tbuckley/cabot-search huggingface dataset:
Anti-lymphocyte function associated antigen-1 inhibits T-helper 2 function of human allergen-specific CD4+ T cells
Authors: M.R. Ardern-Jones, A.P. Black, G.S. Ogg
Journal: British Journal of Dermatology (2008)

Background Blockade of lymphocyte function associated antigen‐1 (LFA‐1) is proving successful in the management of psoriasis and other inflammatory skin conditions including atopic dermatitis (AD), but the dependence of allergen‐specific CD4+ T‐cell function on LFA‐1 has not been studied extensively. Objectives We sought to investigate the potential ability of LFA‐1 inhibition to influence keratinocyte presentation of allergen to specific T‐helper (Th) 2 cell clones. Methods Using human leucocyte antigen class II tetrameric complexes, we generated Der p 1‐specific DRB1*1501‐restricted CD4+ T‐cell lines (n =5) and clones (n =4) from the peripheral blood of five adults with AD. Results Using doses of anti‐LFA‐1 present in vivo, we observed significant inhibition (P <0·05) of allergen‐specific CD4+ T‐cell production of interleukin‐4 with such inhibition occurring during presentation of allergen by keratinocytes. Conclusions These data show that at doses present in vivo, LFA‐1 blockade inhibits keratinocyte presentation to allergen‐specific Th2 cells, suggesting one mechanism through which anti‐LFA‐1 may be beneficial therapeutically.
Patterns of clinical use of omalizumab in Spain: A 5-year "real-life" study
Authors: Luis Pérez de Llano, José Manuel Zubeldia, Lys Herráez
Journal: European Respiratory Journal (2014)

Background:  Significant clinical experience has been gained after five years from the approval of omalizumab in Spain.   Objective:  To describe patterns of use of omalizumab in current clinical practice in Spain.   Methods:  Retrospective, multicenter, study based on medical records from patients treated with omalizumab between Jan-2006 and Sep-2011.   Results:  464 patients (63.8% female, mean age 45.6±19.3 years) were included. Omalizumab was mainly prescribed for the treatment of asthma (84.5%), followed by chronic urticaria (5.6%), food allergy (5.2%), atopic dermatitis (2.4%) and allergic bronchopulmonary aspergillosis (1.7%). The disease was severe in 76.7% of cases. During the year before omalizumab was started, asthma patients required an average of 2.7±3.7 emergency visits and 0.4±1.2 hospital admissions with a mean stay of 10.8±11.2 days. Mean number of unscheduled primary and specialized care visits were 3.5±3.9 and 1.8±2.3 respectively. The average lost working days was 7.9±22.3. The main reasons to start omalizumab treatment were the lack of efficacy with conventional (93.1%) or alternative therapy (22.0%), and the appearance of adverse events with other drugs (18.5%). Modifications of omalizumab dosage/frequency were detected in 17.5% of cases. Overall efficacy of omalizumab was rated as good/excellent in 64.4%. Efficacy was evaluated on the basis of clinical improvement (87.7%), disease control (77.6%), reduction of exacerbations (72.2%) and quality of life (33.4%).   Conclusions:  Severe asthma was the main indication for omalizumab prescription, albeit other serious and long-standing immunological diseases were identified. Omalizumab is a good therapeutic option for all the evaluated indications.
“Minimal Deviation” Hepatomas: A Critical Review of the Terminology, Including a Commentary on the Correlation of Enzyme Activity with Growth Rate of Hepatomas&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Chung Wu
Journal: JNCI Journal of the National Cancer Institute (1967)

A survey of the enzyme activities of various metabolic pathways in 15 transplantable rat hepatomas showed that, in mostinstances, no correlation existed between the enzyme activity and the growth rate or the chromosome number of these hepatomas. Furthermore, the comparative study revealed the heterogeneity of the Morris hepatomas in that their enzyme activities varied widely. This divergence in enzyme activities of the Morris hepatomas indicated that none of the tumors really showed a “minimal deviation” from rat liver. Since the term “minimal deviation” does not properly describe the characteristics of this group of hepatomas, its use should be discontinued.
Pathways of angiogenic resistance in glioblastoma: Adaptations in growth factor signaling in response to VEGF and HGF attenuation
Authors: Christian A. Graves, Kevin Camphausen
Journal: Clinical Cancer Research (2010)

Abstract Background: Glioblastoma is the most common and lethal central nervous system malignancy with a median survival often less than 18 months. Despite promising initial responses to anti-angiogenic therapies many patients with this disease develop resistance to treatment via poorly understood mechanisms. Here we demonstrate that glioblastoma cell lines grown under growth factor antagonizing conditions exhibit an altered phenotype with changes in growth factor signaling, gene expression as well as in vivo tumorigenesis. Methods: U87 cells were cultured under constant pressure with bevacizumab (3.0 mg/mL), AMG102 (1.0 µg/mL), or a combination of both drugs long term (seven or more passages) in adherent culture. In vitro expression analysis was carried out by growth factor and receptor tyrosine kinase arrays, cDNA microarray, and ELISA. Intracranial xenograft studies demonstrated resultant differences in growth kinetics and survival. Results: Hepatocyte growth factor (HGF), glial derived neurotrophic factor (GDNF), and platelet-derived growth factor AA (PDGFAA) were elevated at 5.3, 4.5, and 3.9 fold in combinatorially treated cells versus controls, respectively. These changes correlated with relative increases in corresponding receptor mRNA and protein expression. Furthermore, AMG102 and combinatorially pressured cells were highly tumorigenic as compared to control and bevacizumab treated cells in vivo (Median survival 10 ± 1 vs. 32 ± 2 days, respectively). Conclusion: Herein we describe concomitant increases of various oncogenic growth factors which might potentiate tumor survival and therapeutic resistance. These results suggest several potential molecular bypass mechanisms facing proposed angiogenic strategies. Evaluation of resistant phenotypes provides insight on the adaptive complexity of glioblastoma and offers potential for targeting recurrent disease.
Retinoid-Induced Adhesion in Cultured, Transformed Mouse Fibroblasts
Authors: Sergio Adamo, Luigi M. De Luca, Irene Akalovsky, Pangala V. Bhat
Journal: JNCI Journal of the National Cancer Institute (1979)

Cultured, spontaneously transformed mouse fibroblasts (Balb/3T12-3 cells) were readily detached from the dish surface in an EDTA-mediated detachment assay. Retinoic acid-treated cells displayed increased adhesion to the culture dish surface. The effect of retinoic acid on the adhesion of Balb/3T12-3 cells was dose-dependent in the range of 0.05–5 μg/ml (0.17–17 μM) In an assay performed on cells cultured for 3 days in the presence of the retinoid. The earliest effect on adhesion was detected at 2 days of culture in the presence of 17 μM retinoic acid. The increase in adhesion displayed by retinoic acid-treated cells was rapidly lost upon removal of the retinold from the culture medium. Synthetic retinoids were tested for their activity in inducing adhesion of cultured Balb/3T12-3 cells. Retinol, retinoic acid, and their 5,6-epoxy derivatives were the most active, showing activity at 1 μg/ml. 13-cis-Retinoic acid and the dimethylacetylcyclopentenyl and trimethylmethoxyphenyl derivatives were active at 10 μg/ml. However, active derivatives of retinoic acid invariably lost their activity upon chemical esterification or amide formation. Retinoids without biologic activity in other systems were also inactive in inducing adhesion. Among these were the synthetic derivatives of retinol, anhydroretinol and perhydromonoeneretinol, and the phenyl derivative of retinoic acid. β-ionone, abscisic acid, and juvenile hormone were also inactive. Results showed that this adhesion assay may be used as an additional test for the biologic activity of retinoids containing a free carboxylic or carbinolic function. The phenomenon of induced adhesion may also aid in the study of the metabolic function of vitamin A.
Three parallel randomized phase II trials of dasatinib plus hormone therapy (HT) in advanced ER+ breast cancer (ER+ ABC).
Authors: L. C. Strauss, J. O'Shaughnessy, J. Jackson, D. Paul, G. L. Wright, A. Rybicki, A. Gold-irsch
Journal: Journal of Clinical Oncology (2010)

TPS133 Background: Resistance of ER+ ABC to HT remains an unmet medical need. In addition, detecting benefit of targeted therapy is challenging without predictive markers. Preclinical evidence indicates that SRC-family kinases (SFK) have a role in growth and metastasis of breast cancer, including ER signaling and HT resistance. SFKs are also highly expressed in osteoclasts and have a key role in osteoclast function in normal bone and bone metastases. Many SRC-related biomarkers may correlate with benefit. Dasatinib is a potent SFK inhibitor that has antitumor and antimetastatic effects on breast cancer cells and antiosteoclast activity. Methods: We initiated 3 phase II studies in patients with ER+ ABC to combine dasatinib 100 mg once daily with letrozole, exemestane or fulvestrant; each randomized 1:1 vs HT alone. Safety monitoring boards are implemented as tolerability is of high priority. Bone-specific endpoints are included due to the role of SFKs in osteoclast function and importance of bone metastases in this population. Quantitative analysis of tumor tissues across the studies for a hypothesis-driven panel of potential ER/SFK-related biomarkers provides an opportunity to detect a subpopulation with benefit from dasatinib. Utilizing these data, we anticipate improved decision making in design of future phase III trials. Study NCT00696072 NCT00767520 NCT00754325 Comparator Letrozole Exemestane Fulvestrant N 120 156 100 HER2 amplified No Allowed Allowed Prior aromatase inhibitor (AI) Any, >1 yr after adjuvant AI PD during nonsteroidal (NS) AI (or ≤1 yr post adjuvant) PD during any AI (or ≤1 yr post adjuvant) Chemotherapy for advanced disease 0-1 allowed None 0-1 allowed Measurable lesion Not required Tumor sample Required (prior surgery) Placebo control No Yes; blinded No Bone endpoints Pain, uNTX, bone mineral density Pain, uNTX Pain, uNTX Primary endpoint Clinical benefit rate PFS PFS Key stratification factor DFI ≤2 vs. >2 yrs NS AI in adjuvant vs. advanced DFI ≤2 vs. >2 yrs Statistical design Noncomparative Comparative Noncomparative Optional crossover to combination arm Yes No Yes Abbreviations: DFI, disease-free interval; PD, progressive disease; PFS, progression-free survival; uNTx, urinary N-telopeptide. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Phase 1/2 study of oral rucaparib: Final phase 1 results.
Authors: Rebecca Sophie Kristeleit, Howard A. Burris, Patricia LoRusso, Manish R. Patel, Uzma Saddia Asghar, Fatima El-Khouly, Alan Hilary Calvert, Jeffrey R. Infante, John Frederick Hilton, Sara M. Tolaney, Muaiad Kittaneh, Heidi Giordano, Jennifer Borrow, Sarah S. Jaw-Tsai, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2014)

2573 Background: Rucaparib is a potent, oral PARP inhibitor (PARPi) that induces synthetic lethality in homologous recombination deficient (HRD) tumors (e.g. BRCA mutation). The primary objectives of the Phase 1 portion were to define the MTD, RP2D and PK of continuous rucaparib. Methods: A 3+3 dose escalation design was used. Intra-patient dose escalation was allowed. Patients (pts) aged ≥18 with advanced solid tumors that had progressed on standard treatments were recruited. Measurable disease was not required. Rucaparib was taken orally QD or BID continuously. Plasma PK assessments included full profile and trough levels. Results: Phase 1 is complete with 56 pts (median age 51 yrs [range 21-71]; 51 female; 29 ECOG PS=0; 27 breast cancer (BC), 20 ovarian/peritoneal cancer (OC), 9 other tumor) enrolled in 10 dose cohorts (40 QD-840 mg BID). 600 mg BID was identified as the optimal RP2/3D based on maximum exposure, manageable toxicity and promising clinical activity. Exposures exhibited dose proportional kinetics up to the RP2/3D with low inter- and intra-pt variability, an important attribute for uniform flat dosing strategies. At 360 mg BID, 1 pt had a DLT of Grade (G) 3 nausea, with no others at higher dose levels. The incidence and severity of myelosuppression, a known PARPi effect, was dose-dependent with ~50% of pts at the RP2/3D having at least one G2 or G3 event (% G2/G3): anemia (29%/29%), thrombocytopenia (0/14%), neutropenia (29%/0). All G3 events were post-Cycle 1 and were successfully managed with dose reduction. Treatment-related AEs (mostly G1/2) reported in ≥10% of all pts include fatigue (30%), nausea (30%), vomiting (23%), diarrhea (13%), anorexia (11%). No G4 AEs have occurred. RECIST and/or CA-125 responses occurred at doses ≥ 300 mg QD (2 CRs, 7 PRs, 3 CA-125). At these doses, disease control rate (CR+ PR + SD≥24 weeks) was 70% (7/10) in gBRCA OC pts. At the RP2/3D, 4/5 (80%) OC (3/4) and BC (1/1) pts had a RECIST or CA125 response. All responders had a BRCA 1/2 mutation. Responses were seen in platinum-sensitive and platinum-resistant OC pts. Conclusions: Rucaparib has a desirable PK profile and is well tolerated with promising clinical benefit in OC, BC, and pancreatic cancer. Three studies are ongoing in OC pts (ARIEL2, ARIEL3, Phase 2 portion of this trial). Clinical trial information: NCT01482715.
Guidance is published on sharing data from publicly funded trials
Authors: I. Torjesen
Journal: BMJ (2015)

Guidance for researchers on good practice in sharing data that are produced from publicly funded clinical trials has been published and endorsed by leading UK research bodies.1

The guidance, produced with funding from the UK Medical Research Council’s network of hubs for trials methodology research, emphasises that sharing data makes clinical trials more useful to researchers, maximises the contribution made by trial participants, and helps prevent unnecessary duplication of research.

The document outlines a series of practical principles for sharing anonymised data on individual patients and provides …
Adenotonsillectomy in children with mild symptoms: Authors' reply
Authors: Anne G M Schilder, Maroeska M Rovers, E Henriette van den Akker, Birgit K van Staaij, Arno W Hoes
Journal: BMJ (2004)

General practitioners say that evidence based information is changing practiceEditor-As the publishers of the BMJ's Clinical Evidence we have more than a passing interest in the extent to which the provision of evidenced based information changes clinical practice.In this context, the results of an evaluation of Clinical Evidence commissioned by us assumed some importance.A total of 5960 general practitioners in England were contacted by Stingray Research, an independent market research company, and asked to provide some broad perceptions about the role of evidence in their day to day practice and to pass judgment on Clinical Evidence.The response rate was 838/5960 (14.1%).Some findings were not surprising.Seventy five per cent of general practitioner respondents reported that their patients were likely to show interest in the latest research findings.Ninety seven per cent of the general practitioners had used an information resource to find the latest evidence, and 45% expected to do so at least once every fortnight.Subject matter ranged across the broad spectrum of disease.Clinical Evidence was used mainly around clinical consultations-before, during, and after.However, other uses, such as education and teaching, and assisting the development of practice guidelines, were also reported by 77% and 52% of respondents, respectively.The most crucial findings related to the proportion of doctors, 75%, who reported that they had changed their practice as a result of using Clinical Evidence.Two thirds of these had done so in the previous six months.Change of practice in response to Clinical Evidence was most likely in younger doctors, but was also reported by 56% of respondents aged over 55.Quotes from respondents underlined the message; that provision of evidence from an independent, trusted source supported them in developing their practice and improved the quality of their consultations.There are limitations to this evaluation.We don't know what the non-respondents thought, for example.However, the evidence seems to imply that there is a substantial body of clinicians of all ages-in this case English general practitioners, but we know that similar results have been found among Italian 1 and US doctors-who are motivated to use evidence based sources to improve their care for patients.
Enhancement of the Antitumor Effect of 1,3-Bis(2-Chloroethyl)-1-Nitrosourea by Vitamin A and Caffeine&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Martin H. Cohen
Journal: JNCI Journal of the National Cancer Institute (1972)

Therapy of murine L1210 leukemia with a combination of vitamin A, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and caffeine markedly increased survival over treatment with BCNU alone. For optimal therapeutic results, vitamin A was given 6 hours before BCNU and caffeine was given 15–30 minutes after BCNU. Despite extensive literature suggesting that the main action of caffeine in antitumor therapy is inhibition of DNA repair, this seems a less likely mechanism for the caffeine potentiation observed. Although the literature indicates that caffeine may inhibit cellular energy metabolism to a degree sufficient to impede repair of cellular membranes, no direct evidence is available to support this as the mechanism of action of caffeine in these experiments.
Detection of AmpC β-lactamases in Escherichia coli, Klebsiella spp., Salmonella spp. and Proteus mirabilis in a regional clinical microbiology laboratory
Authors: J.D.D. Pitout, P.G. Le, K.L. Moore, D.L. Church, D.B. Gregson
Journal: Clinical Microbiology and Infection (2009)
Effects of use of Boussignac CPAP on development of post-operative atelectasis
Authors: Serife Savas Bozbas, Balam Er Dedekarginoglu, Serap Cakir, Feza Yarbug Karakayali, Fusun Oner Eyuboglu
Journal: European Respiratory Journal (2012)

Background : Boussignac CPAP system is a method to apply CPAP through a special valve system.

Aim: Patients who had a high likelyhood of postoperative atelectasis undergoing abdominal surgery were included in the study. It was aimed to evaluate the development of atelectasis and its effects on PFT parameters through utilisation of Boussignac CPAP system.

Patients and method: A total of 28 patients were included in our study and were randomized into two groups. Conventional methods (incentive spirometry, respiratory physiotherapy) were scheduled for the first group and Boussignac CPAP treatment in addition to conventional methods was scheduled for the second group. Boussignac CPAP system was applied to patients with spontaneous respiration for 3 days as 6 times and 15 minutes on each session. Pre and post application pulmonary function tests(PFT) parameters, chest X-Ray findings and radiological atelectasis scores were evaluated.

Findings : Mean age was 65.4 years and 57.1% were male. There was not any significant differences in the Boussignac CPAP group and control group between location of incision, operation time and presence of pulmonary disease. Preoperative chest X-Ray findings were similar(p>0.05). In the Boussignac CPAP group, postoperative radiological atelectasis score was significantly lower than control group(p<0.05). In CPAP group, no decline in oxygen saturation and oxygen partial pressure was observed unlike control group. Significant decrease was observed in FVC that is one of PFT parameters in postoperative period.

Conclusion : Our findings suggest that development of post-operative atelectasis might be decreased, thus oxygenation might be improved by use of Boussignac CPAP.
Authors’ reply to Hamilton and King
Authors: Adrian Plunkett, Jeremy Tong
Journal: BMJ (2015)

Hamilton highlights an important topic of debate regarding sepsis management in children.1 2 The study he mentions was a well conducted trial with robust outcome data and we do not disagree with its conclusions. We decided not to discuss this trial because the case selection and context of a randomised controlled trial constrain the applicability of the results. The FEAST investigators studied children with septic shock, without …
Modular Transcriptional Repertoire Analyses of Adults With Systemic Lupus Erythematosus Reveal Distinct Type I and Type II Interferon Signatures
Authors: Laurent Chiche, Noémie Jourde‐Chiche, Elizabeth Whalen, Scott Presnell, Vivian Gersuk, Kristen Dang, Esperanza Anguiano, Charlie Quinn, Stéphane Burtey, Yvon Berland, Gilles Kaplanski, Jean‐Robert Harle, Virginia Pascual, Damien Chaussabel
Journal: Arthritis & Rheumatology (2014)

The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients.Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis.Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ.Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.
Rapid detection of mycobacterial growth in in vitro cultures by VOC analysis
Authors: Roman Purkhart, Gunther Becher, Petra Reinhold, Heike Köhler
Journal: European Respiratory Journal (2014)

Introduction  Volatile organic compounds (VOCs) are increasingly studied as potential biomarkers for various applications, such as diagnosis of diseases or detection of bacterial growth. In a study with  Mycobacterium avium  subsp.  paratuberculosis  (MAP) as model organism, we investigated if bacterial growth in in vitro cultures can be detected by VOC analysis already after 1 week of cultivation.  Methods  The headspace of MAP in vitro cultures was analyzed one week after inoculation with a GC-differential-ion-mobility-spectrometer (SIONEX). For comparison, culture media with no bacterial growth were included. Headspace was collected with a disposable PTFE tube. The spectra were analyzed by a statistical program based on cluster analysis.  Results  Cluster analysis resulted in 160 independent clusters. The headspace of bacterial in vitro cultures showed highly significant differences (p  Discussion  The study showed that VOC analysis can be a very fast and reliable method to detect bacterial growth in in vitro cultures. For MAP, growth can [KH1] be detected just one week after inoculation, which is much faster than currently used methods which take at least 4 to 6 weeks.