tbuckley/cabot-search huggingface dataset:
Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice
Authors: Konstantin Salojin, Jian Zhang, Mark Cameron, Bruce Gill, Guillermo Arreaza, Atsuo Ochi, Terry L. Delovitch
Journal: The Journal of Experimental Medicine (1997)

Nonobese diabetic (NOD) mouse thymocytes are hyporesponsive to T cell antigen receptor (TCR)-mediated stimulation of proliferation, and this T cell hyporesponsiveness may be causal to the onset of autoimmune diabetes in NOD mice. We previously showed that TCR-induced NOD T cell hyporesponsiveness is associated with a block in Ras activation and defective signaling along the PKC/Ras/MAPK pathway. Here, we report that several sequential changes in TCR-proximal signaling events may mediate this block in Ras activation. We demonstrate that NOD T cell hyporesponsiveness is associated with the (a) enhanced TCR-β–associated Fyn kinase activity and the differential activation of the Fyn–TCR-ζ–Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-ζ; (b) relative inability of the murine son of sevenless (mSOS) Ras GDP releasing factor activity to translocate from the cytoplasm to the plasma membrane; and (c) exclusion of mSOS and PLC-γ1 from the TCR-ζ–associated Grb2/pp36–38/ZAP70 signaling complex. Our data suggest that altered tyrosine phosphorylation and targeting of the Grb2/pp36–38/ZAP70 complex to the plasma membrane and cytoskeleton and the deficient association of mSOS with this Grb2-containing complex may block the downstream activation of Ras and Ras-mediated amplification of TCR/CD3-mediated signals in hyporesponsive NOD T cells. These findings implicate mSOS as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells.
Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma
Authors: Paul G. Richardson, Pieter Sonneveld, Michael W. Schuster, David Irwin, Edward A. Stadtmauer, Thierry Facon, Jean-Luc Harousseau, Dina Ben-Yehuda, Sagar Lonial, Hartmut Goldschmidt, Donna Reece, Jesus F. San-Miguel, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, William S. Dalton, Anthony L. Boral, Dixie L. Esseltine, Jane B. Porter, David Schenkein, Kenneth C. Anderson
Journal: New England Journal of Medicine (2005)

This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression.Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone.Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.
Evidence for a genetic susceptibility to lung carcinoma
Authors: C Carlin
Journal: Thorax (2005)

▴ Jonsson S, Thorsteinsdottir U, Gudbjartsson DF, et al . Familial risk of lung carcinoma in the Icelandic population. JAMA2004;292:2977–83 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Previous studies of the genetic epidemiology of lung cancer have suggested a modest (twofold) increased risk associated with a family history of lung cancer. It has been unclear whether the increased risk observed reflected genetic factors specific to lung cancer, genetic modifiers of nicotine addiction (leading to increased tobacco … [1]: {openurl}?query=rft.jtitle%253DJAMA%26rft.stitle%253DJAMA%26rft.issn%253D0002-9955%26rft.aulast%253DJonsson%26rft.auinit1%253DS.%26rft.volume%253D292%26rft.issue%253D24%26rft.spage%253D2977%26rft.epage%253D2983%26rft.atitle%253DFamilial%2BRisk%2Bof%2BLung%2BCarcinoma%2Bin%2Bthe%2BIcelandic%2BPopulation%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.292.24.2977%26rft_id%253Dinfo%253Apmid%252F15613665%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1001/jama.292.24.2977&link_type=DOI [3]: /lookup/external-ref?access_num=15613665&link_type=MED&atom=%2Fthoraxjnl%2F60%2F4%2F287.atom [4]: /lookup/external-ref?access_num=000225841900031&link_type=ISI
Shortening versus isometric contractions in isolated human failing and non-failing left ventricular myocardium: dependency of external work and force on muscle length, heart rate and inotropic stimulation
Authors: C Holubarsch
Journal: Cardiovascular Research (1998)

Background: For reasons of simplicity, studies on isolated human myocardium have been conducted using exclusively isometric contractions, although positive inotropic interventions may differently influence force development, extent of shortening and myocardial work performance. We investigated human left ventricular failing and non-failing preparations comparing isometric versus isotonic, i.e., shortening contractions. Results: (1) When muscle length is increased from 90% to 100% lmax, peak developed force increases by 36% and 43% (p<0.05) in non-failing and failing human left ventricular myocardium, respectively. Maximum performed work increases similarly in non-failing but decreases in failing myocardium. It can be shown that this discrepancy is due to significantly higher resting tension and does not present an insufficient intrinsic shortening capacity in failing myocardium. (2) When stimulation rate is increased from 0.5 to 2.0 Hz, isometric force increases significantly by 59% in non-failing and decreases by 27% in failing myocardium, whereas maximum performed work increases by 98% and decreases by 46%, respectively. (3) Pharmacological positive inotropic interventions by 7.2 mM calcium (n = 9), 3×10−8 M isoproterenol (n = 7), 3×10−8 M ouabain (n = 5), and 10−5 M EMD 57033 (n = 3) equally increased force development and extent of shortening: When the fractional effect on shortening (y) was correlated to the fractional effect on force (x), the following linear regression equation was obtained: y = 0.91x+0.26 (r = 0.86; p<0.001). Conclusions: The data presented are of clinical and pharmacological importance: (1) The Frank-Starling mechanism is demonstrated to be existent in the failing human myocardium regarding both isometric force developed and maximum work performed. (2) Both force-frequency relations and – to a greater extent – work-frequency relations are reversed in failing human myocardium. (3) Independent of the pharmacological mode of action, positive inotropic compounds increase developed isometric force to the same extent as isotonic shortening and therefore potentiate maximum performed work.
Vascular endothelial growth factor (VEGF) in inflammatory and malignant pleural effusions
Authors: D R Thickett, L Armstrong, A B Millar
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Investigation and management of pleural effusions is an important clinical problem yet the pathogenesis of pleural fluid accumulation is poorly understood. Vascular endothelial growth factor (VEGF) is a potent inducer of capillary permeability that is produced by both malignant and inflammatory cells. A study was undertaken to determine whether VEGF has a potential pathogenic role in the development of pleural effusions and whether VEGF receptors are present on human pleural mesothelial cells. <h3>METHODS</h3> Normal and inflamed pleura were examined immunohistochemically for the presence of FLT-1 (the fms-like tyrosine kinase receptor of VEGF). VEGF levels were measured by ELISA in 78 consecutive patients presenting with undiagnosed unilateral pleural effusions and the levels were correlated with the aetiology of the effusions. <h3>RESULTS</h3> Immunohistochemical staining of normal and diseased pleura demonstrated the presence of the FLT-1 VEGF receptor on human mesothelial cells. Median VEGF levels were 2500 pg/ml in the malignant group and 305 pg/ml in the non-malignant group (median difference 1397.5 pg/ml (95% CI 851 to 2693), p&lt;0.005). Median VEGF levels varied according to tumour histology. VEGF levels were also significantly raised compared with transudates (median 36.5 pg/ml) in empyema (4651 pg/ml (95% CI 833 to 10 000), p&lt;0.001) and parainfectious effusions (360 pg/ml (95% CI 46 to 597), p&lt;0.005). <h3>CONCLUSIONS</h3> This first report of VEGF receptors on pleural mesothelial cells has indicated a potential mechanism for the biological activity of VEGF on pleural tissue. VEGF levels are raised in the majority of exudative effusions, implying a pathogenic role for this molecule in the development of pleural effusions.
Drug Discovery in the Next Millennium
Authors: Eliot H. Ohlstein, Robert R. Ruffolo Jr, John D. Elliott
Journal: The Annual Review of Pharmacology and Toxicology (2000)

Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. This review addresses these technological advances as well as several new areas that have been created by necessity to deal with this new paradigm, such as bioinformatics, cheminformatics, and functional genomics. With many of these key components of future drug discovery now in place, it is possible to map out a critical path for this process that will be used into the new millennium.
Evaluation of quantitative magnetic resonance imaging as a noninvasive technique for measuring renal scarring in a rabbit model of antiglomerular basement membrane disease.
Authors: M H de Miguel, H N Yeung, M Goyal, J W Noh, A M Aisen, S H Phan, R C Wiggins
Journal: Journal of the American Society of Nephrology (1994)

Renal function tests are an insensitive means of detecting progressive scarring of the kidney such as occurs in chronic allograft rejection and lupus nephritis. Alternative approaches for the measurement of small progressive changes in renal structure on a repetitive basis are needed. Quantitative magnetic resonance imaging (proton T1 relaxation time) was assessed for this purpose. A rabbit model of antiglomerular basement membrane disease that develops glomerular and interstitial inflammation followed by scarring of the renal cortex was used. Longitudinal studies of cortical T1 showed a marked prolongation of T1 during the initial inflammation and edema associated with glomerular crescent formation (Day 7). The T1 remained prolonged up to Day 120 in animals with significant fibrosis and crescent formation when the wet/dry weight ratio (a measure of edema) had returned to baseline. T1 was a more sensitive index of renal injury than was serum creatinine for all of the end points measured (cortical hydroxyproline per dry weight, percent crescent formation, or histologic fibrosis score). It was concluded from these studies that measurement of renal cortical T1 is quite a sensitive index of renal injury, probably more sensitive than the measurement of serum creatinine, but that this method does not discriminate between edema and scarring.
Palliation of malignant tracheal strictures using silicone T tubes.
Authors: R L Insall, G N Morritt
Journal: Thorax (1991)

The use of silicone T tubes for intubation of malignant tracheobronchial strictures may provide some degree of palliation of this distressing condition. It was used in seven patients with malignant lesions and two with benign strictures (resulting from tracheal trauma and lung transplantation). Four patients (two with cancer) are still alive and well with the tube in position. All patients noted improvement in dyspnoea and stridor. The main problems were tube migration (one patient), tracheo-oesophageal fistula (one patient), and blockage of the tube by tumour (two patients) or encrusted secretions (three patients). Airway patency was restored when the tube was blocked by cleaning or by laser resection of the tumour. With careful supervision and education of the patient intubation can give useful palliation to patients with distressing upper airways obstruction.
Increased serum NG-hydroxy-L-arginine in patients with rheumatoid arthritis and systemic lupus erythematosus as an index of an increased nitric oxide synthase activity
Authors: R. Wigand, J. Meyer, R. Busse, M. Hecker
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVES</h3> To determine the feasibility of monitoring the serum concentration of N<sup>G</sup>-hydroxy-l-arginine (l-NHA) as an index of an increased nitric oxide (NO) synthase activity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) compared with nitrate (NO<sub>3</sub><sup>−</sup>), the major circulating metabolite of NO whose concentration is influenced by dietary intake. <h3>METHODS</h3> The serum concentrations ofl-NHA, l-arginine (l-Arg), and NO<sub>3</sub><sup>−</sup> were determined in 33 patients with RA, 25 patients with SLE and, 29 healthy subjects. <h3>RESULTS</h3> Serum l-NHA was significantly increased in RA patients with high disease activity (287% of control, p&lt;0.01), but not with low disease activity (115%), as well as in patients with SLE (173%, p&lt;0.01). In contrast, serum NO<sub>3</sub><sup>−</sup> did not differ significantly between either group of patients and the respective control group. <h3>CONCLUSION</h3> NO synthase activity or expression, or both, is upregulated in RA patients with high disease activity and in patients with SLE. Serum l-NHA seems to be a more specific and reliable index of an increased activity of this enzyme in patients with acute or chronic inflammatory diseases than NO<sub>3</sub><sup>−</sup>.
Progesterone-induced urticaria-need it be autoimmune?
Authors: S.M. WILKINSON, M.H. BECK, T.P. KINGSTON
Journal: British Journal of Dermatology (2006)

Journal Article Progesterone‐induced urticaria—need it be autoimmune? Get access S.M. WILKINSON, S.M. WILKINSON The Skin Hospital, Chapel Street, Salford M60 9EP, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.H. BECK, M.H. BECK The Skin Hospital, Chapel Street, Salford M60 9EP, U.K. Search for other works by this author on: Oxford Academic Google Scholar T.P. KINGSTON T.P. KINGSTON The Skin Hospital, Chapel Street, Salford M60 9EP, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 133, Issue 5, 1 November 1995, Pages 792–794, https://doi.org/10.1111/j.1365-2133.1995.tb02759.x Published: 01 November 1995 Article history Accepted: 22 December 1994 Published: 01 November 1995
Opioid Use and Risk of Nonvertebral Fractures in Adults With Rheumatoid Arthritis: A Nested Case–Control Study Using Administrative Databases
Authors: Francisco A. Acurcio, Cristiano S. Moura, Sasha Bernatsky, Louis Bessette, Elham Rahme
Journal: Arthritis & Rheumatology (2015)

To assess the risk of nonvertebral fractures in patients with rheumatoid arthritis (RA) who were exposed to opioids.A population-based, nested case-control study was conducted using health services administrative databases (Quebec, Canada) from 1997 to 2012. Among RA patients, cases of nonvertebral fractures from 2007 to 2012 were identified using a validated algorithm. The date of the first fracture was the index date for the case and his/her matched control. Controls were selected using incidence density sampling and were matched 5:1 to cases for age, sex, and date of RA diagnosis. Opioid exposure was classified as current use, recent past use, remote past use, and nonuse. Conditional logistic regression was used to assess the association of nonvertebral fractures with opioid exposure, adjusting for comorbidity, indicators of RA severity, drugs influencing fracture risk, and health care utilization.In total, 1,723 cases and 8,046 controls were identified. Among these patients, 2,595 (722 cases and 1,873 controls) had been exposed to opioids. Current use (versus nonuse) increased the risk of nonvertebral fracture. Cumulative current use of opioids according to the quartile distribution was also associated with the risk of nonvertebral fracture: for continuous use for 1-20 days before the index date, odds ratio (OR) 11.49 (95% confidence interval [95% CI] 8.81-14.99); for 21-155 days, OR 1.75 (95% CI 1.31-2.33); for 156-355 days, OR 1.54 (95% CI 1.17-2.04); and for ≥356 days, OR 1.73 (95% CI 1.31-2.30). No association between the risk of nonvertebral fractures and recent past use or remote past use of opioids was observed.Among RA patients, the risk of nonvertebral fracture is increased in those treated with opioids.
Investigation of the putative immunodominant T cell epitopes in coeliac disease
Authors: H J Ellis
Journal: Gut (2003)

Coeliac disease (CD) is an enteropathy mediated by gluten specific T cells which secrete interferon gamma (IFN-gamma) when stimulated by gluten peptides presented by HLA-DQ2 or DQ8 molecules. Residues 62-75 of alpha(2) gliadin have been proposed as the immunodominant epitope in the majority of CD patients. Deamidation by tissue transglutaminase (tTG) of the glutamine (Q) at position 65 to glutamic acid (E) is essential for T cell stimulation.
Esomeprazole does not improve asthma control
Authors: J Alagaratnam
Journal: Thorax (2009)

Current American asthma guidelines recommend assessing patients with poorly controlled asthma for gastro-oesophageal reflux disease (GORD) and treating silent GORD. However, these recommendations were based on studies on patients with GORD symptoms. This study is the first of its kind to evaluate whether the addition of proton pump inhibitors (PPIs) in silent GORD may …
Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth<i>In vivo</i>and Bypass Pathways Are Activated in AZD0530-Resistant Tumors
Authors: Yi Chen, Natalia Guggisberg, Merce Jorda, Ana Gonzalez-Angulo, Bryan Hennessy, Gordon B. Mills, Chen-Keat Tan, Joyce M. Slingerland
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Antiestrogens are used to treat estrogen receptor (ER)-α-positive breast cancers and cause a p27-dependent G1 arrest. Estrogen-bound ER recruits Src to mediate proteolysis of p27 and drive cell proliferation. Here, we tested the antitumor efficacy of combined Src and aromatase inhibition for ER-positive breast cancer. Experimental Design: Antiproliferative effects of the aromatase inhibitor, anastrozole, and Src inhibitor, AZD0530, alone or in combination were tested in vitro and in vivo on aromatase-transfected MCF-7Arom5 xenografts. Xenografts were analyzed by immunohistochemistry and proteomic analysis to identify potential biomarkers of drug response and resistance. Results: AZD0530 and anastrozole together increased p27 and caused greater G1 cell cycle arrest than either drug alone. AZD0530 monotherapy initially retarded xenograft growth in vivo, but drug resistance rapidly emerged. Combined anastrozole/AZD0530 reduced drug resistance and showed greater antitumor efficacy in vivo with greater Src and epidermal growth factor receptor inhibition and a greater increase in p27 and reduction of Ki-67 than either drug alone, supporting further evaluation of these putative predictors of response to combined Src/aromatase inhibition in vivo. Anastrozole alone stimulated Src activity both in vitro and in vivo. AZD0530-resistant tumors showed activation of bypass pathways including MEK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin, raising the possibility that MEK, mammalian target of rapamycin (mTOR), or PI3K inhibitors may augment Src inhibitor efficacy. Conclusions: These data support clinical investigation of anastrozole-AZD0530 therapy for postmenopausal ER-positive breast cancer. Loss of p27 and increased Ki-67 may predict response and further clinical studies should evaluate for activation of bypass pathways including MEK and PI3K pathways during Src inhibitor therapy.
Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma
Authors: S. A Little
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. <h3>METHODS</h3> Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25.9 (17.3) years, and baseline forced expiratory volume in one second (FEV<sub>1</sub>) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a β agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. <h3>RESULTS</h3> Baseline NO levels correlated with the percentage improvement in FEV<sub>1</sub>from baseline to the post-steroid, post-bronchodilator value (<i>r</i><sub>s</sub> = 0.47, p = 0.003), with an NO level of &gt;10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV<sub>1</sub> of ⩾15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (⩾4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV<sub>1</sub> of ⩾15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). <h3>CONCLUSION</h3> Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.