tbuckley/cabot-search huggingface dataset:
S121 Lung Clearance Index to Evaluate the Effect of Ivacaftor on Lung Function in Subjects with CF Who Have the G551D-CFTR Mutation and Mild Lung Disease
Authors: JCD Davies, HS Sheridan, PSL Lee, TS Song, AS Stone, FR Ratjen
Journal: Thorax (2012)

<h3>Background</h3> Ivacaftor has been shown to lead to significant improvement in lung function, exacerbation rate, weight gain and quality of life in adolescents and adults with CF and the <i>G551D-CFTR</i> mutation. <h3>Objectives</h3> Drugs targeting the basic defect of CF may hold potential for patients with early stage disease, but establishing benefit is more difficult. If FEV<sub>1</sub> is normal, a more sensitive test may be useful. LCI has been shown to become abnormal at an earlier stage of disease than FEV<sub>1</sub> and thus may be a more sensitive outcome measure in this group of patients. <h3>Methods</h3> This Phase 2, randomised, double-blind, placebo-controlled, multicenter, crossover study evaluated the effect of ivacaftor on LCI derived from multibreath washout of SF<sub>6</sub> using an Innocor device. Subjects were ≥6 years with the <i>G551D-CFTR</i> mutation, FEV<sub>1</sub> &gt;90% predicted, and LCI &gt;7.4 (upper limit of normal). Ivacaftor 150 mg or placebo was administered twice daily for two 4-week periods with a 4-week washout in between. <h3>Results</h3> Twenty-one subjects were randomised and 20 received a dose of ivacaftor. Seventeen subjects completed both periods. Mean (SD) age was 16.6 (10.9) years. Mean (SD) baseline LCI was 9.0 (1.5). The treatment effect of ivacaftor for adjusted mean change from baseline in LCI at Day 29 was –2.1 (<i>P</i>=0.0004). Mean (SD) baseline FEV1 was 97.2% predicted (10.6%). Treatment difference for the mean change from baseline in FEV1 at Day 29 was 7.0 percentage points (<i>P</i>=0.0117). Treatment difference for the mean change from baseline in sweat chloride at Day 29 was –45.9 mmol/L (<i>P</i>&lt;0.0001). Treatment effect for the change from baseline in pooled CFQ-R Respiratory Domain score was 4.1 points versus placebo (<i>P</i>=0.4020). In the ivacaftor period, AEs and SAEs were reported in 13 and 2 subjects, respectively. In the placebo period, AEs and SAEs were reported in 15 and 1 subject, respectively. <h3>Conclusions</h3> In CF patients with mild lung disease, ivacaftor improved ventilation inhomogeneity as measured by LCI and respiratory function as measured by percent predicted FEV1. LCI is more sensitive to change in this mildly affected group of subjects and may be a useful outcome measure for future interventional trials in such patients.
Increasing Diagnosis of Thyroid Papillary Carcinoma Follicular Variant in South-East Anatolian Region: Comparison of Characteristics of Classical Papillary and Follicular Variant Thyroid Cancers
Authors: Sibel Ertek, Nuray Can Yılmaz, Arrigo F. Cicero, Özgül Vurupalmaz, Ahu Senem Demiröz, Gürbüz Erdoğan
Journal: Endocrine Pathology (2012)
Functional Properties of Mouse Connexin30.2 Expressed in the Conduction System of the Heart
Authors: Maria M. Kreuzberg, Goran Söhl, Jung-Sun Kim, Vytas K. Verselis, Klaus Willecke, Feliksas F. Bukauskas
Journal: Circulation Research (2005)

Gap junction channels composed of connexin (Cx) 40, Cx43, and Cx45 proteins are known to be necessary for impulse propagation through the heart. Here, we report mouse connexin30.2 (mCx30.2) to be a new cardiac connexin that is expressed mainly in the conduction system of the heart. Antibodies raised to the cytoplasmic loop or the C-terminal regions of mCx30.2 recognized this protein in mouse heart as well as in HeLa cells transfected with wild-type mCx30.2 or mCx30.2 fused with enhanced green fluorescent protein (mCx30.2-EGFP). Immunofluorescence analyses of adult hearts yielded positive signals within the sinoatrial node, atrioventricular node, and A-V bundle of the cardiac conduction system. Dye transfer studies demonstrated that mCx30.2 and mCx30.2-EGFP channels discriminate poorly on the basis of charge, but do not allow permeation of tracers >400 Da. Both mCx30.2 and mCx30.2-EGFP gap junctional channels exhibited weak sensitivity to transjunctional voltage (Vj) and a single channel conductance of approximately 9 pS, which is the lowest among all members of the connexin family measured in HeLa cell transfectants. HeLa mCx30.2-EGFP transfectants when paired with cells expressing Cx40, Cx43, or Cx45 formed functional heterotypic gap junction channels that exhibited low unitary conductances (15 to 18 pS), rectifying open channel I-V relations and asymmetric Vj dependence. The electrical properties of homo- and hetero-typic junctions involving mCx30.2 may contribute to slow propagation velocity in nodal tissues and directional asymmetry of excitation spread in the AV nodal region.
Effect of lipoprotein (a) on platelet activation induced by platelet-activating factor: role of apolipoprotein (a) and endogenous PAF-acetylhydrolase
Authors: L TSIRONIS, J MITSIOS, H MILIONIS, M ELISAF, A TSELEPIS
Journal: Cardiovascular Research (2004)

Lipoprotein (a) [Lp(a)] is considered an atherogenic lipoprotein, which is also implicated in thrombosis. Lp(a) binds to platelets and modulates the effects of various platelet agonists. Platelet activating factor (PAF) is a potent platelet agonist degraded and inactivated by PAF-acetylhydrolase (PAF-AH), which in plasma is associated with lipoproteins. Lp(a) is enriched in PAF-AH, thus a functional characteristic of this lipoprotein is its capability to hydrolyze and inactivate PAF. In the present study, we investigated the effect of Lp(a) on PAF-induced platelet activation. The potential roles of the apo(a) moiety and especially of the PAF-AH content of Lp(a) on the above effect were also addressed.Lp(a) was isolated by affinity chromatography from plasma of apparently healthy fasting donors with serum Lp(a) concentrations >/=20 mg/dl. Reduced Lp(a) [Lp(a-)] was prepared by incubation of Lp(a) with dithiothreitol (DTT), whereas inactivation of Lp(a)-associated PAF-AH was performed by incubation of Lp(a) with pefabloc [pefa-Lp(a)]. Platelet-rich plasma (PRP) or washed platelets were prepared from peripheral venous blood samples of normolipidemic, apparently healthy fasting donors with their serum Lp(a) levels lower than 0.8 mg/dl. The surface expression of the platelet integrin-receptor alpha(IIb)beta3 and the fibrinogen binding to the activated alpha(IIb)beta3 was studied by flow cytometry.Lp(a), at doses higher than 20 microg/ml, inhibits PAF-induced platelet activation in a dose-dependent manner. Pefa-Lp(a), lacking PAF-AH activity, exhibited a similar to Lp(a) inhibitory effect. Importantly, the Lp(a) inhibitory effect was not influenced by the apo(a) isoform size, whereas Lp(a-) was a more potent inhibitor compared to Lp(a). Similarly to PAF, Lp(a) inhibits platelet aggregation induced by ADP or Calcium ionophore A23187. Lp(a), pefa-Lp(a) or Lp(a-) effectively inhibited PAF- or ADP-induced surface expression of alphaIIbbeta3, the Lp(a-) being more potent compared to Lp(a) or to pefa-Lp(a). Finally, Lp(a) significantly inhibited fibrinogen binding to platelets activated with PAF.Lp(a) inhibits PAF-induced platelet activation in a non-specific manner. The Lp(a)-associated PAF-AH does not play any important role in this effect, whereas the apo(a) moiety of Lp(a) significantly reduces its inhibitory effect. The inhibition of alpha(IIb)beta3 activation and fibrinogen binding to the activated platelets may represent the major mechanism by which Lp(a) inhibits PAF-induced platelet aggregation.
Mechanism of formation of human IgE-binding factors (soluble CD23): III. Evidence for a receptor (Fc epsilon RII)-associated proteolytic activity.
Authors: M Letellier, T Nakajima, G Pulido-Cejudo, H Hofstetter, G Delespesse
Journal: The Journal of Experimental Medicine (1990)

There is mounting evidence that Fc epsilon RII (CD23) and its soluble fragments (IgE-binding factors [BFs] or soluble CD23) have pleiotropic activities. IgE-BFs are formed mainly by the proteolytic cleavage of surface Fc epsilon RII; they are first released as 37- and 33-kD unstable molecules that are subsequently transformed into 25-kD IgE-BFs. In this study, purified and radioiodinated 37-kD IgE-BFs as well as 45-kD Fc epsilon RII were used as substrates to identify the proteases leading to the formation of 25-kD IgE-BFs. These substrates generate 25-kD IgE-BFs when incubated with several Fc epsilon RII-bearing cells, including CHO1-7 cells (transfected with Fc epsilon RII cDNA); by contrast Fc epsilon RII- cells, including CHO control cells, have no effect. Highly purified unlabeled native 37-kD and recombinant 29-kD IgE-BFs also cleave labeled 45-kD Fc epsilon RII into 25-kD IgE-BFs. The proteolytic activity of these purified IgE-BFs is specifically removed by immunoprecipitation with an antibody against IgE-BFs. These data strongly suggest that Fc epsilon RII and some of its soluble fragments play an active role in the proteolytic mechanism generating IgE-BFs. They are supported by the observation that IgE-BFs released by CHO1-7 cells are cleaved exactly at the same sites as B cell-derived IgE-BFs. Taken collectively, the results are compatible with an autoproteolytic process.
Therapeutic Targeting of the Hedgehog-GLI Pathway in Prostate Cancer
Authors: Pilar Sanchez, Virginie Clement, Ariel Ruiz i Altaba
Journal: Cancer Research (2005)

Abstract The Hedgehog-GLI signaling pathway is important in animal development and tumorigenesis. Recent findings indicate that the growth and survival of human prostate cancer cells rely upon sustained signaling from the Hedgehog-GLI pathway. These findings have prompted a novel rational strategy for therapeutic treatment of prostate tumors, including metastatic tumors.
Toxicology Comes of Age
Authors: John Doull
Journal: The Annual Review of Pharmacology and Toxicology (2001)

This paper contains recollections of some of the people and events that influenced the development of toxicology as an academic discipline. It also describes my experiences in pharmacology at the University of Chicago and the University of Kansas Medical Center and concludes with speculation concerning the future of toxicology. Moderation in all things/Ne quid nimis. --Terence in Andria
β blockers for elective surgery in elderly patients: population based, retrospective cohort study
Authors: Donald Redelmeier, Damon Scales, Alexander Kopp
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To test whether atenolol (a long acting β blocker) and metoprolol (a short acting β blocker) are associated with equivalent reductions in risk for elderly patients undergoing elective surgery. <b>Design</b> Population based, retrospective cohort analysis. <b>Setting</b> Acute care hospitals in Ontario, Canada, over one decade. <b>Participants</b> Consecutive patients older than 65 who were admitted for elective surgery, without symptomatic coronary disease. <b>Main outcome measure</b> Death or myocardial infarction. <b>Results</b> 37 151 patients were receiving atenolol or metoprolol before surgery, of which the most common operations were orthopaedic or abdominal procedures. As expected, the two groups were similar in demographic characteristics, medical therapy, and type of surgery. 1038 patients experienced a myocardial infarction or died, a rate that was significantly lower for patients receiving atenolol than for those receiving metoprolol(2.5% <i>v</i> 3.2%, P &lt; 0.001). The decreased risk with atenolol persisted after adjustment for measured demographic, medical, and surgical factors; extended to comparisons of other long acting and short acting βblockers; was accentuated in analyses that focused on patients with the clearest evidence β blocker treatment; and reflected the immediate postoperative interval. <b>Conclusions</b> Patients receiving metoprolol do not have as low a perioperative cardiac risk as patients receiving atenolol, in accord with possible acute withdrawal after missed doses.
Treatment of massive haemoptysis with microcoil embolization after en bloc double-lung transplantation with bronchial artery revascularization
Authors: J Carlsen, UG Svendsen, F Efsen, G Pettersson
Journal: European Respiratory Journal (1997)

Successful treatment of a severe haemoptysis with microcoil embolization in an en block double-lung transplanted patient is described. A 53 year old woman with advanced bronchiolitis obliterans syndrome experienced severe haemoptysis 26 months after an en bloc double-lung transplantation with direct bronchial artery revascularization using the left internal mammary artery. Bronchoscopy showed that the haemoptysis originated from the lingula. Only two months after the transplant, left internal mammary arteriograms revealed proliferation and enlargement of the bronchial arteries in the lingula. The early occurrence of the vascular malformation indicated a pre-existing bronchiectasis in the donor lung, possibly due to tobacco smoking. After uncomplicated microcoil embolization of the left internal mammary artery, the patient experienced no further episodes of haemoptysis. Microcoil embolization can be used successfully to treat massive haemoptysis related to proliferated and enlarged bronchial arteries in transplanted lungs with bronchial artery revascularization.
Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors
Authors: H.A. Wakelee, A. Patnaik, B.I. Sikic, M. Mita, N.L. Fox, R. Miceli, S.J. Ullrich, G.A. Fisher, A.W. Tolcher
Journal: Annals of Oncology (2009)
Ice-skating and roller disco injuries in Dublin.
Authors: C. Horner, M. J. McCabe
Journal: British Journal of Sports Medicine (1984)

A comparative study was carried out on a series of 72 ice-skating and 57 roller skating injuries over a sixteen month period. The average patient age was 20.5 years in the ice-skating group and 16.5 years in the roller skating group. Females predominated in both groups accounting for 72% of ice-skaters injured and 77% of roller skaters injured. Ice-skaters sustained more serious injuries than roller skaters as was evident from the significant difference in fracture numbers in the two groups. Ice-skating fractures accounted for 40% of all injuries while roller skating fractures were only 14% of their total injuries. The majority of ice-skating fractures occurred in females. As a result of our study we recommended several preventative measures.
The −251T Allele of the Interleukin-8 Promoter Is Associated with Increased Risk of Gastric Carcinoma Featuring Diffuse-Type Histopathology in Chinese Population
Authors: Wei-Ping Lee, Dar-In Tai, Keng-Hsin Lan, Anna Fen-Yau Li, Hou-Ching Hsu, En-Ju Lin, Yi-Ping Lin, Meei-Ling Sheu, Chung-Pin Li, Full-Young Chang, Yee Chao, Shang-Heu Yen, Shou-Dong Lee
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1β polymorphisms, which enhance the cytokine production, are associated with increased risk of gastric cancer. The −251A/T polymorphism of the IL-8 promoter is involved in several human diseases. Particularly, the −251A is associated with decreased risk of colorectal cancer. We aimed to determine whether the −251 allele resulting in high IL-8 expression was associated with increased risk of gastric carcinoma. Experimental Design: The −251A/T promoters were cloned and analyzed by luciferase assay. Binding of nuclear proteins to the −251A/T promoters was analyzed by electrophoretic mobility shift assay. The −251A/T promoters were differentiated by PCR-RFLP. Comparison of gastric cancer risk between the −251A/T promoters was done by a case-control study. Results: The −251T allele possessed transcriptional activity 2- to 5-fold stronger than the −251A counterpart. Electrophoretic mobility shift assay showed that the −251A promoter had strong ability to bind to an unknown protein or multiprotein complex. The −251T allele was associated with increased risk of noncardia (Ptrend = 0.012) and cardia (Ptrend = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (χ2 = 6.816; P = 0.033); however, the high-risk −251T allele was associated with &amp;gt;2-fold increased risk of diffuse-type (AA versus AT + TT: odds ratio, 2.52; 95% confidence interval, 1.16-5.49; P = 0.017) and mixed-type (AA versus AT + TT: odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = 0.019) carcinomas. Conclusions: The IL-8 −251T allele is significantly associated with increased risk of gastric carcinoma, particularly the diffuse and mixed types in Chinese population.
Prognostic Impact of Minimal Residual Disease in<i>CBFB-MYH11</i>–Positive Acute Myeloid Leukemia
Authors: Andrea Corbacioglu, Claudia Scholl, Richard F. Schlenk, Karina Eiwen, Juan Du, Lars Bullinger, Stefan Fröhling, Peter Reimer, Mathias Rummel, Hans-Günter Derigs, David Nachbaur, Jürgen Krauter, Arnold Ganser, Hartmut Döhner, Konstanze Döhner
Journal: Journal of Clinical Oncology (2010)

To evaluate the prognostic impact of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) expressing the CBFB-MYH11 fusion transcript.Quantitative reverse transcriptase polymerase chain reaction (PCR) was performed on 684 bone marrow (BM; n = 331) and/or peripheral blood (PB; n = 353) samples (median, 13 samples per patient) from 53 younger adult (16 to 60 years old) patients with AML treated in prospective German-Austrian AML Study Group treatment trials. Samples were obtained at diagnosis (BM, n = 45; PB, n = 48), during treatment course (BM, n = 153; PB, n = 122), and at follow-up (BM, n = 133; PB, n = 183). To evaluate the applicability of PB for MRD detection, 198 paired BM and PB samples obtained at identical time points were analyzed.The following three clinically relevant checkpoints were identified during consolidation and early follow-up that predicted relapse: achievement of PCR negativity in at least one BM sample during consolidation therapy (2-year relapse-free survival [RFS], 79% v 54% for PCR positivity; P = .035); achievement of PCR negativity in at least two BM or PB samples during consolidation therapy and early follow-up (< or = 3 months; 2-year RFS, P = .001; overall survival, P = .01); and conversion from PCR negativity to PCR positivity with copy ratios of more than 10 after consolidation therapy. Analysis of paired BM and PB samples revealed BM samples to be more sensitive during the course of therapy, whereas for follow-up, PB samples were equally informative.We defined clinically relevant MRD checkpoints that allow for the identification of patients with CBFB-MYH11-positive AML who are at high risk of relapse. Monitoring of CBFB-MYH11 transcript levels should be incorporated into future clinical trials to guide therapeutic decisions.
Medical nanoparticles for next generation drug delivery to the lungs
Authors: Sabine H. van Rijt, Thomas Bein, Silke Meiners
Journal: European Respiratory Journal (2014)

Respiratory diseases are an increasing burden for the ageing population. Although our understanding of these diseases has improved significantly over the past decades, diagnostic and therapeutic options for treating lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and lung cancer, remain limited. Multidisciplinary approaches that bridge the gap between medicinal and materials sciences will likely contribute to promising new therapeutic and diagnostic solutions. One such multidisciplinary approach is the use of nanoparticles as carriers for the delivery of drugs. The advantages of using nanoparticles to deliver drugs include: increased drug concentration at the disease site; minimised drug degradation and loss; ease of creating inhalable formulations; and the possibility of specific cell targeting. This article gives a brief overview on the emerging field of nanocarriers as drug delivery vehicles for the treatment of lung diseases.
The Pathology of Social Phobia Is Independent of Developmental Changes in Face Processing
Authors: Karina S. Blair, Marilla Geraci, Katherine Korelitz, Marcela Otero, Ken Towbin, Monique Ernst, Ellen Leibenluft, R.J.R. Blair, Daniel S. Pine
Journal: American Journal of Psychiatry (2011)

While social phobia in adolescence predicts the illness in adulthood, no study has directly compared the neural responses in social phobia in adults and adolescents. The authors examined neural responses to facial expressions in adults and adolescents with social phobia to determine whether the neural correlates of adult social phobia during face processing also manifest in adolescent social phobia.Blood-oxygen-level-dependent (BOLD) responses were compared in 39 medication-free participants with social phobia (25 adults and 14 adolescents) and 39 healthy comparison subjects (23 adults and 16 adolescents) matched on age, IQ, and gender. During fMRI scans, participants saw angry, fearful, and neutral expression stimuli while making a gender judgment.Significant diagnosis-by-emotion interactions were observed within the amygdala and the rostral anterior cingulate cortex, as has previously been hypothesized. In these regions, both the adolescent and adult social phobia patients showed significantly increased BOLD responses relative to their respective age-matched comparison subjects, and there was no evidence of age-related modulation of between-group differences. These enhanced responses occurred specifically when viewing angry (rostral anterior cingulate cortex) and fearful (amygdala and rostral anterior cingulate cortex) expressions but not when viewing neutral expressions. In addition, the severity of social phobia was significantly correlated with the enhanced rostral anterior cingulate cortex response in the adults.The neural correlates of adult social phobia during face processing also manifest in adolescents. Neural correlates that are observed in adult social phobia may represent the persistence of profiles established earlier in life rather than adaptive responses to such earlier perturbations or maturational changes. These cross-sectional observations might encourage longitudinal fMRI studies of adolescent social phobia.
<i>FGFR3</i>and<i>PIK3CA</i>mutations are involved in the molecular pathogenesis of solar lentigo
Authors: C. Hafner, R. Stoehr, J.M.M. van Oers, E.C. Zwarthoff, F. Hofstaedter, M. Landthaler, A. Hartmann, T. Vogt
Journal: British Journal of Dermatology (2008)

Solar lentigines (SL) are frequent benign skin lesions appearing on sun-exposed areas especially in elderly people and therefore represent a hallmark of (photo)aged skin. It has been proposed that SL may subsequently evolve into adenoid seborrhoeic keratosis (SK). However, little is known about the genetic basis of SL. In human SK, FGFR3 and PIK3CA mutations have recently been identified.To analyse SL for potential FGFR3 and PIK3CA mutations.We screened 30 SL for FGFR3 mutations using a SNaPshot multiplex assay. For PIK3CA mutations we used direct sequencing of exon 9 and a SNaPshot assay for the H1047R hotspot mutation (exon 20). Because psoralen plus ultraviolet A (PUVA) lentigines show the V600E BRAF hotspot mutation, we additionally investigated this mutation in SL by allele-specific polymerase chain reaction.FGFR3 mutations were detected in five of 30 (17%) SL and PIK3CA mutations in two of 28 (7%) SL. None of 28 SL available for BRAF analysis revealed the V600E mutation.Our results suggest that FGFR3 and PIK3CA mutations are involved in the pathogenesis of SL. The occurrence of these mutations in both SL and SK suggests a common genetic basis. Our findings furthermore substantiate previous speculations that UV exposure may be a causative factor for FGFR3 and PIK3CA mutations in human skin.