Pharmacology Commons^™

Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular carcinoma (HCC) is one of the deadliest cancers, with variable presentation, high chemotherapy resistance and early tumor recurrence. In this dissertation, we have systematically enriched, identified and characterized HCC cancer stem cells (CSCs) from 3 different HCC cell lines (Hepa1-6, HepG2, and Hep3B) using in vitro serum-free culture method. Enriched spheroids acquired CSC properties, primarily self-renewal capability, spheroid formation ability, and drug resistance. Heterogeneous CSCs enriched from Hepa1-6 cells demonstrated higher tumor initiation and proliferation capability in vivo, compared to control HCC cells in orthotopic immunocompetent mouse model. EpCAM+ CSCs were significantly enriched within heterogeneous Hepa1-6 CSC spheroids. Consequently, …

A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease In Type 2 Diabetes., Qian Lin

Electronic Theses and Dissertations

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1^△HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1^△HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1^△HBS to 2-month-old db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and …

Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller

Electronic Theses and Dissertations

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …

The Role Of Perivascular Fibrosis In Post-Stroke Glymphatic Impairment And Cerebral Amyloid Angiopathy, Matthew D. Howe

Dissertations and Theses (Open Access)

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral …

Hiv Integrase Inhibitor Pharmacogenetics And Clinical Outcomes: An Exploratory Association Study, Derek E. Murrell

Electronic Theses and Dissertations

As HIV is now primarily a chronic condition, treatment is given life-long with changes as necessitated by alterations in tolerability and efficacy. Thus, personalized medicine may be useful in the prevention of unnecessary drug exposure and avoidable side effects. Three of the four currently available HIV integrase strand transfer inhibitors (INSTIs), raltegravir, elvitegravir, and dolutegravir, are widely utilized antiretrovirals in the USA and exhibit variations in outcomes among subjects. To interrogate differences among subjects receiving these drugs, we investigated the association of several single nucleotide polymorphisms (SNPs) with drug exposure, clinical outcomes, and subject-reported adverse events. HIV+ adults (≥18 years …

One-Compound-Two-Pharmacophores: Design, Synthesis And Antimalarial Activities Of Chloroquinoline-Cassiarin, Thobias M. Kalenga, Monica M. Ndoile, Quintino A. Mgani

Tanzania Journal of Science

This paper describes the design and synthesis of a potential antimalarial compound, chloroquinoline-cassiarin (6) using 4,7-dichloroquinoline and the natural product barakol (1) extracted from the leaves of Cassia siamea as starting materials. In this paper a one compound-two-pharmacophores concept is introduced in which coupling of two known pharmacophores into one has been described. The concept is not only useful to organic synthesis but also to drug development researches. The synthesized compound 6 exhibited potent in vitro antimalarial activity at IC50 = 0.51 µM, and low toxicity where at 20 µM, 80% viability of HeLa cells was observed.

Levels Of Heavy Metals In Deposited Dust And Soil From Selected Primary Schools In Dar Es Salaam, Joseph Yoeza Naimani Philip, Eliamini Ismail Mkenga, Othman Chande Othman

Tanzania Journal of Science

The objective of this study was to examine the levels of heavy metals, lead, manganese, nickel, copper, chromium and cadmium in standard one and kindergarten classroom dusts and playing ground soils from selected primary schools along Morogoro road highway (Kimara, Mbezi, Kibamba and Kiluvya primary schools) and away from Morogoro road highway (Makabe, Msumi and Mbopo primary schools) as well as in the Dar es Salaam city center (Uhuru, Mzimuni, Dr. Omari Ali Juma, Manzese and Ubungo National House primary schools), Tanzania. The samples were acid digested and the supernatant analyzed using inductively coupled plasma optical emission spectrometer (ICP-OES). The …

Levels Of Heavy Metals In Selected Facial Cosmetics Marketed In Dar Es Salaam, Tanzania, Joseph Yoeza Naimani Philip, Silvia John, Othman Chande Othman

Tanzania Journal of Science

The aim of this study was to determine the levels of heavy metals: lead, cadmium, copper, zinc, arsenic and mercury in facial cosmetics (lipstick, lip glossy, facial powder, foundation, eyeliner, eye shadow and mascara) which were purchased randomly in Dar es Salaam, Tanzania. The levels of lead, cadmium, copper and zinc were determined using Atomic Absorption Spectrometry (AAS). The levels of arsenic were determined using Hydride Generation Atomic Absorption Spectrometry (HGAAS), and levels of mercury were determined using Cold Vapour Atomic Absorption Spectrometry. Prior to determination of the concentration of heavy metals, the samples were acid digested. The average order …

Anti-Tumor Activity Of Phenoxybenzamine And Its Inhibition Of Histone Deacetylases, Mario A. Inchiosa

NYMC Faculty Publications

The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several "off label" indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact …

Off-Target Based Drug Repurposing Using Systems Pharmacology, Brent M. Kuenzi

USF Tampa Graduate Theses and Dissertations

The goal of this study was to identify novel drug repurposing opportunities in cancer by utilizing the off-target profiles of clinically relevant kinase inhibitors. This was based on the observation that the global target profiles of compounds are largely ignored and that many compounds have activity that cannot be explained by their cognate target alone. Additionally, by utilizing clinically relevant compounds, any results would hold a high potential for eventual clinical implementation. We utilized a systems pharmacology approach utilizing cell viability-based drug screening to identify compounds with beneficial off-target activity and then using chemical and phosphoproteomics in order to elucidate …

Radical Social Ecology As Deep Pragmatism: A Call To The Abolition Of Systemic Dissonance And The Minimization Of Entropic Chaos, Arielle Brender

Student Theses 2015-Present

This paper aims to shed light on the dissonance caused by the superimposition of Dominant Human Systems on Natural Systems. I highlight the synthetic nature of Dominant Human Systems as egoic and linguistic phenomenon manufactured by a mere portion of the human population, which renders them inherently oppressive unto peoples and landscapes whose wisdom were barred from the design process. In pursuing a radical pragmatic approach to mending the simultaneous oppression and destruction of the human being and the earth, I highlight the necessity of minimizing entropic chaos caused by excess energy expenditure, an essential feature of systems that aim …

Systematic Pan-Cancer Analysis Of Somatic Allele Frequency., Liam Spurr, Muzi Li, Nawaf Alomran, Qianqian Zhang, Paula Restrepo, Mercedeh Movassagh, Chris Trenkov, Nerissa Tunnessen, Tatiyana Apanasovich, Keith A Crandall, Nathan Edwards, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Imbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA). We analyzed the allele frequency in the context of the variant and gene functional features and linked it with changes in …

Combined Mtor And Mek Inhibition Is An Effective Therapy In A Novel Mouse Model For Angiosarcoma, Michelle L. Chadwick, Adam Lane, Dana Thomas, Amanda R. Smith, Angela R. White, Dominique Davidson, Benjamin Feng, Elisa Boscolo, Yi Zheng, Denise M. Adams, Anita Gupta, Andre Veillette, Lionel M L Chow

Peer Reviewed Articles

Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little is known about its molecular pathology and clinical trials have been extremely difficult to conduct. Development of animal models for rare diseases like angiosarcoma is critical to improve our understanding of tumorigenesis and to test novel treatment regimens. A genetically engineered mouse model for angiosarcoma was generated by conditional deletion of Trp53, Pten, and Ptpn12 in …

Melatonin-Micronutrients Osteopenia Treatment Study (Mots): A Translational Study Assessing The Effects Of Melatonin, Strontium Citrate, Vitamin D3 And Vitamin K2 On Bone Density, Bone Turnover Markers And Health-Related Quality Of Life In Postmenopausal Osteopenic Women Following A One-Year Double-Blind Randomized Placebo-Controlled Trial And On Osteoblast-Osteoclast Co-Cultures, Sifat Maria

Electronic Theses and Dissertations

Objective: The purpose of this study was to assess if a novel combination of melatonin and three other natural bone-aiding micronutrients: strontium citrate, vitamins D₃ and K₂ (MSDK) could improve bone health by modulating the activity of osteoblasts and osteoclasts in favor of balanced bone remodeling and by improving the overall health-related quality of life in postmenopausal osteopenic women.

Methods: The Melatonin-micronutrients Osteopenia Treatment Study (MOTS) is a translational research study that used both clinical and in vitro approaches to assess the efficacy of MSDK on bone health in women and to identify potential mechanisms for its effects. …

Disruption Of Neonatal Cardiomyocyte Physiology Following Exposure To Bisphenol-A., Manelle Ramadan, Meredith Sherman, Rafael Jaimes, Ashika Chaluvadi, Luther Swift, Nikki Gillum Posnack

Pharmacology and Physiology Faculty Publications

Bisphenol chemicals are commonly used in the manufacturing of polycarbonate plastics, polyvinyl chloride plastics, resins, and thermal printing applications. Humans are inadvertently exposed to bisphenols through contact with consumer products and/or medical devices. Recent reports have shown a link between bisphenol-a (BPA) exposure and adverse cardiovascular outcomes; although these studies have been limited to adult subjects and models. Since cardiac physiology differs significantly between the developing and adult heart, we aimed to assess the impact of BPA exposure on cardiac function, using a neonatal cardiomyocyte model. Neonatal rat ventricular myocytes were monitored to assess cell viability, spontaneous beating rate, beat …

Assessment Of Heavy Metal And Radioactivity Levels In Spinach (Spinacia Oleracea) Grown At Bahi Wetlands In Dodoma Region, Najat K. Mohammed, Boniface Haule

Tanzania Journal of Science

This study reports on the levels of heavy metals and radionuclides in Spinach (Spinacia oleracea) grown in Bahi wetlands in Dodoma Region. The farm soil in Bahi wetland has been reported to contain elevated concentrations of 238U, 232Th and 40K due to the existence of shallow uranium deposit in the area. In this study, spinach (Spinacia oleracea) grown in three zones of Bahi district were analyzed for heavy metals and radioactivity associated with the uranium deposit in the area. The concentrations of elements were determined by Energy Dispersive X-ray Analysis (EDXRF) of Tanzania Atomic Energy Commission, Arusha. The activities of …

Heavy Metals And Cyanide Distribution In The Villages Surrounding Buzwagi Gold Mine In Tanzania, Edwin Sifuel Gomezulu, Agnes Mwakaje, Jamidu, H.Y. Katima

Tanzania Journal of Science

The study aimed at assessing the levels of heavy metals and cyanide in water and sediments in villages surrounding Buzwagi gold mine, both during wet and dry seasons.  A total of 56 samples of water (28 from each season) and 44 samples of sediments (22 from each season) were collected from the wells in the area and were analyzed for total cyanide and heavy metals.  The total cyanide was analyzed spectrophotometrically whilst the heavy metals were analyzed by an Inductively Coupled Plasma (ICP). The Pb and Fe levels in water were found to exceed 10 µg/L and 2000 µg/L respectively, …

Levels Of Heavy Metals In Drinking Water, Cosmetics And Fruit Juices From Selected Areas In Dar Es Salaam, Tanzania, John Am Mahugija

Tanzania Journal of Science

Heavy metals were determined in samples of drinking water, cosmetics (nail polish, lip glosses and hair dye) and fresh fruit juices in Dar es Salaam. The samples were analyzed using Atomic Absorption Spectrometry (AAS) after digestion with concentrated acids, filtration and dilution. Lead, zinc and iron were detected in the water samples and the concentration ranges were below detection limit (BDL) to 0.114, 0.01 to 1.47 and 0.027 to 0.39 mg/L, respectively, whereas cadmium was not detected. The concentrations of lead in 70.83% of the samples exceeded the WHO permissible limit, implying that the water in most of the areas …

Status Of Selected Heavy Metals Dispersion From Top Soil In And Around Automobile Workshop Areas In Zanzibar Municipality, Tanzania, John Am Mahugija, Hawa M Sheikh

Tanzania Journal of Science

The distributions of selected heavy metals in top soil in areas with and without automobile workshops in Zanzibar municipality were investigated. Sampling was done during dry and rainy seasons. The samples were digested with aqua regia (HCl and HNO3, 3:1) and analysed by Atomic Absorption Spectrophotometry. The concentrations of zinc, copper and lead in the samples ranged 0.27–419.2, 0.10–167 and 0.02–271 mg/kg dry weight, respectively. The concentrations were higher in areas with automobile workshops than those without. The concentrations of the heavy metals were highest at point sources and decreased with increase in distance during the dry season. The concentrations …

Investigation Of P-Glycoprotein (Pgp) Induction By Pgp Substrates To Induce Paclitaxel Resistance In Ovarian Cancer Cells, Ryker Penn

Theses & Dissertations

The purpose of this study was to investigate the development of chemotherapeutic resistance to paclitaxel in ovarian cancer cells after treatment with drugs that are substrates for P-glycoprotein (PGP). A core concept of this experiment was to identify if PGP substrate drugs could also act as PGP inducers after prolonged treatment in SKOV-3 ovarian cancer cells. In order to test this, SKOV-3 cells were exposed to either fexofenadine, a PGP substrate used as an antihistamine, or the chemotherapeutic drug vinblastine. After 42 days of drug treatment, ABCB1 gene expression was measured by qRT-PCR. Analysis of ABCB1 expression in treated cells …