Medical Toxicology Commons^™

Lessons From Toxicology: Developing A 21st‑Century Paradigm For Medical Research, Gill Langley, Christopher P. Austin, Anil K. Balapure, Linda S. Birnbaum, John R. Bucher, Julia Fentem, Suzanne C. Fitzpatrick, John R. Fowle Iii, Robert J. Kavlock, Hiroaki Kitano, Brett A. Lidbury, Alysson R. Muotri, Shuang-Qing Peng, Dmitry Sakharov, Troy Seidle, Thales Trez, Alexander Tonevitsky, Anja Van De Stolpe, Maurice Whelan, Catherine Willett

Gill Langley, Ph.D.

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual ...

Developing A More Clinically-Relevant Mouse Model Of Cisplatin-Induced Nephrotoxicity., Cierra N. Sharp

Electronic Theses and Dissertations

Cisplatin is a nephrotoxic chemotherapeutic that causes acute kidney injury (AKI) in 30% of patients. Although recovery can occur after one episode of cisplatin-induced AKI, studies have indicated multiple episodes may lead to the development of chronic kidney disease (CKD), an irreversible disease with no current treatments. The standard mouse model of cisplatin-induced AKI consists of one, high dose of cisplatin (> 20 mg/kg) that is lethal to the animal three days later. This model doesn’t accurately reflect the repeated dosing regimen patients receive, and doesn’t allow for long-term outcome studies of pathologies associated with CKD. We have ...

Reprogramming Of Mtor Signaling By Perinatal Exposure To Brominated Flame Retardant, Cassandra Thorburn, Benjamin Kim, Michael Panchenko, Aser Abrha, Ahmed Khalil, Alexander Suvorov

UMass Center for Clinical and Translational Science Research Retreat

Mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin, is a known metabolic master-switch. In conditions of starvation, mTOR suppresses biosynthetic programs and increases the recycling of proteins and organelles. Upon stimulation by nutrients and growth factors, however, mTOR causes activation of biosynthesis and suppression of autophagy. The mTOR-centered molecular pathway is a major pathway of growth regulation and metabolism, linked to aging and the development of cancer, obesity, type 2 diabetes, neurodevelopmental and neurodegenerative diseases. Currently, the role of environmental factors in the modulation of the mTOR pathway remains largely unknown. The present study suggests that ...

Long-Lasting Effects Of Perinatal Exposure To Brominated Flame Retardant On Male Reproductive Outcomes In Rat Model, Ahmed Khalil, Daneal Portman, Jake Jensen, Michael Panchenko, Alexander Suvorov

UMass Center for Clinical and Translational Science Research Retreat

Meta-analysis of 101 studies published between 1934 and 1996 indicates that mean sperm concentration decreased around 50% during this period. More recent studies have found alarmingly poor semen quality in the general population of Northern Europe. Additional adverse trends include increased incidence of testicular cancer, and congenital malformations such as cryptorchidism and hypospadias. Testicular germ cell cancers increased by about 400% over the period of 50 years in industrialized countries. Decreased quality of male reproductive health has been linked to environmental endocrine disruptors exposure. However, the ability of xenobiotics to produce long-lasting effects and mechanisms of perturbation of the male ...

Predisposed Health Conditions Of Children Exposed To Methamphetamine In Utero, Seth Peters

UMass Center for Clinical and Translational Science Research Retreat

Methamphetamine (MA) use and abuse is a growing problem worldwide [United Nations World Drug Report]. It is common knowledge that MA use affects not only the user, but also friends, family, and the communities close to them [NIDA]. One area of impact that is lacking sufficient study is the effects of MA use by expectant mothers on her child later in life. That is to say, a child who was exposed to MA in utero may be more likely than an unexposed fetus to have predispositions to a variety of health conditions. After an extensive PubMed database search, it is ...

Associations Of Peripubertal Serum Dioxin And Polychlorinated Biphenyl Concentrations With Pubertal Timing Among Russian Boys, Jane S. Burns, Mary M. Lee, Paige Williams, Susan Korrick, Oleg Sergeyev, Thuy Lam, Boris Revich, Russ Hauser

Open Access Articles

BACKGROUND: Dioxins, furans, and polychlorinated biphenyls (PCBs), dioxin-like and nondioxin-like, have been linked to alterations in puberty.

OBJECTIVES: We examined the association of peripubertal serum levels of these compounds (and their toxic equivalents (TEQs)) with pubertal onset and maturity among Russian boys enrolled at ages 8-9 years and followed prospectively through ages 17-18 years.

METHODS: At enrollment, 473 boys had serum dioxin-like compounds and PCBs measured. At the baseline visit and annually until age 17-18 years, a physician performed pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV)]. 315 subjects completed the follow-up visit at 17-18 years of age ...

Role Of Phosphodiesterase-4 In Alcohol-Induced Organ Injury., Diana Veronica Avila

Electronic Theses and Dissertations

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. Alcohol metabolism leads to generation of free radicals and oxidative stress with a resultant formation of lipid peroxidation products, which, in turn, contribute to the development of ALD. Alcohol induced hepatic steatosis is the earliest and most frequent manifestation of ALD and a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signaling has been shown to significantly regulate lipid metabolism. Moreover, agents that increase cAMP have been shown to effectively mitigate oxidative stress ...

Acrolein Is A Critical Mediator Of Alcohol-Induced Liver And Intestinal Injury In Alcoholic Liver Disease., Wei-Yang (Jeremy) Chen 1980-

Electronic Theses and Dissertations

Alcohol consumption can cause alcoholic liver disease (ALD), which remains a major cause of morbidity and mortality in the United States. Chronic alcohol consumption causes a pro-oxidant environment in the liver and increases hepatic lipid peroxidation. Acrolein is the most reactive and toxic aldehyde generated through lipid peroxidation. Acrolein forms protein adducts and triggers endoplasmic reticulum (ER) stress and hepatocyte apoptosis, which are recognized etiologic factors in ALD. Several studies have established the critical role of the gut-liver axis in ALD pathogenesis, wherein alcohol-induced gut barrier dysfunction contributes to liver injury. This study investigates, in vitro and in vivo, the ...

The Future Of Teratology Research Is In Vitro, Jarrod Bailey, Andrew Knight, Jonathan Balcombe

Andrew Knight, BSc (Vet Biol), BVMS, MANZCVS, DipECAWBM (AWSEL), DACAW, PhD, MRCVS, SFHEA

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and manhours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite ...

Continuous Safety Monitoring Of Excess Toxicity In Single Arm Early Phase Biomarker Driven Trials, Racky Daffe

Scholar Archive

No abstract provided.

Structure-Activity Relationships Governing The Interaction Of Nanoparticles With Mammalian Cells- Predictive Models For Toxicology And Medical Appliancesd, Marcus A. Maher

Doctoral

Nanoscience is seen as one of the key enabling technologies of the 20th century and as its range of applications increases it is important to look at how nanomaterials interact with biological environments. Some of these interactions have given rise to toxic effects and thus, the creation of the field of nanotoxicology, it has also been noted that current methods of evaluating toxicity may not be sufficient to keep up with the rapidly emerging range of nanomaterials becoming available. It is clear that alternatives are necessary. In this thesis, a phenomenological rate equation model is constructed to simulate nanoparticle uptake ...

Stable Isotope Resolved Metabolomics Studies In Ex Vivo Tissue Slices, Teresa W-M Fan, Andrew N. Lane, Richard M. Higashi

Toxicology and Cancer Biology Faculty Publications

An important component of this methodology is to assess the role of the tumor microenvironment on tumor growth and survival. To tackle this problem, we have adapted the original approach of Warburg (Warburg, 1923), by combining thin tissue slices with Stable Isotope Resolved Metabolomics (SIRM) to determine detailed metabolic activity of human tissues. SIRM enables the tracing of metabolic transformations of source molecules such as glucose or glutamine over defined time periods, and is a requirement for detailed pathway tracing and flux analysis. In our approach, we maintain freshly resected tissue slices (both cancerous and non- cancerous from the same ...

Utilizing An Ingestible Biosensor To Assess Real-Time Medication Adherence, Peter Chai, Jose Castillo-Mancilla, Eric Buffkin, Chad Darling, Rochelle Rosen, Keith Horvath, Edwin Boudreaux, Gregory Robbins, Patricia Hibberd, Edward Boyer

Edwin D. Boudreaux

Medication adherence monitoring has relied largely on indirect measures of pill ingestion including patient self-report, pharmacy refills, electronically triggered pill bottles, and pill counts. Our objective is to describe an ingestible biosensor system comprising a radio-frequency identification (RFID)-tagged gelatin capsule. Once the capsule dissolves in the stomach, the RFID tag activates to transmit a unique signal to a relay device which transmits a time-stamped message to a cloud-based server that functions as a direct measure of medication adherence. We describe a constellation of mobile technologies that provide real-time direct measures of medication adherence. Optimizing connectivity, relay design, and interactivity ...

Metabolomics Workbench: An International Repository For Metabolomics Data And Metadata, Metabolite Standards, Protocols, Tutorials And Training, And Analysis Tools, Manish Sud, Eoin Fahy, Dawn Cotter, Kenan Azam, Ilango Vadivelu, Charles Burant, Arthur Edison, Oliver Fiehn, Richard M. Higashi, K. Sreekumaran Nair, Susan Sumner, Shankar Subramaniam

Toxicology and Cancer Biology Faculty Publications

The Metabolomics Workbench, available at www.metabolomicsworkbench.org, is a public repository for metabolomics metadata and experimental data spanning various species and experimental platforms, metabolite standards, metabolite structures, protocols, tutorials, and training material and other educational resources. It provides a computational platform to integrate, analyze, track, deposit and disseminate large volumes of heterogeneous data from a wide variety of metabolomics studies including mass spectrometry (MS) and nuclear magnetic resonance spectrometry (NMR) data spanning over 20 different species covering all the major taxonomic categories including humans and other mammals, plants, insects, invertebrates and microorganisms. Additionally, a number of protocols are provided ...

Role Of Sulfiredoxin Interacting Proteins In Lung Cancer Development, Hedy Chawsheen

Theses and Dissertations--Toxicology and Cancer Biology

Sulfiredoxin (Srx) is an antioxidant enzyme that can be induced by oxidative stress. It promotes oncogenic phenotypes of cell proliferation, colony formation, migration, and metastasis in lung, skin and colon cancers. Srx reduces the overoxidation of 2-cysteine peroxiredoxins in cells, in addition to its role of removing glutathione modification from several proteins. In this study, I explored additional physiological functions of Srx in lung cancer through studying its interacting proteins. Protein disulfide isomerase (PDI) family members, thioredoxin domain containing protein 5 (TXNDC5) and protein disulfide isomerase family A member 6 (PDIA6), were detected to interact with Srx. Therefore, I proposed ...

The Role Of Pxr And Ikkβ Signaling In Cardiometabolic Disease, Robert N. Helsley

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive ...

13C Tracer Studies Of Metabolism In Mouse Tumor Xenografts, Andrew N. Lane, Jun Yan, Teresa W-M Fan

Toxicology and Cancer Biology Faculty Publications

Mice are widely used for human tumor xenograft studies of cancer development and drug efficacy and toxicity. Stable isotope tracing coupled with metabolomic analysis is an emerging approach for assaying metabolic network activity. In mouse models there are several routes of tracer introduction, which have particular advantages and disadvantages that depend on the model and the questions addressed. This protocol describes the bolus i.v. route via repeated tail vein injections of solutions of stable isotope enriched tracers including ¹³C₆-glucose and ¹³C₅,¹⁵N₂-glutamine. Repeated injections give higher enrichments and over longer labeling ...

Imstrong: Deployment Of A Biosensor System To Detect Cocaine Use, Stephanie Carreiro, Hua Fang, Jianying Zhang, Kelley Wittbold, Shicheng Weng, Rachel Mullins, David Smelson, Edward Boyer

Hua Julia Fang

Biosensor systems are increasingly promoted for use in behavioral interventions. Portable biosensors might offer advancement over self-report use and can provide improved opportunity for detection and intervention in patients undergoing drug treatment programs. Fifteen participants wore a biosensor wristband capable of detecting multiple physiologic markers of sympathetic nervous system (SNS) arousal for 30 days. Urine drug screening and drug use self-report were obtained twice per week. A parameter trajectory description method was applied to capture abrupt changes in magnitude of three measures of SNS activity: Electrodermal activity (EDA), skin temperature and motion. Drug use events detected by the biosensor were ...

Lessons From Toxicology: Developing A 21st‑Century Paradigm For Medical Research, Gill Langley, Christopher P. Austin, Anil K. Balapure, Linda S. Birnbaum, John R. Bucher, Julia Fentem, Suzanne C. Fitzpatrick, John R. Fowle Iii, Robert J. Kavlock, Hiroaki Kitano, Brett A. Lidbury, Alysson R. Muotri, Shuang-Qing Peng, Dmitry Sakharov, Troy Seidle, Thales Trez, Alexander Tonevitsky, Anja Van De Stolpe, Maurice Whelan, Catherine Willett

Animal Research, Testing, and Experimentation

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual ...

Ngo's Bpa Report Intended To Frighten, Not Enlighten., Robert L. Brent Dr.

The Selected Works of Robert Brent

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