tbuckley/cabot-search huggingface dataset:
Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?
Authors: A. Bush, S. Pedersen, G. Hedlin, E. Baraldi, A. Barbato, F. de Benedictis, K. C. Lodrup Carlsen, J. de Jongste, G. Piacentini
Journal: European Respiratory Journal (2011)

There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 μg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting β(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous β(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.
Calcineurin-Mediated Hypertrophy Protects Cardiomyocytes From Apoptosis In Vitro and In Vivo
Authors: Leon J. De Windt, Hae W. Lim, Tyler Taigen, Detlef Wencker, Gianluigi Condorelli, Gerald W. Dorn, Richard N. Kitsis, Jeffery D. Molkentin
Journal: Circulation Research (2000)

Abstract —We have previously shown that the calcium-calmodulin–regulated phosphatase calcineurin (PP2B) is sufficient to induce cardiac hypertrophy that transitions to heart failure in transgenic mice. Given the rapid onset of heart failure in these mice, we hypothesized that calcineurin signaling would stimulate myocardial cell apoptosis. However, utilizing multiple approaches, we determined that calcineurin-mediated hypertrophy protected cardiac myocytes from apoptosis, suggesting a model of heart failure that is independent of apoptosis. Adenovirally mediated gene transfer of a constitutively active calcineurin cDNA (AdCnA) was performed in cultured neonatal rat cardiomyocytes to elucidate the mechanism whereby calcineurin affected myocardial cell viability. AdCnA infection, which induced myocyte hypertrophy and atrial natriuretic factor expression, protected against apoptosis induced by 2-deoxyglucose or staurosporine, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) labeling, caspase-3 activation, DNA laddering, and cellular morphology. The level of protection conferred by AdCnA was similar to that of adenoviral Bcl-x L gene transfer or hypertrophy induced by phenylephrine. In vivo, failing hearts from calcineurin-transgenic mice did not demonstrate increased TUNEL labeling and, in fact, demonstrated a resistance to ischemia/reperfusion–induced apoptosis. We determined that the mechanism whereby calcineurin afforded protection from apoptosis was partially mediated by nuclear factor of activated T cells (NFAT3) signaling and partially by Akt/protein kinase B (PKB) signaling. Although calcineurin activation protected myocytes from apoptosis, inhibition of calcineurin with cyclosporine was not sufficient to induce TUNEL labeling in Gqα-transgenic mice or in cultured cardiomyocytes. Collectively, these data identify a calcineurin-dependent mouse model of dilated heart failure that is independent of apoptosis.
Collagenase increases shortening of human bronchial smooth muscle in vitro.
Authors: A M Bramley, C R Roberts, R R Schellenberg
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The recent demonstration of increased shortening of asthmatic airway smooth muscle could result from increased contractility of the muscle itself or from a decreased load that must be overcome by the smooth muscle to shorten. To evaluate the role of smooth muscle-associated extracellular matrix in limiting smooth muscle responses, we investigated the effect of collagenase on the mechanical responses of human bronchial smooth muscle strips. Contractile responses of second- to fourth-generation bronchi were evoked by electrical field stimulation, and measurements of length and tension were made at preloads between 0 and 2.5 g. The passive tension, active isometric, and isotonic responses were obtained at each preload before and after 90 min of incubation with 20 U/ml collagenase. Shortening to 10(-4) M histamine was also measured. Collagenase treatment caused a significant decrease in passive tension, with the most pronounced change occurring below Lmax (optimal length for force generation). At optimal lengths for shortening, the degree of shortening, expressed as a percentage of starting length, increased significantly from 8.9 +/- 1.4% before to 13.8 +/- 2.9% after collagenase treatment (n = 7) (p < 0.02). Shortening to histamine also increased from 14.3 +/- 2.5% before to 23.5 +/- 5.3% after collagenase treatment (n = 7) (p < 0.02). These results suggest that degradation of the collagenous matrix surrounding muscle in the airway wall reduces the load on the muscle, allowing increased smooth muscle shortening.
Translation Initiation Factor eIF3b Expression in Human Cancer and Its Role in Tumor Growth and Lung Colonization
Authors: Hong Wang, Yuanbin Ru, Marta Sanchez-Carbayo, Xuejiao Wang, Jeffrey S. Kieft, Dan Theodorescu
Journal: Clinical Cancer Research (2013)

Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here, we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models.We examined mRNA expression of eIF3b in bladder (N = 317) and prostate (N = 566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regard to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth, and lung colonization.eIF3b mRNA expression correlated to tumor grade, stage, and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1-S cell-cycle transition by changing protein but not RNA expression of cyclin A, E, Rb, and p27Kip1; inhibited migration; and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b-depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization.eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth, and thus a candidate therapeutic target.
Ganglioside GM2-Activator Protein and Vesicular Transport in Collecting Duct Intercalated Cells
Authors: THOMAS M. MUNDEL, HANS W. HEID, DON J. MAHURAN, WILHELM KRIZ, PETER MUNDEL
Journal: Journal of the American Society of Nephrology (1999)

This study describes the molecular characterization of an antigen defined by an autoantibody from a woman with habitual abortion as GM2-activator protein. The patient showed no disorder of renal function. Accidentally with routine serum screening for autoantibodies, an immunoreactivity was found in kidney collecting duct intercalated cells. Three distinct patterns of immunostaining of intercalated cells were observed: staining of the apical pole, basolateral pole, and diffuse cytoplasmic labeling. Ultrastructurally, the immunoreactivity was associated with "studs," which represent the cytoplasmic domain of the vacuolar proton pump in intercalated cells. This pump is subjected to a shuttling mechanism from cytoplasmic stores to the cell membrane, which exclusively occurs in intercalated cells. Peptide sequences of a 23-kD protein purified from rat kidney cortex showed complete identity with corresponding sequences of GM2-activator protein. In the brain, GM2-activator protein is required for hexosaminidase A to split a sugar from ganglioside GM2. Because neither ganglioside GM2 nor GM1 (its precursor) is present in significant amounts in the kidney, the previous finding that this tissue contains the highest level of activator protein in the body was confusing. In this study, a novel role for GM2-activator protein in intercalated cells is proposed, and possible roles in the shuttling mechanism are discussed.
Differential effects of caffeine on hair shaft elongation, matrix and outer root sheath keratinocyte proliferation, and transforming growth factor‐β2/insulin‐like growth factor‐1‐mediated regulation of the hair cycle in male and female human hair follicles<i>in vitro</i>
Authors: T.W. Fischer, E. Herczeg‐Lisztes, W. Funk, D. Zillikens, T. Bíró, R. Paus
Journal: British Journal of Dermatology (2014)

Caffeine reportedly counteracts the suppression of hair shaft production by testosterone in organ-cultured male human hair follicles (HFs).We aimed to investigate the impact of caffeine (i) on additional key hair growth parameters, (ii) on major hair growth regulatory factors and (iii) on male vs. female HFs in the presence of testosterone.Microdissected male and female human scalp HFs were treated in serum-free organ culture for 120 h with testosterone alone (0·5 μg mL(-1)) or in combination with caffeine (0·005-0·0005%). The following effects on hair shaft elongation were evaluated by quantitative (immuno)histomorphometry: HF cycling (anagen-catagen transition); hair matrix keratinocyte proliferation; expression of a key catagen inducer, transforming growth factor (TGF)-β2; and expression of the anagen-prolonging insulin-like growth factor (IGF)-1. Caffeine effects were further investigated in human outer root sheath keratinocytes (ORSKs).Caffeine enhanced hair shaft elongation, prolonged anagen duration and stimulated hair matrix keratinocyte proliferation. Female HFs showed higher sensitivity to caffeine than male HFs. Caffeine counteracted testosterone-enhanced TGF-β2 protein expression in male HFs. In female HFs, testosterone failed to induce TGF-β2 expression, while caffeine reduced it. In male and female HFs, caffeine enhanced IGF-1 protein expression. In ORSKs, caffeine stimulated cell proliferation, inhibited apoptosis/necrosis, and upregulated IGF-1 gene expression and protein secretion, while TGF-β2 protein secretion was downregulated.This study reveals new growth-promoting effects of caffeine on human hair follicles in subjects of both sexes at different levels (molecular, cellular and organ).
Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
Authors: Mathieu Epardaud, Kutlu G. Elpek, Mark P. Rubinstein, Ai-ris Yonekura, Angelique Bellemare-Pelletier, Roderick Bronson, Jessica A. Hamerman, Ananda W. Goldrath, Shannon J. Turley
Journal: Cancer Research (2008)

Abstract Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8+ T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15Rα. Here, we report that in vivo delivery of IL-15/IL-15Rα complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15Rβ+ cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15Rα complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8+ T cells. Our data provide novel insights into the use of IL-15/IL-15Rα complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections. [Cancer Res 2008;68(8):2972–83]
Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue
Authors: S Daum
Journal: Gut (2001)

BACKGROUND Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-β in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-β in IELs using immunohistochemistry and for clonal TCR-γ gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS Clonal TCR-γ gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-β staining, and 100% for detection of a clonal TCR-γ gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-β staining in all investigated patients with EITCL. CONCLUSIONS Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term “sprue-like intestinal T cell lymphoma” is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a “sprue-like intestinal T cell lymphoma”. This latter entity is a complication of coeliac disease. * EITCL : enteropathy-type intestinal T cell lymphoma IELs : intraepithelial T lymphocytes non-EITCL : non-enteropathy-type intestinal T cell lymphoma TCR : T cell receptor PCR : polymerase chain reaction
5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype
Authors: F V Castro, O J McGinn, S Krishnan, G Marinov, J Li, A J Rutkowski, E Elkord, D J Burt, M Holland, R Vaghjiani, A Gallego, V Saha, P L Stern
Journal: Leukemia (2012)
The Man Behind the Eponym
Authors: Eoin T. O'Brien
Journal: New England Journal of Medicine (1981)

The name Corrigan is familiar to medical students and doctors the world over. Indeed, in Victorian days Corrigan's contributions to clinical medicine were acknowledged by a host of eponyms — maladie de Corrigan, Corrigan's cirrhosis, Corrigan's sign, venous Corrigan, Corrigan's button, and Corrigan's hammer1; and in the town of Arcachon near Bordeaux, Allée Corrigan bore testimony of the citizens' gratitude to him for extolling the climatic benefits of their seaside resort. Nowadays little is known of the man behind these eponyms, and it is timely to reappraise the achievements of this remarkable Victorian.Dominic John Corrigan's first task, after . . .
TCTAP A-083 Impact of Diabetes on Heavily Calcified Plaque in Extremely Late In-stent Restenosis Lesions After Bare-metal Stent Implantation
Authors: Takahiro Watanabe, Kazuhiko Yumoto, Yoshiyasu Takeda, Yuichi Hanaki, Yasutoshi Shinoda, Tatsuhiko Murase, Tagayasu Anzai, Tomoyuki Fukuzawa, Yoshihisa Naruse, Seigen I, Jyunji Kawagoe, Hajime Aoki, Shinya Kowase, Kenji Kurosaki, Kenichi Katou
Journal: Journal of the American College of Cardiology (2014)
Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.
Authors: W T Clusin, M Buchbinder, A K Ellis, R S Kernoff, J C Giacomini, D C Harrison
Journal: Circulation Research (1984)

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.
Another view on the prediction of outcomes in patients with community-acquired pneumonia
Authors: P. Schuetz, W. Zimmerli, B. Mueller
Journal: European Respiratory Journal (2011)

From the authors:

We thank S. Kruger and co-workers for their thoughtful comments and suggestions.

With regard to the Pneumonia Severity Index (PSI), most subsequent risk scores and prognostic markers in community-acquired pneumonia (CAP) research focused on 30-day mortality despite the well-known limitations of this end-point. Mortality may not be a directly related to infection, but rather due to comorbidities, advanced age or secondary complications within the follow-up period. In fact, within the Procalcitonin-Guided Antibiotic Therapy and Hospitalisation in Patients with Lower Respiratory Tract Infections (ProHOSP) study, deaths were evenly distributed within the 30-day follow-up, as demonstrated in the Kaplan–Meier plot. When restricting our analysis to short-term mortality within the first 3 days after admission, procalcitonin (PCT) showed a superior prognostic performance (area under the curve (AUC) 0.68). Also, considering not only initial but also follow-up PCT levels within our study significantly improved the prognostic performance of PCT. This was also true in a previous Legionella sp. CAP study [1] and intensive care unit (ICU) studies [2, 3]. Therefore, we advocate the use of PCT for prognostication in an in-patient CAP setting primarily in combination with a clinical risk score that also incorporates static risk factors, such as age and comorbidities, and consideration of the kinetic of the marker …
Bronchial responsiveness and airway inflammation in trained subjects
Authors: M R Bonsignore, N Scichilone, G Morici
Journal: Thorax (2007)

We read with interest the paper by Shaaban and coworkers1 on the protective effect of physical activity against bronchial hyperreactivity (BHR) in the general population. The authors suggest that a beneficial effect of deep inspirations during exercise could account for the lower prevalence of BHR in physically active subjects compared with sedentary subjects, while the accompanying editorial2 favours an “anti-inflammatory” effect of exercise as the most plausible explanation.

We have studied lung function and airway cell biology …