Pharmacology, Toxicology and Environmental Health Commons^™

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

Type 1 Diabetes Alters Lipid Handling And Metabolism In Human Fibroblasts And Peripheral Blood Mononuclear Cells, Albert R. Jones Iv, Emily L. Coleman, Nicholas R. Husni, Jude T. Deeney, Forum Raval, Devin Steenkamp, Hans Dooms, Barbara S. Nikolajczyk, Barbara E. Corkey

Clinical and Translational Science Faculty Publications

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences …

Sustained Sensitizing Effects Of Tumor Necrosis Factor Alpha On Sensory Nerves In Lung And Airways, Ruei-Lung Lin, Qihai Gu, Mehdi Khosravi, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 hours later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and …

High Burden Of Subclinical Lead Toxicity After Phase Out Of Lead From Petroleum In Pakistan, Hafsa Majid, Aysha Habib, Nadeem Ullah Khan, Imran Siddiqui, Farooq Ghani, Lena Jafri

Department of Pathology and Laboratory Medicine

Objective: To evaluate the frequency of subclinical lead toxicity.
Study design: Cross-sectional study.
Place and duration of study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2011 to December 2014.
Methodology: Analysis of laboratory data for blood lead levels (BLL) was performed. Lead was tested by atomic absorption spectrometer. For all subjects, only initial test results were included while the results of repeated testing were excluded. Exemption was sought from institutional ethical review committee. BLL of 2-10 ug/dl and 10-70 ug/dl in children and adults, respectively were taken as subclinical lead toxicity.
Result: Amongst …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

Adipose Tissue As A Site Of Toxin Accumulation, Erin Jackson, Robin C. Shoemaker, Nika Larian, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

We examine the role of adipose tissue, typically considered an energy storage site, as a potential site of toxicant accumulation. Although the production of most persistent organic pollutants (POPs) was banned years ago, these toxicants persist in the environment due to their resistance to biodegradation and widespread distribution in various environmental forms (e.g., vapor, sediment, and water). As a result, human exposure to these toxicants is inevitable. Largely due to their lipophilicity, POPs bioaccumulate in adipose tissue, resulting in greater body burdens of these environmental toxicants with obesity. POPs of major concern include polychlorinated biphenyls (PCBs), polychlorinated dibenzo‐p‐dioxins and furans …

Internal Mammary Artery Flow In Different Racial Groups Of Pakistan, Mudassir Iqbal Dar, Asim Hassan Dar, Mansoor Ahmed, Abdul Haseeb, Muhammad Bilal

Department of Biological & Biomedical Sciences

Objective: To find out any differences in free flow of internal mammary artery among different ethnic groups.
Methods: This observational, cross-sectional study was conducted at the Civil Hospital, Karachi, from January 2013 to December 2015, and comprised patients who underwent coronary artery bypass grafting. The participants were divided into 5 groups, i.e. Sindhi, Muslim migrants from India, Punjabi, Pathan and Balochi patients. Free flow of internal mammary artery was measured immediately after harvesting within a syringe, and its flow was measured in 30 seconds. SPSS 18 was used for data analysis.
Results: Of the 158 patients, 44(27.8%) …

An Ethnobotanical Examination Of Traditional Medicine In Ngezi Forest Reserve, Tyler Tsang

Independent Study Project (ISP) Collection

Traditional medicine is an important aspect of the both the culture and health of communities worldwide. Ngezi Forest Reserve is a protected area on Pemba Island which is part of the Zanzibar Archipelago. This forest contains a wealth of botanical diversity which includes many species of medicinal plants. Traditional healers (waganga) use these medicinal plants to heal members of the community. Interviews and forest walks with these healers were supplemented by consultations with a botanist to determine medicinal value of the forest and the surrounding areas. In compiling information from 15 healers in the area, 98 species of medicinal plants …

An Objective Assessment Of The Variability In Number Of Drops Per Bottle Of Glaucoma Medication, Daniel B. Moore, Judy Beck, Richard J. Kryscio

Ophthalmology and Visual Science Faculty Publications

Background: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications.

Methods: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume …

Toxic And Essential Trace Element Content Of Commonly Administered Pediatric Oral Medications, Robert A. Yokel, Sarah E. Seger, Jason M. Unrine

Pharmaceutical Sciences Faculty Publications

OBJECTIVES: The aim of this study was to test the hypothesis that commonly administered pediatric oral medications are a significant source of toxic elements. The concentrations of 16 elements were determined in 14 frequently used pediatric oral medications.

METHODS: Samples were prepared for analysis by dilution or nitric acid microwave-assisted digestion and analyzed by inductively coupled plasma mass spectrometry. The intake of each element from administration for 1 week of the medication's maximum recommended daily dose to 6-month-olds was calculated and compared to an exposure guideline for that element. Exposure guidelines used for adverse effects were minimal risk levels, oral …

Pharmacology, Pharmacokinetics, And Metabolism Of The Dna-Decoy Ayx1 For The Prevention Of Acute And Chronic Post-Surgical Pain, Julien Mamet, Scott Harris, Michael Klukinov, David C. Yeomans, Renee R. Donahue, Bradley K. Taylor, Kelly Eddinger, Tony Yaksh, Donald C. Manning

Physiology Faculty Publications

Background: AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord.

Results: The effects of ascending dose-levels of AYX1 on mechanical …

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the …

Effect Of Cigarette Smoke Exposure And Mutant Kras Overexpression On Pancreatic Cell Proliferation, Howard P. Glauert, R. Scott Elliott, Sung Gu Han, Mark Athey, Eun Young Lee, C. Gary Gairola

Pharmacology and Nutritional Sciences Faculty Publications

Pancreatic cancer is the fourth leading cause of cancer‑associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas^G12D) in the pancreas as well as wild‑type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure …

Effect Of Systemic Antioxidant Allopurinol Therapy On Skin Flap Survival, M Ardakani, Kaveh Alizadeh, A Moghadam

NYMC Faculty Publications

No abstract provided.

Inhibition Of The Integrin/Fak Signaling Axis And C-Myc Synergistically Disrupts Ovarian Cancer Malignancy, B. Xu, Jason R. Lefringhouse, Z. Liu, D. West, Lauren A. Baldwin, C. Ou, L. Chen, Dana L. Napier, Luksana Chaiswing, Lawrence D. Brewer, Daret K. St Clair, Olivier Thibault, John R. Van Nagell, Binhua P. Zhou, R. Drapkin, J.-A. Huang, M. L. Lu, Frederick R. Ueland, X. H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 …

Sodium-Myoinositol Cotransporter-1, Smit1, Mediates The Production Of Reactive Oxygen Species Induced By Hyperglycemia In The Heart, Anne Van Steenbergen, Magali Balteau, Audrey Ginion, Laura Ferté, Sylvain Battault, Christophe De Meester De Ravenstein, Jean-Luc Balligand, Evangelos-Panagiotis Daskalopoulos, Patrick Gilon, Florin Despa, Sanda Despa, Jean-Louis Vanoverschelde, Sandrine Horman, Hermann Koepsell, Gerard Berry, Louis Hue, Luc Bertrand, Christophe Beauloye

Pharmacology and Nutritional Sciences Faculty Publications

Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to …

Chloroquine-Inducible Par-4 Secretion Is Essential For Tumor Cell Apoptosis And Inhibition Of Metastasis, Ravshan Burikhanov, Nikhil Hebbar, Sunil K. Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S. Watt, Danny R. Welch, Jodi Maranchie, Akihiro Harada, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings …

The [E]Motionless Body No Longer: Tracing The Historical Intersections Of Mental Illness And Movement In The American Asylum, Holly Adele Herzfeld

Senior Projects Spring 2017

Senior Project submitted to The Division of Multidisciplinary Studies of Bard College.

The Role Of Progesterone Receptor Membrane Component 1 In Receptor Trafficking And Disease, Kaia K. Hampton

Theses and Dissertations--Pharmacology and Nutritional Sciences

The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor …

Perampanel, Michael A. Rogawski

Michael A. Rogawski

No abstract provided.