tbuckley/cabot-search huggingface dataset:
Low-Dose Thalidomide Ameliorates Cytopenias and Splenomegaly in Myelofibrosis With Myeloid Metaplasia: A Phase II Trial
Authors: Monia Marchetti, Giovanni Barosi, Francesca Balestri, Gianluca Viarengo, Sara Gentili, Sara Barulli, Jean-Loup Demory, Fiorella Ilariucci, Antonio Volpe, Dominique Bordessoule, Alberto Grossi, Marie Caroline Le Bousse-Kerdiles, Andrea Caenazzo, Alessandro Pecci, Antonietta Falcone, Giorgio Broccia, Cesarina Bendotti, Fredric Bauduer, Francesco Buccisano, Brigitte Dupriez
Journal: Journal of Clinical Oncology (2004)

A phase II dose-escalation trial was conducted to ascertain low-dose thalidomide safety and response in patients with advanced myelofibrosis with myeloid metaplasia (MMM).Thalidomide was administered together with current therapy to 63 patients, starting at 50 mg daily and increasing to 400 mg as tolerated.Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients and transfusions were eliminated in 39% of transfusion-dependent patients. Platelet count increased by 50 x 10(9)/L or more in 22% of patients with an initial count lower than 100 x 10(9)/L. Splenomegaly decreased by more than 50% of the initial size in 19% of patients. Reduction of an overall disease severity score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis).Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.
Studies in chronic allergic bronchopulmonary aspergillosis. 3. Immunological findings.
Authors: J L Malo, J Longbottom, J Mitchell, R Hawkins, J Pepys
Journal: Thorax (1977)

Precipitin tests by two different methods, double-diffusion (DD) and counterimmunoelectrophoresis (CIE), and measurements of total and specific IgE against Aspergillus fumigatus were made in 50 patients with chronic allergic bronchopulmonary aspergillosis and in three control groups--atopics with a positive immediate prick test to A. fumigatus but no evidence of allergic aspergillosis, atopics with a negative prick test to A. fumigatus, and non-atopics. Precipitins were found in 84% and 78% of the patients with aspergillosis by the DD and CIE methods respectively. Precipitins were also found in 6 out of 27 (22%) patients with a positive prick test to A. fumigatus but no evidence of aspergillosis and in 1 of 24 patients with a negative prick test to A. fumigatus. The means of specific and total IgE values were significantly higher in the group of patients with aspergillosis than in the three other groups of patients. The increase in specific but not total IgE showed a statistically significant correlation with positive precipitin tests in the patients with aspergillosis. Total IgE but not specific IgE values were significantly higher (0-02 less than P less than 0-05) in patients who had had a transient radiographic shadow in the previous three months. Positive precipitin tests were also significantly correlated with the number of transient shadows in the past and with the interval of time since the last transient shadow.
The Role of Vascular Endothelial Growth Factor in Neurodegeneration and Cognitive Decline
Authors: Timothy J. Hohman, Susan P. Bell, Angela L. Jefferson
Journal: JAMA Neurology (2015)

A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration.To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes.Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing.Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers.Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01).Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared strongest in the presence of enhanced AD biomarkers, suggesting that VEGF may be particularly beneficial in individuals showing early hallmarks of the AD cascade. Future work should evaluate the interaction between VEGF expression in vitro and pathologic burden to address potential mechanisms.
Is reflex sympathetic dystrophy a valid concept?
Authors: Mikael Elam
Journal: Behavioral and Brain Sciences (1997)

Patients with reflex sympathetic dystrophy (RSD) affecting one limb show similar sympathetic traffic in nerves supplying the affected and unaffected limb, despite unilateral autonomic effector dysfunction. This argues against the notion that RSD is mediated by a reflex change in the pattern of sympathetic discharge and underlines the fact that autonomic effector disturbances give little information about underlying nerve traffic. [blumberg et al.]
Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of Castration-Resistant Prostate Cancer
Authors: Dana E. Rathkopf, Michael J. Morris, Josef J. Fox, Daniel C. Danila, Susan F. Slovin, Jeffrey H. Hager, Peter J. Rix, Edna Chow Maneval, Isan Chen, Mithat Gönen, Martin Fleisher, Steven M. Larson, Charles L. Sawyers, Howard I. Scher
Journal: Journal of Clinical Oncology (2013)

Purpose ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC. Patients and Methods Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [ 18 F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose. Results Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. Conclusion ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.
Screening in brief intervention trials targeting excessive drinkers in general practice: systematic review and meta-analysis
Authors: A. Beich
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To determine the effectiveness of programmes of screening in general practice for excessive alcohol use and providing brief interventions. <b>Design</b> Systematic review and meta-analysis of randomised controlled trials that used screening as a precursor to brief intervention. <b>Setting</b> General practice. <b>Main outcome measures</b> Number needed to treat, proportion of patients positive on screening, proportion given brief interventions, and effect of screening. <b>Results</b> The eight studies included for meta-analysis all used health questionnaires for screening, and the brief interventions included feedback, information, and advice. The studies contained several sources of bias that might lead to overestimates of the effects of intervention. External validity was compromised because typically three out of four people identified by screening as excessive users of alcohol did not qualify for the intervention after a secondary assessment. Overall, in 1000 screened patients, 90 screened positive and required further assessment, after which 25 qualified for brief intervention; after one year 2.6 (95% confidence interval 1.7 to 3.4) reported they drank less than the maximum recommended level. <b>Conclusions</b> Although even brief advice can reduce excessive drinking, screening in general practice does not seem to be an effective precursor to brief interventions targeting excessive alcohol use. This meta-analysis raises questions about the feasibility of screening in general practice for excessive use of alcohol.
Changes in estimated right ventricular systolic pressure predict mortality and pulmonary hypertension in a cohort of scleroderma patients
Authors: Ami A Shah, Shang-En Chung, Fredrick M Wigley, Robert A Wise, Laura K Hummers
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. We evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients. Methods The study population consisted of scleroderma patients who had at least three echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality and change in RVSP/year, adjusted for relevant covariates. Results 613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05–1.11) and 1.12 (95% CI 1.08–1.15) per 1 mm Hg increase in RVSP/year, respectively. Compared with patients with a stable RVSP, the relative hazards for the development of PAH were 1.90 (95% CI 0.91–3.96), 5.09 (95% CI 2.53–10.26) and 6.15 (95% CI 3.58–10.56) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year. Compared with the same reference group, the relative hazards for death were 0.92 (95% CI 0.48–1.73), 2.16 (95% CI 1.16–4.01) and 5.05 (95% CI 3.47–7.34) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year. Conclusions In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.
Urinary Proteomics in Diabetes and CKD
Authors: Kasper Rossing, Harald Mischak, Mohammed Dakna, Petra Zürbig, Jan Novak, Bruce A. Julian, David M. Good, Joshua J. Coon, Lise Tarnow, Peter Rossing
Journal: Journal of the American Society of Nephrology (2008)

Urinary biomarkers for diabetes, diabetic nephropathy, and nondiabetic proteinuric renal diseases were sought. For 305 individuals, biomarkers were defined and validated in blinded data sets using high-resolution capillary electrophoresis coupled with electrospray-ionization mass spectrometry. A panel of 40 biomarkers distinguished patients with diabetes from healthy individuals with 89% sensitivity and 91% specificity. Among patients with diabetes, 102 urinary biomarkers differed significantly between patients with normoalbuminuria and nephropathy, and a model that included 65 of these correctly identified diabetic nephropathy with 97% sensitivity and specificity. Furthermore, this panel of biomarkers identified patients who had microalbuminuria and diabetes and progressed toward overt diabetic nephropathy over 3 yr. Differentiation between diabetic nephropathy and other chronic renal diseases reached 81% sensitivity and 91% specificity. Many of the biomarkers were fragments of collagen type I, and quantities were reduced in patients with diabetes or diabetic nephropathy. In conclusion, this study shows that analysis of the urinary proteome may allow early detection of diabetic nephropathy and may provide prognostic information.
Targeting Cyclooxygenase-2 in Recurrent Non–Small Cell Lung Cancer: A Phase II Trial of Celecoxib and Docetaxel
Authors: Ildiko Csiki, Jason D. Morrow, Alan Sandler, Yu Shyr, John Oates, Myles K. Williams, Thao Dang, David P. Carbone, David H. Johnson
Journal: Clinical Cancer Research (2005)

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non-small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m(2) every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre- and post-celecoxib levels of urinary 11alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E(2) (PGE(2)). We enrolled 56 patients (35 men, 21 women; median age, 61 years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001). When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE(2) synthesis in NSCLC seems warranted.
Mature T cell reactivity altered by peptide agonist that induces positive selection.
Authors: E Sebzda, T M Kündig, C T Thomson, K Aoki, S Y Mak, J P Mayer, T Zamborelli, S G Nathenson, P S Ohashi
Journal: The Journal of Experimental Medicine (1996)

Recent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic beta2-microglobulin-deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce efficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells.
Pulmonary Hypertension and Cor Pulmonale during Severe Acute Chest Syndrome in Sickle Cell Disease
Authors: Armand Mekontso Dessap, Rusel Leon, Anoosha Habibi, Ruben Nzouakou, Françoise Roudot-Thoraval, Serge Adnot, Bertrand Godeau, Frederic Galacteros, Christian Brun-Buisson, Laurent Brochard, Bernard Maitre
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Steady-state mild pulmonary hypertension is a risk factor for death in adults with sickle cell disease. Acute pulmonary hypertension has been reported during exercise and vasoocclusive pain crisis in these patients.The aim of the present study was to evaluate changes in pulmonary pressures and cardiac biomarkers during severe acute chest syndrome and their associations with mortality.We prospectively evaluated 70 consecutive adults who received standardized treatment in our intensive care unit for a total of 84 episodes. At admission, cardiac biomarkers were measured. Transthoracic echocardiography was performed for pulmonary hypertension assessment via measurement of tricuspid regurgitant jet velocity and was repeated when possible after resolution.Tricuspid jet velocity was less than 2.5 m/second in 34 (40%) of the 84 episodes, 2.5 to 2.9 m/second in 19 (23%), and 3 m/second or greater in 31 episodes (37%). Cor pulmonale occurred in 11 (13%) episodes. Tricuspid jet velocity showed significant positive correlations with B-type natriuretic peptide (rho = 0.54, P < 0.01) and cardiac troponin I (rho = 0.42, P < 0.01). Pulmonary pressures increased compared with steady state then decreased after resolution. All five patients who required invasive ventilation and all four patients who died during the immediate hospital course had jet velocity values of 3 m/second or greater. Overall mortality was 12.9% (9 patients) and survival was significantly lower in patients whose jet velocity was 3 m/second or greater during at least one episode, compared with the other patients (P < 0.01).Pulmonary pressures increase during severe acute chest syndrome, and pulmonary hypertension is associated with cardiac biomarker elevation and a higher risk of death.
Different patterns of gas exchange response to exercise in asbestosis and idiopathic pulmonary fibrosis
Authors: AG Agusti, J Roca, R Rodriguez-Roisin, A Xaubet, A Agusti-Vidal
Journal: European Respiratory Journal (1988)

To analyse the pattern of pulmonary gas exchange during maximal exercise (Emax) in asbestosis, we compared nine subjects with this disease (1 female/8 male), aged 54 +/- 11 yrs (mean +/- SD), to nine patients (1 female/8 male) with idiopathic pulmonary fibrosis (IPF) of a similar age, height, weight and smoking history, both at rest and during Emax. No differences were observed in dynamic and static lung volumes between the groups. However, patients with IPF had a lower DLCOsb and KCO (p less than 0.005 and 0.05, respectively). At rest, both groups showed mild arterial hypoxaemia (76 +/- 11, asbestosis, vs 77 +/- 11 mmHg, IPF), widened AaPO2 (32 +/- 14 vs 31 +/- 13 mmHg) and slight increases in VD/VT (47 +/- 12 vs 46 +/- 11%), respectively. During Emax, PaO2 fell to 51 +/- 7 mmHg in patients with IPF whereas those with asbestosis had PaO2 of 73 +/- 21 mmHg (p less than 0.05). Conversely, those with asbestosis were able to reduce VD/VT (from 47 +/- 12 to 39 +/- 10%, p = 0.01) as opposed to those with IPF (from 46 +/- 11 to 47 +/- 13%). Furthermore, DLCOsb and AaPO2 during Emax were highly correlated only in IPF (r: -0.84, p less than 0.01). Despite the finding that both diseases represent a diffuse pulmonary fibrosis with a similar degree of resting ventilatory impairment, the pattern of gas exchange during exercise is different in each. These differences may be related to the underlying morphology of each process, which probably includes more airway disease and less pulmonary vascular involvement and/or a different degree of interstitial fibrotic change in asbestosis.
iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe
Authors: LiLi Jiang, Michelle K.Y. Siu, Oscar G.W. Wong, Kai-Fai Tam, Xin Lu, Eric W-F. Lam, Hextan Y.S. Ngan, Xiao-Feng Le, Esther S.Y. Wong, Lara J. Monteiro, Hoi-Yan Chan, Annie N.Y. Cheung
Journal: Clinical Cancer Research (2011)

iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity.Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed.The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P = 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode.Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy.