tbuckley/cabot-search huggingface dataset:
The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation
Authors: Martijn P. Lolkema, Hilde H. Bohets, Hendrik-Tobias Arkenau, Ann Lampo, Erio Barale, Maja J.A. de Jonge, Leni van Doorn, Peter Hellemans, Johann S. de Bono, Ferry A.L.M. Eskens
Journal: Clinical Cancer Research (2015)

The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor.We performed a phase I dose-escalation study according to the standard 3+3 design.Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active.Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.
Morbid anatomy of 'erosive osteoarthritis' of the interphalangeal finger joints: an optimised scoring system to monitor disease progression in affected joints
Authors: G. Verbruggen, R. Wittoek, B. V. Cruyssen, D. Elewaut
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objectives</h3> To develop and validate a quantitative radiographic scoring system, the Ghent University Scoring System (GUSS), with better ability to detect progression over a shorter period of time in erosive osteoarthritis (OA) of the interphalangeal (IP) finger joints compared with the existing anatomic phase scoring system. <h3>Methods</h3> Thirty IP finger joints showing erosive features at baseline or follow-up were selected from 18 patients with erosive hand OA. Posteroanterior radiographs of these joints obtained at baseline, 6 and 12 months—totalling 90 images—were used for the study. All joints were first scored according to the original anatomic phase scoring system. Erosive progression and signs of repair or remodelling were then scored by indicating the proportion of normal subchondral bone, subchondral plate and joint space on an 11-point rating scale (range 0–100 with 10 unit increases). Inter- and intrareader reproducibility was studied using intraclass correlation coefficients (ICCs). Based on the within-variance of two readers, the smallest detectable change (SDC) was calculated and allowed identification of joints with changes above the SDC as 'progressors'. <h3>Results</h3> Longitudinal inter-reader ICC scores rated well for all variables and the total score (ICC 0.86–0.93). To identify 'real' change over background noise, a change of at least 40 units on the total score (range 0–300) over 12 months (SDC 0–12:36.0), and 50 units over 6 months (SDC 0–6:47.6) had to be present. 60% of the 30 joints were identified as 'progressors' over 6 months compared with 33.3% with the classical anatomical scoring system, and 70% versus 56.6%, respectively, over 12 months. <h3>Conclusion</h3> GUSS, is a reliable method to score radiographic change over time in erosive IP OA and detects more progression over a shorter period of time than the classical scoring system.
In vivo trans-splicing of 5′ and 3′ segments of Pre-mRNA directed by corresponding DNA sequences delivered by gene transfer
Authors: Robert G Pergolizzi, Alexander E Ropper, Rachel Dragos, Alicia C Reid, Katsutoshi Nakayama, Yadi Tan, John R Ehteshami, Struhan H Coleman, Randi B Silver, Neil R Hackett, André Menez, Ronald G Crystal
Journal: Molecular Therapy (2003)

We have developed a new paradigm of in vivo gene transfer termed "segmental trans-splicing" (STS), in which individual "donor" and "acceptor" DNA sequences, delivered in vitro or in vivo, generate pre-mRNAs with 5' and 3' splice signals, respectively, and complementary hybridization domains through which the two pre-mRNAs interact, facilitating trans-splicing of the two mRNA fragments. To demonstrate STS, we used alpha-cobratoxin, a neurotoxin that binds irreversibly to postsynaptic nicotinic acetylcholine receptors. Cells or animals receiving both donor and acceptor plasmids, but neither plasmid alone, yielded RT-PCR products with the correct sequence of mature alpha-cobratoxin mRNA, suggesting that trans-splicing had occurred. Mice receiving intravenous administration of > or = 7.5 microg donor + acceptor plasmids, but not either plasmid alone, died within 6 h. These data demonstrate that segmental trans-splicing occurs in vivo. This approach should permit the intracellular assembly of molecules hitherto too large to be accommodated within current gene transfer vectors.
NAD<sup>+</sup>-dependent histone deacetylases (sirtuins) as novel therapeutic targets
Authors: Jörg Schemies, Urszula Uciechowska, Wolfgang Sippl, Manfred Jung
Journal: Medicinal Research Reviews (2009)

Histone deacetylases (HDACs) are enzymes that cleave off acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Four different classes of HDACs have been identified in humans so far. Although classes I, II, and IV are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD+) for their catalytic activity. According to their homology to Sir2p, a yeast histone deacetylase, the class III is also termed sirtuins. Seven members have been described in humans so far. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with the pathogenesis of cancer, HIV, metabolic, or neurological diseases. Herein, we present an overview over sirtuins including their biology, targets, inhibitors, and activators and their potential as new therapeutic agents. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 6, 861–889, 2010
Fatty acid amide hydrolase deficiency limits early pregnancy events
Authors: H. Wang
Journal: Journal of Clinical Investigation (2006)

Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine–selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate “anandamide tone” for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Δ9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah–/– mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.
Multigene Assays to Improve Assessment of Recurrence Risk and Benefit From Chemotherapy in Early-Stage Colon Cancer: Has the Time Finally Arrived, or Are We Still Stage Locked?
Authors: Josep Tabernero, José Baselga
Journal: Journal of Clinical Oncology (2010)

growth of cardiac myocytes: Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 273:10261-10269, 1998 14. de Korte MA, de Vries EG, Lub-de Hooge MN, et al: 111Indiumtrastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: A clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer 43:2046-2051, 2007 15. Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 13:228-233, 2007 16. Gianni L, Eiermann W, Semiglazov V, et al: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2negative cohort. Lancet 375:377-384, 2010
Methicillin-Resistant<i>Staphylococcus aureus</i>Disease in Three Communities
Authors: Scott K. Fridkin, Jeffrey C. Hageman, Melissa Morrison, Laurie Thomson Sanza, Kathryn Como-Sabetti, John A. Jernigan, Kathleen Harriman, Lee H. Harrison, Ruth Lynfield, Monica M. Farley
Journal: New England Journal of Medicine (2005)

Methicillin-resistant Staphylococcus aureus (MRSA) infection has emerged in patients who do not have the established risk factors. The national burden and clinical effect of this novel presentation of MRSA disease are unclear.
Stimulation of migration of human aortic smooth muscle cells by vitronectin: implications for atherosclerosis
Authors: S. L Brown, C. H Lundgren, T. Nordt, S. Fujii
Journal: Cardiovascular Research (1994)

Migration of smooth muscle cells into the neointima has been implicated in atherogenesis. Vitronectin, a serum factor that promotes cell spreading and attachment, accumulates in atherosclerotic human tissues. The aim of this study was to determine the role of vitronectin and its receptor (integrin alpha V beta 3) in migration of smooth muscle cells.Human aortic smooth muscle cell migration was studied in modified Boyden chambers. Expression of vitronectin receptor was determined by northern blotting of receptor mRNA and immunoprecipitation of receptor protein.Vitronectin dose dependently increased smooth muscle cell migration by an amount comparable to that induced by platelet derived growth factor, (PDGF)-BB. Antiserum to alpha V beta 3 diminished vitronectin driven migration. Northern blot analysis showed low constitutive expression of alpha V and beta 3 mRNA by smooth muscle cell and rapid induction with transforming growth factor beta (TGF-beta) and thrombin. Immunoprecipitation confirmed increased synthesis of the alpha V beta 3 vitronectin receptor complex by TGF-beta or thrombin. Smooth muscle cells pretreated with TGF-beta or thrombin showed increased vitronectin driven migration. cAMP suppressed induction of migration, but inhibition of protein kinase C increased it.These results show that vitronectin-induced human aortic smooth muscle cell migration is mediated by alpha V beta 3 vitronectin receptor and expression of the receptor is induced by TGF-beta and thrombin, which in turn induce vitronectin driven, vitronectin receptor modulated smooth muscle cell migration.
Induction of Tissue Factor by Urokinase in Lung Epithelial Cells and in the Lungs
Authors: Sreerama Shetty, Yashodhar P. Bhandary, Shwetha K. Shetty, Thirunavukkarasu Velusamy, Praveenkumar Shetty, Khalil Bdeir, Margaret R. Gyetko, Douglas B. Cines, Steven Idell, Pierre F. Neuenschwander, Clemens Ruppert, Andreas Guenther, Edward Abraham, Rashmi S. Shetty
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Urokinase-type plasminogen activator (uPA) regulates extracellular proteolysis in lung injury and repair. Although alveolar expression of uPA increases, procoagulant activity predominates.Objectives: This study was designed to investigate whether uPA alters the expression of tissue factor (TF), the major initiator of the coagulation cascade, in lung epithelial cells (ECs).Methods: Bronchial, primary airway ECs and C57B6 wild-type, uPA-deficient (uPA−/−) mice were exposed to phosphate-buffered saline, uPA, or LPS. Immunohistochemistry, protein, cellular, and molecular techniques were used to assess TF expression and activity.Measurements and Main Results: uPA enhanced TF mRNA and protein expression, and TF-dependent coagulation in lung ECs. uPA-induced expression of TF involves both increased synthesis and enhanced stabilization of TF mRNA. uPA catalytic activity had little effect on induction of TF. By contrast, deletion of the uPA receptor binding growth factor domain from uPA markedly attenuated the induction of TF, suggesting that uPA receptor binding is sufficient for TF induction. Lung tissues of uPA-deficient mice expressed less TF protein and mRNA compared with wild-type mice. In addition, intratracheal instillation of mouse uPA increased TF mRNA and protein expression and accelerated coagulation in lung tissues. uPA−/− mice exposed to LPS failed to induce TF.Conclusions: uPA increased TF expression and TF-dependent coagulation in the lungs of mice. We hypothesize that uPA-mediated induction of TF occurs in lung ECs to promote increased fibrin deposition in the airways during acute lung injury.
Barriers to Insulin Initiation
Authors: Andrew J. Karter, Usha Subramanian, Chandan Saha, Jesse C. Crosson, Melissa M. Parker, Bix E. Swain, Howard H. Moffet, David G. Marrero
Journal: Diabetes Care (2010)

OBJECTIVE Reasons for failing to initiate prescribed insulin (primary nonadherence) are poorly understood. We investigated barriers to insulin initiation following a new prescription. RESEARCH DESIGN AND METHODS We surveyed insulin-naïve patients with poorly controlled type 2 diabetes, already treated with two or more oral agents who were recently prescribed insulin. We compared responses for respondents prescribed, but never initiating, insulin (n = 69) with those dispensed insulin (n = 100). RESULTS Subjects failing to initiate prescribed insulin commonly reported misconceptions regarding insulin risk (35% believed that insulin causes blindness, renal failure, amputations, heart attacks, strokes, or early death), plans to instead work harder on behavioral goals, sense of personal failure, low self-efficacy, injection phobia, hypoglycemia concerns, negative impact on social life and job, inadequate health literacy, health care provider inadequately explaining risks/benefits, and limited insulin self-management training. CONCLUSIONS Primary adherence for insulin may be improved through better provider communication regarding risks, shared decision making, and insulin self-management training.
Only a minority of serious patient safety incidents are reported, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2008)

Only 5-10% of serious incidents in the NHS with the potential to compromise patients’ safety are actually reported, MPs have been told.

Witnesses giving evidence to MPs on the parliamentary health select committee last week admitted that under-reporting of patient safety incidents was significant but defended the system.

Committee members, who were taking evidence for their inquiry into patient safety, asked witnesses from the Department of Health and the National Patient Safety Agency how much harm the NHS did to patients.

Martin Fletcher, the agency’s chief executive, said that statistics from his organisation’s national reporting and learning system (covering England and Wales) for 2007-8 showed that 796 142 patient safety incidents were reported by staff, most of which (583 000) came from the acute …
Quality Improvement in Public Health Emergency Preparedness
Authors: Michael Seid, Debra Lotstein, Valerie L. Williams, Christopher Nelson, Kristin J. Leuschner, Allison Diamant, Stefanie Stern, Jeffrey Wasserman, Nicole Lurie
Journal: Annual Review of Public Health (2007)

Quality improvement (QI) methods have been used in many industries to improve performance and outcomes. This chapter reviews key QI concepts and their application to public health emergency preparedness (PHEP). We conclude that for QI to flourish and become standard practice, changes to the status quo are necessary. In particular, public health should build its capabilities in QI, enhance implementation, and align incentives to facilitate use of QI.
Applying the Diabetes Quality Improvement Project Indicators in the Indian Health Service Primary Care Setting
Authors: K. J. Acton, R. Shields, S. Rith-Najarian, B. Tolbert, J. Kelly, K. Moore, L. Valdez, B. Skipper, D. Gohdes
Journal: Diabetes Care (2001)

With publication of the Diabetes Quality Improvement Project (DQIP) measures, the Indian Health Service National Diabetes Program applied the DQIP format to its IHS Diabetes Care and Outcomes Audit for comparison and benchmarks.Since 1986 the IHS Diabetes Care and Outcomes Audit has been conducted by medical record review in >75% of IHS and tribal facilities. Each year systematic random sample of charts is drawn from local diabetes registries. Chart reviews are conducted by, trained professionals according to standard definitions and instructions. Abstracted data are entered into a microcomputer-based epidemiologic software package. Local, regional, and national rates are constructed for each item. During the period 1995-1997, 150 facilities submitted data for compilation, representing participation from all 12 IHS administrative regions. The IHS Diabetes Care and Outcomes Audit collected virtually all of the DQIP measures, with the exception of LDL cholesterol (which was added to the record review in 1998).In 1995, 1996, and 1997, a total of 9,557, 9,985, and 9,626 individuals, respectively, were included in the total IHS audit sample. The reviews for 1995, 1996, and 1997 revealed that of all subjects: 55, 65, and 80%, respectively, had more than one HbA1c test during the year (P < 0.001); 42, 38, and 34%, respectively; had a high-risk HbA1c (>9.5%) (P < 0.001); 83, 81, and 84%, respectively, were tested for macroproteinuria (P < 0.11) and 16, 17, and 23%, respectively were tested for microproteinuria (P < 0.001); total cholesterol was assessed in 80, 81, and 85%, respectively (P < 0.001), and corresponding proportions of those with values <5.17 mmol/l were 48, 50, and 52%, respectively; triglyceride values were measured for 75,75, and 80%, respectively (P < 0.001), and the corresponding median triglyceride levels were 199, 198, and 193 mg/dl, respectively (P < 0.001); the proportion of clients with a blood pressure <140/90 mmHg was 64, 64, and 66%, respectively (P < 0.05); 55, 56, and 55%, respectively, had a dilated eye exam (P < 0.053); and the proportion of clients who had a comprehensive foot exam were 59, 59, and 61%, respectively (P < 0.05).The DQIP accountability and quality improvement measures could be easily applied to the IHS Diabetes Care and Outcomes Audit, and the process can prove to be practical. However, data alone are not sufficient to effect change. Use of the measures to ensure that the quality of care improves must also be stressed, because measuring alone will not guarantee such improvement.
Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer
Authors: Randall J. Kimple, Molly A. Smith, Grace C. Blitzer, Alexandra D. Torres, Joshua A. Martin, Robert Z. Yang, Chimera R. Peet, Laurel D. Lorenz, Kwangok P. Nickel, Aloysius J. Klingelhutz, Paul F. Lambert, Paul M. Harari
Journal: Cancer Research (2013)

Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.
Telomere Length, Telomerase Activity, and Replicative Potential in HIV Infection: Analysis of CD4+ and CD8+T Cells from HIV-discordant Monozygotic Twins
Authors: Larry D. Palmer, Nan-ping Weng, Bruce L. Levine, Carl H. June, H. Clifford Lane, Richard J. Hodes
Journal: The Journal of Experimental Medicine (1997)

To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.