tbuckley/cabot-search huggingface dataset:
Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling
Authors: Tatsukata Kawagoe, Shintaro Sato, Andreas Jung, Masahiro Yamamoto, Kosuke Matsui, Hiroki Kato, Satoshi Uematsu, Osamu Takeuchi, Shizuo Akira
Journal: The Journal of Experimental Medicine (2007)

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.
Mechanisms of in Vivo DNA Electrotransfer: Respective Contributions of Cell Electropermeabilization and DNA Electrophoresis
Authors: Saulius Satkauskas, Michel F. Bureau, Marko Puc, Abderrahim Mahfoudi, Daniel Scherman, Damijan Miklavcic, Lluis M. Mir
Journal: Molecular Therapy (2002)

Efficient cell electrotransfection can be achieved using combinations of high-voltage (HV; 800 V/cm, 100 μs) and low-voltage (LV; 80 V/cm, 100 ms) pulses. We have developed equipment allowing the generation of various HV and LV combinations with precise control of the lag between the HV and LV pulses. We injected luciferase-encoding DNA in skeletal muscle, before or after pulse delivery, and measured luciferase expression after various pulse combinations. In parallel, we determined permeabilization levels using uptake of 51Cr-labeled EDTA. High voltage alone resulted in a high level of muscle permeabilization for 300 seconds, but very low DNA transfer. Combinations of one HV pulse followed by one or four LV pulses did not prolong the high permeabilization level, but resulted in a large increase in DNA transfer for lags up to 100 seconds in the case of one HV + one LV and up to 3000 seconds in the case of one HV + four LV. DNA expression also reached similar levels when we injected the DNA between the HV and LV pulses. We conclude that the role of the HV pulse is limited to muscle cell permeabilization and that the LV pulses have a direct effect on DNA. In vivo DNA electrotransfer is thus a multistep process that includes DNA distribution, muscle permeabilization, and DNA electrophoresis. Efficient cell electrotransfection can be achieved using combinations of high-voltage (HV; 800 V/cm, 100 μs) and low-voltage (LV; 80 V/cm, 100 ms) pulses. We have developed equipment allowing the generation of various HV and LV combinations with precise control of the lag between the HV and LV pulses. We injected luciferase-encoding DNA in skeletal muscle, before or after pulse delivery, and measured luciferase expression after various pulse combinations. In parallel, we determined permeabilization levels using uptake of 51Cr-labeled EDTA. High voltage alone resulted in a high level of muscle permeabilization for 300 seconds, but very low DNA transfer. Combinations of one HV pulse followed by one or four LV pulses did not prolong the high permeabilization level, but resulted in a large increase in DNA transfer for lags up to 100 seconds in the case of one HV + one LV and up to 3000 seconds in the case of one HV + four LV. DNA expression also reached similar levels when we injected the DNA between the HV and LV pulses. We conclude that the role of the HV pulse is limited to muscle cell permeabilization and that the LV pulses have a direct effect on DNA. In vivo DNA electrotransfer is thus a multistep process that includes DNA distribution, muscle permeabilization, and DNA electrophoresis.
Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment
Authors: V. Grunwald, M. Hidalgo
Journal: JNCI Journal of the National Cancer Institute (2003)

Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells. Preclinical studies have demonstrated that pharmacologic interventions that abrogate EGFR dysfunction result in antitumor effects. On the basis of these findings, therapeutic strategies to inhibit EGFR and EGFR-related pathways, including the use of monoclonal antibodies against the extracellular ligand-binding domain of EGFR and small-molecule inhibitors of the tyrosine kinase activity of EGFR, have entered clinical testing where they have demonstrated favorable safety profiles and adequate clinical pharmacology. Further development of these agents has been fueled by evidence of their antitumor activities, both as single agents and in combination with chemotherapy and radiation therapy. Areas that require investigation are the definition of patient populations most likely to derive benefits from these drugs, the implementation of biologic correlative studies to aid the selection of pharmacodynamically relevant doses and schedules, the characterization of population pharmacokinetic parameters and pharmacogenomic variables, and the most appropriate clinical scenario for proceeding with the clinical development of these agents.
Abstract 672: Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1
Authors: Sabine Wittemer-Rump, Charlotte Kopitz, Hung Huynh, Lars Lindbom, Bernhard Beckermann, Motonobu Osada, Dirk Laurent, Jörg Lippert
Journal: Cancer Research (2014)

Abstract BAY 1179470 is a human immunoglobulin (IgG) antibody directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed on cancer cells during tumorigenesis and metastasis. Anti-tumor efficacy of BAY 1179470 has been demonstrated in FGFR2-expressing gastric cancer mouse and rat xenograft models. No toxicologically relevant findings were observed in the repeated dose preclinical safety studies in rats and monkeys. Therefore, toxicity was not an appropriate endpoint for the first-in-man (FIM) study and dose selection was decided to be based on PK/PD modeling and predictions from preclinical efficacy data. All preclinical PK and tumor response data from mouse models were used to create a model framework to describe the PK and PK/PD as functions of BAY 1179470 dose, regimen and time. In a subsequent confirmatory step the PK/PD model derived from mouse efficacy data was applied to predict the efficacy in rats. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure were combined with the PK/PD model developed from mouse models to assess the expected efficacy for a range of human tumor doubling rates. Minimal effective doses, maximum effect and maximum effect doses, and maximal effective doses in humans were derived for various dosing intervals (1 day to 6 weeks). From the maximum effect dose the target AUC in humans was calculated and doses for the FIM study selected accordingly. The FIM study is currently ongoing in Japan (NCT01881217). Citation Format: Sabine Wittemer-Rump, Charlotte Kopitz, Hung Huynh, Lars Lindbom, Bernhard Beckermann, Motonobu Osada, Dirk Laurent, Jörg Lippert. Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 672. doi:10.1158/1538-7445.AM2014-672
HGF and BMP-7 Ameliorate High Glucose–Induced Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelium
Authors: Min-A Yu, Kyung-Sook Shin, Jung Hye Kim, Yong-Il Kim, Soon Sup Chung, Sun-Hee Park, Yong-Lim Kim, Duk-Hee Kang
Journal: Journal of the American Society of Nephrology (2009)

Over time, peritoneal dialysis results in functional and structural alterations of the peritoneal membrane, but the underlying mechanisms and whether these changes are reversible are not completely understood. Here, we studied the effects of high levels of glucose, which are found in the dialysate, on human peritoneal mesothelial cells (HPMCs). We found that high concentrations of glucose induced epithelial-to-mesenchymal transition (EMT) of HPMC, suggested by decreased expression of E-cadherin and increased expression of alpha-smooth muscle actin, fibronectin, and type I collagen and by increased cell migration. Normalization of glucose concentration on day 2 reversed the phenotypic transformation, but the changes were irreversible after 7 d of stimulation with high glucose. In addition, exposure of HPMC to high glucose resulted in a decreased expression of the antifibrotic cytokines, hepatocyte growth factor (HGF) and bone morphogenic protein 7 (BMP-7). Exogenous treatment with HGF resulted in a dosage-dependent prevention of high glucose-induced EMT. Both BMP-7 peptide and gene transfection with an adenoviral vector of BMP-7 also protected HPMCs from EMT. Furthermore, adenoviral BMP-7 transfection decreased peritoneal EMT and ameliorated peritoneal thickening in an animal model of peritoneal dialysis. In summary, high concentrations of glucose induce a reversible EMT of HPMCs, associated with decreased production of HGF and BMP-7. Treatment of HPMCs with HGF or BMP-7 blocks high glucose-induced EMT, and BMP-7 ameliorates peritoneal fibrosis in an animal model of peritoneal dialysis.
Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia.
Authors: J B Rubins, D Charboneau, C Fasching, A M Berry, J C Paton, J E Alexander, P W Andrew, T J Mitchell, E N Janoff
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Pneumolysin, the major Streptococcus pneumoniae cytotoxin, contributes to the early pathogenesis of invasive pneumococcal pneumonia by facilitating intrapulmonary bacterial growth and invasion into the blood. Pneumolysin is a multifunctional toxin, with distinct cytolytic ("hemolytic") and complement-activation ("complement") activities that have been mapped to several regions of the molecule. To characterize the specific contributions of pneumolysin's hemolytic and complement properties to the pathogenesis of pneumococcal pneumonia, we compared the in vivo effects of type 2 S. pneumoniae mutant strains, which produce pneumolysins deficient in these activities. The absence of either pneumolysin's hemolytic or complement activities rendered mutant strains less virulent than the wild-type strain during pulmonary infection. Pneumolysin's hemolytic activity correlated with acute lung injury and bacterial growth at 3 and 6 h after endotracheal instillation. In contrast, pneumolysin's complement activity correlated with bacterial growth and bacteremia at 24 h after pulmonary infection. Pneumolysin's complement activity was not associated with the degree of alveolar-capillary injury or recruitment of leukocytes during initial pulmonary infection. However, pneumolysin's complement activity inhibited killing of mutant bacteria in an in vitro complement-dependent neutrophil killing assay. Thus, both pneumolysin's hemolytic and complement activities made specific contributions to the early pathogenesis of pneumococcal pneumonia at different stages of infection and by different mechanisms.
Continuous recording of direct high fidelity arterial pressure and electrocardiogram in ambulant patients
Authors: M. PAGANI, R. FURLAN, S. DELL'ORTO, P. PIZZINELLI, G. LANZI, G. BASELLI, C. SANTOLI, S. CERUTTI, F. LOMBARDI, A. MALLIANI
Journal: Cardiovascular Research (1986)

Journal Article Continuous recording of direct high fidelity arterial pressure and electrocardiogram in ambulant patients Get access MASSIMO PAGANI, MASSIMO PAGANI **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar RAFFAELLO FURLAN, RAFFAELLO FURLAN **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar SIMONETTA DELL'ORTO, SIMONETTA DELL'ORTO **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar PAOLO PIZZINELLI, PAOLO PIZZINELLI **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar GIORGIO LANZI, GIORGIO LANZI **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar GIUSEPPE BASELLI, GIUSEPPE BASELLI ‡From the Electronics Department, Milan Polytechnic, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar CARMINE SANTOLI, CARMINE SANTOLI †From the Division of Thoracic Surgery, L Sacco Hospital, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar SERGIO CERUTTI, SERGIO CERUTTI ‡From the Electronics Department, Milan Polytechnic, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar FEDERICO LOMBARDI, FEDERICO LOMBARDI **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar ALBERTO MALLIANI ALBERTO MALLIANI **From the Institute of Cardiovascular Research, L Sacco Hospital, University of Milan, Milan, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 20, Issue 5, May 1986, Pages 384–388, https://doi.org/10.1093/cvr/20.5.384 Published: 01 May 1986
Association Between Serum Concentrations of Persistent Organic Pollutants and Insulin Resistance Among Nondiabetic Adults
Authors: Duk-Hee Lee, In-Kyu Lee, Soo-Hee Jin, Michael Steffes, David R. Jacobs
Journal: Diabetes Care (2007)

We reported strong relations between serum concentrations of persistent organic pollutants (POPs), especially organochlorine (OC) pesticides or nondioxin-like polychlorinated biphenyls (PCBs), and prevalence of diabetes in a U.S population with background exposure to POPs. Here, we investigated POPs and insulin resistance, a frequent pathogenic precursor of type 2 diabetes.Serum POPs and homeostasis model assessment of insulin resistance (HOMA-IR) were investigated cross-sectionally in 749 nondiabetic participants aged > or = 20 years. Nineteen POPs in five subclasses were selected, detectable in > or = 60% of participants.Among subclasses, OC pesticides were most strongly associated with HOMA-IR. Adjusted geometric means of HOMA were 3.27, 3.36, 3.48, and 3.85 (P for trend <0.01) across quartiles of OC pesticides. The relationship strengthened with increasing HOMA-IR percentile: adjusted odds ratios comparing the highest versus lowest POPs quartile were 1.8 for being > or = 50th percentile of HOMA-IR, 4.4 for being > or = 75th percentile, and 7.5 for being > or = 90th percentile. Associations with elevated HOMA-IR appeared to be specific to oxychlordane and trans-nonachlor but also were found for two nondioxin-like PCBs. No HOMA-IR associations were seen in the other three POP subclasses. The association between OC pesticides and HOMA-IR tended to strengthen as waist circumference increased, with no apparent association in the lowest quartile of OC pesticide concentrations.These findings, coupled with those concerning diabetes prevalence, suggest that OC pesticides and nondioxin-like PCBs may be associated with type 2 diabetes risk by increasing insulin resistance, and POPs may interact with obesity to increase the risk of type 2 diabetes.
Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects.
Authors: C M Salome, R E Schoeffel, A J Woolcock
Journal: Thorax (1981)

In order to determine the effect of drugs on bronchial hyperreactivity in subjects with asthma, 12 atopic asthmatic volunteers underwent bronchial challenge with either histamine or methacholine on three separate days. Before the challenges no medication was given on the first day, on the second 400 microgram of aerosol fenoterol and on the third 5 mg of oral fenoterol were administered. The aerosol fenoterol caused the dose response curves to both histamine and methacholine to be shifted to the right in all subjects. The oral dose produced no significant change from the control values. The slope of the dose response curves was not altered by either the oral or the aerosol drug. It is concluded that aerosol but not oral fenoterol in the clinical dosage, causes a change in the sensitivity but not in the reactivity of the airway of patients with atopic asthma.
Adding Gemcitabine to Paclitaxel/Carboplatin Combination Increases Survival in Advanced Non–Small-Cell Lung Cancer: Results of a Phase II-III Study
Authors: Adriano Paccagnella, Francesco Oniga, Alessandra Bearz, Adolfo Favaretto, Maurizia Clerici, Fausto Barbieri, Alberto Riccardi, Antonio Chella, Umberto Tirelli, Giovanni Ceresoli, Salvatore Tumolo, Ruggero Ridolfi, Rita Biason, Maria Ornella Nicoletto, Paolo Belloni, Fabrizio Veglia, Maria Grazia Ghi
Journal: Journal of Clinical Oncology (2006)

Purpose Paclitaxel/carboplatin (PC) is one of the reference combinations in the treatment of non–small-cell lung cancer (NSCLC). No triplet novel agent combination has until now shown superiority over a two-drug combination for advanced NSCLC. We therefore conducted a clinical trial to test if paclitaxel/carboplatin/gemcitabine (PCG) increases overall survival (OS) and response rate (RR) over PC. Methods Stage IIIB patients not suitable for radical radiation treatment and stage IV chemotherapy-naive patients with measurable disease and performance status of 0 to 2 were randomly assigned to PC arm (paclitaxel 200 mg/m 2 and carboplatin area under the concentration-time curve 6 day 1/q21 days) or the PCG arm (paclitaxel 200 mg/m 2 and carboplatin area under the concentration-time curve 6 day 1, and gemcitabine 1,000 mg/m 2 days 1 and 8 every 21 days). Results A total of 324 patients were randomly assigned to the two arms. The RR for PC arm and PCG arm were 20.2% and 46% (P &lt; .0001). The median time to the progression was 5.1 months in the PC group and 7.6 months in the PCG group (P = .012; hazard ratio [HR] 1.34; 95% CI: 1.06 to 1.72). Median OS was 8.3 months and 10.8 months (P = .032; HR 1.309; 95% CI: 1.03 to 1.67) in favor of the PCG arm. One-year survival was 34% (PC arm) and 45% (PCG arm; P = .032). Only hematologic toxicity (neutropenia, thrombocytopenia, and anemia) was significantly increased in the PCG arm and the experimental arm required more platelet and red blood cell transfusions, and more granulocyte colony-stimulating factor usage. No toxic/early deaths were observed. Conclusion The PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced NSCLC patients.
Dynamics of oxidative stress parameters in exhaled breath condensate at controller treatment of bronchial asthma in patients with cold airway hyperpesponsiveness
Authors: Juliy M. Perelman, Nelly M. Goryachkina, Anna G. Prikhodko, Evgeny A. Borodin
Journal: European Respiratory Journal (2011)

Background:  Oxidative stress is an important factor of inflammation and airway hyperresponsiveness. Little is known about its dynamics during controller treatment of bronchial asthma (BA). Aim of the study was to evaluate the dynamics of oxidative stress products in exhaled breath condensate (EBC) after two-week controller treatment in BA patients with cold airway hyperresponsiveness (CAHR).   Methods:  EBC from 49 BA patients with CAHR were studied before and after two-week controller treatment with inhaled glucocorticosteroids. The products of lipid peroxidation (diene conjugates (A232), ketodiens conjugated with triglyceride (A278)) were measured by spectrophotometric assay. Hydrogen peroxide (H 2 O 2 ) was found out by electrochemical method with the help of biosensors on the basis of Prussian blue. The degree of cold bronchoconstriction was defined according to the fall of FEV 1  (ΔFEV 1 ) after 3-minute hyperventilation by cold (-20°C) air.   Results:  After 2-week treatment high airway response to cold air hyperventilation (ΔFEV 1  -14.7±1.83% vs. -12.4±1.87%; p>0.05) was remained, but there was a significant decrease of H 2 O 2  level from 1.10±0.07 till 0.95±0.06 nmole/ml (p 1  and the level of H 2 O 2  in EBC (r=-0.37; p   Conclusion:  The obtained data suggested the suppression of lipid peroxidation and damaging effect of airway cooling under inhaled glucocorticosteroids influence.
Yellow fever and dengue: a threat to Europe?
Authors: P Reiter
Journal: Eurosurveillance (2010)

The introduction and rapidly expanding range of Aedes albopictus in Europe is an iconic example of the growing risk of the globalization of vectors and vector-borne diseases. The history of yellow fever and dengue in temperate regions confirms that transmission of both diseases could recur, particularly if Ae. aegypti, a more effective vector, were to be re-introduced. The article is a broad overview of the natural history and epidemiology of both diseases in the context of these risks.
Body Composition Changes in Hypertensive Subjects on Long-term Oral Diuretic Therapy
Authors: J. J. Healy, T. J. McKenna, B. St. J. Canning, T. G. Brien, G. J. Duffy, F. P. Muldowney
Journal: BMJ (1970)

Hypertensive patients were treated with either chlorthalidone or frusemide for periods of two to four months. Reduction in blood pressure was seen with chlorthalidone but not with frusemide. This hypotensive effect appeared to be independent of the natriuretic effect. A significant reduction in total exchangeable potassium (K<sub>E</sub>) was seen with both agents, but no patient showed adverse symptoms or signs. There was no alteration in maximal urinary concentration or acidification, or in intravenous glucose tolerance or plasma insulin. It is concluded that potassium depletion of this degree does not require replacement therapy on a routine basis in hypertensive patients.