Chemicals and Drugs Commons^™

Letter: When Less Is More: Dexamethasone Dosing For Brain Tumors, Minesh Mehta

Minesh Mehta

No abstract provided.

Detecting, Preventing, And Treating Sexually Transmitted Diseases Among Adolescent Arrestees: An Unmet Public Health Need, Christopher Salvatore, Steven Belenko, Richard Dembo, Matthew Rollie, Kristina Childs

Christopher Salvatore

Studies of detained and incarcerated adolescent offenders in the United States indicate that these juveniles have an elevated risk of sexually transmitted diseases (STDs). However, many more arrestees enter the “front end” of the juvenile justice system that is detained or incarcerated, and research into the STD risk profiles and service needs of this larger group is lacking. An expansion of STD testing (including of asymptomatic youths), prevention, and treatment is needed, as is improved knowledge about gender- and race-specific services. A pilot program in Florida has shown that juvenile justice and public health systems can collaborate to implement STD …

Preserving A Precious Resource: Rationalizing The Use Of Antibiotics, Eric Kades

Eric A. Kades

No abstract provided.

Proton Pump Inhibitors Increase The Severity Of Hepatic Encephalopathy In Cirrhotic Patients, Matthew J. Fasullo, Prashanth Rau, Dong-Qi Liu, Erik Holzwanger, Jomol Mathew, Yurima Guilarte-Walker, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Liver cirrhosis is the late stage of hepatic fibrosis and is characterized by portal hypertension that can clinically lead to decompensation in the form of ascites, esophageal/gastric varices or encephalopathy. The most common sequelae associated with liver cirrhosis are neurologic and neuropsychiatric impairments labeled as hepatic encephalopathy (HE). Well established triggers for HE include infection, gastrointestinal bleeding, constipation, and medications. Alterations to the gut microbiome is one of the leading ammonia producers in the body, and therefore may make patients more susceptible to HE.

AIM: To investigate the relationship between the use of proton pump inhibitors (PPIs) and HE …

Iiv-6 Inhibits Nf-Kappab Responses In Drosophila, Cara C. West, Florentina Rus, Ying Chen, Anni Kleino, Monique Gangloff, Don B. Gammon, Neal S. Silverman

Neal Silverman

The host immune response and virus-encoded immune evasion proteins pose constant, mutual selective pressure on each other. Virally encoded immune evasion proteins also indicate which host pathways must be inhibited to allow for viral replication. Here, we show that IIV-6 is capable of inhibiting the two Drosophila NF-kappaB signaling pathways, Imd and Toll. Antimicrobial peptide (AMP) gene induction downstream of either pathway is suppressed when cells infected with IIV-6 are also stimulated with Toll or Imd ligands. We find that cleavage of both Imd and Relish, as well as Relish nuclear translocation, three key points in Imd signal transduction, occur …

Control Of Antiviral Innate Immune Response By Protein Geranylgeranylation, Shigao Yang, Zhaozhao Jiang, Katherine A. Fitzgerald, Donghai Wang

Katherine A. Fitzgerald

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates …

Changes In Anticoagulant Utilization Among United States Nursing Home Residents With Atrial Fibrillation From 2011 To 2016, Matthew Alcusky, David D. Mcmanus, Anne L. Hume, Marc Fisher, Jennifer Tjia, Kate L. Lapane

Jennifer Tjia

Background: Nursing home residents with atrial fibrillation are at high risk for ischemic stroke and bleeding events. The most recent national estimate (2004) indicated less than one third of this high-risk population was anticoagulated. Whether direct-acting oral anticoagulant ( DOAC ) use has disseminated into nursing homes and increased anticoagulant use is unknown.

Methods and Results: A repeated cross-sectional design was used to estimate the point prevalence of oral anticoagulant use on July 1 and December 31 of calendar years 2011 to 2016 among Medicare fee-for-service beneficiaries with atrial fibrillation residing in long-stay nursing homes. Nursing home residence was determined …

Lipoprotein(A) Plasma Levels, Bone Mineral Density And Risk Of Hip Fracture: A Post Hoc Analysis Of The Women's Health Initiative, Usa, Bernhard Haring, Carolyn J. Crandall, Laura Carbone, Simin Liu, Wenjun Li, Karen C. Johnson, Jean Wactawski-Wende, Aladdin H. Shadyab, Margery L. Gass, Victor Kamensky, Jane A. Cauley, Sylvia Wassertheil-Smoller

Wenjun Li

OBJECTIVES: Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women.

DESIGN: Post hoc analysis of data from the Women's Health Initiative (WHI), USA.

SETTING: 40 clinical centres in the USA.

PARTICIPANTS: The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and …

Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman

Neal Silverman

Fruit flies elicit effective defense responses against numerous microbes. The responses against Gram-negative bacteria are mediated by the Imd pathway, an evolutionarily conserved NF-kappaB pathway recognizing meso-diaminopimelic acid (DAP)-type peptidoglycan from bacterial cell walls. Several reviews already provide a detailed view of ligand recognition and signal transduction during Imd signaling, but the formation and regulation of the signaling complex immediately downstream of the peptidoglycan-sensing receptors is still elusive. In this review, we focus on the formation of the Imd amyloidal signaling center and post-translational modifications in the assembly and disassembly of the Imd signaling complex.

Pnaktide Attenuates Steatohepatitis And Atherosclerosis By Blocking Na/K-Atpase/Ros Amplification In C57bi6 And Apoe Knockout Mice Fed A Western Diet, K Sodhi, K Srikanthan, P Goguet-Rubio, A Nichols, A Mallick, A Nawab, R Martin, P Shah, M Chaudhry, S Sigdel, M El-Hamdani, J Liu, Z Xie, Nader Abraham, J Shapiro

Nader G. Abraham

We have previously reported that the alpha1 subunit of sodium potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a "western" diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted …

Vegf/Neuropilin Signaling In Cancer Stem Cells, Arthur M. Mercurio

Arthur M. Mercurio

The function of vascular endothelial growth factor (VEGF) in cancer extends beyond angiogenesis and vascular permeability. Specifically, VEGF-mediated signaling occurs in tumor cells and this signaling contributes to key aspects of tumorigenesis including the self-renewal and survival of cancer stem cells (CSCs). In addition to VEGF receptor tyrosine kinases, the neuropilins (NRPs) are critical for mediating the effects of VEGF on CSCs, primarily because of their ability to impact the function of growth factor receptors and integrins. VEGF/NRP signaling can regulate the expression and function of key molecules that have been implicated in CSC function including Rho family guanosine triphosphatases …

Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo

Gyongyi Szabo

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage- and pathogen-associated molecular patterns contribute to a self-perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM-1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand-independent TREM-1 inhibitory peptides that were formulated into human high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA/E31-HDL. As revealed …

Pubertal Lipid Levels Are Significantly Lower In Youth With Type 1 Diabetes Who Experienced Partial Clinical Remission, Benjamin U. Nwosu, Shwetha Rupendu, Emily Zitek-Morrison, Deepa Patel, Tony R. Villalobos-Ortiz, Gabrielle Jasmin, Bruce A. Barton

Benjamin U. Nwosu

Importance: The physiologic changes in lipids during puberty in type 1 diabetes (T1D) is unclear as subjects in previous studies were not stratified by partial clinical remission (PCR) status.

Aim: To determine the effect of PCR on lipid changes during puberty in youth with T1D.

Subjects and Methods: A retrospective cross-sectional study of 194 subjects consisting of 71 controls of age 12.9±1.3y and 123 subjects with T1D stratified into remitters (n=44, age 13.0±0.8y) and non-remitters (n=79, age 11.2±0.6y). PCR was defined as insulin-dose adjusted HbA1c of ≤9. Pubertal status was determined by Tanner staging.

Results: Among the pubertal cohort, low-density …

An Automated Bayesian Pipeline For Rapid Analysis Of Single-Molecule Binding Data, Carlas Smith, Karina Jouravleva, Maximiliaan Huisman, Samson M. Jolly, Phillip D. Zamore, David Grünwald

David Grünwald

Single-molecule binding assays enable the study of how molecular machines assemble and function. Current algorithms can identify and locate individual molecules, but require tedious manual validation of each spot. Moreover, no solution for high-throughput analysis of single-molecule binding data exists. Here, we describe an automated pipeline to analyze single-molecule data over a wide range of experimental conditions. In addition, our method enables state estimation on multivariate Gaussian signals. We validate our approach using simulated data, and benchmark the pipeline by measuring the binding properties of the well-studied, DNA-guided DNA endonuclease, TtAgo, an Argonaute protein from the Eubacterium Thermus thermophilus. We …

Children With Type 1 Diabetes Who Experienced A Honeymoon Phase Had Significantly Lower Ldl Cholesterol 5 Years After Diagnosis, Benjamin U. Nwosu, Bo Zhang, Sanaa S. Ayyoub, Stephanie Choi, Tony R. Villalobos-Ortiz, Laura C. Alonso, Bruce A. Barton

Benjamin U. Nwosu

IMPORTANCE: Landmark studies showed that partial clinical remission in new-onset type 1 diabetes is associated with reduced prevalence of long-term complications, but early clinical indicators of this favorable outcome are poorly characterized.

AIM: To determine if there were any differences in lipid parameters, especially LDL-cholesterol, between remitters and non-remitters 4 to 5 years after the diagnosis of type 1 diabetes after controlling for hemoglobin A1c, body mass index, and pubertal status.

SUBJECTS AND METHODS: A longitudinal retrospective cohort study of 123 subjects of mean age 11.9 +/- 2.9 years, [male 11.7 +/- 2.9 years, (n = 55); female 12.0 +/- …

Lipopolysaccharide Induced Map Kinase Activation In Raw 264.7 Cells Attenuated By Cerium Oxide Nanoparticles, Vellaisamy Selvaraj, Niraj Nepa, Steven Rogers, Nandini D.P.K. Manne, Ravi K. Arvapalli, Kevin M. Rice, Shinichi Asano, Erin Fankenhanel, J. Y. Ma, Tolou Shokuhfar, Mani Maheshwari, Eric R. Blough

Mani Maheshwari

High mortality rates are associated with the life threatening disease of sepsis. Improvements in septic patient survivability have failed to materialize with currently available treatments. This article represents data regarding a study published in biomaterials (Vellaisamy et al., Biomaterials, 2015, in press). with the purpose of evaluating whether severe sepsis mortality and associated hepatic dysfunction induced by lipopolysaccharide (LPS) can be prevented by cerium oxide nanoparticles (CeO2NPs) treatment in male Sprague Dawley rats. Here we provide the information about the method and processing of raw data related to our study publish in Biomaterials and Data in Brief (Vellaisamy et al., …

Www.Cd-Genomics.Com, Rachel Ann

Rachel Ann

No abstract provided.

Crystal Structure Of Apobec3a Bound To Single-Stranded Dna Reveals Structural Basis For Cytidine Deamination And Specificity, Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffer

Celia A. Schiffer

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active site …

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a small protein …

Inhibition Of Cholinergic Signaling Causes Apoptosis In Human Bronchioalveolar Carcinoma, Jamie K. Lau, Kathleen C. Brown, Brent A. Thornhill, Clayton M. Crabtree, Aaron M. Dom, Theodore R. Witte, W. Elaine Hardman, Christopher A. Mcnees, Cody A. Stover, A. Betts Carpenter, Haitao Luo, Yi C. Chen, Brandon S. Shiflett, Piyali Dasgupta

Kathleen C. Brown

Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by α7-, α3β2-, and β3-nAChRs, ChAT and VAChT pathways. We observed that …

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency. …

Theaflavin-3, 3'-Digallate Decreases Human Ovarian Carcinoma Ovcar-3 Cell-Induced Angiogenesis Via Akt And Notch-1 Pathways, Not Via Mapk Pathways, Ying Gao, Gary O. Rankin, Youying Tu, Yi Charlie Chen

Gary O. Rankin

Theaflavin-3, 3'-digallate (TF3) is a black tea polyphenol produced from polymerization and oxidization of the green tea ployphenols epicatechin gallate and (-)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anticancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the present study, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cell-induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by downregulating HIF-1α and VEGF. …

A New Sv2a Ligand For Epilepsy, Michael A. Rogawski

Michael A. Rogawski

The Changing Landscape Of Biosimilars In Rheumatology, Thomas Dorner, Vibeke Strand, Paul Cornes, Joao Goncalves, Laszlo Gulacsi, Jonathan Kay, Tore K. Kvien, Josef S. Smolen, Yoshiya Tanaka, Gerd R. Burmester

Jonathan Kay

Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health-economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities …

Proton Pump Inhibitors: The Perils Of Turning 30, Beth Careyva Md, Katarzyna Jabbour Pharmd, Ahmad Rasheed

Beth A. Careyva, M.D.

No abstract provided.

Which Drugs Cause Cancer?, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

Animal tests yield misleading results.

Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

The regulation of human exposures to potential carcinogens constitutes society’s most important use of animal carcinogenicity data. However, for environmental contaminants of greatest U.S. concern, we found that in most cases (58.1%; 93/160) the U.S. Environmental Protection Agency (EPA) considered the animal data inadequate to support a classification of probable human carcinogen or noncarcinogen.

The World Health Organisation’s International Agency for Research on Cancer (IARC) is a leading international authority on carcinogenicity assessments. For chemicals lacking human exposure data (the great majority), IARC classifications of identical chemicals were significantly more conservative than EPA classifications (p

Tolerability Of Induction Chemotherapy Dosing Practices In Acute Myeloid Leukemia Patients, Kaylene M. Peric, David J. Reeves

David Reeves

For patients with high body surface areas (BSA), differing chemotherapy dosing strategies have been utilized in attempts to reduce toxicity. In a retrospective evaluation, we compared the effects of chemotherapy dosing in acute myeloid leukemia patients with high BSA (>2 m2) who received capped doses (n = 12) to those who received uncapped doses (n = 24), and to patients with BSA ≤ 2 m2 (n = 42). There were no statistically significant differences among groups (BSA ≤ 2 m2, BSA > 2 m2 capped, and BSA > 2 m2 uncapped) in the incidences of febrile neutropenia (85.7, 66.7, and 75.0%, …

Successful Desensitization To Docetaxel After Severe Hypersensitivity Reactions In Two Patients, David J. Reeves, Michael J. Callahan, Gregory P. Sutton

David Reeves

Purpose Two cases of successful desensitization to docetaxel after severe hypersensitivity reactions are reported. Summary Two patients with gynecological malignancies (uterine leiomyosarcoma and ovarian adenocarcinoma) experienced severe hypersensitivity reactions with docetaxel, including flushing, numbness, sharp radiating pain, severe nausea and vomiting, apnea, and unresponsiveness. Both patients received ondansetron before docetaxel. One patient received dexamethasone, diphenhydramine, and famotidine premedication before docetaxel, as she had previously reacted to paclitaxel. Docetaxel infusions were stopped, and the reactions were treated with diphenhydramine and dexamethasone (one patient also received famotidine). After resolution of symptoms, the docetaxel was not reinitiated due to the nature of the …

Drug-Drug Interaction Between Methotrexate And Levetiracetam Resulting In Delayed Methotrexate Elimination, Emily Bain, Ruemu E. Birhiray, David J. Reeves

David Reeves

Objective: To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. Case Report: A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle …