tbuckley/cabot-search huggingface dataset:
Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants.
Authors: G Tricot, J R Sawyer, S Jagannath, K R Desikan, D Siegel, S Naucke, S Mattox, D Bracy, N Munshi, B Barlogie
Journal: Journal of Clinical Oncology (1997)

PURPOSE Although important predictors of survival in myeloma patients have been identified, it is well recognized that better prognostic factors for this disease are needed. Because cytogenetics play a dominant role in the outcome of patients with acute leukemia, their prognostic value was evaluated in a large group of newly diagnosed and previously treated myeloma patients receiving autotransplants. METHODS A total of 427 either newly diagnosed (26%) or previously treated patients (74%) received tandem transplants, supported by mobilized peripheral-blood stem cells. Numerous variables, including cytogenetics, were analyzed for their impact on complete remission, event-free survival (EFS), and overall survival (OS). RESULTS Abnormal karyotypes were detected in 37% of our patients and were very complex, irrespective of the duration of standard therapy before the first autotransplant. In addition to previously recognized unfavorable implications of partial or complete deletion of chromosome 13 and 11q abnormalities, we now observed that the presence of any translocation likewise portended poor outcome (unfavorable karyotypes). On multivariate analysis, the absence of an unfavorable karyotype was the most favorable variable for both EFS (P = .0001) and OS (P = .0001). Other favorable factors were duration of standard therapy and a low beta-2 microglobulin (B2M) level before the first autotransplant. A risk-based classification system was developed according to the number of these favorable variables present, showing highly significant differences in event-free and overall survival. CONCLUSION Cytogenetics play a dominant role in myeloma and were independent of previously recognized important prognostic factors, such as B2M and duration of prior standard therapy.
Detection of mesothelin in the pleural effusion has a higher diagnostic utility than in serum for diagnostic of malignant mesothelioma
Authors: Massimiliano Sivori, Paola Ferro, Pieraldo Canessa, Enrico Battolla, Paolo Dessanti, Maria Cristina Franceschini, Luigi Chiaffi, Anna Morabito, Vincenzo Fontana, Riccardo Pezzi, Franco Fedeli, Maria Pia Pistillo, Silvio Roncella
Journal: European Respiratory Journal (2013)

BACKGROUND: Soluble mesothelin-related peptide(SMRP) is a biomarker approved by the U.S. Food and Drug Administration for diagnosing and monitoring of malignant pleural mesothelioma (MPM).We compared the diagnostic performances of SMRP levels in the pleural effusion (PESMRP) and in serum (SSMRP) of MPM patients.  METHODS:We assessed 102 thoracoscopies performed for a pleural effusion (PE) of unknown origin .PE and serum were drawn at the same time from each patient.SMRP levels were measured by the MesoMark ELISA assay.The diagnostic performance of SMRP were estimated through the ROC analysis ,the SMRP cut-off discrimination point was obtained by using the Youden index and the association between dichotomized SSMRP or PESMRP with disease status was evaluated through tha diagnostic odds ratio(DOR).  RESULTS:The study comprised 43 patients affected by MPM, 23 patients with metastatic cancers and 36 patients suffering from benign diseases.We found that the best cut-off point discrimination level for MPM was 12.70 nM in PESMRP and 1.08 nM in SSMRP.At these cut-off levels,PESMRP showed better diagnostic performance than SSMRP (area under the ROC curve %=81.6 vs 70.5;Sensitivity % =69.8 vs 46.5; Specificity %=88.1 vs 84.7; DOR=17.1 vs 4.8).In SSMRP-negative patients,PESMRP conserved acceptable diagnostic performances.In contrast ,in PESMRP-negative patients,the diagnostic paaraameters were not significant (Sensitivity %=47.8 vs 15.4; DOR=8.3 vs 1.2;P-value=0.001 vs 0.858).  CONCLUSIONS:Both PESMRP and SSMRP may help in the diagnosis of MPM but,in maatched serum and PE,the diagnostic accuracy of PESMRP is superior to that of SSMRP.
Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen--a new intensive therapy protocol: a report from the Childrens Cancer Study Group.
Authors: P G Steinherz, P Gaynon, D R Miller, G Reaman, A Bleyer, J Finklestein, R G Evans, P Meyers, L J Steinherz, H Sather
Journal: Journal of Clinical Oncology (1986)

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.
Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders
Authors: Azmy Faisal, Bader J. Alghamdi, Casey E. Ciavaglia, Amany F. Elbehairy, Katherine A. Webb, Josuel Ora, J. Alberto Neder, Denis E. O’Donnell
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown.To examine whether the relationship between inspiratory neural drive to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions.We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements.In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt.Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.
Risk of anaphylaxis after vaccination in children and adults
Authors: Michael M McNeil, Eric S Weintraub, Jonathan Duffy, Lakshmi Sukumaran, Steven J Jacobsen, Nicola P Klein, Simon J Hambidge, Grace M Lee, Lisa A Jackson, Stephanie A Irving, Jennifer P King, Elyse O Kharbanda, Robert A Bednarczyk, Frank DeStefano
Journal: Journal of Allergy and Clinical Immunology (2015)
Repeated inhalation of bradykinin attenuates adenosine 5'-monophosphate (AMP) induced bronchoconstriction in asthmatic airways
Authors: R Polosa, K Rajakulasingam, MK Church, ST Holgate
Journal: European Respiratory Journal (1992)

Repeated bronchial challenges with inhaled bradykinin lead to a rapid loss of the bronchoconstrictor response and this has been suggested to be due to depletion of contractile neuropeptides from sensory nerve endings. If adenosine 5'-monophosphate (AMP), another potent bronchoprovocant in asthma, and bradykinin share a common pathway in inducing bronchoconstriction in asthmatic subjects, then repeated bradykinin bronchoprovocation tests should reduce the response to subsequent inhalation of AMP. We examined this hypothesis in eight asthmatic subjects in a double-blind, randomized study. On the histamine study day, two consecutive concentration-response studies with inhaled histamine were followed by a third consecutive challenge with AMP and the provocation concentration producing a 20% fall in forced expiratory volume in one second from the post-diluent baseline value (PC20 FEV1) for this agonist was calculated. On the bradykinin study day, two consecutive bronchoprovocation tests with bradykinin were followed by a third inhalation challenge to obtain the PC20AMP value. On a further occasion, the asthmatic subjects underwent two consecutive concentration-response studies with inhaled bradykinin followed by a third consecutive challenge with histamine. On the histamine study day, the geometric mean PC20AMP value was 28.1 mg.ml-1, whilst on the bradykinin study day, the fifteenfold reduction in bradykinin responsiveness after the second bradykinin challenge was accompanied by a significant reduction of the airway responsiveness to AMP, the PC20AMP being 59.8 mg.ml-1. A similar reduction in bradykinin responsiveness failed to alter the airway response to a subsequent inhalation with histamine.(ABSTRACT TRUNCATED AT 250 WORDS)
LSC 2012 abstract - TGFβ1 compensates cigarette smoke induced disruption of tight junctions in the bronchial epithelium
Authors: Andrea Forkert, Nikica Mise, Oliver Eickelberg
Journal: European Respiratory Journal (2012)

Rationale: The airway epithelium protects the body from inhaled insults, such as smoke, or allergens. The integrity of this epithelial barrier is crucial for bronchial homeostasis. COPD and asthma have been associated with defective airway barrier function. Tight junctions (TJ) represent the major junctional components, determining the permeability of an epithelial sheet. Cigarette smoke extract (CSE) has been described to impair TJ integrity. The aim of this study was to investigate if CSE also promotes EMT in human bronchial epithelial cells (HBEC), thereby contributing to small airway diseases.  Methods and results: Normal HBECs (16HBE) underwent EMT-like processes in response to TGFβ1 treatment, as characterized by elevated mesenchymal markers (FN1, SNAI1, or ZEB1). Epithelial junctional markers (e.g. CDH1, JAM1, or ZO1) were upregulated or unaltered upon TGFβ1 stimulation. 16HBE cells do not change morphological or migrational upon TGFβ1 treatment, as demonstrated by IF or live imaging. CSE downregulated TJ-associated protein expression and destabilized TJ, as observed by IF. Combined long-term treatment (7 days) of 16HBE cells with TGFβ1 and CSE resulted in restored mRNA and protein levels of TJ proteins. This was accompanied by altered MAP kinase signaling.  Conclusion: TGFβ1 and CSE resulted in EMT-like changes in HBECs. CSE induced TJ disruption, which was compensated by TGFβ1 through modified signaling processes. Thus, TGFβ1 could serve as a protective factor for bronchial epithelial cell homeostasis.
Improvement in lung function during the 1st year of life in infants diagnosed with CF through newborn screening (NBS)
Authors: Lena Thia, Ah-Fong Hoo, Thanh-Diem Nguyen, Deeba Ahmed, Sooky Lum, Jane Chudleigh, Colin Wallis, Andrew Bush, Angie Wade, Janet Stocks
Journal: European Respiratory Journal (2011)

Despite early diagnosis and specialist treatment, NBS CF infants showed reduced lung function (LF) within the 1st year of life [1]. We have reported a significantly elevated lung clearance index (LCI) and reduced forced expiratory volume and flow (FEV0.5 and FEF75 z-scores) in CF vs healthy controls (HC) by age 3 months [2].

Hypothesis: These reductions in LF persist to 1 year of age.

Methods: Multiple breath washout and raised volume techniques were performed in CF infants from 6 tertiary CF centres in London, UK and prospectively recruited HC.

Results: 35 CF and 18 HC infants have completed paired measurements at 3 months (T1) and 1y (T2). Significant improvements in the CF group were seen in anthropometry, LCI, FEV0.5 and FEF75 z-scores by T2, with no significant differences from HC at this stage, except for a slightly elevated LCI.

View this table:

Table 1. Lung function results (mean [SD])





![Figure][1] 



Conclusions: CF infants improved their LF within the 1st year of life with our standard respiratory and nutritional management. Furthermore, most NBS CF babies may do so well in the 1st year of life on standard therapy that novel treatments could be deferred.

References: 

*   1. Linnane. AJRCCM 2008.

*   2. Thia. Ped Pulm 2010.

 [1]: pending:yes
Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy for Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Study of the International Letrozole Breast Cancer Group
Authors: Henning Mouridsen, Mikhail Gershanovich, Yan Sun, Ramón Pérez-Carrión, Corrado Boni, Alain Monnier, Justus Apffelstaedt, Robert Smith, Harm P. Sleeboom, Fritz Jänicke, Anna Pluzanska, Magdolna Dank, Dominique Becquart, Poonamalle P. Bapsy, Eeva Salminen, Ray Snyder, Mercedes Lassus, J. Arnold Verbeek, Beatrix Staffler, Hilary A. Chaudri-Ross, Margaret Dugan
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P = .0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P = .0006), as was the rate of clinical benefit (49% v 38%; P = .001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Pediatric Pulseless Arrest With “Nonshockable” Rhythm
Authors: Robert C. Tasker, Adrienne G. Randolph
Journal: JAMA (2015)

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<i>ERAP2</i>functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers
Authors: Philip C Robinson, Eugene Lau, Patricia Keith, Max C Lau, Gethin P Thomas, Linda A Bradbury, Matthew A Brown, Tony J Kenna
Journal: Annals of the Rheumatic Diseases (2015)

Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2 knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS.Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR.There was no significant difference in HLA-class I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls.Large differences were not seen in HLA-B27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.
Abstract 5088: Exercise Training Increases Endothelial Progenitor Cells and Decreases Asymmetrical Dimethylarginine in Patients With Intermittent Claudication
Authors: Oliver Schlager, Aura Giurgea, Othmar Schuhfried, Michael Gschwandtner, Renate Koppensteiner, Sabine Steiner
Journal: Circulation (2009)

Background - Exercise training is a well-established, non-invasive method to improve peripheral arterial perfusion and walking capacity in PAD patients. Hypothesis - We designed a prospective randomized controlled trial to test the effect of training on laboratory markers of angiogenesis. Methods - Thirty patients with intermittent claudication were randomized to supervised training twice a week for 6 months or standard medical therapy. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+CD133+KDR+) and cell culture assays (colony forming units/CFU and circulating angiogenic cells/CAC) at baseline, 3-months and 6-months after training as well as 12-months after study begin. Plasma ADMA was determined by immunoassay. In addition, changes in maximum walking distance were recorded. Results - EPC measured by flow cytometry increased significantly three and six months after training paralleled by a significant decrease of ADMA (asymmetric dimethylarginine), a major endogenous inhibitor of NO synthase (see table ). The number of CFUs and CACs were significantly higher after 6-months compared to baseline upon exercise (P&lt;0.05). No differences were observed in the standard group in timecourse. However, 6-months after training cessation the number of EPC and ADMA levels were similar to baseline. Exercise training showed a benefit on treadmill maximum walking distance with a trendwise increase at 6-months (training: baseline 116.6m±12.8 (mean±SEM) vs. 6-months 149.1m±17.8, P=0.08; standard: baseline 125.2m±23.9 vs. 6-months 108m±19.9, P=0.3). The benefit was sustained 6 months after training cessation in the exercise group (training: 12-months 157.5m±18.4, P=0.07; standard: 12-months 129.5m±26.9). Conclusions - The beneficial effect of exercise training in PAD patients might partly be due to EPC mobilization mediated by improved NO synthesis as we observed reduced ADMA levels. EPC and ADMA levels in timecourse
Increased liver enzyme levels during azathioprine treatment: beware of concomitant use of proton pump inhibitors
Authors: J. van der Schaft, R.H.N. van Schaik, M.P.H. van den Broek, C.A.F.M. Bruijnzeel-Koomen, M.S. de Bruin-Weller
Journal: British Journal of Dermatology (2015)

Azathioprine (AZA) is a purine antagonist, which is frequently used off label in chronic inflammatory skin diseases. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) influence the metabolism of AZA. A reduced enzymatic activity of TMPT is associated with increased 6-thioguaninie nucleotide (6-TGN) levels which may cause severe leukopenia. High TPMT activity is associated with increased 6-methylmercaptopurine (6-MMP) levels (toxic 6-MMP >5700 pmol/8x10(8) RBCs), which is associated with liver toxicity.(1) Alanine transaminase (ALT) >3 upper limits of normal has been identified as a sensitive, but not necessarily specific signal of liver toxicity.(2) In daily practice AZA is often started with a test dose of 50 mg/day for 1-2 weeks. If laboratory tests show no abnormalities, the dose is increased to up to 150-200 mg/day. This article is protected by copyright. All rights reserved.