Medical Sciences Commons^™

Creation Of A Mouse With A Humanized Fpgs Gene Compatible With Normal Development, Linying Xie

Theses and Dissertations

Abstract: Folylpoly-γ-glutamate synthetase (FPGS) catalyzes the formation of polyglutamate forms of the reduced folates and antifolates such as methotrexate (MTX) and pemetrexed; this allows the retention of folates and antifolate cancer drugs inside the cell. The enzyme activity of FPGS is essential for cell proliferation and survival. The mouse fpgs gene contains two promoters spaced 10 kb apart which are activated in a tissue-specific manner. The upstream promoter (P1) and exons A1a and A1b are used in some differentiated tissues, mainly liver and kidney, whereas the downstream promoter (P2) and exon 1 are used in rapidly dividing cells. In contrast, …

Borderline Personality Disorder: An Overview Of History, Diagnosis And Treatment In Adolescents, Linah Al-Alem, Hatim A. Omar

Pharmacology and Nutritional Sciences Faculty Publications

Borderline personality disorder (BPD) is a cluster B personality disorder. It is characterized by erratic behaviors, emotional instability and one of its hallmarks is self injurious behavior, which starts in adolescence. Patients with BPD are difficult to treat, most have a history of child sexual abuse, about a quarter present with sexual abuse from a caretaker. Although personality disorders are diagnosed only in adults, BPD manifests itself in adolescence in the form of uncontrollable anger, self mutilations, dissociation and other such behaviors. Hence, there is a growing number of scientists discussing the possibility of diagnosing BPD in adolescents. Here, we …

Identification Of Pharmacological And Molecular Mechanisms Involved In Nicotine Withdrawal, Kia Jackson

Theses and Dissertations

Tobacco dependence is the leading cause of preventable death in the United States. Despite currently available smoking cessation therapies, there is a high rate of relapse in smoking among those attempting to quit. While the somatic signs of nicotine withdrawal (insomnia, increased appetite, weight gain) contribute to the continuation of smoking behavior, it has been hypothesized that the affective signs (depression, anxiety, craving, irritability) are greater motivators of relapse and continued tobacco use. There are few studies that assess the molecular and receptor-mediated mechanisms of nicotine withdrawal; therefore, our studies focus on identifying the nicotinic acetylcholine receptor (nAChR) subtypes and …

Overexpression Of Matrix Metalloproteinase 9 In Tumor Epithelial Cells Correlates With Colorectal Cancer Metastasis., David S Zuzga, Ahmara Vivian Gibbons, Peng Li, Wilhelm Johannes Lubbe, Inna Chervoneva, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Colorectal cancer mortality largely reflects metastasis, the spread of the disease to distant organs. Matrix metalloproteinase 9 (MMP-9) is a key regulator of metastasis and a target for anticancer strategies in colon cancer. Here, the overexpression of MMP-9 in pure tumor epithelial, but nor stromal, cell populations was associated with metastatic progression of colorectal cancer, as defined by reverse transcriptase-polymerase chain reaction (qRT-PCR) and confirmed by immunostaining. Thus, cancer cell MMP-9 represents a novel, selective prognostic and predictive factor that may be exploited for more effective disease stage stratification and therapeutic regimen selection in patients with colorectal cancer.

The Aryl Hydrocarbon Receptor Binds To E2f1 And Inhibits E2f1-Induced Apoptosis., Jennifer L Marlowe, Yunxia Fan, Xiaoqing Chang, Li Peng, Erik S Knudsen, Ying Xia, Alvaro Puga

Kimmel Cancer Center Faculty Papers

Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr(-/-) fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, gammaH2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of …

Promotion Of Tumor Cell Death Through The Induction Of, Tuyen Nguyen

Theses and Dissertations

Microtubule poisons have proven to be effective in the treatment of a variety of malignancies. Although taxol-based derivatives promote microtubule stabilization, there is continuing interest in compounds that, like colchicines, act as microtubule destabilizing agents. Previous work from this laboratory showed that the novel microtubule poison, JG- 03-14, was active against breast tumor cells, promoting autophagic cell death. In the current work, we studied the influence of JG-03-14 on p53 wild type HCT116 colon carcinoma cells. A crystal violet sensitivity assay indicated that JG-03-14 induced growth inhibition, with 75% suppression of growth evident at a concentration of 500 nM. Time …

El Virus De La Diarrea Viral En Bovinos Criollos De La Provincia De Melgar, Puno, Q. Richard Quispe, Ccama Albert S., Hermelinda G. Rivera, Mariluz Araínga

Journal Articles: Pharmacology & Experimental Neuroscience

The prevalence of bovine viral diarrhea virus (BVDV) infection in 347 evaluated was criollo cattle of both sexes and older than 6 months of age in small herds of the province of Melgar, Puno. Serum samples were tested for antibodies against BVDV using the viral neutralization test. The 48.7 ± 0.1% (166/347) of the samples had antibodies against BVDV. Animals carrying on the virus, virus were not detected. Antibodies were detected in all sampled herds and the prevalence varied from 15.7 to 94.1%. Antibodies titers varied from 2 to >256, showing that BVDV infection is widespread in the local cattle …

Enterotoxin Preconditioning Restores Calcium-Sensing Receptor-Mediated Cytostasis In Colon Cancer Cells, Giovanni Mario Pitari, Jieru E. Lin, Fawad J. Shah, Wilhelm J. Lubbe, David Zuzga, Peng Li, Stephanie Schulz, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), inhibits colorectal cancer cell proliferation by co-opting Ca(2+) as the intracellular messenger. Similarly, extracellular Ca(2+) (Ca(2+)(o)) opposes proliferation and induces terminal differentiation in intestinal epithelial cells. In that context, human colon cancer cells develop a phenotype characterized by insensitivity to cytostasis imposed by Ca(2+)(o). Here, preconditioning with ST, mediated by GCC signaling through cyclic nucleotide-gated channels, restored Ca(2+)(o)-dependent cytostasis, reflecting posttranscriptional regulation of calcium-sensing receptors (CaRs). ST-induced GCC signaling deployed CaRs to the surface of human colon cancer cells, whereas elimination of GCC signaling in mice nearly abolished …

Drug Overdose: A Wake Up Call! Experience At A Tertiary Care Centre In Karachi, Pakistan, Muhammad Junaid Patel, Muhammad Shahid, Mehmood Riaz, Waqaruddin Kashif, Syed Imran Ayaz, Muhammad Shoaib Khan, A. Jawwad Samdani, Ayesha L Sorathia, Muhammad Furqan

Department of Emergency Medicine

OBJECTIVE: To study the characteristics of patients admitted with drug overdose caused either by accidental overdose of the prescribed medications or as an act of deliberate self harm (DSH) at a tertiary care hospital in Karachi, Pakistan.METHODS: A retrospective case series review was conducted at the Aga Khan University Hospital from January 2002 to October 2006. Three hundred and twenty four adult patients admitted with drug overdose were included in the study.RESULTS: Our sample group revealed mean age of 36.2 +/- 17.0 years, more females (59%), housewives (34%), and students (20%). Fifty six percent of patients committing DSH were married …

Prescription Of Medicines By Medical Students Of Karachi, Pakistan: A Cross-Sectional Study, Syed Nabeel Zafar, Reema Syed, Sana Waqar, Faria A. Irani, Sarah Saleem

Community Health Sciences

Background: Prescription of medicines by non-doctors is an issue with serious global implications. To our knowledge prescription of drugs by medical and non-medical students has not been studied before. We aimed to determine the practice and attitudes of drug prescription by medical students and: a) how non-medical students respond to this practice, b) How this compares with the attitudes and practices of non-medical students. Methods: A cross-sectional study was conducted on a sample of 600 students randomly selected from 2 medical and 2 non-medical universities. Ethical requirements were ensured and data was collected using self administered questionnaires. The Chi square …

The Synthetic Triterpenoid Cddo-Methyl Ester Modulates Microglial Activities, Inhibits Tnf Production, And Provides Dopaminergic Neuroprotection, Thi A. Tran, Melissa K. Mccoy, Michael B. Sporn, Malú G. Tansey

Dartmouth Scholarship

Recent animal and human studies implicate chronic activation of microglia in the progressive loss of CNS neurons. The inflammatory mechanisms that have neurotoxic effects and contribute to neurodegeneration need to be elucidated and specifically targeted without interfering with the neuroprotective effects of glial activities. Synthetic triterpenoid analogs of oleanolic acid, such as methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me, RTA 402) have potent anti-proliferative and differentiating effects on tumor cells, and anti-inflammatory activities on activated macrophages. We hypothesized that CDDO-Me may be able to suppress neurotoxic microglial activities while enhancing those that promote neuronal survival. Therefore, the aims of our study were to identify specific …

Hpr6 Mutants And Uses Thereof, Rolf Joseph Craven

Pharmacology and Nutritional Sciences Faculty Patents

Methods and agents that interfere with Hpr6 function in non-sarcoma tumor cells are disclosed. Anti-Hpr6 agents are used to enhance the killing effect of anti-cancer agents in non-sarcoma tumor cells and to teat non-sarcoma tumors.

Composites Comprising Cholesterol And Carboxymethyl Cellulose, Vuk Uskoković

Pharmacy Faculty Articles and Research

Whereby cholesterol presents one of the major fatty substances in human body, carboxymethyl cellulose is a water-soluble derivative of cellulose, the most abundant dietary fiber. Whereas on one hand in vivo precipitation of cholesterol is the major cause of atherosclerosis, dietary fibers are on the other hand known for their ability to clean the fatty plaque deposited on intestinal pathways, and prevent its build-up in other critical areas within the organism. In this work, a method for the preparation of a composite material comprising cholesterol and carboxymethyl cellulose from 1-hexanol/water biphase mixtures is reported. Specificity of the interaction between the …

Morphine Exacerbates Hiv-1 Tat-Induced Cytokine Production In Astrocytes Through Convergent Effects On [Ca2+]I, Nf-Κb Trafficking And Transcription, Nazira El-Hage, Annadora J. Bruce-Keller, Tatiana Yakovleva, Igor Bazov, Georgy Bakalkin, Pamela E. Knapp, Kurt F. Hauser

Pharmacology and Toxicology Publications

Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-κB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-κB inhibitor parthenolide provided evidence that Tat±morphine-induced …

Long Lasting Synchronization Of Calcium Oscillations By Cholinergic Stimulation In Isolated Pancreatic Islets, Min Zhang, Bernard Fendler, Bradford Peercy, Pranay Goel, Richard Bertram, Arthur Sherman, Leslie Satin

Pharmacology and Toxicology Publications

Abstract

Individual mouse pancreatic islets exhibit oscillations in [Ca²⁺]_i and insulin secretion in response to glucose in vitro, but how the oscillations of a million islets are coordinated within the human pancreas in vivo is unclear. Islet to islet synchronization is necessary, however, for the pancreas to produce regular pulses of insulin. To determine whether neurohormone release within the pancreas might play a role in coordinating islet activity, [Ca²⁺]_i changes in 4–6 isolated mouse islets were simultaneously monitored before and after a transient pulse of a putative synchronizing agent. The degree of synchronicity was …

Gap Junction Coupling And Calcium Waves In The Pancreatic Islet, Richard K.P. Benninger, Min Zhang, W. Steven Head, Leslie S. Satin, David W. Piston

Pharmacology and Toxicology Publications

Abstract

The pancreatic islet is a highly coupled, multicellular system that exhibits complex spatiotemporal electrical activity in response to elevated glucose levels. The emergent properties of islets, which differ from those arising in isolated islet cells, are believed to arise in part by gap junctional coupling, but the mechanisms through which this coupling occurs are poorly understood. To uncover these mechanisms, we have used both high-speed imaging and theoretical modeling of the electrical activity in pancreatic islets under a reduction in the gap junction mediated electrical coupling. Utilizing islets from a gap junction protein connexin 36 knockout mouse model together …

Off-Label Psychopharmacologic Prescribing For Children: History Supports Close Clinical Monitoring., Julie M Zito, Albert T Derivan, Christopher J Kratochvil, Daniel J Safer, Joerg M Fegert, Laurence L Greenhill

Department of Psychiatry and Human Behavior Faculty Papers

The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring.

Endocannabinoid Modulation Of Spatial Memory In Aversively And Appetitively Motivated Barnes Maze Tasks, John Pinckney Harloe

Theses and Dissertations

Genetic deletion or pharmacological blockade of the CB1 receptor has been reported to impair extinction learning in aversive conditioning (i.e., conditioned fear and Morris water maze) paradigms, but not in operant procedures in which food reinforcement is earned. It is difficult to discern whether the differential effects caused by CB1 receptor disruption on extinction result from the hedonics (i.e., aversive vs. appetitive) or is related to the required responses associated with these disparate tasks. In order to evaluate whether the hedonics is the determining factor, we used either aversive (i.e., escape from bright lights and air turbulence) or appetitive (i.e., …

Examining The Behavioral And Molecular Aspects Of Adolescent Nicotine Dependence: Implications For Vulnerability To Drugs Of Abuse, Dena Heath Kota

Theses and Dissertations

Approximately 200 million men and 100 million women smoke worldwide. In the United States, an estimated 25.9 million men (23.9 percent) and 20.7 million women (18.1 percent) are smokers. The commencement of smoking at a young age is thought to increase addiction liability, decrease the probability of successful cessation, and correlate with a higher number of cigarettes smoked per day. Studies from the World Health Organization indicate that between 80,000 and 100,000 children start smoking every day worldwide. These statistics suggest that adolescence is a critical phase for developing nicotine dependence. The work in this dissertation contributes to the further …

Tumor Epithelial Cell Matrix Metalloproteinase 9 (Mmp-9) Is A Prognostic Marker In Colorectal Cancer, Ds Zuzga, Av Gibbons, P Li, Wj Lubbe, I Chervoneva, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Presented at American Association Cancer Research in 2008

Zuzga D.S., Gibbons A.V., Li P., Lubbe W.J., Chervoneva I., Pitari G.M. “Tumor epithelial cell MMP-9 is a prognostic marker in colorectal cancer”. In: American Association for Cancer Research Special Conference, Molecular Diagnostics in Cancer Therapeutic Development: Proceedings; 2008 Sept 22-25; Philadelphia, PA. Abstract A40.

Colorectal cancer is the second leading cause of cancer-related mortality indeveloped nations. Mortality from colon cancer largely reflects metastasis, thespread of the disease to distant sites. Early diagnosis of pre-metastatic diseaseand accurate stratification of patients with metastasis is pivotal to decreasemortality rates from colon cancer by effectively …