tbuckley/cabot-search huggingface dataset:
Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Authors: Luca Richeldi, Ulrich Costabel, Moises Selman, Dong Soon Kim, David M. Hansell, Andrew G. Nicholson, Kevin K. Brown, Kevin R. Flaherty, Paul W. Noble, Ganesh Raghu, Michèle Brun, Abhya Gupta, Nolwenn Juhel, Matthias Klüglich, Roland M. du Bois
Journal: New England Journal of Medicine (2011)

Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity.A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
Definition of a FoxA1 Cistrome That Is Crucial for G1 to S-Phase Cell-Cycle Transit in Castration-Resistant Prostate Cancer
Authors: Chunpeng Zhang, Liguo Wang, Dayong Wu, Hongyan Chen, Zhong Chen, Jennifer M. Thomas-Ahner, Debra L. Zynger, Jérôme Eeckhoute, Jindan Yu, Jun Luo, Myles Brown, Steven K. Clinton, Kenneth P. Nephew, Tim H.-M. Huang, Wei Li, Qianben Wang
Journal: Cancer Research (2011)

The enhancer pioneer transcription factor FoxA1 is a global mediator of steroid receptor (SR) action in hormone-dependent cancers. In castration-resistant prostate cancer (CRPC), FoxA1 acts as an androgen receptor cofactor to drive G₂ to M-phase cell-cycle transit. Here, we describe a mechanistically distinct SR-independent role for FoxA1 in driving G₁ to S-phase cell-cycle transit in CRPC. By comparing FoxA1 binding sites in prostate cancer cell genomes, we defined a codependent set of FoxA1-MYBL2 and FoxA1-CREB1 binding sites within the regulatory regions of the Cyclin E2 and E2F1 genes that are critical for CRPC growth. Binding at these sites upregulate the Cyclin E2 and Cyclin A2 genes in CRPC but not in earlier stage androgen-dependent prostate cancer, establishing a stage-specific role for this pathway in CRPC growth. Mechanistic investigations indicated that FoxA1, MYBL2, or CREB1 induction of histone H3 acetylation facilitated nucleosome disruption as the basis for codependent transcriptional activation and G₁ to S-phase cell-cycle transit. Our findings establish FoxA1 as a pivotal driver of the cell-cycle in CRPC which promotes G₁ to S-phase transit as well as G₂ to M-phase transit through two distinct mechanisms.
A 78-joints ultrasonographic assessment is associated with clinical assessments and is highly responsive to improvement in a longitudinal study of patients with rheumatoid arthritis starting adalimumab treatment
Authors: H. B. Hammer, M. Sveinsson, A. K. Kongtorp, T. K. Kvien
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To examine associations between ultrasonography (US) assessments (B-mode (BM) and power Doppler (PD)) of a large number of joints and traditional assessments of disease activity, and to examine the sensitivity to change of the US scores and clinical measures in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Twenty patients with RA initiating adalimumab treatment were examined at baseline and after 1, 3, 6 and 12 months with US (BM and PD) using an Outcome Measures in Rheumatoid Arthritis Clinical Trial semiquantitative scoring (0–3) of 78 joints as well as assessment of clinical and laboratory variables with calculation of composite indexes. <h3>Results</h3> The US scores were associated with composite scores as well as clinical and laboratory variables (r=0.41–0.84, p&lt;0.05–0.001 at 12-months9 follow-up). Compared with clinical assessments, US detected higher numbers of inflamed joints. The US scores decreased after 1 and 3 months (p&lt;0.005) and PD showed the highest percentage improvement. Both BM and PD had high standardised response means throughout the study (−0.83 to −1.27), of similar magnitude to composite indexes, but higher than the clinical and laboratory variables. <h3>Conclusions</h3> The comprehensive US assessments were associated with clinical and laboratory variables of disease activity and were highly sensitive to change during treatment with biological agents.
Studies of thrombin-induced proteoglycan release in the degradation of human and bovine cartilage.
Authors: E Furmaniak-Kazmierczak, T D Cooke, R Manuel, A Scudamore, H Hoogendorn, A R Giles, M Nesheim
Journal: Journal of Clinical Investigation (1994)

Because fibrin is commonly observed within arthritic joints, studies were undertaken to determine whether purified coagulation and fibrinolytic proteases degrade cartilage in vitro and to seek evidence for the activation of coagulation in arthritic joints through measurements of the levels of inhibitor-enzyme complexes and several other proteins associated with coagulation and fibrinolysis. The concentrations of 13 plasma proteins and complexes of thrombin and Factor Xa with antithrombin III were measured in synovial fluids recovered at the time of knee replacement surgery. All zymogens necessary to constitute the coagulation cascade were present. Thrombin and the combination of prothrombin plus prothrombinase induced proteoglycan release from both normal and arthritic cartilages. Factor Xa and plasmin induced release from diseased cartilage only, and urokinase, tissue plasminogen activator, and activated protein C were without effect at the levels used. At saturating levels of thrombin (> or = 2.0 microM) 80% of the proteoglycan content of normal cartilage was released within 24 h. Thrombin, which is cationic, reversibly binds cartilage with Kd = 7.0 +/- 1.0 microM and Bmax = 820 +/- 70 ng/mg of human cartilage. Levels of thrombin-antithrombin III complexes in synovial fluids and arthritis were 4-fold higher in osteo (OA) and 43-fold higher in rheumatoid (RA) than in controls (0.98 nM). Factor Xa-antithrombin III complex levels were threefold lower in OA and fivefold higher in RA than in controls (0.24 nM). These elevated levels of enzyme-inhibitor complexes imply a history of activation of coagulation within the joint, especially in RA. Since thrombin degrades cartilage in vitro and had been generated in vivo, as inferred by the existence of thrombin-antithrombin III complexes, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosis.
A Placebo-Controlled Study of Fluoxetine Versus Imipramine in the Acute Treatment of Atypical Depression
Authors: P J McGrath, J W Stewart, M N Janal, E Petkova, F M Quitkin, D F Klein
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The atypical subtype of depression appears to be both well validated and common. Although monoamine oxidase inhibitors are effective in treating atypical depression, their side effects and prescription-associated dietary restrictions reduce their suitability as a first-line treatment. The objective of this study was to estimate the efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the treatment of major depression with atypical features. METHOD: One hundred fifty-four subjects with DSM-IV major depression who met the Columbia criteria for atypical depression were randomly assigned to receive fluoxetine, imipramine, or placebo for a 10-week clinical trial. Imipramine was included because its known efficacy for treatment of atypical depression helped to calibrate the appropriateness of the study group. RESULTS: In both intention-to-treat and completer groups, the effectiveness of both fluoxetine and imipramine was significantly better than that of placebo. The two medications did not differ from each other in effectiveness. Significantly more patients dropped out of treatment with imipramine than with fluoxetine. Before treatment, patients on average rated themselves as very impaired on psychological dimensions of general health and moderately impaired on physical dimensions, compared with population norms. The self-ratings of patients who responded to treatment essentially normalized on these measures. CONCLUSIONS: Despite earlier data that SSRIs might be the treatment of choice, fluoxetine appeared to be no better than imipramine in the treatment of atypical depression, although fluoxetine was better tolerated than imipramine.
An Antibody–Drug Conjugate Targeting the Endothelin B Receptor for the Treatment of Melanoma
Authors: Jyoti Asundi, Chae Reed, Jennifer Arca, Krista McCutcheon, Ronald Ferrando, Suzanna Clark, Elizabeth Luis, Janet Tien, Ron Firestein, Paul Polakis
Journal: Clinical Cancer Research (2011)

To identify and evaluate targets amenable to antibody therapy in melanoma.We searched for mRNA transcripts coding for cell-surface proteins with expression patterns similar to that of the melanoma oncogene MITF. One such candidate, the endothelin B receptor (EDNBR), was first analyzed for a functional contribution to tumor growth by conditional induction of shRNA. Second, antibodies were raised to the receptor, conjugated with monomethyl auristatin E, and tested for efficacy against melanoma tumor models generated from cell lines.Conditional knockdown of the receptor in tumor xenograft models resulted in only a modest impact on tumor growth. A monoclonal antibody reactive with the N-terminal tail of EDNBR was found to internalize rapidly into melanoma cells. When conjugated with monomethyl auristatin E, the antibody-drug conjugate (ADC) showed remarkable efficacy against human melanoma cell lines and xenograft tumor models that was commensurate with levels of receptor expression. Comparative immunohistochemistry revealed a range of EDNBR expression across a panel of human melanomas, with the majority expressing levels equivalent to or greater than that in the models responsive to the ADC.An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma.
Prospective Evaluation of the Relationship of Patient Age and Paclitaxel Clinical Pharmacology: Cancer and Leukemia Group B (CALGB 9762)
Authors: Stuart M. Lichtman, Donna Hollis, Antonius A. Miller, Gary L. Rosner, Chris A. Rhoades, Eric P. Lester, Frederick Millard, John Byrd, Stephen A. Cullinan, D. Marc Rosen, Robert A. Parise, Mark J. Ratain, Merrill J. Egorin
Journal: Journal of Clinical Oncology (2006)

To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old.Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years).Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45).Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.
A Novel Targeted T-Cell Modulator, Efalizumab, for Plaque Psoriasis
Authors: Mark Lebwohl, Stephen K. Tyring, Tiffani K. Hamilton, Darryl Toth, Scott Glazer, Naji H. Tawfik, Patricia Walicke, Wolfgang Dummer, Xiaolin Wang, Marvin R. Garovoy, David Pariser
Journal: New England Journal of Medicine (2003)

Interactions between leukocyte-function-associated antigen type 1 (LFA-1) and intercellular adhesion molecules are important in the pathogenesis of psoriasis. Efalizumab, a humanized monoclonal antibody, binds to the alpha subunit (CD11a) of LFA-1 and inhibits the activation of T cells.In a phase 3, multicenter, randomized, placebo-controlled, double-blind study, we assign 597 subjects with psoriasis to receive subcutaneous efalizumab (1 or 2 mg per kilogram of body weight per week) or placebo for 12 weeks. Depending on the response after 12 weeks, subjects received an additional 12 weeks of treatment with efalizumab or placebo. Study treatments were discontinued at week 24, and subjects were followed for an additional 12 weeks.At week 12, there was an improvement of 75 percent or more in the psoriasis area-and-severity index in 22 percent of the subjects who had received 1 mg of efalizumab per kilogram per week and 28 percent of those who had received 2 mg of efalizumab per kilogram per week, as compared with 5 percent of the subjects in the placebo group (P<0.001 for both comparisons). Efalizumab-treated subjects had greater improvement than those in the placebo group as early as week 4 (P<0.001). Among the efalizumab-treated subjects who had an improvement of 75 percent or more at week 12, improvement was maintained through week 24 in 77 percent of those who continued to receive efalizumab, as compared with 20 percent of those who were switched to placebo (P<0.001 for both comparisons). After the discontinuation of efalizumab at week 24, an improvement of 50 percent or more in the psoriasis area-and-severity index was maintained in approximately 30 percent of subjects during the 12 weeks of follow-up. Efalizumab was well tolerated, and adverse events were generally mild to moderate.Efalizumab therapy resulted in significant improvements in plaque psoriasis in subjects with moderate-to-severe disease. Extending treatment from 12 to 24 weeks resulted in both maintenance and improvement of responses.
Nasal NO screening for primary ciliary dyskinesia in neonates and infants
Authors: Flurina Büchel, Rinderer Bernhard, Christian Bieli, Alexander Möller, Salfeld Peter, Andreas Jung
Journal: European Respiratory Journal (2014)

Background: Nasal NO (nNO) measurement is the recommended screening tool for primary ciliary dyskinesia (PCD) from the age of 5 years. While reliable velum-closure and non-velum-closure techniques are now available from the age of 2 years, no data on nNO determination exist for younger individuals. This study aims to assess feasibility and values of nNO in healthy and symptomatic neonates and infants.  Methods: Nasal NO was assessed in sleeping neonates and infants with and without respiratory symptoms using the NIOX MINO device in tidal breathing. For validation, results were compared to a gold standard device (NIOX FLEX).  Results: 27 neonates (median age 3 days [quartiles 2, 3]) and 38 infants (41.5 days [30.8, 100.3]) were included in the analysis so far. All neonates and 24 (63%) of the infants were free of respiratory symptoms. Nasal NO measurement was successfully applied in 100% of all subjects. Median nNO values were comparable in both age groups for healthy subjects using the NIOX MINO (neonates 23 ppb [17, 31], infants 28 ppb (17, 42), whereas infants with respiratory symptoms had lower nNO values (12 ppb [5, 47]). nNO values were higher in neonates when NIOX FLEX was applied (34 ppb [26, 50]).  Conclusion: Nasal NO measurement is feasible in neonates and infants using the NIOX MINO device. In this preliminary analysis, nNO values are far below the cuff-off values of older children even in healthy individuals. A control group consisting of infants with PCD is currently being recruited and will be compared with the results of subjects with and without respiratory symptoms to answer the question if nasal NO determination can be applied as a reliable screening tool for PCD in very young children.
IFN-γ–dependent transcription of MHC class II IA is impaired in macrophages from aged mice
Authors: Carmen Herrero, Laura Marqués, Jorge Lloberas, Antonio Celada
Journal: Journal of Clinical Investigation (2001)

To determine the effect of aging on IFN-γ–induced MHC class II antigen expression, we produced bone marrow–derived macrophages in vitro. In these conditions, we analyzed the effect of aging on the genomic expression of macrophages without the influence of other cell types that may be affected by aging. Although macrophages from young and aged mice showed an identical degree of differentiation, after incubation with IFN-γ, the expression at the cell surface of the IA complex and the levels of IAβ protein and mRNA were lower in aged macrophages. Moreover, the transcription of the IAβ gene was impaired in aged macrophages. The amount of transcription factors that bound to the W and X, but not to the Y, boxes of the IAβ promoter gene was lower in aged macrophages. Similar levels of CIITA mRNA were found after IFN-γ treatment of both young and aged macrophages. This shows that neither the initial cascade that starts after the interaction of IFN-γ with the receptor nor the second signals involved in the expression of CIITA are impaired in aged macrophages. These data indicate that aging is associated with low levels of MHC class II gene induction by IFN-γ because of impaired transcription.
Delivery of salbutamol to nonventilated preterm infants by metered-dose inhaler, jet nebulizer, and ultrasonic nebulizer
Authors: TF Fok, K Lam, PC Ng, TF Leung, HK So, KL Cheung, W Wong
Journal: European Respiratory Journal (1998)

To identify the most efficient device for the delivery of bronchodilator aerosol to nonventilated preterm infants with chronic lung disease, we compared the metered dose inhaler (MDI) used in conjunction with a non-valved spacer, an ultrasonic nebulizer with a small medication cup, and two jet nebulizers. The subjects were enrolled in two double-blind randomized crossover studies. In study A (n=10), each infant was given a nominal dose of 200 microg of salbutamol by a MDI (Ventolin) at 4 h intervals, and in random sequence via an Aerochamber (Neonatal Aerochamber) with its one-way valve removed, an ultrasonic nebulizer with a small cone-shaped medication cup (Siemens Electronics), and a jet nebulizer (Side-stream). Their functional residual capacity (FRC) and static respiratory system mechanics were measured before, and at 15, 30, 60, and 120 min after aerosol delivery. Study B (n=10) was carried out in an identical manner, but with a different jet nebulizer (Hudson). In both studies, administration of salbutamol aerosol via the MDI Aerochamber or ultrasonic nebulizer resulted in a significantly greater reduction in respiratory system resistance than via jet nebulizers. Furthermore, the use of MDI Aerochamber or ultrasonic nebulizer was associated with a greater degree of post-treatment tachycardia and improvement in FRC. The bronchodilating effect of salbutamol delivered via the ultrasonic nebulizer appeared to be slightly greater than that via the MDI-Aerochamber, receiving significance only in Study B. We conclude that both the metered-dose inhaler used with a nonvalved Aerochamber and the ultrasonic nebulizer with a small medication cup are both more efficient than the jet nebulizers in preterm infants.