tbuckley/cabot-search huggingface dataset:
Inhibition of Spleen Tyrosine Kinase Prevents Mast Cell Activation and Airway Hyperresponsiveness
Authors: Shigeki Matsubara, Guiming Li, Katsuyuki Takeda, Joan E. Loader, Polly Pine, Esteban S. Masuda, Nobuaki Miyahara, Satoko Miyahara, Joseph J. Lucas, Azzeddine Dakhama, Erwin W. Gelfand
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor-mediated signaling.To determine the activity of a specific Syk inhibitor (R406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo.AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, FcepsilonRI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMCs) before cross-linking with allergen.The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine BMMCs and inhibited the production of interleukin (IL)-13, tumor necrosis factor alpha, IL-2, and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR, which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive d (20 min/d), as well as pulmonary eosinophilia and goblet cell metaplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge.This study delineates a functional role for Syk in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.
Complete Response to the Combination Therapy with Androgen Blockade and Somatostatin Analogue in a Patient with Advanced Prostate Cancer: Magnetic Resonance Imaging with 1H-Spectroscopy
Authors: Alessandro Sciarra, Valeria Panebianco, Mauro Ciccariello, Stefano Salciccia, Alessandro Gentilucci, Danilo Lisi, Roberto Passariello, Vincenzo Gentile, Franco Di Silverio
Journal: European Urology (2007)
Hepatocyte Growth Factor and Its Receptor Are Expressed in Cardiac Myocytes During Early Cardiogenesis
Authors: Daniel A. Rappolee, Anand Iyer, Yogesh Patel
Journal: Circulation Research (1996)

Abstract In the mouse, the heart primordium arises when mesoderm is set aside during gastrulation, is induced by pharyngeal endoderm, migrates ventrally to the midline of the embryo, forms a tube, and begins beating. Little is known of the molecular mechanisms that mediate the determination, mitosis, differentiation, and migration that lead to the beating heart. Transcripts for hepatocyte growth factor/scatter factor (HGF) and its receptor are coexpressed transiently and dynamically in the premyocardium but not in other heart progenitor cells. Transcripts for HGF ligand and receptor are first detected before cardiac function and looping and persist through the first looping stage, when heart morphology begins to elaborate. HGF ligand and receptor mRNA are detectable after the putative heart transcription factor, Csx/Nkx2-5, and concomitantly with the heart structural gene, cardiac actin. HGF receptor mRNA is detected in the mesoderm of the headfold stage and persists in myocardial precursors of the ventricles and atria (but not in the outflow-tract smooth muscle cells) through the 14-somite stage at ≈8.75 days after fertilization (day E8.75). At the headfold stage, between E7.5 and E8.0, HGF receptor mRNA was detected in myocardial cells before fusion at the ventral midline. HGF ligand and receptor mRNA transcripts are coexpressed in the embryo, except in the headfold stage (when only the HGF receptor can be detected) and in the heart at the 14- to 18-somite stage (when only HGF ligand can be detected). The dynamic pattern of coexpression suggests an autoregulatory role for HGF and its receptor in early heart development.
Synovial fluid hydroxyapatite crystals: detection thresholds of two methods.
Authors: T Cunningham, D Uebelhart, J M Very, G H Fallet, T L Vischer
Journal: Annals of the Rheumatic Diseases (1989)

A method of synovial fluid preparation giving optimal hydroxyapatite detection as well as definitions of the threshold masses of hydroxyapatite in viscous synovial fluid detectable by x ray diffraction and scanning electron microscopy with energy dispersive analysis is reported. Use of an equal volume of 100% hydrazine with the synovial fluid optimised detection of hydroxyapatite. By x ray diffraction the threshold mass of hydroxyapatite was 500 micrograms and by scanning electron microscopy with associated energy dispersive analysis 5 micrograms.
MHC class I–specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice
Authors: Richard T. Strait, Wyenona Hicks, Nathaniel Barasa, Ashley Mahler, Marat Khodoun, Jörg Köhl, Keith Stringer, David Witte, Nico Van Rooijen, Brian M. Susskind, Fred D. Finkelman
Journal: The Journal of Experimental Medicine (2011)

Transfusion-related acute lung injury (TRALI), a form of noncardiogenic pulmonary edema that develops during or within 6 h after a blood transfusion, is the most frequent cause of transfusion-associated death in the United States. Because development of TRALI is associated with donor antibodies (Abs) reactive with recipient major histocompatibility complex (MHC), a mouse model has been studied in which TRALI-like disease is caused by injecting mice with anti–MHC class I monoclonal Ab (mAb). Previous publications with this model have concluded that disease is caused by FcR-dependent activation of neutrophils and platelets, with production of reactive oxygen species that damage pulmonary vascular endothelium. In this study, we confirm the role of reactive oxygen species in the pathogenesis of this mouse model of TRALI and show ultrastructural evidence of pulmonary vascular injury within 5 min of anti–MHC class I mAb injection. However, we demonstrate that disease induction in this model involves macrophages rather than neutrophils or platelets, activation of complement and production of C5a rather than activation of FcγRI, FcγRIII, or FcγRIV, and binding of anti–MHC class I mAb to non-BM–derived cells such as pulmonary vascular endothelium. These observations have important implications for the prevention and treatment of TRALI.
<i>FGFR3</i> and <i>Tp53</i> Mutations in T1G3 Transitional Bladder Carcinomas: Independent Distribution and Lack of Association with Prognosis
Authors: Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Roberto Jaramillo, Alex Amorós, Adonina Tardón, Reina García-Closas, Consol Serra, Alfredo Carrato, Núria Malats, Francisco X. Real
Journal: Clinical Cancer Research (2005)

Abstract FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.
Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive pulmonary disease
Authors: JG Hay, P Stone, J Carter, S Church, A Eyre-Brook, MG Pearson, AA Woodcock, PM Calverley
Journal: European Respiratory Journal (1992)

Partial bronchodilator reversibility can be demonstrated in many patients with stable chronic obstructive pulmonary disease (COPD), but its relevance to exercise capacity and symptoms is uncertain. Previous data suggest that anticholinergic bronchodilators do not improve exercise tolerance in such patients. We studied 32 patients with stable COPD, mean age 65 yrs, in a double-blind, placebo-controlled, cross-over trial of the inhaled anticholinergic drug, oxitropium bromide. From the within and between day placebo spirometry, we derived the spontaneous variation in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of this population (FEV1 140 ml; FVC 390 ml) and considered responses beyond this to be significant. Oxitropium bromide increased baseline FEV1 from 0.70 (0.28) l (mean (SD)) to 0.88 (0.36) l. The 6 min walking distance increased by 7% compared with placebo, whilst resting breathlessness scores fell from 2.0 to 1.23 at rest and 4.09 to 3.28 at the end of exercise after the active drug. Improvements in walking distances and symptoms were unrelated to changes in either FEV1 or FVC, indicating that routine reversibility testing is not a good predictor of symptomatic benefit in these patients.
Do Genes Allow Inflammation to Kill or Not to Kill?
Authors: Csaba P. Kovesdy, Kamyar Kalantar-Zadeh
Journal: Journal of the American Society of Nephrology (2009)

Cardiovascular disease is principally responsible for the high mortality in patients with ESRD.1 Extending to dialysis patients therapies proven successful in the general population has thus far been of limited success,2 indicating the critical need for alternative interventions in this patient population. The metabolic complexity of renal failure encourages a variety of processes that increase cardiovascular complications and mortality. One such mechanism is enhanced chronic inflammation brought on, in part, by low GFR and, of course, various dialysis-specific proinflammatory signals.3

Inflammation initiates and propagates atherosclerosis4 through chemokines that mobilize inflammatory cell influx and proliferation during atherosclerotic plaque formation.5 Chemokines—the word itself stemming from an abbreviation of chemoattractant cytokines—are small (8 to 14 kD) proteins that regulate leukocyte trafficking, cell adhesion, phagocytosis, cytokine secretion, cell activation, proliferation, apoptosis, and angiogenesis during inflammation.6 Chemokines are classified into four groups on the basis of the number and position of conserved cysteine residues in their amino acid structure (CC, XC, CXC, and CX3C), and their receptors are accordingly designated as CCR, XCR, CXCR, or CX3CR followed by a number corresponding to the chronological order in which they were identified.5 One chemokine receptor attracting substantial interest is CCR5,7 because it also serves as …
Association of Pretherapeutic Expression of Chemotherapy-Related Genes with Response to Neoadjuvant Chemotherapy in Barrett Carcinoma
Authors: Rupert Langer, Katja Specht, Karen Becker, Philipp Ewald, Melitta Bekesch, Mario Sarbia, Raymonde Busch, Marcus Feith, Hubert J. Stein, Jörg-Rüdiger Siewert, Heinz Höfler
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemotherapy. Experimental Design: Pretherapeutic, paraffin-embedded, formalin-fixed endoscopic esophageal tumor biopsies of 38 patients with locally advanced esophageal adenocarcinomas (Barrett adenocarcinoma) were included. All patients underwent two cycles of cisplatin and 5-fluorouracil (5-FU) therapy with or without additional paclitaxel followed by abdominothoracal esophagectomy. RNA expression levels of 5-FU metabolism-associated genes thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, MAP7, and ELF3, of platinum- and taxane-related genes caldesmon, ERCC1, ERCC4, HER-2/neu, and GADD45, and of multidrug resistance gene MRP1 were determined using real-time reverse transcriptase-PCR. Expression levels were correlated with response to chemotherapy, histopathologically assessed in surgically resected specimens. Results: Responding patients showed significantly higher pretherapeutic expression levels of MTHFR (P = 0.012), caldesmon (P = 0.016), and MRP1 (P = 0.007). In addition, patients with high pretherapeutic MTHFR and MRP1 levels had a survival benefit after surgery (P = 0.013 and P = 0.015, respectively). Additionally, investigation of intratumoral heterogeneity of gene expression of relevant genes (MTHFR, caldesmon, HER-2/neu, ERCC4, and MRP1), verified in nine untreated Barrett adenocarcinomas by examination of five distinct tumor areas, revealed no significant heterogeneity in gene expression indicating that expression profiles obtained from biopsy material may yield a representative genetic expression profile of total tumor tissue. Conclusions: Our results indicate that determination of mRNA levels of few genes may be useful for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced Barrett adenocarcinoma.
US psychiatrist steps down after questions about drug company payments
Authors: J. Hopkins Tanne
Journal: BMJ (2008)

<b>Background:</b> Chronic rhinitis is a common co-existing disease and risk factor for obstructive sleep apnea(OSA). Current evidence on efficacy of intranasal steroid as a treatment in this population is scarce. <b>Methods:</b> A prospective randomized, double-blind, placebo-controlled trial was conducted in patients with moderate to severe OSA with coexisting chronic rhinitis indicated by total nasal symptom score (TNSS) ≥ 6. We randomized the patients to receive intranasal fluticasone furoate, 110 mcg/day or placebo once daily for one-month duration. The primary end point was the change in apnea hypopnea index(AHI). The secondary end points included the changes in respiratory disturbance index(RDI), sleep architectures, TNSS and Thai version of the Pittsburgh sleep quality index(PSQI). <b>Results:</b> A total of 26 patients were randomly assigned to receive intranasal steroid(N=14) and placebo(N=12). The adjusted percentage change of AHI and adjusted absolute difference change of AHI did not show significant difference between two groups 23% [95%CI; -25.8 to 72; p=0.33] and 11.6 events/hour [95%CI; -6.23 to 29.44; p=0.19]; respectively). Interestingly, significant reduction in non-supine RDI (59.03 events/hour [95% CI; 31.61 to 86.45; p=0.006]) and total time awake after sleep onset (19 minutes [95%CI; 1.26 to 37.57; p=0.037]) were observed in intranasal steroid group compared to placebo group. <b>Conclusions:</b> The use of intranasal steroid improved continuity of sleep and may be considered in conjunction with supine position avoidance as alternative OSA treatment in this population.
Single and repeat dose safety and pharmacodynamics studies with the selective intranasal TLR7 agonist GSK2245035
Authors: Diana Quint, Jo Hessey, Amanda Baines, Claire Ambery, Will Powley, Bob Gibbon, Keith Biggadike, Daphne Tsitoura
Journal: European Respiratory Journal (2014)

Introduction  GSK2245035 is a novel selective TLR7 agonist small molecule capable of inducing strong type 1 IFN-mediated immune responses. It is hypothesized that intranasal (IN) administration of GSK2245035 may lead to down-regulation of Th2 adaptive responses to aeroallergens and offer a new form of treatment for allergic rhinitis (AR) and asthma.   Methods  Double-blind, placebo-controlled, randomized studies were conducted to assess safety, tolerability and pharmacodynamic (PD) GSK2245035 responses of single, escalating IN doses in healthy volunteers (HVT) and AR patients (NCT01480271) and of four repeat weekly IN doses in patients with AR and mild asthma (NCT01607372).   Results  Single IN dosing, from 2-100ng, was found overall tolerated. In HVT transient, mild to moderate adverse events (AE) related to TLR7-mediated cytokine release (CRS), such as fever, headache, myalgia and nausea, were observed at doses ≥ 40ng in a dose-dependent manner. In AR patients mild CRS-related AE were reported up to 40ng the maximum dose tested. Activation of the TLR7 pathway was confirmed in both HVT and AR patients at doses ≥20ng, as dose-dependent increase of IP-10 levels in the serum and nasal lavage and of IFNα-stimulated genes in nasal scrapes were detected.  Following repeat IN weekly dosing, mild, potentially CRS-related Aes were noted with placebo (20%), 40ng (67%) and 80ng (14%). PD biomarkers, such as serum and nasal IP-10, demonstrated consistent increase after each dosing with no evidence for amplification or tolerization.   Conclusions  Single and repeat GSK2245035 IN administration has an acceptable safety profile at doses that induce local TLR7-mediated immune responses.
Expression of Human Telomerase Reverse Transcriptase in Lymphangioleiomyomatosis
Authors: Fumiyuki Kumaki, Kazuyo Takeda, Zu-Xi Yu, Joel Moss, Victor J. Ferrans
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Telomerase synthesizes nucleotide hexameric repeats (telomeres) at the ends of chromosomes, replacing base sequences that are lost from these sites during each mitotic cycle and protecting these ends against the action of exonucleases and ligases. Therefore, telomerase is essential for maintaining cellular replication. To evaluate the role of telomerase in the proliferation of abnormal smooth muscle cells (lymphangioleiomyomatosis [LAM] cells) in LAM, we performed immunostaining and in situ hybridization studies to identify telomerase protein and messenger RNA (mRNA), respectively, in pulmonary (n = 18) and extrapulmonary (n = 4) lesions from 22 women with LAM (14 untreated and 8 treated with progesterone or tamoxifen). Immunoreactivity and hybridization signals for telomerase were observed in 5 to 20% of LAM cells, mostly of the spindle-shaped type, in 21 of the 22 patients, and were less intense in the treated group. Other types of cells were unreactive in both groups. Telomerase colocalized in the same cells with alpha-smooth muscle actin, but only rarely with HMB-45 antibody (a marker for epithelioid LAM cells); colocalization with proliferating cell nuclear antigen was incomplete. The telomerase-positive LAM cells may constitute the sources of renewal of LAM cells. Modulation of telomerase may be involved in the control of LAM cell proliferation.
Visceral hypersensitivity in endometriosis: a new target for treatment?
Authors: B Issa, T S Onon, A Agrawal, C Shekhar, J Morris, S Hamdy, P J Whorwell
Journal: Gut (2011)

<h3>Objective</h3> In women presenting to gynaecological clinics with lower abdominal pain, the cause is frequently attributed to endometriosis irrespective of whether it is found to be minimal or extensive at laparoscopy. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. <h3>Methods</h3> Visceral sensitivity to balloon distension, symptoms and psychological status were assessed following laparoscopy in 20 women with minimal to mild endometriosis, 20 with moderate to severe endometriosis, 20 with laparoscopy negative abdominal pain and 20 asymptomatic women undergoing laparoscopic sterilisation who acted as controls, and compared with 20 women with IBS. <h3>Results</h3> Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p&lt;0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. Patients with laparoscopy negative pain had symptoms and visceral sensitivity similar to patients with IBS. Controls undergoing laparoscopy had normal sensitivity, indicating that the laparoscopic procedure was not inducing hypersensitivity. <h3>Conclusion</h3> Visceral hypersensitivity is extremely common in endometriosis and could be intensifying the pain. This finding might explain why mildly affected individuals often complain of severe symptoms out of proportion to the extent of their disease. This study has introduced a completely new concept into the understanding of pain in endometriosis and could open up new opportunities for treatment.
IQoL-32: A new ichthyosis-specific measure of quality of life
Authors: Isabelle Dreyfus, Charles Taïeb, Sébastien Barbarot, Aude Maza, Isabelle Galera, Emmanuelle Bourrat, Christine Chiaverini, Khaled Ezzedine, Anne Le Rhun, Juliette Mazereeuw-Hautier
Journal: Journal of the American Academy of Dermatology (2013)
Drug resistance trends and patterns of mycobacterium tuberculosis isolates from pulmonary tuberculosis patients at a tertiary care hospital in Turkey
Authors: Esra Ertan Yazar, Birsen Pinar Yildiz, Gülsah Günlüoglu, Sedat Altin, Veysel Yilmaz, Derya Hirçin Cenger
Journal: European Respiratory Journal (2012)

OBJECTIVE:  To determine the proportions and patterns of resistance to commonly used tuberculosis (TB) drugs (isoniazid [INH], rifampicin [R], ethambutol [E] and streptomycin[S]) among pulmonary TB patients and assess potential risk factors for drug resistance.  METHODOLOGY:  Strains were collected from 1584 sputum smear negative or positive pulmonary TB patients with culture positive in tertiary care hospital of Turkey. Specimens were cultured in liquid and solid media, and drug susceptibility tests were performed for first-line drugs including isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide.  RESULTS:  Drug susceptibility testing (DST) has been obtained from all samples 442 (27.9 %) of 1584 isolates were resistant to at least one of five antibiotics tested. 300 (18.9 %) isolates were resistant to isoniazid; 168 (10.6 %) to streptomycin; 137 (8.6 %) to ethambutol; 220 (13.9 %) to rifampin. 146 isolates (9.2 %) were multidrug resistant, Results also showed 49 % of patients were below the age of 40 years.  CONCLUSION:  Regardless of previous treatment history, the high resistance observed in isoniazid, which is a first-line drug. Treating culture-positive TB patients based on DOTS together with strengthened control programs should therefore be considered in the management of TB patients.