tbuckley/cabot-search huggingface dataset:
Potential synergism of drugs with anti-viral and pulmonary oedema clearance activity may be advantageous for influenza patients
Authors: Hendrik Fischer, Bernhard Fischer, Susan Tzotzos, Helmut Pietschmann, Rudolf Lucas
Journal: European Respiratory Journal (2011)

Influenza is a serious public health problem that causes severe illnesses and deaths for higher risk populations. Large numbers of people need hospital treatment and many die from the disease every year. 30% of hospitalised patients with Influenza infection require intensive care and despite medical treatment 10% die. The most common cause of death is viral pneumonia and ARDS. Antiviral drugs like oseltamivir and zanamivir block increase and spreading of the virus in the body. Already existing virus particles will not be affected. In case of complications, 2/3 of patients show infiltrates on chest radiographs, giving strong evidence for ARF and pulmonary oedema that can deteriorate to ALI/ARDS. However, it has been shown that the AP301 peptide, representing the TIP domain of TNFa, has alveolar liquid clearance activity. It was proposed that a combination of anti-viral and anti-oedema substances would act synergistically. This was assessed in mice having been sublethally infected with Influenza strain A/PR8/34 per nasal. On day of infection, mice were treated with oseltamivir. AP301 peptide was applied intratracheally on days 0, 2 and 4 post infection. On day 9 post infection the effect on wet-dry weight ratio and pulmonary microvascular permeability was assessed. AP301 peptide alone had a beneficial effect compared to untreated mice. The additive effect of the combination of AP301/oseltamivir combination was greater for reduction of lung oedema, which was in the range of control-treated but uninfected mice. In conclusion, these preliminary experiments suggest a benefit of combining anti-viral drugs and substances with alveolar liquid clearing activity.
A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy
Authors: W. Zhang, T. Winder, Y. Ning, A. Pohl, D. Yang, M. Kahn, G. Lurje, M.J. LaBonte, P.M. Wilson, M.A. Gordon, S. Hu-Lieskovan, D.J. Mauro, C. Langer, E.K. Rowinsky, H.-J. Lenz
Journal: Annals of Oncology (2010)
Variation in Diagnostic Coding of Patients With Pneumonia and Its Association With Hospital Risk-Standardized Mortality Rates
Authors: Michael B. Rothberg, Penelope S. Pekow, Aruna Priya, Peter K. Lindenauer
Journal: Annals of Internal Medicine (2014)

Most U.S. hospitals publicly report 30-day risk-standardized mortality rates for pneumonia. Rates exclude severe cases, which may be assigned a secondary diagnosis of pneumonia and a principal diagnosis of sepsis or respiratory failure. By assigning sepsis and respiratory failure codes more liberally, hospitals might improve their reported performance.To examine the effect of the definition of pneumonia on hospital mortality rates.Cross-sectional study.329 U.S. hospitals.Adults hospitalized for pneumonia (as a principal diagnosis or secondary diagnosis paired with a principal diagnosis of sepsis or respiratory failure) between 2007 and 2010.Proportion of patients with pneumonia coded with a principal diagnosis of sepsis or respiratory failure and risk-standardized mortality rates excluding versus including a principal diagnosis of sepsis or respiratory failure.When the definition of pneumonia was limited to patients with a principal diagnosis of pneumonia, the risk-standardized mortality rate was significantly better than the mean in 4.3% of hospitals and significantly worse in 6.4%. When the definition was broadened to include patients with a principal diagnosis of sepsis or respiratory failure, this rate was better than the mean in 11.9% of hospitals and worse in 22.8% and the outlier status of 28.3% of hospitals changed. Among hospitals in the highest quintile of proportion of patients coded with a principal diagnosis of sepsis or respiratory failure, outlier status under the broader definition improved in 7.6% and worsened in 40.9%. Among those in the lowest quintile, 20.0% improved and none worsened.Only inpatient mortality was studied.Variation in use of the principal diagnosis of sepsis or respiratory failure may bias efforts to compare hospital performance regarding pneumonia outcomes.Agency for Healthcare Research and Quality.
Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer
Authors: Ricardo M. Attar, Maria Jure-Kunkel, Aaron Balog, Mary Ellen Cvijic, Janet Dell-John, Cheryl A. Rizzo, Liang Schweizer, Thomas E. Spires, J. Suso Platero, Mary Obermeier, Weifang Shan, Mark E. Salvati, William R. Foster, Joseph Dinchuk, Shen-Jue Chen, Gregory Vite, Robert Kramer, Marco M. Gottardis
Journal: Cancer Research (2009)

Abstract Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (&amp;gt;1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition &amp;gt;90% versus &amp;lt;50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the ∼30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer. [Cancer Res 2009;69(16):6522–30]
Severe hypotension due to potassium-induced pericardial injury.
Authors: H Ceuppens, J F Hitchcock, J Damen, G Jambroes, R Ae Dion
Journal: Thorax (1982)

The occurrence of iatrogenic pericarditis after the administration of drugs such as procaine amide, hydralazine, and phenylbutazone and traumatic pericarditis has been previously reported.' 2 We report a case in which potassium chloride was accidentally injected intrapericar- dially, leading to acute pericardial irritation. Case reportA 59-year-old man underwent coronary artery bypass grafting for disabling angina pectoris.The operation was uneventful.Before the pericardium was closed a direct right atrial line was introduced.After operation blood loss from the drains was minimal and the patient's clinical con- dition was stable.An electrocardiogram (ECG) showed minor non-specific ST-T changes.There were no signs of infarction.The laboratory results and postoperative chest radiograph were normal.The right atrial line was used intermittently for potassium administration (20 mmol potassium chloride in 60 ml 5% dextrose in water) to con- trol occasional ventricular extrasystoles.Two hours after operation the patient complained of a sudden constricting and severe retrosternal pain and breathlessness.An ECG monitor strip showed ST segment elevation.The pain gradually subsided and a full 12-lead ECG then showed slight ST elevation in leads II, III, aVF and aVL without reciprocal ST depression.One and a half hours later the patient had a further attack of pain, this time more incapacitating.He was now having nitroglycerine sublin- gually and intravenously.Again the ECG strip showed ST-segment elevation, now associated with horizontal depression of the PR-(PTa) segment (fig A).The pain con- tinued to increase and the patient developed both pro- nounced tachypnoea and bradycardia.The blood pressure fell rapidly to a mean of 25 mm Hg.At this time the mean right atrial and mean pulmonary artery wedge pressures were both 20 mm Hg.Frequent ventricular extrasystoles appeared.The patient was paced via the epicardial leads with an external pacemaker and was intubated and venti- lated with 100% oxygen.Ephedrine chloride, calcium chloride and dopamine were given via the right atrial line and the right atrial opening of a Swan-Ganz catheter.There was no real improvement.At this time it was noted that no blood could be aspirated from the right atrial line, but that a few millilitres of serohaemorrhagic fluid were
Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis
Authors: Gisela Ruiz-Heiland, Yi Zhao, Anja Derer, Tobias Braun, Klaus Engelke, Elena Neumann, Ulf Mueller-Ladner, Yi Liu, Jochen Zwerina, Georg Schett
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest–specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. <h3>Methods</h3> Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3<sup>−/−</sup>) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase–PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3<sup>−/−</sup> and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. <h3>Results</h3> Tyro3<sup>−/−</sup> mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3<sup>−/−</sup> mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3<sup>−/−</sup> mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. <h3>Conclusions</h3> These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.
Novel Vascular Endothelial Growth Factor Binding Domains of Fibronectin Enhance Vascular Endothelial Growth Factor Biological Activity
Authors: Errol S. Wijelath, Jacqueline Murray, Salman Rahman, Yatin Patel, Atsushi Ishida, Kurt Strand, Salim Aziz, Carlos Cardona, William P. Hammond, Geoffrey F. Savidge, Shahin Rafii, Michael Sobel
Journal: Circulation Research (2002)

Interactions between integrins and growth factor receptors play a critical role in the development and healing of the vasculature. This study mapped two binding domains on fibronectin (FN) that modulate the activity of the angiogenic factor, vascular endothelial growth factor (VEGF). Using solid-phase assays and surface plasmon resonance analysis, we identified two novel VEGF binding domains within the N- and C-terminus of the FN molecule. Native FN bound to VEGF enhanced endothelial cell migration and mitogen-activated protein (MAP) kinase activity, but FN that is devoid of the VEGF binding domains failed to do so. Coprecipitation studies confirmed a direct physical association between VEGF receptor-2 (Flk-1) and the FN integrin, α 5 β 1 , which required intact FN because FN fragments lacking the VEGF binding domains failed to support receptor association. Thrombin-activated platelets released intact VEGF/FN complexes, which stimulated endothelial cell migration and could be inhibited by soluble high affinity VEGF receptor 1 and antibodies to α 5 β 1 integrin. This study demonstrates that FN is potentially a physiological cofactor for VEGF and provides insights into mechanisms by which growth factor receptors and integrins cooperate to influence cellular behavior.
Endothelium-Derived Nitric Oxide Contributes to the Regulation of Venous Tone in Humans
Authors: Daniel J. Blackman, Jayne A. Morris-Thurgood, John J. Atherton, Gethin R. Ellis, Richard A. Anderson, John R. Cockcroft, Michael P. Frenneaux
Journal: Circulation (2000)

Although nitric oxide (NO) is known to play an important part in the regulation of arterial tone, little is known about its role in veins. The aim of this study was to investigate the role of basal and stimulated NO activity in the regulation of tone of the human venous capacitance bed.We measured venous tone using radionuclide forearm venous plethysmography in 24 healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO activity was assessed by measuring the effects on venous tone of an intra-arterial infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA). In the remaining 11 subjects, stimulated NO activity was evaluated by measuring the effects of an intra-arterial infusion of incremental doses of carbachol, followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused dose-dependent venodilation, with a maximal reduction in forearm venous tone of 40.1+/-12.5% (P<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA (48.9+/-6.2% reversal of maximal venodilation, P<0.01). Infusion of L-NMMA alone caused venoconstriction (9.1+/-6.4% increase in venous tone, P=0.002).Human forearm capacitance veins exhibit both stimulated and basal NO activity, which indicates that NO contributes not only to the regulation of venous tone but also to resting venous tone in healthy human subjects.
ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution
Authors: David R. Holmes, Jeffrey A. Becker, Christopher B. Granger, Marian C. Limacher, Robert Lee Page, Cathy Sila, Joseph P. Drozda, Joseph G. Cacchione, Blair D. Erb, Robert A. Harrington, Jerry D. Kennett, Harlan M. Krumholz, Frederick A. Masoudi, Eric D. Peterson, Athena Poppas, David J. Sahn, Mark L. Sanz, David M. Shahian, John R. Windle, Janet F. Wyman
Journal: Journal of the American College of Cardiology (2011)
Effect of antibiotic treatment on sputum elastase in bronchiectatic outpatients in a stable clinical state.
Authors: R A Stockley, S L Hill, H M Morrison
Journal: Thorax (1984)

The pharmaceutical and biotechnology industries have long been challenged with setting appropriate cosmetic defect size acceptance criteria on glass vials. Limits are rarely data-driven and scarce information is available on defect survivability through shipping and handling downstream of final product visual inspection. This study was undertaken to quantitatively understand cosmetic defect dynamics on glass vials and their impact on patient safety. Scratch and bruise defects were artificially manufactured on product or placebo-filled, inspected, and glass defect–free tubing vials. The vials were processed and filled using commercial filling operations (i.e., vial washing, heat tunnel, conveyors, lyophilization, etc.). The defects were quantitatively characterized, subjected to automated packaging simulations, manually packaged in the approved commercial configurations, and subjected to ASTM Level I (highest intensity) shipping simulations in both pallet and small package configurations. The defects showed no statistically significant or applicable level of propagation, post-packaging and shipping simulation. Additionally, all test vials were subjected to dye leak testing, post-shipping simulation. All vials, except for one, met acceptance criteria for dye leak testing. Data-driven cosmetic defect dimensions for scratches and bruises were established based on this study. <i>LAY ABSTRACT:</i> When delivering life saving medicines from the manufacturing plant to the patient, it is of great importance that the medicines arrive without damage that might harm the patient. In the case of medicines filled into glass vials, it is paramount that manufacturers understand whether minor cosmetic defects in the glass (such as small scratches and bruises) may weaken the vial enough to cause damage that might allow contamination of the contents. This study was performed to determine if scratches and bruises on the glass vials might propagate during operations that occur downstream of the manufacturer9s final vial inspection. The study vials were filled with product or placebo on the commercial filling lines to fully simulate environmental factors in a typical run. Scratches and bruises were then artificially created on the vials. Each defect was measured microscopically and labeled. The study population was then manually packaged into the approved configurations and subjected to the highest level intensity shipping simulations (ASTM Level 1). Upon completion of the simulations, the vials were unpackaged and defects re-measured microscopically. The defects showed no statistically significant or applicable level of propagation. Additionally, all test vials were subjected to dye leak testing, post-shipping simulation. All vials, except for one, met acceptance criteria. Data-driven cosmetic defect dimensions for scratches and bruises were established based on this study.
Should Malpractice Settlements Be Secret?
Authors: Michelle M. Mello, Jeffrey N. Catalano
Journal: JAMA Internal Medicine (2015)

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Cytolytic responses: cadherins put out the fire
Authors: Marco Colonna
Journal: The Journal of Experimental Medicine (2006)

Cytotoxic lymphocytes, such as natural killer (NK) cells and CD8+ T cells, provide an essential defense against intracellular pathogens and tumors. During target cell recognition, these cells receive both activating and inhibitory signals. The cell must evaluate these opposing signals and determine the appropriate response: activation or inhibition. Classically, inhibitory signals are mediated by receptors that recognize MHC class I molecules (1). But recent studies, including one in this issue, suggest that MHC class I-independent inhibitory signals can also result in inhibition of cytotoxic cells.
Induction of specific immune unresponsiveness with purified mixed leukocyte culture-activated T lymphoblasts as autoimmunogen. II. An analysis of the effects measured at the cellular and serological levels.
Authors: M Aguet, L C Andersson, R Andersson, E Wight, H Binz, H Wigzell
Journal: The Journal of Experimental Medicine (1978)

T lymphoblasts specific for foreign histocompatibility antigens and purified via mixed leukocyte culture (MLC) and 1 g velocity sedimentation procedures can be used as autoimmunogen to produce specific immunological unresponsiveness in adult animals. This unresponsiveness is positively correlated to the production of autoanti-idiotypic antibodies in the blast immunized animals and no evidence of coexisting alloimmunity was found. We consider this autoanti-idiotypic immunity to be the specific inducing agent of the immune tolerance. The blast immunization procedure will lead to selective reduction in T-cell reactivity against the relevant alloantigens as measured by MLC, cell-mediated lympholysis, or graft-versus-host assays. However, in individual animals, dichtomy in suppression between two T-cell assays could sometimes be observed indicating elimination of only a select group of idiotypic functionally distinct population of T cells in these blast-immunized animals. Attempts to abrogate already immune animals by the autoblast procedure were successful, in part suggesting the use of the present procedure when trying to induce in accelerated reversion of such immunity.
Glutathione <i>S</i>-transferase P1 Genotype and Prognosis in Hodgkin's Lymphoma
Authors: Stefan Hohaus, Annalisa Di Ruscio, Annalaura Di Febo, Giuseppina Massini, Francesco D'Alo', Francesco Guidi, Giovanna Mansueto, Maria Teresa Voso, Giuseppe Leone
Journal: Clinical Cancer Research (2005)

Glutathione S-transferase P1 (GSTP1) is a member of the GST enzyme superfamily that is important for the detoxification of several cytotoxic drugs and their by-products. A single nucleotide polymorphism results in the substitution of isoleucine (Ile) to valine (Val) at codon 105, causing a metabolically less active variant of the enzyme. We assessed the impact of the GSTP1 codon 105 genotype on treatment outcome in patients with Hodgkin's lymphoma.The Ile(105)Val polymorphism in the GSTP1 gene was analyzed using a PCR-RFLP technique. Ninety-seven patients with Hodgkin's lymphoma were included and associations with patient characteristics and treatment outcome were analyzed.The GSTP1 Ile(105)Val polymorphism was associated in a dose-dependent fashion with an improved failure-free survival in patients with Hodgkin's lymphoma (P = 0.02). The probability of 5-year survival for patients homozygous for the (105)Val/(105)Val GSTP1 genotype was 100%, for heterozygous patients 74% (95% confidence interval, 56-85), and for patients homozygous for the (105)Ile/(105)Ile genotype 43% (95% confidence interval, 23-61). The Cox multivariate analysis showed that GSTP1 codon 105 genotype was an independent prognostic factor.The GSTP1 genotype predicts clinical outcome in patients with Hodgkin's lymphoma.