Medicinal Chemistry and Pharmaceutics Commons^™

Exploration Of Cancer Proliferative Signaling In Chemotherapy Drug Resistance And Mdig-Induced Tumorigenesis, Kai Wu

Wayne State University Dissertations

ABSTRACT

EXPLORATION OF CANCER PROLIFERATIVE SIGNALING IN CHEMOTHERAPY DRUG RESISTANCE AND MDIG-INDUCED TUMORIGENESIS

by

KAI WU

August 2016

Advisor: Dr. Fei Chen

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Aberrant intracellular signaling pathway is one of the major driving forces of malignancy through multiple stages of human cancers. Our study demonstrates that in cancer cells, the signaling pathways are profoundly and actively intertwined with each other so they can synergistically affect cell biology, including promoting development of malignancy and compensating the loss of proliferation or survival signals in responses to anti-tumor drug. Moreover, cancer cells can also adopt “non-canonical” mechanisms …

Mechanisms Of Pancreatic Beta Cell Dysfunction In Diabetes, Vaibhav Sidarala

Wayne State University Dissertations

Diabetes is a serious medical condition characterized by decreased insulin secretion from pancreatic β-cells and decreased insulin sensitivity in the peripheral tissues, resulting in elevated levels of blood glucose. According to the International Diabetes Federation, about 387 million cases have been reported worldwide in the year 2013 and it is estimated that about 500 million people would be affected by 2050. Type 2 diabetes, which accounts for about 90% of the total number of cases, is caused by decreased insulin sensitivity in the peripheral tissues and decreased glucose-stimulated insulin secretion from the pancreatic β-cells. The underlying mechanisms involved in β-cell …

The Effectiveness Of A Preoperative Multimodal Antiemetic Regimen On Reducing Early Postoperative Nausea And Vomiting In Total Joint Arthroplasty Patients, Jerry Mosley

Doctoral Projects

Postoperative nausea and vomiting (PONV) occurs frequently in all types of surgeries including after total joint orthopedic procedures. The resulting PONV can lead to many unwanted occurrences including immobilization, distress, and many serious adverse health complications. These unwanted occurrences may then lead to increased cost to the patient and healthcare facility. Administration of a preoperative multimodal regimen known to reduce PONV has the potential to reduce such unwanted anesthetic side effects influencing a reduction in overall healthcare cost. The purpose of this study is to determine the effectiveness of the preoperative kit which includes the administration of metoclopramide, famotidine, ondansetron, …

Street Drug Markets Beyond Favelas In Belo Horizonte, Brazil, Elenice De Souza Oliveira, Braulio Figueiredo Alves Silva, Marcos Oliveira Prates

Department of Justice Studies Faculty Scholarship and Creative Works

This study examines whether social disorganization mechanisms that explain clusters of street drug markets in socially disorganized neighborhoods in developed countries can also help explain geographical patterns of drug dealing across neighborhoods in Belo Horizonte, Brazil. Data for this study includes drug arrests from 2007 to 2011 and socio demographic data from the 2010 Census. To examine the influence of exploratory variables on drug market locations, the Negative Binominal regression model was used at two levels of analysis—the Belo Horizonte city center and other neighborhoods including favelas. The findings show that a high hot spot of street drug markets located …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Anticancer Activity Of Some Boronic Acid Arylidene Heterocycles, Joy Kim

Honors Theses

This research was done in order to investigate the anticancer activity of boronic acid arylidene heterocycles. Boronic acid, heterocycles, and aryl compounds have all independently exhibited various anti-microbial properties and have shown potential to be used in pharmaceuticals for the treatment of viruses and cancers. Using a one-step protocol developed by Dr. Murray, several different arylheterocyclic compounds were combined with an arylboronic acid to synthesize novel compounds. These were then tested for their anti-cancer activity on glioblastoma brain cancer cells. Although varied in potency, all had some amount of anti-cellular effect on the cancer cells. This is only the start …

Lack Of Resistance Of Plasmodium Falciparum To Dihydroartemisinin In Uganda Based On Parasitogolgical And Molecular Assays, Roland A. Cooper, Melissa D. Conrad, Quentin D. Watson, Stephanie J. Huezo, Harriet Ninsiima, Patrick Tumwebaze, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

• Artemisinin-­‐based combination therapy is now standard treatment for falciparum malaria. However, this regimen is threatened by resistance to artemisinins, manifest as delayed clearance of parasitemia after therapy, in southeast Asia.

• Artemisinin resistance in southeast Asia is associated with increased parasitemias in culture, compared to those in sensi0ve parasites, 72 hours a=er a 6 hour pulse with 700 nM dihydroartemisinin (DHA), and with propeller domain polymorphisms in the Plasmodium falciparum kelch (K13; PF3D7_1343700) gene

• Given that artemether/lumefantrine has been adopted as standard therapy for malaria within the last decade in Uganda, we characterized artemisinin sensiBvity in fresh P. falciparum isolates from …

  ---

  Go to article

Mutations In The Plasmodium Falciparum Chloroquine Resistance Transporter, Pfcrt, Enlarge The Parasite's Food Vacuole And Alter Drug Sensitivities, Serena Pulcini, Henry M. Staines, Andrew H. Lee, Sarah H. Shafik, Guillaume Bouyer, Catherine M. Moore, Daniel A. Daley, Matthew J. Hoke, Lindsey M. Altenhofen, Heather J. Painter, Jianbing Mu, David J. P. Ferguson, Manuel Llinas, Rowen E. Martin, David A. Fidock, Roland Cooper, Sanjeev Krishna

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction …

Development Of Polymer Peptide Conjugates For Enhanced Pancreatic Cancer Imaging, Wen Shi

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US with very poor prognosis. All clinically available biomarkers and diagnostic tools either fail to detect early stage PDAC or suffer from low specificity and sensitivity. There is an urgent need for diagnostic agents with greater efficacy for PDAC detection and staging. Nanomaterials such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers can effectively target tumors, and offer novel opportunities for the development of effective diagnostic agents for cancer. However, a major problem of many nanomaterials-based diagnostics is their opsonization and sequestration by the mononuclear phagocyte system (MPS), leading …

Macrophage Uptake And Cytotoxicity Of Paclitaxel Nanocrystals, Deborah Lee, Emeri Zhang, Wei Gao, Tonglei Li

The Summer Undergraduate Research Fellowship (SURF) Symposium

Effective drug delivery remains one of the most challenging tasks in combatting cancer cells. Anti-cancer drugs such as Paclitaxel (PTX) often struggle in having a high drug effect because they are often phagocytized by macrophages in Reticuloendothelial System (RES) before reaching the cancer cells. To combat this problem, PTX was inserted in a nanocrystal, coated with non-ionic surfactant F68; it is speculated that this formulation will minimize the particle aggregation and decrease the cellular uptake in the RES, which will increase the overall efficacy of the drug in the target areas. The aim of this project was to compare the …

Lack Of Artemisinin Resistance In Plasmodium Falciparum In Uganda Based On Parasitological And Molecular Assays, Roland A. Cooper, Melissa D. Conrad, Quentin D. Watson, Stephanie J. Huezo, Harriet Ninsiima, Patrick Tumwebaze, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

We evaluated markers of artemisinin resistance in Plasmodium falciparum isolated in Kampala in 2014. By standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (DHA). By the ring-stage survival assay, after a 6-h DHA pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. Two of 53 isolates had nonsynonymous K13-propeller gene polymorphisms but did not have the mutations associated with resistance in Asia. Thus, we did not see evidence for artemisinin resistance in Uganda.

Combating Infectious Diseases In Aquaculture With An Original Probiotic Product, Meagan Hamblin, Saebom Sohn, Christine Ahn Dao, Marta Gomez-Chiarri, David R. Nelson, David Worthen, David Rowley

Senior Honors Projects

Oyster production in Rhode Island accounts for over $2.5 million in annual revenue, making it the top aquaculture product in the state. However, larval tank infections significantly constrain production and create substantial economic losses for commercial hatcheries. In most cases antibiotics may not be used to prevent or treat larval tank infections. A probiotic, or beneficial microbe which competes with pathogens, is a safer and “green” approach to preventing infections. Vibriosis, a common cause of oyster larval mortality, is the result of Vibrio species infections. Previous studies have shown that a native Rhode Island microbe, Bacillus pumilus RI06-95, protects oyster …

Investigating The Bioactive Constituents Of The Edible Blue-Green Alga Spirulina Platensis, Georgette Appiah-Pippim

Honors Scholar Theses

More people die annually from cardiovascular disease than from any other cause. Two risk factors for cardiovascular disease are hyperlipidemia and inflammation. Current drugs that are prescribed to regulate lipid levels often have adverse effects such as liver dysfunction. Blue-green algae (BGA), also known as cyanobacteria, have been consumed for years for their health benefits because they are believed to increase energy and prevent disease. One genus of edible blue-green algae is Spirulina plantesis (SP, Spirulina). Various studies have shown that Spirulina may have anti-cancer and anti-inflammation and anti-bacterial properties. In a previous study, Spirulina platensis lowered triglyceride and cholesterol …

The Impact Of Stress History Of Deformable Dry Granules On The Mechanical Properties Of Tablets, Biplob K Mitra

Open Access Dissertations

A mechanistic understanding of the relationship among the granule composition, individual granule property, downstream robust processing, and the final tablet attributes is critical for rational development of a quality tablet. However, in the dry granulation literature, milled granules that are polydisperse in solid fraction, size, and shape are extensively used for compaction studies. Thus, the effect of an individual granule property or an individual component on the compaction properties of dry granules was not adequately separated. To advance the mechanistic understanding of the effect of dry granulation on tensile strength of tablets, individual granule properties such as size, solid fraction, …

Impact Of Antimalarial Treatment And Chemoprevention On The Drug Sensitivity Of Malaria Parasites Isolated From Ugandan Children, Patrick Tumwebaze, Melissa D. Conrad, Andrew Walakira, Norbert Leclair, Oswald Byaruhanga, Christine Nakazibwe, Benjamin Kozak, Jessica Bloome, Jaffer Okiring, Abel Kakuru, Victor Bigira, James Kapisi, Jennifer Legac, Jiri Gut, Roland A. Cooper, Moses R. Kamya, Diane V. Havlir, Grant Dorsey, Bryan Greenhouse, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. …

Increasing Expression Of Hepatitis B Surface Antigen In Maize Through Breeding, Erin Suzanne Miller

Master's Theses

The hepatitis B virus (HBV) is a common virus, with two billion people infected worldwide. It causes approximately 600,000 deaths each year, despite the availability of an effective vaccine since 1982. Maize as a platform for oral vaccination can supply a heat stable vaccine, which does not require syringes or trained personnel to administer. The Hepatitis B Surface antigen was transformed into maize and this seed was used to evaluate expression levels through the breeding process. The transgene was transferred into two elite maize inbreds by backcrossing. Highest expressing ears were selected each generation until approximately 99% commercial parent was …

Repeated Effects Of The Neurotensin Receptor Agonist Pd149163 In Three Animal Tests Of Antipsychotic Activity: Assessing For Tolerance And Cross-Tolerance To Clozapine, Shinnyi Chou, Collin Davis, Sean Jones, Ming Li

Department of Psychology: Faculty Publications

Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether …

Development Of Non-Traditional Platinum Anticancer Agents: Trans-Platinum Planar Amine Compounds And Polynuclear Platinum Compounds, Daniel E. Lee

Theses and Dissertations

Development of Non-Traditional Platinum Anticancer Agents: trans-Platinum Planar Amine Compounds and Polynuclear Platinum Compounds

By Daniel E. Lee, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015

Major Director: Nicholas P Farrell, Ph.D., Professor, Department of Chemistry

Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied …

A Retrospective Cohort Study Of High Prevalence Of St131 Among Extended Spectrum Β-Lactamase Producing E. Coli Among Inpatients In The Metropolitan Detroit Area, Pansy Awasthy

Wayne State University Theses

ABSTRACT

HIGH PREVALENCE OF ST131 AMONG EXTENDED SPECTRUM Β-LACTAMASE PRODUCING E. COLI AMONG INPATIENTS IN THE METROPOLITAN DETROIT AREA

by

PANSY AWSTHY

2015

Advisor: Dr. Emily T. Martin

Major: Pharmaceutical Sciences

Degree: Master of Science

Objectives: E.coli ST131 multi-locus sequence type (MLST) has been associated with extended spectrum β-lactamase (ESBL) production, conferring antimicrobial resistance, with increased virulence and with healthcare-associated infection. The high prevalence of multidrug antimicrobial resistance in ESBL-producing ST131 E.coli infections creates unique challenges in the studying patient outcomes and analysis are required to study ST131 E.coli amongst a large population of ESBL-producers. Our objective was to determine …

Protein Ubiquitination In Primary Human Skeletal Muscle Cells Under Hyperinsulinemic Hyperglycemic Conditions, Majed Abdullah Alharbi

Wayne State University Theses

Ubiquitin proteasome system is a relatively newly discovered pathway for protein degradation. Many studies have successfully pointed out the critical functions that UPS plays in regulating many physiological processes. On the other hand, recent studies suggested that abnormal UPS activities might be involved in the pathophysiology of several disorders including type 2 diabetes. However, the specific changes in UPS during the development of insulin resistance and consequently T2D are still unclear.

UPS is composed of two major steps, a reversible ubiquitin conjugation to the targeted substrate followed by proteasomal degradation of the ubiquitinated proteins. In this study, we examined the …