tbuckley/cabot-search huggingface dataset:
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis
Authors: Scott M. Wilhelm, Christopher Carter, LiYa Tang, Dean Wilkie, Angela McNabola, Hong Rong, Charles Chen, Xiaomei Zhang, Patrick Vincent, Mark McHugh, Yichen Cao, Jaleel Shujath, Susan Gawlak, Deepa Eveleigh, Bruce Rowley, Li Liu, Lila Adnane, Mark Lynch, Daniel Auclair, Ian Taylor, Rich Gedrich, Andrei Voznesensky, Bernd Riedl, Leonard E. Post, Gideon Bollag, Pamela A. Trail
Journal: Cancer Research (2004)

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
Role of cardiac chloride currents in changes in action potential characteristics and arrhythmias
Authors: M Hiraoka
Journal: Cardiovascular Research (1998)

Various types of Cl− currents have been recorded in cardiac myocytes from different regions of the heart and in different species. With few exceptions, most of these currents are not active under basal conditions, but are activated under the influence of various agonists and by physical stress. These channels are distributed nonuniformly, depending on the cell type, tissue and region of the heart. Therefore, Cl− current activation may influence membrane potential and impulse formation differently in different cells, and may play a role in arrhythmogenesis. Among these Cl− currents, the protein kinase A-activated Cl− current (ICl.PKA), the stretch- or swelling-activated Cl− current (ICl.SWELL) and the Ca2+-activated Cl− current (ICl.Ca) comprise the major anion currents that modify cardiac electrical activity. These currents exhibit outward-going rectification, or are predominantly activated at depolarized voltages and, thus, contribute significantly to shortening of the action potential duration but little to diastolic depolarization. The action potential shortening by Cl− current activation may not only perpetuate reentry by shortening the refractory period in a reentry pathway, but may also prevent the development of early afterdepolarization and triggered activity caused by the prolongation of action potentials. ICl.Ca contributes to delayed afterdepolarization at diastolic potentials in Ca2+-overloaded cells. Another factor limiting the influence of Cl− currents on diastolic potentials is the presence of a predominantly opposing background K+ current, except at the nodal regions that lack these K+ channels, or under conditions of decreased K+ conductance. Therefore, the contribution of Cl− currents to the genesis of arrhythmias may depend on their association with the conductance of other ions, especially that of K+.
Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3
Authors: Saad Z. Usmani, Alan Mitchell, Sarah Waheed, John Crowley, Antje Hoering, Nathan Petty, Tracy Brown, Twyla Bartel, Elias Anaissie, Frits van Rhee, Bart Barlogie
Journal: Blood (2013)
THE RELATIONSHIP OF NEUROTIC TRAITS TO THE ELECTROENCEPHALOGRAM IN CHILDREN WITH BEHAVIOR DISORDERS
Authors: JOSEPH J. MICHAELS, LAZARUS SECUNDA
Journal: American Journal of Psychiatry (1944)

1. In 122 children with behavior disorders, enuresis was reported more frequently (38 or 31.2 percent) than any other neurotic trait. 2. Male children and those in the age group of 13 to 18 years had abnormal EEGs more commonly than females or children in a younger age group, suggesting that age and sex are important variables that must be controlled in a study of this kind. 3. A history of enuresis in children with behavior disorders was associated in a positive manner with electroencephalographic abnormality, whereas behavior disorders without enuresis were not positively associated with electroencephalographic abnormality. 4. The EEG does not correlate with the vague and complex syndrome of behavior disorder but with certain specific aspects of this syndrome.
Pulmonary exacerbations in cystic fibrosis and bronchiectasis
Authors: J S Elborn, S C Bell
Journal: Thorax (2007)

concept that individual diseases exhibit unique characteristics.Taking these characteristics into account should enable a more accurate assessment of disease severity.Numerous examples exist of disease-specific scores that outperform generic scores, 13 14 including the PSI in the context of patients hospitalised with CAP. 15 The study by Barlow et al extends this view to CURB65 in relation to SEWS and SIRS.However, the patient cohort in this study differs from other CAP cohorts in two substantial ways: (1) only 52% of the patients had chest radiographic confirmation of pneumonia and (2) the overall mortality of the cohort was high (19%) compared with other CAP studies such as the study by Man et al 3 in which the mortality rate was 8.6% (mean age of the cohorts was 74 years and 72 years, respectively).Confirmation of these findings in a separate cohort is therefore desirable.Generic scores such as SIRS and SEWS have their roots in critical care and anaesthesia.These areas of medicine manage patients with diverse surgical and medical illnesses.The use of generic scores to triage and assess a wide casemix of patients in a standardised manner is helpful.However, when managing an individual patient with a specific disease, they should be used alongside diseasespecific severity scores that are likely to be more accurate, as is the case for CAP.Where to from here?In the assessment of CAP we now have two validated tools that are reasonably good at stratifying patients according to mortality-the PSI and the CURB65 score.Each of these tools has advantages and disadvantages. 16 17Centres should therefore adopt the tool that best suits the local healthcare setting.With regard to research, further validation of these tools in different patient cohorts, though desirable, should not detract from the pressing need to determine whether the use of severity assessment tools in the management of CAP ultimately leads to improved clinical outcomes. 18Such intervention studies are needed if optimal management strategies for patients in different prognostic groups are to be defined.
Molecular Magnetic Resonance Imaging of Angiogenesis <i>In Vivo</i> using Polyvalent Cyclic RGD-Iron Oxide Microparticle Conjugates
Authors: Stavros Melemenidis, Andrew Jefferson, Neil Ruparelia, Asim M Akhtar, Jin Xie, Danny Allen, Alastair Hamilton, James R Larkin, Francisco Perez-Balderas, Sean C Smart, Ruth J Muschel, Xiaoyuan Chen, Nicola R Sibson, Robin P Choudhury
Journal: Theranostics (2015)

Angiogenesis is an essential component of tumour growth and, consequently, an important target both therapeutically and diagnostically. The cell adhesion molecule α(v)β(3) integrin is a specific marker of angiogenic vessels and the most prevalent vascular integrin that binds the amino acid sequence arginine-glycine-aspartic acid (RGD). Previous studies using RGD-targeted nanoparticles (20-50 nm diameter) of iron oxide (NPIO) for magnetic resonance imaging (MRI) of tumour angiogenesis, have identified a number of limitations, including non-specific extravasation, long blood half-life (reducing specific contrast) and low targeting valency. The aim of this study, therefore, was to determine whether conjugation of a cyclic RGD variant [c(RGDyK)], with enhanced affinity for α(v)β(3), to microparticles of iron oxide (MPIO) would provide a more sensitive contrast agent for imaging of angiogenic tumour vessels. Cyclic RGD [c(RGDyK)] and RAD [c(RADyK)] based peptides were coupled to 2.8 μm MPIO, and binding efficacy tested both in vitro and in vivo. Significantly greater specific binding of c(RGDyK)-MPIO to S-nitroso-n-acetylpenicillamine (SNAP)-stimulated human umbilical vein endothelial cells in vitro than PBS-treated cells was demonstrated under both static (14-fold increase; P < 0.001) and flow (44-fold increase; P < 0.001) conditions. Subsequently, mice bearing subcutaneous colorectal (MC38) or melanoma (B16F10) derived tumours underwent in vivo MRI pre- and post-intravenous administration of c(RGDyK)-MPIO or c(RADyK)-MPIO. A significantly greater volume of MPIO-induced hypointensities were found in c(RGDyK)-MPIO injected compared to c(RADyK)-MPIO injected mice, in both tumour models (P < 0.05). Similarly, administration of c(RGDyK)-MPIO induced a greater reduction in mean tumour T(2)* relaxation times than the control agent in both tumour models (melanoma P < 0.001; colorectal P < 0.0001). Correspondingly, MPIO density per tumour volume assessed immunohistochemically was significantly greater for c(RGDyK)-MPIO than c(RADyK)-MPIO injected animals, in both melanoma (P < 0.05) and colorectal (P < 0.0005) tumours. In both cases, binding of c(RGDyK)-MPIO co-localised with α(v)β(3) expression. Comparison of RGD-targeted and dynamic contrast enhanced (DCE) MRI assessment of tumour perfusion indicated sensitivity to different vascular features. This study demonstrates specific binding of c(RGDyK)-MPIO to α(v)β(3) expressing neo-vessels, with marked and quantifiable contrast and rapid clearance of unbound particles from the blood circulation compared to NPIO. Combination of this molecular MRI approach with conventional DCE MRI will enable integrated molecular, anatomical and perfusion tumour imaging.
Cetuximab for the Treatment of Advanced Bronchioloalveolar Carcinoma (BAC): An Eastern Cooperative Oncology Group Phase II Study (ECOG 1504)
Authors: Suresh S. Ramalingam, Ju-Whei Lee, Chandra P. Belani, Seena C. Aisner, Jill Kolesar, Craig Howe, Mario R. Velasco, Joan H. Schiller
Journal: Journal of Clinical Oncology (2011)

Purpose Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have demonstrated modest anticancer activity in advanced bronchioloalveolar carcinoma (BAC). We conducted a phase II study to evaluate cetuximab for the treatment of advanced BAC. Patients and Methods Patients with advanced-stage pure BAC or adenocarcinoma with BAC features, fewer than two prior chemotherapy regimens, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible. Those with prior EGFR inhibitor therapy were excluded. Cetuximab was given as a weekly intravenous infusion at 250 mg/m 2 after an initial loading dose of 400 mg/m 2 in week 1. The primary end point was determination of response rate. EGFR and KRAS mutations were evaluated by pyrosequencing. Results Seventy-two patients were enrolled and 68 met eligibility requirements. Characteristics of patients included median age, 71 years; sex, 57% females; PS 0 or 1, 88% of patients; and smoking status, 19% never-smokers. Central pathology review confirmed the diagnosis in 45 of 49 available specimens. Approximately 50% of patients received more than two cycles of therapy (&gt; 8 weeks). Skin rash was the most common toxicity (grade 3, 15%). The confirmed response rate was 7%, and stable disease was observed in 35%. The median survival and progression-free survival were 13 and 3.3 months, respectively. Only one of the six patients with an EGFR mutation and one of the seven patients with a KRAS mutation had a partial response. Conclusion Cetuximab was associated with modest efficacy in patients with advanced BAC, despite a low response rate. EGFR and KRAS mutations were not predictive of response to cetuximab.
Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade
Authors: S PHILIPP, X YANG, L CUI, A DAVIS, J DOWNEY, M COHEN
Journal: Cardiovascular Research (2006)

Ischemic postconditioning protects the reperfused heart from infarction, and this protection is dependent on the occupancy of adenosine receptors. We further explored the role of adenosine receptors in this salvage.In situ rabbit hearts underwent 30 min of regional ischemia and 3 h of reperfusion, and postconditioning was effected with four cycles of 30-s reperfusion/30-s coronary artery occlusion at the end of ischemia.Postconditioning reduced infarct size from 40.2+/-3.4% of the risk zone in untreated hearts to 15.5+/-2.5%. Protection by postconditioning was blocked by either the non-selective adenosine receptor blocker 8-p-(sulfophenyl)theophylline or the A2b-selective antagonist MRS 1754, injected intravenously 5 min before reperfusion. The protein kinase C (PKC) antagonist chelerythrine also aborted postconditioning's salvage, indicating a PKC-dependent mechanism. Neither the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine nor the A2a-selective antagonist 8-(13-chlorostyryl)caffeine had an effect on protection. The non-selective but A2b-potent adenosine agonist 5'-(N-ethylcarboxamido)adenosine (NECA) infused from 5 min before to 1h after reperfusion mimicked postconditioning's effect on infarct size (17.2+/-2.7% infarction) and MRS 1754 blocked the NECA-induced cardioprotection, confirming that A2b activation was protective. The PKC activator phorbol 12-myristate 13-acetate delivered just before reperfusion also duplicated the protective effect of postconditioning (16.3+/-4.1% infarction), and co-administration of the PKC antagonist chelerythrine aborted PMA's protection, confirming that the protection was the result of PKC activation. NECA's protective effect was not affected by chelerythrine, but rather MRS 1754 blocked PMA's salutary effect (42.8+/-1.0% infarction), suggesting that the A2b receptor's effect is under control of PKC. Finally, wortmannin, a blocker of phosphatidylinositol 3-kinase, also abrogated protection by PMA.Salvage of ischemic myocardium by postconditioning is dependent on activation of A2b receptors, which in turn depends on activation of PKC. It is still unclear why PKC activation is required to make the heart's adenosine become protective.
Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality
Authors: C.Michael Gibson, Duane S. Pinto, Sabina A. Murphy, David A. Morrow, Hans-Peter Hobbach, Stephen D. Wiviott, Robert P. Giugliano, Christopher P. Cannon, Elliott M. Antman, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2003)
S136 Fungal sputum culture in patients with severe asthma is associated with a reduced post bronchodilator FEV1
Authors: J. Agbetile, A. Fairs, M. Bourne, B. Hargadon, K. Mutalithas, W. Monteiro, R. Edwards, J. Morley, D. Desai, C. E. Brightling, P. H. Bradding, R. H. Green, I. D. Pavord, A. J. Wardlaw, C. H. Pashley
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> IgE sensitisation to fungal allergens is common in severe asthma, but the clinical relevance of this, and the relationship to airway colonisation with fungi, is not known. Many of the fungi that can grow at body temperature are filamentous moulds from the genera <i>Aspergillus</i> and <i>Pencillium</i>. We report here the relationship between lung function and fungal sputum culture in patients with severe asthma. <h3>Methods</h3> We recruited 126 patients attending a tertiary referral centre with a diagnosis of asthma and 18 healthy volunteers. 93% of patients were on GINA treatment step 4 or higher. At a single stable visit subjects underwent: spirometry with reversibility to 200 μg salbutamol; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel (+ve ≥3 mm); specific IgE to <i>Aspergillus fumigatus</i> by CAP (positive &gt;0.35 kU/l). Fungi were identified by morphology and species identity confirmed by sequencing regions of the nuclear ribosomal operon. <h3>Results</h3> Patients had a mean age of 56 years (21–84 years); 48% were males with median ICS dose of 800 μg Fluticasone equivalent. 60% were atopic to common aeroallergens, 45% were IgE sensitised to one fungal allergen and 27% to ≥2 fungal allergens. 64% of patients cultured a mould in their sputum, 7% more than one species. This compared with three healthy subjects (17%) culturing any mould (p&lt;0.01). <i>Aspergillus</i> species were most frequently cultured (n=58) followed by <i>Penicillium</i> species (n=15) and <i>Thermoascus</i> species (n=2), others (n=8). Four fungal genera were cultured from healthy volunteers sputum,-<i>Aspergillus</i>, <i>Penicillium, Coprinus</i> and one other. Post bronchodilator FEV<sub>1</sub>% predicted was 71% in those with a positive fungal culture vs 84% in those who were culture negative, (p&lt;0.01). There were no differences in the sputum cell differential between culture positive and negative patients. <h3>Conclusions</h3> In addition to IgE fungal sensitisation, sputum culture focused towards detection of moulds is frequently positive and associated with impaired post-bronchodilator FEV1. Colonisation of the airways with mould in asthma could be responsible for the development of fixed airflow obstruction.
Flt3 Ligand–treated Neonatal Mice Have Increased Innate Immunity Against Intracellular Pathogens and Efficiently Control Virus Infections
Authors: Sabine Vollstedt, Marco Franchini, Hans P. Hefti, Bernhard Odermatt, Meredith O'Keeffe, Gottfried Alber, Bettina Glanzmann, Matthias Riesen, Mathias Ackermann, Mark Suter
Journal: The Journal of Experimental Medicine (2003)

Flt-3 ligand (FL), a hematopoetic growth factor, increases the number of dendritic cells (DCs), B cells, and natural killer cells in adult mice but the effect in neonates was unknown. We show that FL treatment of newborn mice induced a >100-fold increase in the innate resistance against infection with herpes simplex virus type 1 and Listeria monocytogenes. This resistance required interferon (IFN)-alpha/beta for viral and interleukin (IL)-12 for bacterial infections. Long-term survival after viral but not bacterial infection was increased approximately 100-fold by FL treatment. After treatment, CD11c(+)/major histocompatibility complex type II(+) and CD11c(+)/B220(+) DC lineage cells were the only cell populations increased in the spleen, liver, peritoneum, and skin. DC induction was independent of IFNs, IL-2, -4, -7, -9, -15, and mature T and B cells. The data suggest that FL increases the number of DCs in neonates and possibly in other immune-compromised individuals, which in turn improves IFN-alpha/beta- and IL-12-associated immune responses.
Assessing the effect of deep inhalation on airway calibre: a novel approach to lung function in bronchial asthma and COPD
Authors: R Pellegrino, PJ Sterk, JK Sont, V Brusasco
Journal: European Respiratory Journal (1998)

Bronchoconstriction in bronchial asthma and chronic obstructive pulmonary disease (COPD) may be due to decreased airway calibre and/or to the inability of the airways to distend after a deep inhalation (DI). The purpose of this review is to discuss the physiological and clinical relevance of this latter mechanism. During induced constriction, DI shows remarkable bronchodilatation in normal subjects, but a blunted or null effect in asthmatics. In contrast, during spontaneous bronchospasm DI tends to decrease airway calibre. From a functional point of view, airway inflammation, remodelling, and peripheral bronchoconstriction could prevent airway smooth muscle from stretching. Therapeutic intervention improving lung function may change the response to DI. For example, bronchodilators allow expiratory airflow before DI to increase more than after DI, because of decreased bronchial hysteresis. This suggest that bronchodilation might be systematically underestimated from parameters derived from maximal expiratory manoeuvres. Inhaled corticosteroids tend to increase the dilator effect of DI, likely due to decreased bronchial and peribronchial oedema. In conclusion, measuring the effects of deep inhalation on lung function is an easy and simple test able to evaluate the structural changes occurring in the airways and to monitor the effectiveness of therapy.
Reversible Renal Failure and Myositis Caused by Phenytoin Hypersensitivity
Authors: John R. Michael
Journal: JAMA (1976)

A 38-year old woman receiving phenytoin (diphenylhydantoin) noticed maculopapular erythema as the first manifestation of a syndrome that included acute renal failure and myositis in addition to fever, lymphadenopathy, exfoliative dermatitis, and hepatitis. Prednisolone sodium phosphate therapy resulted in resolution of this hypersensitivity reaction, and she recovered from renal insufficiency. The occurrence of renal failure and myositis in the spectrum of phenytoin hypersensitivity reactions is discussed, and the importance of a morbilliform rash in a patient receiving phenytoin is emphasized.
Is Disability Obesity's Price of Longevity?
Authors: Edward W. Gregg, Jack M. Guralnik
Journal: JAMA (2007)

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Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination
Authors: C. Catania, M. Medici, E. Magni, E. Munzone, D. Cardinale, L. Adamoli, G. Sanna, I. Minchella, D. Radice, A. Goldhirsch, F. Nolè
Journal: Annals of Oncology (2007)