Medical Toxicology Commons^™

Optimal Scheduling Of Bevacizumab And Pemetrexed/Cisplatin Dosing In Non-Small Cell Lung Cancer, Benjamin K. Schneider, Arnaud Boyer, Joseph Ciccolini, Fabrice Barlesi, Kenneth Wang, Sebastien Benzekry, Jonathan P. Mochel

Biomedical Sciences Publications

Bevacizumab-pemetrexed/cisplatin (BEV-PEM/CIS) is a first line therapeutic for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab potentiates PEM/CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV-PEM/CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV-PEM/CIS pharmacodynamic modeling in NSCLC-bearing mice to estimate the optimal gap in the scheduling of sequential BEV-PEM/CIS. We predicted the optimal gap in BEV-PEM/CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy ...

A Clinically Relevant Mouse Model Of Cisplatin-Induced Kidney Injury., Cierra Nichole Sharp

Electronic Theses and Dissertations

Cisplatin is a potent chemotherapeutic used for the treatment of many solid cancers, including testicular, ovarian, and lung cancer. Cisplatin causes many adverse side effects, of which nephrotoxicity leading to acute kidney injury is dose-limiting. Approximately 30% of patients will develop nephrotoxicity with cisplatin, and will either have their next dose of cisplatin lowered, skipped, or be switched to a less nephrotoxic chemotherapeutic altogether. These outcomes are not ideal when trying to treat cancer. Previously, it was believed that patients could recover from cisplatin-induced acute kidney injury with little to no lasting effects, but recent longitudinal studies have shown this ...

Nanoparticle-Mediated Therapeutic Agent Delivery For Treating Metastatic Breast Cancer—Challenges And Opportunities, Yunfei Li, Brock Humphries, Chengfeng Yang, Zhishan Wang

Toxicology and Cancer Biology Faculty Publications

Breast cancer (BC) is the second leading cause of cancer-related death in American women and more than 90% of BC-related death is caused by metastatic BC (MBC). This review stresses the limited success of traditional therapies as well as the use of nanomedicine for treating MBC. Understanding the biological barriers of MBC that nanoparticle in vivo trafficking must overcome could provide valuable new insights for translating nanomedicine from the bench side to the bedside. A view about nanomedicine applied in BC therapy has been summarized with their present status, which is gaining attention in the clinically-applied landscape. The progressions of ...

Preclinical Evaluation Of Novel Fatty Acid Synthase Inhibitors In Primary Colorectal Cancer Cells And A Patient-Derived Xenograft Model Of Colorectal Cancer, Yekaterina Y. Zaytseva, Piotr G. Rychahou, Anh-Thu Le, Timothy L. Scott, Robert M. Flight, Ji Tae Kim, Jennifer Harris, Jinpeng Liu, Chi Wang, Andrew J. Morris, Theru A. Sivakumaran, Teresa Fan, Hunter Moseley, Tianyan Gao, Eun Young Lee, Heidi L. Weiss, Timothy S. Heuer, George Kemble, B. Mark Evers

Toxicology and Cancer Biology Faculty Publications

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial.

However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition.

CRC cells and PDXs ...

Comparative Cytotoxicity Study Of Nicotine And Cotinine On Mrc-5 Cell Line, Ana-Maria Vlasceanu, Daniela Luiza Baconi, Bianca Galateanu, Miriana Stan, Cristian Balalau

Journal of Mind and Medical Sciences

Nicotine has several health hazards regarding carcinogenic potential. It also imparts increased risk for respiratory, cardiovascular, and gastrointestinal disorders. Several mechanisms have been proposed for the carcinogenic potential, including effects on cell proliferation, inducing oxidative stress, DNA mutation, or inhibition of apoptosis. The cotinine metabolite is generally thought to have effects similar to nicotine in some experimental systems. The purpose of this study was to assess the nicotine and cotinine cytotoxicity on MRC-5 lung fibroblasts. The pulmonary fibroblasts were treated with various concentrations of nicotine or cotinine (in the range 1 µM – 2 mM) for 24 or 48 h and ...

An Aged Canid With Behavioral Deficits Exhibits Blood And Cerebrospinal Fluid Amyloid Beta Oligomers, Clare Rusbridge, Francisco J. Salguero, Monique Antoinette David, Kiterie M. E. Faller, Jose T. Bras, Rita J. Guerreiro, Angela C. Richard-Londt, Duncan Grainger, Elizabeth Head, Sebastian G. P. Brandner, Brian Summers, John Hardy, Mourad Tayebi

Pharmacology and Nutritional Sciences Faculty Publications

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides. We report that soluble oligomers were specifically detected in the dog's blood ...

Wearable Biosensors To Evaluate Recurrent Opioid Toxicity After Naloxone Administration: A Hilbert Transform Approach, Keerthi Kumar. Chintha, Premananda Indic, Brittany Chapman, Edward W. Boyer, Stephanie Carreiro

UMass Center for Clinical and Translational Science Supported Publications

Opioid abuse is a rapidly escalating problem in the United States. Effective opioid reversal is achieved with the antidote naloxone, but often does not last as long as the offending opioid, necessitating in-hospital observation. Continuous physiologic monitoring using wearable biosensors represents a potential option to extend monitoring capability outside the clinical setting across the spectrum of opioid abuse including post- naloxone administration. The present study aims to identify the physiologic change that marks the cessation of naloxone's effect. Eleven participants were recruited in the Emergency Department after naloxone administration for an opioid overdose and continuously monitored using a wearable ...

Low-Energy Bluetooth For Detecting Real-World Penetrance Of Bystander Naloxone Kits: A Pilot Study, Jeffrey T. Lai, Brittany Chapman, Katherine L. Boyle, Edward W. Boyer, Peter R. Chai

Open Access Articles

Opioid overdose is a growing public health emergency in the United States. The antidote naloxone must be administered rapidly after opioid overdose to prevent death. Bystander or "take-home" naloxone programs distribute naloxone to opioid users and other community members to increase naloxone availability at the time of overdose. However, data describing the natural history of take-home naloxone in the hands of at-risk individuals is lacking. To understand patterns of naloxone uptake in at-risk users, we developed a smart naloxone kit that uses low-energy Bluetooth (BLE) to unobtrusively detect the transit of naloxone through a hospital campus. In this paper, we ...

Childhood Lead Poisoning, Javeria Fatima

Global Issues in Public Health

Childhood lead poisoning is a non-communicable disease that has a long history and fatal effects. Although the disease’s source is from a natural element, lead, human handling of lead has affected individuals negatively worldwide. Through the use of lead in everyday situations or items such as in mines, the paint in houses, and lead water pipes, lead poisoning is easily attainable and has lasting effects. The impacts on lead poisoning on children has been investigated over the years and the devastating cognitive and physical impacts of the disease have been studied. This report aims to examine the factors that ...

A Ninja Initiative At Children's Mercy, Richard Ogden, Bradley A. Warady, Vimal Chadha, Wendy Hoebing

Posters

No abstract provided.

The Effects Of A Human Food Additive, Titanium Dioxide Nanoparticles E171, On Drosophila Melanogaster - A 20 Generation Dietary Exposure Experiment, Boris Jovanović, Nikola Jovanović, Vladimir J. Cvetković, Sanja Matić, Snežana Stanić, Elizabeth M. Whitley, Tatjana Lj. Mitrović

Natural Resource Ecology and Management Publications

In this study, fruit flies (Drosophila melanogaster) were exposed to an estimated daily human E171 consumption concentration for 20 generations. Exposure to E171 resulted in: a change in normal developmental and reproductive dynamics, reduced fecundity after repetitive breeding, increased genotoxicity, the appearance of aberrant phenotypes and morphologic changes to the adult fat body. Marks of adaptive evolution and directional selection were also exhibited. The larval stages were at a higher risk of sustaining damage from E171 as they had a slower elimination rate of TiO2 compared to the adults. This is particularly worrisome, since among the human population, children tend ...

Parallelization Of A Three-Dimensional Full Multigrid Algorithm To Simulate Tumor Growth, Dylan Goodin, Chin F. Ng, Hermann B. Frieboes

Commonwealth Computational Summit

We present the performance gains of an openMP implementation of a fully adaptive nonlinear full multigrid (FMG) algorithm to simulate three-dimensional multispecies desmoplastic tumor growth on computer systems of varying processing capabilities. The FMG algorithm is applied to solve a recently published thermodynamic mixture model that uses a diffuse interface approach with fourth-order reaction-advection-diffusion PDEs (Cahn-Hilliard-type equations) that are coupled, nonlinear, and numerically stiff. The model includes multiple cell species and extracellular matrix (ECM), with adhesive and elastic energy contributions in chemical potential terms, as well as including blood and lymphatic vessels represented as continuous vasculatures. Advection-reaction-diffusion PDEs are employed ...

Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou

Toxicology and Cancer Biology Faculty Publications

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein ...

Mutsβ Abundance And Msh3 Atp Hydrolysis Activity Are Important Drivers Of Ctg•Cag Repeat Expansions, Norma Keogh, Kara Y. Chan, Guo-Min Li, Robert S. Lahue

Toxicology and Cancer Biology Faculty Publications

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSβ (Msh2-Msh3 heterodimer). To evaluate properties of MutSβ that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSβ, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSβ. Msh3^−/− cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3^−/− cells provide a single, isogenic system ...

Chemotherapy-Induced Tissue Injury: An Insight Into The Role Of Extracellular Vesicles-Mediated Oxidative Stress Responses, Chontida Yarana, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

The short- and long-term side effects of chemotherapy limit the maximum therapeutic dose and impair quality of life of survivors. Injury to normal tissues, especially chemotherapy-induced cardiomyopathy, is an unintended outcome that presents devastating health impacts. Approximately half of the drugs approved by the Food and Drug Administration for cancer treatment are associated with the generation of reactive oxygen species, and Doxorubicin (Dox) is one of them. Dox undergoes redox cycling by involving its quinone structure in the production of superoxide free radicals, which are thought to be instrumental to the role it plays in cardiomyopathy. Dox-induced protein oxidation changes ...

Correlation Between Preconception Maternal Non-Occupational Exposure To Interior Decoration Or Oil Paint Odour And Average Birth Weight Of Neonates: Findings From A Nationwide Cohort Study In China's Rural Areas, Huiting Liu, Shi Chen, Huijuan Zhu, Hongbo Yang, Fengying Gong, Linjie Wang, Yu Jiang, Bill Q. Lian, Chengsheng Yan, Jianqang Li, Qing Wang, Shikun Zhang, Hui Pan

Open Access Articles

BACKGROUND: Birth weight is a critical indicator of neonatal health and foretells people's health in adolescence and even adulthood. Some researchers have warned against the adverse effects on babies' birth weight of exposure to pollutants in interior decoration or oil paint by odour intake. This study evaluated the effects of maternal exposure to such factors before conception on the birth weights of neonates.

METHODS: Data on 213 461 cases in this study were from the database of the free National Pre-pregnancy Checkups Project. Defined as 'exposed' were those women exposed to oil paint odour or interior decoration at home ...

The Role Of Sodium Bicarbonate In The Management Of Some Toxic Ingestions, Aibek E. Mirrakhimov, Taha Ayach, Aram Barbaryan, Goutham Talari, Romil Chadha, Adam Gray

Internal Medicine Faculty Publications

Adverse reactions to commonly prescribed medications and to substances of abuse may result in severe toxicity associated with increased morbidity and mortality. According to the Center for Disease Control, in 2013, at least 2113 human fatalities attributed to poisonings occurred in the United States of America. In this article, we review the data regarding the impact of systemic sodium bicarbonate administration in the management of certain poisonings including sodium channel blocker toxicities, salicylate overdose, and ingestion of some toxic alcohols and in various pharmacological toxicities. Based on the available literature and empiric experience, the administration of sodium bicarbonate appears to ...

Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same ...

Therapeutic Efficacy Of Cerium Oxide Nanoparticles Against Sepsis Induced Multi-Organ Dysfunction Syndrome In Sprague Dawley Rats, Nandini Durga Prasanna Kumar Manne

Nandini Manne

Sepsis is a generalized term that signifies the presence of a pathogen in the blood stream to which the body responds by eliciting a systemic inflammatory response. Although sepsis is the leading cause of death in non-coronary intensive care units in United States, there are currently no FDA approved therapeutic drugs to treat this disorder. Cerium oxide nanoparticles (CeO2) have been shown to exhibit anti-oxidant, anti-inflammatory, and anti-bacterial properties both in vitro and in vivo. Whether CeO2 nanoparticles can be used for the treatment of sepsis is currently unclear. To investigate whether CeO2 nanoparticles can be used to treat moderate ...

Unsuspected Clenbuterol Toxicity In A Patient Using Intramuscular Testosterone, Matthew K. Griswold, Eike Blohm, Roderick Cross, Edward W. Boyer, Jennifer L. Carey

Emergency Medicine Publications and Presentations

Clenbuterol is a beta-agonist that has been abused by fitness-oriented individuals for muscle growth and weight loss. We report a case of a 46-year-old man who presented tachycardic, hypokalemic, and hyperglycemic after injecting testosterone obtained from Brazil. He developed refractory hypotension and was started on an esmolol infusion for suspected beta-agonist toxicity. Laboratory analysis showed a detectable clenbuterol serum concentration. Analysis of an unopened ampule contained boldenone undecylenate, clenbuterol, and vitamin E. This case illustrates a novel exposure that caused beta-agonist toxicity and was treated successfully with rapid-onset beta blocker.