Medicine and Health Sciences Commons^™

Improved Detection Of Common Variants Associated With Schizophrenia And Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate, Ole A. Andreassen, Wesley K. Thompson, Andrew J. Schork, Stephan Ripke, Morten Mattingsdal, John R. Kelsoe, Kenneth S. Kendler, Michael C. O'Donovan, Dan Rujescu, Thomas Werge, Pamela Sklar, J. Cooper Roddey, Chi-Hua Chen, Linda Mcevoy, Rahul S. Desikan, Srdjan Djurovic, Anders M. Dale

Psychiatry Publications

Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional …

Ethanol Regulation Of Serum Glucocorticoid Kinase 1 Expression In Dba2/J Mouse Prefrontal Cortex, Blair N. Costin, Seth M. Dever, Michael F. Miles

Pharmacology and Toxicology Publications

Background

We previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions …

Cannabinoid Cb2 Receptors Regulate Central Sensitization And Pain Responses Associated With Osteoarthritis Of The Knee Joint, James J. Burston, David R. Sagar, Pin Shao, Mingfeng Bai, Emma King, Louis Brailsford, Jenna M. Turner, Gareth J. Hathway, Andrew J. Bennett, David A. Walsh, David A. Kendall, Aron H. Lichtman, Victoria Chapman

Pharmacology and Toxicology Publications

Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies.

Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that …

A Hierarchical Method For Removal Of Baseline Drift From Biomedical Signals: Application In Ecg Analysis, Yurong Luo, Rosalyn H. Hargraves, Ashwin Belle, Ou Bai, Xuguang Qi, Kevin R. Ward, Michael Paul Pfaffenberger, Kayvan Najarian

Computer Science Publications

Noise can compromise the extraction of some fundamental and important features from biomedical signals and hence prohibit accurate analysis of these signals. Baseline wander in electrocardiogram (ECG) signals is one such example, which can be caused by factors such as respiration, variations in electrode impedance, and excessive body movements. Unless baseline wander is effectively removed, the accuracy of any feature extracted from the ECG, such as timing and duration of the ST-segment, is compromised. This paper approaches this filtering task from a novel standpoint by assuming that the ECG baseline wander comes from an independent and unknown source. The technique …

Physical Activity And Sedentary Behavior Of Cancer Survivors And Non-Cancer Individuals: Results From A National Survey, Roy B. Kim, Allison Phillips, Kirsten Herrick, Marieka Helou, Carlin Rafie, Mitchell S. Anscher, Ross B. Mikkelsen, Yi Ning

Anatomy and Neurobiology Publications

Increasing physical activity and decreasing sedentary behavior are associated with a higher quality of life and lower mortality rates for cancer survivors, a growing population group. Studies detailing the behavior of cancer survivors are limited. Therefore, we investigated physical activity and sedentary behavior of cancer survivors using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2010. Participants were those who provided physical activity and sedentary behavior data. Those who were pregnant,old, or10,472 non-cancer participants. After adjustment for age, race, gender, education status, body mass index, and smoking status, cancer survivors (n = 10,472) reported significantly longer duration of …

Contributions Of Vldlr And Lrp8 In The Establishment Of Retinogeniculate Projections, Jianmin Su, Michael A. Klemm, Anne M. Josephson, Michael A. Fox

Anatomy and Neurobiology Publications

Background

Retinal ganglion cells (RGCs), the output neurons of the retina, project to over 20 distinct brain nuclei, including the lateral geniculate nucleus (LGN), a thalamic region comprised of three functionally distinct subnuclei: the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). We previously identified reelin, an extracellular glycoprotein, as a critical factor that directs class-specific targeting of these subnuclei. Reelin is known to bind to two receptors: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2). Here we examined the roles of these canonical reelin …

Paclitaxel-Induced Apoptosis Is Bak-Dependent, But Bax And Bim-Independent In Breast Tumor, Anna V. Miller, Mark A. Hicks, Wataru Nakajima, Amanda C. Richardson, Jolene J. Windle, Hisashi Harada

Philips Institute for Oral Health Research Publications

Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel …

Two-Component System Response Regulators Involved In Virulence Of Streptococcus Pneumoniae Tigr4 In Infective Endocarditis, My Trihn, Xiuchun Ge, Alleson Dobson, Todd Kitten, Cindy Munro, Ping Xu

Philips Institute for Oral Health Research Publications

Streptococci resident in the oral cavity have been linked to infective endocarditis (IE). While other viridans streptococci are commonly studied in relation to IE, less research has been focused on Streptococcus pneumoniae. We established for the first time an animal model of S. pneumoniae IE, and examined the virulence of the TIGR4 strain in this model. We hypothesized that two-component systems (TCS) may mediate S. pneumoniae TIGR4 strain virulence in IE and examined TCS response regulator (RR) mutants of TIGR4 in vivo with the IE model. Thirteen of the 14 RR protein genes were mutagenized, excluding only the essential …

Structure-Based Mechanism For Early Plp-Mediated Steps Of Rabbit Cytosolic Serine Hydroxymethyltransferase Reaction, Martino L. Di Salvo, J. Neel Scarsdale, Galina Kazanina, Roberto Contestabile, Verne Schirch, H. Tonie Wright

Biochemistry and Molecular Biology Publications

Serine hydroxymethyltransferase catalyzes the reversible interconversion of L-serine and glycine with transfer of one-carbon groups to and from tetrahydrofolate. Active site residue Thr254 is known to be involved in the transaldimination reaction, a crucial step in the catalytic mechanism of all pyridoxal 5′-phosphate- (PLP-) dependent enzymes, which determines binding of substrates and release of products. In order to better understand the role of Thr254, we have expressed, characterized, and determined the crystal structures of rabbit cytosolic serine hydroxymethyltransferase T254A and T254C mutant forms, in the absence and presence of substrates. These mutants accumulate a kinetically stable gem-diamine intermediate, and their …

Osu-03012 Sensitizes Breast Cancers To Lapatinib-Induced Cell Killing: A Role For Nck1 But Not Nck2, N. Winston West, Aileen Garcia-Vargas, Charles E. Chalfant, Margaret A. Park

Biochemistry and Molecular Biology Publications

Background

Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms associated with enhancing the activity of lapatinib via combination with other therapies.

Methods

In the present studies, estrogen receptor (ER) positive and ER negative breast cancer cells were genetically manipulated to up- or downregulate eIF2-alpha, its phospho-mutant, Nck1, or Nck2, then treated with OSU-03012, lapatinib or the combination and assayed for cytotoxicity/cytostaticity using clonogenic assays.

Results

Treatment of breast cancer cell lines with lapatinib and OSU-03012 (a small molecule derivative of the Cox-2 …

The Geometry Of Locomotive Behavioral States In C. Elegans, Thomas Gallagher, Theresa Bjorness, Robert Greene, Young-Jai You, Leon Avery

Biochemistry and Molecular Biology Publications

We develop a new hidden Markov model-based method to analyze C elegans locomotive behavior and use this method to quantitatively characterize behavioral states. In agreement with previous work, we find states corresponding to roaming, dwelling, and quiescence. However, we also find evidence for a continuum of intermediate states. We suggest that roaming, dwelling, and quiescence may best be thought of as extremes which, mixed in any proportion, define the locomotive repertoire of C elegans foraging and feeding behavior.

Light-Induced Translocation Of Rgs9-1 And Gβ5l In Mouse Rod Photoreceptors, Mei Tian, Marisa Zallocchi, Weimin Wang, Ching-Kang Chen, Krzysztof Palczewski, Duane Delimont, Dominic Cosgrove, You-Wei Peng

Biochemistry and Molecular Biology Publications

The transducin GTPase-accelerating protein complex, which determines the photoresponse duration of photoreceptors, is composed of RGS9-1, Gβ5L and R9AP. Here we report that RGS9-1 and Gβ5L change their distribution in rods during light/dark adaptation. Upon prolonged dark adaptation, RGS9-1 and Gβ5L are primarily located in rod inner segments. But very dim-light exposure quickly translocates them to the outer segments. In contrast, their anchor protein R9AP remains in the outer segment at all times. In the dark, Gβ5L's interaction with R9AP decreases significantly and RGS9-1 is phosphorylated at S475 to a significant degree. Dim light exposure leads to quick de-phosphorylation of …

Hif- And Non-Hif-Regulated Hypoxic Responses Require The Estrogen-Related Receptor In Drosophila Melanogaster, Yan Li, Divya Padmanabha, Luciana B. Gentile, Catherine I. Dumur, Robert B. Beckstead, Keith D. Baker

Biochemistry and Molecular Biology Publications

Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. …

Optimizing Safe, Comfortable Icu Care Through Multi-Professional Quality Improvement: Just Do It, Alison J. Montpetit, Curtis N. Sessler

School of Nursing Publications

Translating research to the bedside can present significant challenges in the complex ICU environment. In this issue of Critical Care, de Jong and colleagues report on a quality improvement project (NURSE-DO) that led to a decrease in severe pain and serious adverse events during nursing care procedures in their ICU. In this commentary we describe three aspects of this quality improvement study that we think contributed to the overall success of the NURSE-DO project: the hospital environment and culture; multi-professional partnerships; and an evidence-based structured approach.

Epigenetics In Research And Practice, Debra E. Lyon, Susan G. Dorsey, Leorey Saligan

School of Nursing Publications

This special issue focused on the intersection of epigenetics with nursing research and practice. The first paper in this series addresses the role of epigenetic modifications in pain and analgesia response, highlighting the need for future research on epigenomic modification in the development of chronic pain, and summarizes the therapeutic potential to alter epigenetic processes to improve health outcomes. The second studies the epigenetic alterations and an increased frequency of micronuclei in women with fibromyalgia, highlighting a difference in an epigenetic biomarker in participants versus controls. The third paper explored the role of epigenetics in critical illness and the need …

Recruiting For Epigenetic Research: Facilitating The Informed Consent Process, Nancy Jallo, Debra E. Lyon, Patricia Anne Kinser, Debra Lynch Kelly, Victoria Menzies, Colleen Jackson-Cook

School of Nursing Publications

Because the effects of epigenetic (gene-environment interaction) changes have been associated with numerous adverse health states, the study of epigenetic measures provides exciting research opportunities for biobehavioral scientists. However, recruitment for studies focusing on any aspect of genetics poses challenges. Multiple factors, including lack of knowledge regarding a research study, have been identified as barriers to recruitment. Strengthening the informed consent process through extended discussion has been found to be effective in recruiting for research studies in general, yet there is a paucity of information that focused on such a recruitment strategy for epigenetic studies. In this paper, we share …

Psychoneuroimmunology-Based Stress Management During Adjuvant Chemotherapy For Early Breast Cancer, Jo Lynne W. Robins, Nancy L. Mccain, R. K. Elswick Jr., Jeanne M. Walter, D. Patricia Gray, Inez Tuck

School of Nursing Publications

Objective. In a randomized trial of women with early stage breast cancer undergoing adjuvant chemotherapy, two stress management interventions, tai chi training and spiritual growth groups, were compared to a usual care control group, to evaluate psychosocial functioning, quality of life (QOL), and biological markers thought to reflect cancer- and treatment-specific mechanisms. Method. The sample consisted of 145 women aged 27–75 years; 75% were Caucasian and 25% African American. A total of 109 participants completed the study, yielding a 75% retention rate. Grounded in a psychoneuroimmunology framework, the overarching hypothesis was that both interventions would reduce perceived stress, enhance QOL …

Control Group Design: Enhancing Rigor In Research Of Mind-Body Therapies For Depression, Patricia Anne Kinser, Jo Lynne W. Robins

School of Nursing Publications

Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research …

Epigenetic Alterations And An Increased Frequency Of Micronuclei In Women With Fibromyalgia, Victoria Menzies, Debra E. Lyon, Kellie J. Archer, Kimberly Jones, Guimin Gao, Timothy P. York, Colleen Jackson-Cook

School of Nursing Publications

Fibromyalgia (FM), characterized by chronic widespread pain, fatigue, and cognitive/mood disturbances, leads to reduced workplace productivity and increased healthcare expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM () to those seen in comparably aged healthy controls ( (MN); (methylation)). The mean (sd) MN frequency of women with FM (51.4 (21.9)) was significantly higher than that of controls (15.8 (8.5)) (; df = 1; ). Significant differences ( sites) in methylation patterns were observed between cases and controls considering a 5% …

Nosocomial Bloodstream Infections In Brazilian Pediatric Patients: Microbiology, Epidemiology, And Clinical Features, Carlos Albert Pires Pereira, Alexandre R. Marra, Luis Fernando A. Camargo, Antonio Carlos Campos Pignatari, Teresa Sukiennik, Paulo Renato Petersen Behar, Eduardo Alexandrino Servolo Medieros, Julival Ribeiro, Evelyne Girao, Luci Correa, Carla Guerra, Ima Cameiro, Carlos Brites, Marise Reis, Marta Antunes De Souza, Regina Tranchesi, Cristina U. Barata, Michael B. Edmond

Internal Medicine Publications

Background

Nosocomial bloodstream infections (nBSIs) are an important cause of morbidity and mortality and are the most frequent type of nosocomial infection in pediatric patients.

Methods

We identified the predominant pathogens and antimicrobial susceptibilities of nosocomial bloodstream isolates in pediatric patients (≤16 years of age) in the Brazilian Prospective Surveillance for nBSIs at 16 hospitals from 12 June 2007 to 31 March 2010 (Br SCOPE project).

Results

In our study a total of 2,563 cases of nBSI were reported by hospitals participating in the Br SCOPE project. Among these, 342 clinically significant episodes of BSI were identified in pediatric patients …

Fenretinide Causes Emphysema, Which Is Prevented By Sphingosine 1-Phoshate, Masanori Yasuo, Shiro Mizuno, Jeremy Allegood, Donatas Kraskauskas, Harm J. Bogaard, Sarah Spiegel, Norbert F. Voelkel

Internal Medicine Publications

Sphingolipids play a role in the development of emphysema and ceramide levels are increased in experimental models of emphysema; however, the mechanisms of ceramide-related pulmonary emphysema are not fully understood. Here we examine mechanisms of ceramide-induced pulmonary emphysema. Male Sprague-Dawley rats were treated with fenretinide (20 mg/kg BW), a synthetic derivative of retinoic acid that causes the formation of ceramide, and we postulated that the effects of fenretinide could be offset by administering sphingosine 1-phosphate (S1P) (100 µg/kg BW). Lung tissues were analyzed and mean alveolar airspace area, total length of the alveolar perimeter and the number of caspase-3 positive …

Multi-Snp Analysis Of Gwas Data Identifies Pathways Associated With Nonalcoholic Fatty Liver Disease, Qing-Rong Chen, Rosemary Braun, Ying Hu, Chunhua Yan, Elizabeth M. Brunt, Daoud Meerzaman, Arun J. Sanyal, Kenneth Buetow

Internal Medicine Publications

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease; the histological spectrum of which ranges from steatosis to steatohepatitis. Nonalcoholic steatohepatitis (NASH) often leads to cirrhosis and development of hepatocellular carcinoma. To better understand pathogenesis of NAFLD, we performed the pathway of distinction analysis (PoDA) on a genome-wide association study dataset of 250 non-Hispanic white female adult patients with NAFLD, who were enrolled in the NASH Clinical Research Network (CRN) Database Study, to investigate whether biologic process variation measured through genomic variation of genes within these pathways was related to the development of steatohepatitis or cirrhosis. Pathways such as …

Modulation Of The Metabiome By Rifaximin In Patients With Cirrhosis And Minimal Hepatic Encephalopathy, Jasmohan S. Bajaj, Douglas M. Heuman, Arun J. Sanyal, Phillip B. Hylemon, Richard K. Sterling, R. Todd Stravitz, Michael Fuchs, Jason M. Ridlon, Kalyani Daita, Pamela Monteith, Nicole A. Noble, Melanie B. White, Andmorgan Fisher, Masoumeh Sikaroodi, Huzefa Rangwala, Patrick M. Gillevet

Internal Medicine Publications

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE.

Methods

Twenty cirrhotics with MHE …

Peripheral Blood Mononuclear Cells Of Breast Cancer Patients Can Be Reprogrammed To Enhance Anti-Her-2/Neu Reactivity And Overcome Myeloid-Derived Suppressor Cells [Poster Abstract], Kyle K. Payne, Christine K. Zoon, Wen Wan, Khin Marlar, Rebecca C. Keim, Mehrab Nasirir Kenari, Latif Kazim, Harry D. Bear, Masoud H. Manjili

Massey Comprehensive Cancer Center Publications

Barriers limiting the efficacy of adoptive cellular therapy (ACT) for breast cancer patients include immune suppression mediated by myeloid-derived suppressor cells (MDSC) and a low frequency of tumor-reactive memory T cells (Tm). Recently, we developed an ex vivo protocol to reprogram tumor-reactive murine splenocytes; these cells were found to be resistant to MDSC suppression and protected FVBN202 mice from tumor challenge. Here, we evaluated the clinical applicability of reprogramming tumor-sensitized PBMCs isolated from patients with early stage breast cancer by treatment with bryostatin 1 and ionomycin (B/I) combined with IL-2, IL-7 and IL-15. Our data demonstrate that reprogrammed cells are …

Development, Disease, And Regeneration Of Tissues In The Dental-Craniofacial Complex, Brian L. Foster, Yong-Hee P. Chun, Erica L. Scheller, Zhao Lin, Chad M. Novince, Avina Paranjpe

Periodontics Publications

This article has no abstract.

Igfbp-3 Inhibits Cytokine-Induced Insulin Resistance And Early Manifestations Of Atherosclerosis, Lathika Mohanraj, Ho-Seong Kim, Wei Li, Qing Cai, Ki E. Kim, Hye-Jung Shin, Yong-Jae Lee, Woo J. Lee, Jung H. Kim, Youngman Oh

Pathology Publications

Metabolic syndrome is associated with visceral obesity, insulin resistance and an increased risk of cardiovascular diseases. Visceral fat tissue primarily consists of adipocytes that secrete cytokines leading to a state of systemic inflammation in obese conditions. One of the IGF-independent functions of IGFBP-3 is its role as an anti-inflammatory molecule. Our study in obese adolescents show a decrease in total IGFBP-3 levels and increase in proteolyzed IGFBP-3 in circulation when compared to their normal counterparts and establishes a positive correlation between IGFBP-3 proteolysis and adiposity parameters as well as insulin resistance. In human adipocytes, we show that IGFBP-3 inhibits TNF-α-induced …

Biomedical Informatics For Computer-Aided Decision Support Systems: A Survey, Ashwin Belle, Mark A. Kon, Kayvan Najarian

Computer Science Publications

The volumes of current patient data as well as their complexity make clinical decision making more challenging than ever for physicians and other care givers. This situation calls for the use of biomedical informatics methods to process data and form recommendations and/or predictions to assist such decision makers. The design, implementation, and use of biomedical informatics systems in the form of computer-aided decision support have become essential and widely used over the last two decades. This paper provides a brief review of such systems, their application protocols and methodologies, and the future challenges and directions they suggest.

An Entropy-Based Automated Cell Nuclei Segmentation And Quantification: Application In Analysis Of Wound Healing Process, Varun Oswal, Ashwin Belle, Robert Diegelmann, Kayvan Najarian

Computer Science Publications

The segmentation and quantification of cell nuclei are two very significant tasks in the analysis of histological images. Accurate results of cell nuclei segmentation are often adapted to a variety of applications such as the detection of cancerous cell nuclei and the observation of overlapping cellular events occurring during wound healing process in the human body. In this paper, an automated entropy-based thresholding system for segmentation and quantification of cell nuclei from histologically stained images has been presented. The proposed translational computation system aims to integrate clinical insight and computational analysis by identifying and segmenting objects of interest within histological …

Comparative Cardiac Toxicity Of Anthracyclines In Vitro And In Vivo In The Mouse, Stefano Toldo, Rachel W. Goehe, Marzia Lotrionte, Eleonora Mezzaroma, Evan T. Sumner, Giuseppe G. L. Biondi-Zoccai, Ignacio M. Seropian, Benjamin W. Van Tassell, Francesco Loperfido, Giovanni Palazzoni, Norbert F. Voelkel, Antonio Abbate, David A. Gewirtz

VCU Health Publications

Purpose

The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo.

Methods

The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and …

Intracellular Function Of Interleukin-1 Receptor Antagonist In Ischemic Cardiomyocytes, Elena Vecile, Aldo Dobrina, Fadi N. Salloum, Benjamin W. Van Tassell, Antonella Falcione, Edorado Gustini, Samuele Secchiero, Sergio Crovella, Gianfranco Sinagra, Nicoletta Finato, Martin J. Nicklin, Antonio Abbate

VCU Health Publications

Background

Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis.

Methodology/Principal Findings

Synthesis of …