tbuckley/cabot-search huggingface dataset:
Gene Expression Profiling of Human Sarcomas: Insights into Sarcoma Biology
Authors: Kristin Baird, Sean Davis, Cristina R. Antonescu, Ursula L. Harper, Robert L. Walker, Yidong Chen, Arthur A. Glatfelter, Paul H. Duray, Paul S. Meltzer
Journal: Cancer Research (2005)

Sarcomas are a biologically complex group of tumors of mesenchymal origin. By using gene expression microarray analysis, we aimed to find clues into the cellular differentiation and oncogenic pathways active in these tumors as well as potential biomarkers and therapeutic targets. We examined 181 tumors representing 16 classes of human bone and soft tissue sarcomas on a 12,601-feature cDNA microarray. Remarkably, 2,766 probes differentially expressed across this sample set clearly delineated the various tumor classes. Several genes of potential biological and therapeutic interest were associated with each sarcoma type, including specific tyrosine kinases, transcription factors, and homeobox genes. We also identified subgroups of tumors within the liposarcomas, leiomyosarcomas, and malignant fibrous histiocytomas. We found significant gene ontology correlates for each tumor group and identified similarity to normal tissues by Gene Set Enrichment Analysis. Mutation analysis done on 275 tumor samples revealed that the high expression of epidermal growth factor receptor (EGFR) in certain tumors was not associated with gene mutations. Finally, to further the investigation of human sarcoma biology, we have created an online, publicly available, searchable database housing the data from the gene expression profiles of these tumors (http://watson.nhgri.nih.gov/sarcoma), allowing the user to interactively explore this data set in depth.
Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma
Authors: Hung Huynh, Van Chanh Ngo, Joseph Fargnoli, Mark Ayers, Khee Chee Soo, Heng Nung Koong, Choon Hua Thng, Hock Soo Ong, Alexander Chung, Pierce Chow, Pamela Pollock, Sara Byron, Evelyn Tran
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib–induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr1054/1059, increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
P205 Managing the challenges of recruitment of patients with asthma to randomised controlled trials
Authors: D. Morrison, E. Cameron, G. Braganza, N. C. Thomson, R. Chaudhuri, F. S. Mair
Journal: Thorax (2011)

<h3>Introduction</h3> Many trials do not recruit sufficient participants, particularly from primary care settings, making it difficult to get meaningful results. A recent Cochrane systematic review studying recruitment concluded there is still much to learn. Here we describe details of two MRC funded, primary care based, asthma randomised controlled trials, and their recruitment strategies and challenges. <h3>Methods</h3> Trial 1: Examined whether short-term treatment with atorvastatin improves lung function, asthma control and quality of life in smokers with asthma (completed 2009). Trial 2: examined the same question using azithromycin (completed July 2011). The participant flow charts and trial documents of both trials were examined to establish recruitment details. <h3>Results</h3> Trial 1: Target to randomise =80, target to complete =68, study extended by 3 months due to slow recruitment. Actual randomised =71, actual completed =60. 54/438 GP practices approached, participated. 2483 patients from practices and 356 from a database of previous trial participants received two mailings via GP surgeries, and then following an ethics amendment via telephone for a small number of surgeries. 331/2483 (11.7%) patients responded positively, and of these 286 were able to be contacted and telephone screened for eligibility, leaving 131 eligible participants. 129/131 attended a screening visit; 58/129 screen failed (eg, due to deterioration in peak flow, unable to wean off regular asthma medications) leaving 71 randomised (2.5%) of total patients invited. Trial 2: similar picture, completed July 2011, extended by 6 months due to slow recruitment. Target to randomise =80, target to complete =68. Actual completed: 71/8398 (&lt;1%) of those invited. <h3>Conclusion</h3> Achieving the completion target in randomised controlled trials requires significant administrative support, and the capacity to increase support should difficulties in recruitment be encountered. Closer partnership with primary care practitioners, better access to primary care patient databases and direct contact with potential recruits can overcome this. Loss of potential recruits during the run-in phase needs exploration, and is of significant importance to improve the efficiency of screening to randomisation. Addressing these issues will mean fewer trials are underpowered and hence provide better return for grant awarding bodies.
The Impact of Medical Comorbidity on Acute Treatment in Major Depressive Disorder
Authors: Dan V. Iosifescu, Andrew A. Nierenberg, Jonathan E. Alpert, Megan Smith, Stella Bitran, Christina Dording, Maurizio Fava
Journal: American Journal of Psychiatry (2003)

The authors investigated the impact of medical comorbidity on the acute phase of antidepressant treatment in subjects with major depressive disorder.A total of 384 outpatients meeting DSM-III-R criteria for major depressive disorder enrolled in 8-week open treatment with fluoxetine, 20 mg/day. The authors used the Cumulative Illness Rating Scale to measure the burden of medical comorbidity and the 17-item Hamilton Rating Scale for Depression to assess changes in depressive symptoms. The outcome measures were response to treatment (>/=50% reduction in score) and clinical remission (score </=7 at the end of the trial).Compared to responders to fluoxetine, nonresponders had significantly higher Cumulative Illness Rating Scale scores and a greater number of Cumulative Illness Rating Scale categories were endorsed. Compared to subjects who achieved remission with antidepressant treatment, those who did not achieve remission had significantly higher Cumulative Illness Rating Scale scores and a greater number of Cumulative Illness Rating Scale categories were endorsed (i.e., more organs were affected by medical illness). The final Hamilton depression scale score was directly correlated with the total Cumulative Illness Rating Scale score and the number of Cumulative Illness Rating Scale categories endorsed.The total burden of medical illness and the number of organ systems affected by medical illness had a significantly negative predictive value for clinical outcome in the acute phase of treatment in major depressive disorder.
Control and severity of asthma during pregnancy are associated with asthma incidence in offspring: two-stage case-control study
Authors: M-J. Martel, É. Rey, M-F. Beauchesne, J-L. Malo, S. Perreault, A. Forget, L. Blais
Journal: European Respiratory Journal (2009)

The extent to which childhood asthma incidence is influenced by asthma control and severity during pregnancy is unknown. We have studied this association during the child's first 10 yrs of life. A two-stage, case-control study, nested in a cohort of 8,226 children of asthmatic mothers, was conducted using three interlinked databases of Quebec, Canada, and mailed questionnaires. A total of 2,681 asthmatic children and 30,318 age-matched controls were selected (< or =20 controls.case(-1); stage 1), and 3,254 selected mothers were mailed questionnaires to obtain additional information (stage 2). Asthma control and severity was defined using validated indexes and childhood asthma incidence based on at least one asthma-related diagnosis and prescription received within 2 yrs. A total of 44 confounders were considered. Compared with children of mild controlled asthmatic mothers, children whose mothers had moderate-to-severe uncontrolled asthma during pregnancy had an increased risk of asthma (adjusted OR 1.27, 95% CI 1.06-1.52). No increased risk was observed for children of mild uncontrolled and moderate-to-severe controlled mothers. Based on one of the largest studies of children of asthmatic mothers, a significant increase in asthma risk was demonstrated among children whose mothers had poor control and increased severity of asthma during pregnancy, indicating that this element should be added to the expanding list of determinants of childhood asthma. As it constitutes a risk factor where pregnant asthmatic females can intervene, it is of great importance for physicians to optimally treat asthmatic females during pregnancy and to encourage females to be adherent to the prescribed asthma medications.
Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation
Authors: Gordon J. Freeman, Andrew J. Long, Yoshiko Iwai, Karen Bourque, Tatyana Chernova, Hiroyuki Nishimura, Lori J. Fitz, Nelly Malenkovich, Taku Okazaki, Michael C. Byrne, Heidi F. Horton, Lynette Fouser, Laura Carter, Vincent Ling, Michael R. Bowman, Beatriz M. Carreno, Mary Collins, Clive R. Wood, Tasuku Honjo
Journal: The Journal of Experimental Medicine (2000)

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
The effect of combined topical steroids and habit-reversal treatment in patients with atopic dermatitis
Authors: P. NOREN, L. MELIN
Journal: British Journal of Dermatology (1989)

A modified behavioural method called habit-reversal, in combination with potent and weak corticosteroid cream, was compared with the use of the creams alone in the treatment of 45 patients with atopic dermatitis. The patients were randomly assigned to four groups, which received two different cream regimes in combination with the habit-reversal treatment. The patients' skin was assessed before, during and after treatment, and they recorded the amount of scratching during the study. The skin condition improved in all groups, but to a significantly greater degree in the habit-reversal groups. A strong correlation was found between the reduction in scratching and the improvement in skin status.
Evolution of functional diversification of the paired box (Pax) DNA- binding domains
Authors: K. A. Balczarek, Z. C. Lai, S. Kumar
Journal: Molecular Biology and Evolution (1997)

The Pax gene family consists of tissue-specific transcriptional regulators that always contain a highly conserved DNA-binding domain with six alpha-helices (paired domain), and, in many cases, a complete or residual homeodomain. Numerous genes of this family have been identified in animals, with the largest number found in vertebrates. Our evolutionary analyses indicate that the vertebrate Pax gene family consists of four well-defined and statistically supported groups: group I (Pax-1, 9), II (Pax-2, 5, 8), III (Pax-3, 7), and IV (Pax-4, 6). Group I paired domains share a most recent common ancestor with Drosophila Pox meso, group II with Pox neuro, group III with paired and gooseberry, and group IV with the eyeless gene. Two groups containing complete homeodomains (III and IV) are distantly related, and the intergroup relationships are (I,III), (II,IV). These four major groups arose before the divergence of Drosophila and vertebrates prior to the Cambrian radiation of triploblastic metazoan body plans. We conducted an analysis of fixed radical amino acid differences between groups in a phylogenetic context. We found that all four fixed radical amino acid differences between groups I and III are located exclusively in the N-terminal alpha-helices. Similarly, groups II and IV show three fixed radical differences in these alpha-helices but at positions different from those in groups I and III. Implications of such fixed amino acid differences in potentially generating sequence recognition specificities are discussed in the context of some recent experimental findings.
Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation
Authors: W A Brown, S A Skinner, C Malcontenti-Wilson, D Vogiagis, P E O'Brien
Journal: Gut (2001)

BACKGROUND Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer by 40–60% but the mechanism by which this occurs is uncertain. Selective cyclooxygenase 2 inhibitors are potentially ideal chemopreventive agents as they are less toxic than standard NSAIDs. No study has compared the efficacy of these drugs at clinically relevant doses in a tumour model. AIMS To assess the efficacy of a range of NSAIDs with varying activity against the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at anti-inflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation. METHODS Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomethacin 2 mg/kg/day, meloxicam 0.6 mg/kg/day, celecoxib 6 mg/kg/day, and sulindac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dose of 20 mg/kg/day. After 23 weeks the number and volume of tumours per animal were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using an immunohistochemical stain for bromodexoyuridine incorporation. RESULTS Test agents effectively reduced the number and volume of tumours developing in the treatment period. In all groups there was an increase in the rate of tumour apoptosis and a reduced rate of proliferation. CONCLUSIONS These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mechanism for their action may be through induction of apoptosis and inhibition of proliferation.
SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells
Authors: Rainelli B Koumangoye, Thomas Andl, Kenneth J Taubenslag, Steven T Zilberman, Chase J Taylor, Holli A Loomans, Claudia D Andl
Journal: Molecular Cancer (2015)

Tumor metastasis is responsible for 90% of cancer-related deaths. Recently, a strong link between microRNA dysregulation and human cancers has been established. However, the molecular mechanisms through which microRNAs regulate metastasis and cancer progression remain unclear.We analyzed the reciprocal expression regulation of miR-31 and SOX4 in esophageal squamous and adenocarcinoma cell lines by qRT-PCR and Western blotting using overexpression and shRNA knock-down approaches. Furthermore, methylation studies were used to assess epigenetic regulation of expression. Functionally, we determined the cellular consequences using migration and invasion assays, as well as proliferation assays. Immunoprecipitation and ChIP were used to identify complex formation of SOX4 and co-repressor components.Here, we report that SOX4 promotes esophageal tumor cell proliferation and invasion by silencing miR-31 via activation and stabilization of a co-repressor complex with EZH2 and HDAC3. We demonstrate that miR-31 is significantly decreased in invasive esophageal cancer cells, while upregulation of miR-31 inhibits growth, migration and invasion of esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) cell lines. miR-31, in turn, targets SOX4 for degradation by directly binding to its 3'-UTR. Additionally, miR-31 regulates EZH2 and HDAC3 indirectly. SOX4, EZH2 and HDAC3 levels inversely correlate with miR-31 expression in ESCC cell lines. Ectopic expression of miR-31 in ESCC and EAC cell lines leads to down regulation of SOX4, EZH2 and HDAC3. Conversely, pharmacologic and genetic inhibition of SOX4 and EZH2 restore miR-31 expression. We show that SOX4, EZH2 and HDAC3 form a co-repressor complex that binds to the miR-31 promoter, repressing miR-31 through an epigenetic mark by H3K27me3 and by histone acetylation. Clinically, when compared to normal adjacent tissues, esophageal tumor samples show upregulation of SOX4, EZH2, and HDAC3, and EZH2 expression is significantly increased in metastatic ESCC tissues.Thus, we identified a novel molecular mechanism by which the SOX4, EZH2 and miR-31 circuit promotes tumor progression and potential therapeutic targets for invasive esophageal carcinomas.
Non-invasive mechanical ventilation for diagnostic bronchoscopy using a new face mask: an observational feasibility study
Authors: Leo M. A. Heunks, Charlotte J. R. de Bruin, Johannes G. van der Hoeven, Henricus F. M. van der Heijden
Journal: Intensive Care Medicine (2009)

Bronchoscopy is an indispensable tool for invasive pulmonary evaluation with high diagnostic yield and low incidence of major complications. However, hypoxemia increases the risk of complications, in particular after bronchoalveolar lavage. Non-invasive positive pressure ventilation may prevent hypoxemia associated with bronchoalveolar lavage. The purpose of this study is to present a modified total face mask to aid bronchoscopy during non-invasive positive pressure ventilation.A commercially available full face mask was modified to allow introduction of the bronchoscope without interfering with the ventilator circuit. Bronchoscopy with bronchoalveolar lavage was performed in 12 hypoxemic non-ICU patients during non-invasive positive pressure ventilation in the ICU.Patients had severely impaired oxygen uptake as indicated by PaO(2)/FiO(2) ratio 192 +/- 23 mmHg before bronchoscopy. Oxygenation improved after initiation of non-invasive positive pressure ventilation. In all patients the procedure could be completed without subsequent complications, although in one patient SpO(2) decreased until 86% during bronchoscopy. A microbiological diagnosis could be established in 8 of 12 patients with suspected for infection.Our modified face mask for non-invasive positive pressure ventilation is a valuable tool to aid diagnostic bronchoscopy in hypoxemic patients.
CD4 <sup>+</sup> T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy
Authors: Alberto K. De la Herrán-Arita, Birgitte Rahbek Kornum, Josh Mahlios, Wei Jiang, Ling Lin, Tieying Hou, Claudia Macaubas, Mali Einen, Giuseppe Plazzi, Catherine Crowe, Evan W. Newell, Mark M. Davis, Elizabeth D. Mellins, Emmanuel Mignot
Journal: Science Translational Medicine (2013)

Patients with narcolepsy carry CD4 + T cells that react to peptides from both the sleep-regulating neuropeptide hypocretin and a 2009 H1N1 influenza A protein.
Chemoprevention of Head and Neck Cancers: Promising New Biochemical Prospects
Authors: Shailendra Kapoor
Journal: Journal of Clinical Oncology (2008)

pleased to have the opportunity to clarify a very important issue which warrants further attention.We endorse Dr Graham's view that generalization of metaanalysis results to populations not included in the original trials can be misleading.This is a rule that applies to single clinical trials as well as meta-analyses.We would like to point out that in our article we did not extrapolate the results of our meta-analysis to all breast cancer patients.Rather, we note that our conclusions apply to patients with high-risk early breast cancer (eg, the conclusions of the abstract and the Discussion). 1 In the high-risk populations included in our meta-analysis (Ͼ 85% of patients were node positive), we found no interaction between the effect of taxane and estrogen-receptor status, age/menopausal status, and HER2 status.Consequently, all aforegoing subgroups of this high-risk population should benefit from the addition of taxane to adjuvant anthracycline-based therapy.We agree that appropriate estimates of the absolute benefit is a crucial factor when deciding the optimal therapy for the individual patient.Obviously, the benefit is indirectly correlated with the baseline risk assuming a constant hazard ratio.Rather than general indications, we would like to take this opportunity of providing an approximate estimate of the absolute benefit for different risk categories as calculated based on the results of our meta-analysis (Table 1).