Chemicals and Drugs Commons^™

Pediatric Pharmacogenomics: A Systematic Assessment Of Ontogeny And Genetic Variation To Guide The Design Of Statin Studies In Children., Jonathan B. Wagner, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

The dose-exposure-response relationship for drugs may differ in pediatric patients compared with adults. Many clinical studies have established drug dose-exposure relationships across the pediatric age spectrum; however, genetic variation was seldom included. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies.

Tlr4 Mutation Reduces Microglial Activation, Increases Aβ Deposits And Exacerbates Cognitive Deficits In A Mouse Model Of Alzheimer's Disease, Min Song, Jingji Jin, Jinghong Kou, Abhinandan Pattanayak, Jamaal Rehman, Hong-Duck Kim, Ken-Ichiro Fukuchi

NYMC Faculty Publications

BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Aβ deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Aβ deposits and buffer-soluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it …

A Survey Of Oxidative Paracatalytic Reactions Catalyzed By Enzymes That Generate Carbanionic Intermediates: Implications For Ros Production, Cancer Etiology, And Neurodegenerative Diseases, Victoria Bunik, John Schloss, John T. Pinto, Natalia Dudareva, Arthur J L Cooper

NYMC Faculty Publications

Enzymes that generate carbanionic intermediates often catalyze paracatalytic reactions with O2 and other electrophiles not considered “normal” reactants. For example, pyridoxal 5′-phosphate (PLP)—containing pig kidney dopa decarboxylase oxidizes dopamine with molecular O2 to 3,4-dihydroxyphenylacetaldehyde at about 1% of the rate at which it catalyzes nonoxidative dopa decarboxylation. The mutant Y332F enzyme, however, catalyzes stoichiometric conversion of dopa to 3,4-dihydroxyphenylacetaldehyde, suggesting that even minor structural changes may alter or initiate paracatalytic reactions catalyzed by certain enzymes. Carbanions generated by several thiamine diphosphate (ThDP)—dependent enzymes react with different electrophiles, transforming some xenobiotics and endogenous compounds into potentially biologically hazardous products. The detrimental …

Serum 25-Hydroxyvitamin D Level And Acute-Phase Reaction Following Initial Intravenous Bisphosphonate., Tarak Srivastava, Hongying Dai, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Ranolazine Is Effective For Acute Or Chronic Ischemic Dysfunction With Heart Failure, Sudip Nanda Md, Facp, Matthew W. Martinez Md, Tanujit Dey Phd

Department of Medicine

No abstract provided.

Mechanisms Of Oxidant Generation By Catalase, Diane E. Heck, Michael Shakarjian, Hong-Duck Kim, Jeffrey Laskin, Anna M. Vetrano

NYMC Faculty Publications

The enzyme catalase converts solar radiation into reactive oxidant species (ROS). In this study, we report that several bacterial catalases (hydroperoxidases, HP), including Escherichia coli HP-I and HP-II also generate reactive oxidants in response to ultraviolet B light (UVB). HP-I and HP-II are identical except for the presence of NADPH. We found that only one of the catalases, HPI, produces oxidants in response to UVB light, indicating a potential role for the nucleotide in ROS production. This prompts us to speculate that NADPH may act as a cofactor regulating ROS generation by mammalian catalases. Structural analysis of the NADPH domains …

Enalapril In Infants With Single Ventricle: Results Of A Multicenter Randomized Trial., Daphne T. Hsu, Victor Zak, Lynn Mahony, Lynn A. Sleeper, Andrew M. Atz, Jami C. Levine, Piers C. Barker, Chitra Ravishankar, Brian W. Mccrindle, Richard V. Williams, Karen Altmann, Nancy S. Ghanayem, Renee Margossian, Wendy K. Chung, William L. Border, Gail D. Pearson, Mario P. Stylianou, Seema Mital, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown.

METHODS AND RESULTS: The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg . kg(-1) . d(-1)) or placebo who were followed up until 14 months of age. The primary end …

Plant Vaccines: An Immunological Perspective., Douglas C. Hooper

Department of Cancer Biology Faculty Papers

The advent of technologies to express heterologous proteins in planta has led to the proposition that plants may be engineered to be safe, inexpensive vehicles for the production of vaccines and possibly even vectors for their delivery. The immunogenicity of a variety of antigens of relevance to vaccination expressed in different plants has been assessed. The purpose of this article is to examine the utility of plant-expression systems in vaccine development from an immunological perspective.

Atorvastatin May Have No Effect On Acute Phase Reaction In Children After Intravenous Bisphosphonate Infusion., Tarak Srivastava, Connie J. Haney, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Intravenous bisphosphonate therapy is associated with acute phase reaction characterized by fever and musculoskeletal pain. Bisphosphonates have been shown in vitro to activate gammadeltaT-cells to proliferate and produce cytokines, suggesting a role in acute phase reaction, which can be effectively blocked by statins. We conducted a double-blind randomized crossover placebo controlled study in 12 children (12.1 +/- 4.2 yr; 10 girls and 2 boys) receiving intravenous bisphosphonates to evaluate whether statins can be used to prevent acute phase reaction associated with therapy. Children received two cycles given 3-4 mo apart of intravenous bisphosphonate given on 2 consecutive days in each …

Rationale And Design Of A Trial Of Angiotensin-Converting Enzyme Inhibition In Infants With Single Ventricle., Daphne T. Hsu, Seema Mital, Chitra Ravishankar, Renee Margossian, Jennifer S. Li, Lynn A. Sleeper, Richard V. Williams, Jami C. Levine, Brian W. Mccrindle, Andrew M. Atz, Darlene Servedio, Lynn Mahony, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors are known to improve clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology show abnormalities in ventricular function as well as poor growth. The ability of an ACE inhibitor to preserve ventricular function and improve growth in these infants is unknown.

METHODS: The Pediatric Heart Network designed a randomized, double-blind trial to compare outcomes in infants with single-ventricle physiology receiving enalapril or placebo. Neonates < or =45 days old were eligible. The primary outcome is weight-for-age Z-score at 14 months of age. Secondary outcomes include other measures of somatic growth, laboratory and functional measures of heart failure, developmental indices, measures of ventricular size and function, and the relationship of the renin-angiotensin-aldosterone system genotype to the response to enalapril. The incidence and spectrum of adverse events will also be compared between treatment groups.

RESULTS: A total of 1,245 neonates were screened and 533 (43%) were eligible. The consent rate was 43%; 230 subjects were enrolled. Parental reluctance to …

Stat5 Regulation Of Bcl10 Parallels Constitutive Nfkappab Activation In Lymphoid Tumor Cells., Zsuzsanna S Nagy, Matthew J Lebaron, Jeremy A Ross, Abhisek Mitra, Hallgeir Rui, Robert A Kirken

Department of Cancer Biology Faculty Papers

BACKGROUND: Signal Transducer and Activator of Transcription 5 A and B (STAT5) are key survival factors in cells of the lymphoid lineage. Identification of novel, tissue-specific STAT5 regulated genes would advance the ability to combat diseases due to aberrant STAT5 signaling. In the present work a library of human STAT5 bound genomic elements was created and validated. RESULTS: Of several STAT5 responsive genomic regulatory elements identified, one was located within the first intron of the human BCL10 gene. Chromatin immuno-precipitation reactions confirmed constitutive in vivo STAT5 binding to this intronic fragment in various human lymphoid tumor cell lines. Interestingly, non-phosphorylated …

Single Daily Dosing Ceftriaxone And Metronidazole Vs Standard Triple Antibiotic Regimen For Perforated Appendicitis In Children: A Prospective Randomized Trial., Shawn D. St Peter, Kuojen Tsao, Troy L. Spilde, G W. Holcomb Iii, Susan W. Sharp, J Patrick Murphy, Charles L. Snyder, Ronald J. Sharp, Walter S. Andrews, Daniel J. Ostlie

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: Appendicitis is the most common emergency condition in children. Historically, a 3-drug regimen consisting of ampicillin, gentamicin, and clindamycin (AGC) has been used postoperatively for perforated appendicitis. A retrospective review at our institution has found single day dosing of ceftriaxone and metronidazole (CM) to be a more simple and cost-effective antibiotic strategy. Therefore, we performed a prospective, randomized trial to compare efficacy and cost-effectiveness of these 2 regimens.

METHODS: After internal review board approval (IRB no. 04 12-149), children found to have perforated appendicitis at appendectomy were randomized to either once daily dosing of CM (2 total doses per …

Nerve Growth Factor Regulation Of Cyclin D1 In Pc12 Cells Through A P21ras Extracellular Signal-Regulated Kinase Pathway Requires Cooperative Interactions Between Sp1 And Nuclear Factor-Kappab., Francesco Marampon, Mathew C Casimiro, Maofu Fu, Michael J Powell, Vladimir M Popov, Jaime Lindsay, Bianca M Zani, Carmela Ciccarelli, Genichi Watanabe, Richard J Lee, Richard G Pestell

Department of Cancer Biology Faculty Papers

The PC12 pheochromocytoma cell line responds to nerve growth factor (NGF) by exiting from the cell cycle and differentiating to induce extending neurites. Cyclin D1 is an important regulator of G1/S phase cell cycle progression, and it is known to play a role in myocyte differentiation in cultured cells. Herein, NGF induced cyclin D1 promoter, mRNA, and protein expression via the p21(RAS) pathway. Antisense- or small interfering RNA to cyclin D1 abolished NGF-mediated neurite outgrowth, demonstrating the essential role of cyclin D1 in NGF-mediated differentiation. Expression vectors encoding mutants of the Ras/mitogen-activated protein kinase pathway, and chemical inhibitors, demonstrated NGF …

Micro Rna 145 Targets The Insulin Receptor Substrate-1 And Inhibits The Growth Of Colon Cancer Cells, Bin Shi, Laura Sepp-Lorenzino, Marco Prisco, Peter Linsley, Tiziana Deangelis, Renato Baserga

Department of Cancer Biology Faculty Papers

The insulin receptor substrate-1 (IRS-1), a docking protein for both the type 1 insulin-like growth factor receptor (IGF-IR) and the insulin receptor, is known to send a mitogenic, anti-apoptotic, and anti-differentiation signal. Several micro RNAs (miRs) are suggested by the data base as possible candidates for targeting IRS-1. We show here that one of the miRs predicted by the data base, miR145, whether transfected as a synthetic oligonucleotide or expressed from a plasmid, causes down-regulation of IRS-1 in human colon cancer cells. IRS-1 mRNA is not decreased by miR145, while it is down-regulated by an siRNA targeting IRS-1. Targeting of …

Sirtuins, Nuclear Hormone Receptor Acetylation And Transcriptional Regulation, James R. Whittle, Michael J. Powell, Vladimir M. Popov, L. Andrew Shirley, Chenguang Wang, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Endocrine signaling via nuclear receptors (NRs) is known to play an important role in normal physiology as well as in human tumor progression. Hormones regulate gene expression by altering local chromatin structure and, thereby, accessibility of transcriptional co-regulators to DNA. Recently it has been shown that non-histone proteins involved in hormone signaling, such as nuclear receptors and NR co-activators, are regulated by acetylation, resulting in their altered transcriptional activity. NAD-dependent protein deacetylases, the sirtuins (Sir2-related enzymes), directly modify NRs. Because sirtuins have been shown to regulate tumor cellular growth, aging, metabolic signaling and endocrine hormone signaling, they might play a …

Cell Fate Determination Factor Dach1 Inhibits C-Jun-Induced Contact-Independent Growth, Kongming Wu, Manran Liu, Anping Li, Howard Donninger, Mahadev Rao, Xuanmao Jiao, Michael P. Lisanti, Ales Cvekl, Michael Birrer, Richard G. Pestell

Department of Cancer Biology Faculty Papers

The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun-induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-jun(f1/f1) 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli …

Cyclin D1 Repression Of Nuclear Respiratory Factor 1 Integrates Nuclear Dna Synthesis And Mitochondrial Function., Chenguang Wang, Zhiping Li, Yinan Lu, Runlei Du, Sanjay Katiyar, Jianguo Yang, Maofu Fu, Jennifer E Leader, Andrew Quong, Phyllis M Novikoff, Richard Pestell

Department of Cancer Biology Faculty Papers

Cyclin D1 promotes nuclear DNA synthesis through phosphorylation and inactivation of the pRb tumor suppressor. Herein, cyclin D1 deficiency increased mitochondrial size and activity that was rescued by cyclin D1 in a Cdk-dependent manner. Nuclear respiratory factor 1 (NRF-1), which induces nuclear-encoded mitochondrial genes, was repressed in expression and activity by cyclin D1. Cyclin D1-dependent kinase phosphorylates NRF-1 at S47. Cyclin D1 abundance thus coordinates nuclear DNA synthesis and mitochondrial function.

Heparin Modulates The 99-Loop Of Factor Ixa: Effects On Reactivity With Isolated Kunitz-Type Inhibitor Domains, Pierre F. Neuenschwander, Stephen R. Williamson, Armen Nalian, Kimberly J. Baker-Deadmond

Faculty Publications

Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin (enoxaparin). Previous studies by us have suggested that this effect involves allosteric modulation of factor IXa. We examined the reactivity of factor IXa with several isolated Kunitz-type inhibitor domains: basic pancreatic trypsin inhibitor, the Kunitz inhibitor domain of protease Nexin-2, and the first two inhibitor domains of tissue factor pathway inhibitor. We find that enhancement of factor IXa reactivity by enoxaparin is greatest for basic pancreatic trypsin inhibitor (>10-fold), followed by the second tissue factor pathway inhibitor domain (1.7-fold) and the Kunitz inhibitor …

Slbp Is Associated With Histone Mrna On Polyribosomes As A Component Of The Histone Mrnp, Michael L. Whitfield, Handan Kaygun, Judith A. Erkmann, W. H. Davin Townley-Tilson, Zbig Dominski, William F. Marzluff

Dartmouth Scholarship

The stem–loop binding protein (SLBP) binds the 3′ end of histone mRNA and is present both in nucleus, and in the cytoplasm on the polyribosomes. SLBP participates in the processing of the histone pre-mRNA and in translation of the mature message. Histone mRNAs are rapidly degraded when cells are treated with inhibitors of DNA replication and are stabilized by inhibitors of translation, resulting in an increase in histone mRNA levels. Here, we show that SLBP is a component of the histone messenger ribonucleoprotein particle (mRNP). Histone mRNA from polyribosomes is immunoprecipitated with anti-SLBP. Most of the SLBP in cycloheximide-treated cells …

Probucol Prevents Early Coronary Heart Disease And Death In The High-Density Lipoprotein Receptor Sr-Bi/Apolipoprotein E Double Knockout Mouse, Anne Braun, Songwen Zhang, Helena E. Miettinen, Shamsah Ebrahim, Teresa M. Holm, Eliza Vasile, Mark J. Post

Dartmouth Scholarship

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment …

Effects Of Tacrolimus On Ischemia-Reperfusion Injury., Shawn D. St Peter, Adyr A. Moss, David C. Mulligan

Manuscripts, Articles, Book Chapters and Other Papers

In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-kappaB. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important …

Tacrolimus As A Liver Flush Solution To Ameliorate The Effects Of Ischemia/Reperfusion Injury Following Liver Transplantation., Shawn D. St Peter, David J. Post, Manuel I. Rodriguez-Davalos, David D. Douglas, Adyr A. Moss, David C. Mulligan

Manuscripts, Articles, Book Chapters and Other Papers

The goal of this report is to evaluate in a prospective randomized fashion the effect of flushing hepatic allografts with tacrolimus before transplantation. A prospective, double-blinded, randomized trial was performed. Twenty patients receiving orthotopic liver transplants from October 2000 to October 2001 were randomized into two groups. Group 1 (active) was administered tacrolimus, 20 ng/mL, plus Plasma-lyte A (Baxter Healthcare Corp, Deerfield, IL) liver flush solution; and group 2 (placebo) was administered only Plasma-lyte A. Ischemia/reperfusion injury was assessed in both groups after transplantation by means of serum laboratory values to assess hepatocellular damage, synthetic function, and ion transport capacity. …

Regulation Of Collagenase Gene Expression By Il-1 Beta Requires Transcriptional And Post-Transcriptional Mechanisms, Matthew P. Vincenti, Charles I. Coon, Oneil Lee, Constance E. Brinckerhoff

Dartmouth Scholarship

Interleukin-1 beta is believed to contribute to the pathophysiology of rheumatoid arthritis by activating collagenase gene expression. We have used a cell culture model of rabbit synovial fibroblasts to examine the molecular mechanisms of IL-1 beta-mediated collagenase gene expression. Stimulation of rabbit synovial fibroblasts with 10 ng/ml recombinant human IL-1 beta resulted in a 20-fold increase in collagenase mRNA by 12 h. Transient transfection studies using collagenase promoter-CAT constructs demonstrated that proximal sequences responded poorly to IL-1 beta, possibly due to insufficient activation of AP-1 by this cytokine. More distal sequences were required for IL-1 beta responsiveness, with a 4700 …