin

Independent Study Project (ISP) Collection

This research is intended to discuss the rapid development of the “invernaderos” (greenhouses) on the coast of Spain and to expose both the social and environmental repercussions of such a massive agricultural project. The data was gathered through the use of both secondary sources and primary research. The author conducted a number of interviews both on the coast, in Motril and Carchuna, and inland in Granada city -- discussing the subject with owners of “invernaderos”, pesticide sellers, and cooperative workers.

The main conclusion of this research is that while the work of “invernaderos” is a security for many agricultural families …

Pesticide Use And Awareness On Pemba Island, Brooke Shorett, Lauren Crask

Independent Study Project (ISP) Collection

Use and awareness of pesticides by 301 farmers on Pemba Island, Tanzania, were surveyed, in order to assess practices and perceptions of pesticide use. Surveys were conducted in both peri-urban farms and rural farms, which were either irrigated or rain-fed. Results showed that while the overwhelming majority of farmers on irrigated fields used pesticides frequently, farmers located in rain-fed irrigation largely farmed without pesticides. Likewise, peri-urban farmers made use of pesticides far more than rural farmers. Of the farmers who did use pesticides, an average of Tsh 17,219 was spent annually on Rogol, Satunil, Dimethoate, Simithion, Thionex and Dursban. Most …

Aluminium Phosphide Poisoning: A Case Report, Shela Akbar Ali Hirani, Arshalooz Rahman

School of Nursing & Midwifery

This paper reports the case of a family in which three children were presented at Emergency Room (ER) with poisoning after the use of a pesticide at home. Initially, the cases were managed as routine cases of organophosphorus poisoning; however, the death of two children made the health team members realise that the poison's effects were delayed and devastating. Later, the compound was identified as Aluminium Phosphide (ALP), and the life of the last surviving child in the family was saved.

Using Photoactive Vitamin Nanoparticles As Photodynamic Antimicrobial Chemotherapeutic (Pact) Agents To Treat Chronic Wounds, Rahul A. Khanke

All Capstone Projects

The objective of the proposed study is to develop new materials and methods to manage microbial growth in chronic wounds using phototherapy. Chronic wounds are considered as a worldwide health problem. The most common chronic wounds can be classified into three categories: venous ulcers, diabetic ulcers, and pressure ulcers. Venous ulcers, which usually occur in the legs, account for about 70% to 90% of chronic wounds and can become infected easily. Venous ulcers are sores that develop after veins in the legs have been damaged. These ulcers can penetrate deeply into the skin. Occasionally, if a venous ulcer persists for …

Tactical Research Fund – Asfb 2009 Workshop, Department Of Fisheries

Fisheries Occasional Publications

Biodiversity of aquatic ecosystems – What to measure and monitor for fisheries and ecosystem management FRDC Project No. 2008/353.

Trace Metal Concentrations Across Trophic Levels In Cotton Fields Of Xinjiang Province, China, Jessica Quinn

All Student Theses and Dissertations

Trace metals become concentrated in urban and peri-urban soils with the use of agricultural practices and industrial emissions. Fertilizers, liming, sewage sludge, and irrigation water contain metals which accumulate in agricultural fields and pose a risk to humans and wildlife. Coal plants and brickyards release metals into the atmosphere which are deposited on soil and plant surfaces. This research quantifies the concentrations of nine trace metals in three different soil types. A total of 116 rodents were sampled in cotton fields and a desert. Cotton plants and triplicate soil samples were collected with each rodent capture. Soil samples were analyzed …

Ecological Risk Assessment Should Be Value-Relevant But Not Value-Biased, Peter Calow, Valery E. Forbes

Valery Forbes Publications

To be useful in informing environmental management decisions, ecological risk assessments (ERAs) need to be expressed in value-relevant terms (USEPA 2009). Making decisions about accepting more or less ecological resources for more or less economic and social gain depends upon public values. ERAs have been criticized for not delivering value-relevant results and for therefore not being useful as a basis for management decisions (Gibbs 2010). We agree that ERAs need to be value-relevant, but we also must be explicit about what constitutes science and what constitutes values in this process. In a recent editorial, Backhaus et al. (2010) discuss the …