Medical Pharmacology Commons^™

Development Of Dna Vaccination Approach For Tumor Immunotargeting, Nathaniel Sangster

Summer Training Program in Cancer Immunotherapy

The emergence of immunotherapy as a prominent modality to treat cancer is a crucial advancement in the fight against this devastating disease. Although DNA vaccines against cancer have not been effective in treating pre-existing tumors, this approach holds much promise particularly for the activation of immune responses to specific mutant antigens responsible for tumorigenesis. Recent studies demonstrated that Q209L point mutation in the GNAQ (and GNA11) is responsible for the development of more than 70% of uveal melanomas and pre-malignant cutaneous blue nevus in humans. Based on the epitope prediction, we hypothesized that DNA vaccination with mutant GNAQ may result …

Reversal By Rarα Agonist Am580 Of C-Myc-Induced Imbalance In Rarα/Rarγ Expression During Mmtv-Myc Tumorigenesis, Almudena Bosch, Silvina P. Bertran, Yongke Lu, Avalon Garcia, Alexis M. Jones, Marcia I. Dawson, Eduardo F. Farias

Pharmacology, Physiology and Toxicology

Introduction

Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in …

Development Of Natural Cyclic Peptide Inhibitors Of Xrcc4/Xlf Interaction For Radio-Sensitization Of Breast Tumor Cells, Mohaini Mohammed Al

Theses and Dissertations

Breast cancer is the second leading cause of cancer death in women according to the American Cancer Society. The standard treatment regimen for breast cancer involves ionizing radiation combined with surgery and chemotherapy. Ionizing radiation induces a complex signaling response in cells resulting in either growth arrest, senescence or cell death, and the cell killing after exposure to radiation results largely from DNA double-strand breaks (DSBs). There are two main mechanisms in mammalian cells responsible for repairing the DSBs; the primary mechanism is non-homologous end joining (NHEJ) and the secondary mechanism is homologous recombination (HRR). Previous studies showed that breast …

Cell Death And Growth Arrest Pathways Mediating The Actions Of Stilbene 5c In Hct-116 Colon Cancer Cells, Moureq Alotaibi

Theses and Dissertations

Abstract The stilbene derivative, cis-3, 4’, 5-trimethoxy-3’-aminostilbene (stilbene 5c), is a potentially potent antitumor agent that acts via binding to the colchicine-binding pocket in microtubules. Earlier studies have shown that stilbene 5c induces cell death in ovarian cancer cells and leukemic cells. The present study was designed to investigate the effectiveness of this microtubule poison against the HCT-116 human colon cancer cell line and its mechanisms of action. Time course studies demonstrated that stilbene 5c produces a biphasic decrease in cell viability. The capacity of the cells to proliferate was not restored upon removal of the drug after 6 days …

Treatment Options For Vasomotor Symptoms In Menopause: Focus On Desvenlafaxine., Elena M Umland, Laura Falconieri

College of Pharmacy Faculty Papers

Vasomotor symptoms (VMS), including hot flashes and night sweats, occur in as many as 68.5% of women as a result of menopause. While the median duration of these symptoms is 4 years, approximately 10% of women continue to experience VMS as many as 12 years after their final menstrual period. As such, VMS have a significant impact on the quality of life and overall physical health of women experiencing VMS, leading to their pursuance of treatment to alleviate these symptoms. Management of VMS includes lifestyle modifications, some herbal and vitamin supplements, hormonal therapies including estrogen and tibolone, and nonhormonal therapies …

Visualizing Spatiotemporal Dynamics Of Apoptosis After G1 Arrest By Human T Cell Leukemia Virus Type 1 Tax And Insights Into Gene Expression Changes Using Microarray-Based Gene Expression Analysis., Mariluz Araínga, Hironobu Murakami, Yoko Aida

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Human T cell leukemia virus type 1 (HTLV-1) Tax is a potent activator of viral and cellular gene expression that interacts with a number of cellular proteins. Many reports show that Tax is capable of regulating cell cycle progression and apoptosis both positively and negatively. However, it still remains to understand why the Tax oncoprotein induces cell cycle arrest and apoptosis, or whether Tax-induced apoptosis is dependent upon its ability to induce G1 arrest. The present study used time-lapse imaging to explore the spatiotemporal patterns of cell cycle dynamics in Tax-expressing HeLa cells containing the fluorescent ubiquitination-based cell cycle …

Healthy Volunteer Registries And Ethical Research Principles, Erine A. Kupetsky-Rincon, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The dual enrolling of phase I volunteers is a potential risk to subjects. It can also distort study results, threaten study validity, and possibly cause harm to future patients. Existing subject registries differ in structure, funding, and governance. Although the choice of the ideal system is driven by the scope of the risk and the funding mechanism, and is ultimately a value judgment of freedom versus paternalism, none of the registries significantly impinges on the tenets of ethically based research.

Frecuencia De Leptospira Spp En Porcinos De Crianza Tecnificada Y De Traspatio Beneficiados En Dos Mataderos De Lima, Luis Anampa V., Hermelinda Rivera G., Nestor Falcon P., Mariluz Araínga, Mercy Ramirez V.

Journal Articles: Pharmacology & Experimental Neuroscience

The objective of this study was to determine the frequency of antibodies against Leptospira spp in pigs reared in five well-managed farms (n = 163) and from 11 backyard breeding (n = 133) owners in the valley Lima, Peru. Blood samples (n=296) were collected in two slaughterhouses for antibody detection against eight serovars of Leptospira by microaglutination test. The 85.8 ± 3.9% (254/296) of samples had antibodies against one or more serovars of Leptospira. . The 89.6 ± 4.7% (146/163) and 82.1 ± 6.5% (108/133) of samples from well-managed farms and from backyard breeding pigs showed antibodies against Leptospira spp. …

Phosphorylation Of Vasodilator-Stimulated Phosphoprotein Ser239 Suppresses Filopodia And Invadopodia In Colon Cancer., David S Zuzga, Joshua Pelta-Heller, Peng Li, Alessandro Bombonati, Scott A Waldman, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

In colorectal cancer, the antitumorigenic guanylyl cyclase C (GCC) signalome is defective reflecting ligand deprivation from downregulation of endogenous hormone expression. Although the proximal intracellular mediators of that signal transduction system, including cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), are well characterized, the functional significance of its distal effectors remain vague. Dysregulation of ligand-dependent GCC signaling through vasodilator-stimulated phosphoprotein (VASP), an actin-binding protein implicated in membrane protrusion dynamics, drastically reduced cGMP-dependent VASP phosphorylation levels in colorectal tumors from patients. Restoration of cGMP-dependent VASP phosphorylation by GCC agonists suppressed the number and length of locomotory (filopodia) and invasive (invadopodia) …

The Antinociceptive Effects Of Alpha 7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators In Different Animal Pain Models, Kelen Freitas

Theses and Dissertations

The α7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system (CNS) and in the periphery. Positive allosteric modulators (PAMs) of the α7 increase the response to an agonist and are divided into two types depending on whether they also decrease desensitization of the receptor (type II) or not (type I). Therefore, this study aims to investigate whether the enhancement of endogenous α7 nAChR function will result in a beneficial effect in nociceptive, inflammatory and chronic neuropathic pain models. While NS1738 and PNU-120596 were not active to reduce acute thermal pain, measured by hot-plate and tail-flick …

Inhibition Of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations And Ca2+ Dysregulation In Aged Rats, Diana M. Sama, Hafiz Mohmmad Abdul, Jennifer L. Furman, Irina A. Artiushin, David E. Szymkowski, Stephen W. Scheff, Christopher M. Norris

Graduate Center for Gerontology Faculty Publications

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits …

Methodological Challenges And Clinical Applications Of Hair Cortisol Analysis, Evan W. Russell

Electronic Thesis and Dissertation Repository

This thesis examines methodological and clinical aspects of hair cortisol analysis. The methodological study examines the role of sweat as a contributor to hair cortisol concentrations. Hair cortisol analysis is an effective measure of chronic stress. Cortisol is assumed to enter the hair via blood, sebum, and sweat, however the extent to which sweat contributes to hair cortisol content was unknown. This study concluded that human sweat contains cortisol that likely contributes to hair cortisol content. Subjects with prolonged sweating at the time of hair collection may have increased hair cortisol concentrations that cannot be decreased with conventional laboratory washing …

Synaptic And Intrinsic Activation Of Gabaergic Neurons In The Cardiorespiratory Brainstem Network, Julie G. Frank, David Mendelowitz

Pharmacology and Physiology Faculty Publications

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in …

Radiation Sensitization Of Breast Cancer Cells By Vitamin D Through The Promotion Of Autophagic Cell Death, Eden Wilson

Theses and Dissertations

Radiation therapy is a widely used tool in cancer therapy and is frequently offered as the first line of treatment for cancers of the breast. While radiotherapy is often initially effective in killing tumor cells or suppressing their growth, there are factors that confer tumor cell resistance to irradiation. Development of resistance may lead to disease recurrence despite the use of surgery, chemotherapy and radiation therapy. A primary goal of the studies in Dr. Gewirtz’s laboratory is to develop strategies to overcome resistance to radiation (and chemotherapy) in breast cancer, with the ultimate goal of preventing or attenuating disease recurrence. …

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

Dissertations & 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 …

Is Less Really More?: Determining The Efficacy And Advantages Of Low Dose Chemotherapy, Natalie Toews

Senior Honors Theses

Chemotherapy is the preferred treatment for patients with breast cancer nationwide; however, the dosage and duration of this treatment have come under recent scrutiny. The efficacy of high dose chemotherapy is many times inadequate, and the adverse physical effects resulting from this regimen have a negative holistic impact on the patients. Studies suggest that low dose chemotherapy, through antiangiogenesis, affects the spread of breast cancer carcinomas and may produce less harmful side effects in relation to the heart, brain, and eyes. Thus, oncological research proposes that a low dose regimen improves the patient’s quality of life and may be an …

Mitogen Activated Protein Kinase Phosphatase-1 Prevents The Development Of Tactile Sensitivity In A Rodent Model Of Neuropathic Pain, Christian Ndong, Russell P. Landry, Joyce A. Deleo, Edgar A. Romero-Sandoval

Dartmouth Scholarship

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of …

Hydrogen Sulfide As An Allosteric Modulator Of Atp Sensitive Potassium Channels In Colonic Inflammation., Aravind Gade

Theses and Dissertations

The ATP sensitive potassium channel (KATP) in mouse colonic smooth muscle cell is a complex containing a pore forming subunit (Kir6.1) and a sulfonyl urea receptor subunit (SUR2B). These channels are responsible for maintaining the cellular excitability of the smooth muscle cell which in turn regulates the motility patterns in the colon. We used whole-cell voltage-clamp techniques to study the alterations in these channels in smooth muscle cells in experimental model of colitis (colonic inflammation). Colitis was induced in BALB/C mice following an intracolonic administration of trinitrobenzene sulfonic acid (TNBS). KATP currents were measured at Vh -60 mV in high …

Molecular Staging Individualizing Cancer Management, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, ∼30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. J. Surg. Oncol. 2012; 105:468-474. © 2012 Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

Cosmetic Neurology: Enhancement Of The Mind And Attention Deficit Hyperactive Disorder Medication Abuse Among College Students, Mary M. Huff

Senior Honors Theses

Cosmetic neurology is becoming increasingly popular, and it is not just sleep deprived, over worked college students who are interested. People are beginning to seek off-label prescriptions for medications that are typically used to treat disorders such as attention deficit hyperactive disorder (ADHD) or narcolepsy, while researchers are trying to create drugs used solely for mind enhancement purposes. Along with these drugs come many legal and ethical quandaries relating to the regulation of current use as well as the what ifs of future possibilities. A survey was conducted among college students regarding the diagnosis of ADHD, the abuse of ADHD …