tbuckley/cabot-search huggingface dataset:
Molecular networks involved in mouse cerebral corticogenesis and spatio-temporal regulation of Sox4 and Sox11 novel antisense transcripts revealed by transcriptome profiling
Authors: King-Hwa Ling, Chelsee A Hewitt, Tim Beissbarth, Lavinia Hyde, Kakoli Banerjee, Pike-See Cheah, Ping Z Cannon, Christopher N Hahn, Paul Q Thomas, Gordon K Smyth, Seong-Seng Tan, Tim Thomas, Hamish S Scott
Journal: Genome biology (2009)

Development of the cerebral cortex requires highly specific spatio-temporal regulation of gene expression. It is proposed that transcriptome profiling of the cerebral cortex at various developmental time points or regions will reveal candidate genes and associated molecular pathways involved in cerebral corticogenesis. Serial analysis of gene expression (SAGE) libraries were constructed from C57BL/6 mouse cerebral cortices of age embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4 to 6 months. Hierarchical clustering analysis of 561 differentially expressed transcripts showed regionalized, stage-specific and co-regulated expression profiles. SAGE expression profiles of 70 differentially expressed transcripts were validated using quantitative RT-PCR assays. Ingenuity pathway analyses of validated differentially expressed transcripts demonstrated that these transcripts possess distinctive functional properties related to various stages of cerebral corticogenesis and human neurological disorders. Genomic clustering analysis of the differentially expressed transcripts identified two highly transcribed genomic loci, Sox4 and Sox11, during embryonic cerebral corticogenesis. These loci feature unusual overlapping sense and antisense transcripts with alternative polyadenylation sites and differential expression. The Sox4 and Sox11 antisense transcripts were highly expressed in the brain compared to other mouse organs and are differentially expressed in both the proliferating and differentiating neural stem/progenitor cells and P19 (embryonal carcinoma) cells. We report validated gene expression profiles that have implications for understanding the associations between differentially expressed transcripts, novel targets and related disorders pertaining to cerebral corticogenesis. The study reports, for the first time, spatio-temporally regulated Sox4 and Sox11 antisense transcripts in the brain, neural stem/progenitor cells and P19 cells, suggesting they have an important role in cerebral corticogenesis and neuronal/glial cell differentiation.
Effects of beta interferon on human fibroblasts at different population doubling levels. Proliferation, cell volume, thymidine uptake, and DNA synthesis.
Authors: B R Jasny, L M Pfeffer, I Tamm
Journal: The Journal of Experimental Medicine (1984)

Cellular aging had no effect on the ability of beta interferon to increase cell volume and population doubling time in 76-109 cells, a line of human skin fibroblasts. However, DNA synthesis in cells at high population doubling levels (PDL 55-70) was inhibited after 72 h of beta interferon treatment (1,000 U/ml) while no inhibition of DNA synthesis was observed in cells at middle population doubling levels (PDL 30-40).
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C β-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer
Authors: Jeany M. Rademaker-Lakhai, Laurens V. Beerepoot, Niven Mehra, Sandra A. Radema, Rianne van Maanen, Joost S. Vermaat, Els O. Witteveen, Carla M. Visseren-Grul, Luna Musib, Nathan Enas, Gertjan van Hal, Jos H. Beijnen, Jan H.M. Schellens, Emile E. Voest
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin. Experimental Design: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m2 and cisplatin doses were either 60 or 75 mg/m2. Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers. Results: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (≥250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation. Conclusions: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m2 gemcitabine, and 75 mg/m2 cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.
PTSD Following Terrorist Attacks: A Prospective Evaluation
Authors: Arieh Y. Shalev, Sara Freedman
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: This study evaluated the prevalence of posttraumatic stress disorder (PTSD) and the longitudinal course of early PTSD symptoms in survivors of terrorist attacks. It additionally assessed the effect of continuous terrorism on the course of early symptoms of PTSD. METHOD: Thirty-nine survivors of terrorist attacks and 354 survivors of motor vehicle accidents were evaluated upon admission to a general hospital emergency room and 1 week and 4 months later. Heart rate was measured upon admission to the emergency room. Peritraumatic dissociation was assessed at 1 week. PTSD symptoms, anxiety, and depression were measured at 1 week and 4 months. The Clinician-Administered PTSD Scale conferred a diagnosis of PTSD at 4 months. Additionally, the course of early PTSD symptoms during an era of frequent terrorist attacks (N=137) was compared with that seen during years of relative calm (N=256). RESULTS: Survivors of terrorist attacks had higher rates of PTSD than motor vehicle accident survivors (37.8% versus 18.7%). The type of traumatic event, however, did not add to the prediction of PTSD from the emergency room heart rate, peritraumatic dissociation symptoms, and early PTSD symptoms. The longitudinal course of early PTSD symptoms was not affected by the greater frequency of terrorist attacks. CONCLUSIONS: Early symptoms are reliable risk indicators of PTSD across events and circumstances. Converging effects of terror-induced fear, adjustment, and resiliency might explain the lack of effect of intense terrorism on the course of PTSD symptoms.
Direct Comparison of the A to Z and PROVE IT Trials
Authors: B. Greg Brown
Journal: Circulation (2006)

wo similar clinical trials in patients presenting with acute coronary syndromes (ACS), the Aggrastat to Zocor (A to Z) 1 and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 2 trials, each compared intensive versus moderate statin therapies for 2 years.PROVE IT demonstrated a significant benefit from intensive therapy (16% reduction, Pϭ0.005 in its primary end point), whereas A to Z found only a favorable trend (11% reduction, Pϭ0.14 in its somewhat different primary end point).Like many clinicians reading these 2 reports, my first impression was that these data demonstrated the superiority of 80 mg of atorvastatin over 80 mg of simvastatin.Market share shifts soon reflected this perception.Wiviott et al 3 have compared these studies in detail to ask whether the observed differences were explained by true differences in drug efficacy or, alternatively, by differences in trial design or practice differences among the 2 studies' clinical sites (factors that, in this analysis, may be linked to different practice patterns inside or outside the United States).Event rates in the "early" 4-month phase and the "late" 20-month phase were examined separately.This is a wellwritten and well-reasoned post hoc comparison between 2 "similar" trials that nevertheless have certain important hypothesis-generating differences.
Association of Cannabis Smoking and Periodontal Disease—Reply
Authors: W. Murray Thomson
Journal: JAMA (2008)

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A Three-Gene Signature for Outcome in Soft Tissue Sarcoma
Authors: Andreas-Claudius Hoffmann, Kathleen D. Danenberg, Helge Taubert, Peter V. Danenberg, Peter Wuerl
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Finding markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens in soft tissue sarcomas is necessary. In this study, we investigated the prognostic values of hypoxia-inducible factor 1a (HIF1a), heparin-binding epidermal growth factor–like growth factor (HB-EGF), vascular endothelial growth factor (VEGF), and other angiogenesis-related gene expressions, as well as their interrelationships. Experimental Design: Formalin-fixed paraffin-embedded tissue samples were obtained from 45 patients with soft tissue sarcoma (median age 57 years, range 16–85 years). After laser capture microdissection direct quantitative real-time reverse transcription-PCR (TaqMan) assays were done in triplicates to determine HIF1a, HB-EGF, VEGF, and other gene expression levels. Results: Multivariate Cox regression analysis revealed significant independent associations of HB-EGF, HIF1a, and VEGF-C gene expression to the overall survival (P &amp;lt; 0.0001). A combined factor of these three genes showed a relative risk for shorter survival of 5.5, more than twice higher as in an increasing International Union against Cancer Stage. Receiver operating characteristic curve analysis showed a significant sensitivity of 73% and specificity of 82% of this factor for the diagnosis of short (&amp;lt;3 years) versus long (3-9 years) survival (P = 0.0002). VEGF-A showed significant gender differences in the association to survival. Conclusions: Measuring HIF1a, HB-EGF, and VEGF-C expression may contribute to a better understanding of the prognosis of patients with soft tissue sarcoma and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Prospective studies investigating the response to different adjuvant or palliative therapies seem to be warranted. (Clin Cancer Res 2009;15(16):5191–8)
Cat Ownership Is A Risk Factor For Developing Sensitization To Cat But Not Wheeze By Age 5 In A Low Income New York City Birth Cohort
Authors: M.S. Perzanowski, G.L. Chew, A. Divjan, A. Johnson, K. Panjwani, B.J. Sheares, T.A. Platts-Mills, F.P. Perera, R.L. Miller
Journal: Journal of Allergy and Clinical Immunology (2007)
Modulation of Cardiac Contractility by the Phopholamban/SERCA2a Regulatome
Authors: Evangelia G. Kranias, Roger J. Hajjar
Journal: Circulation Research (2012)

Heart disease remains the leading cause of death and disability in the Western world. Current therapies aim at treating the symptoms rather than the subcellular mechanisms, underlying the etiology and pathological remodeling in heart failure. A universal characteristic, contributing to the decreased contractile performance in human and experimental failing hearts, is impaired calcium sequestration into the sarcoplasmic reticulum (SR). SR calcium uptake is mediated by a Ca 2+ -ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and phosphorylation of PLN relieves this inhibition. However, the initial simple view of a PLN/SERCA regulatory complex has been modified by our recent identification of SUMO, S100 and the histidine-rich Ca-binding protein as regulators of SERCA activity. In addition, PLN activity is regulated by 2 phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat shock protein 20, which affect the overall SERCA-mediated Ca-transport. This review will highlight the regulatory mechanisms of cardiac contractility by the multimeric SERCA/PLN-ensemble and the potential for new therapeutic avenues targeting this complex by using small molecules and gene transfer methods.
Impact of Salmeterol/Fluticasone Propionate versus Salmeterol on Exacerbations in Severe Chronic Obstructive Pulmonary Disease
Authors: Peter Kardos, Marion Wencker, Thomas Glaab, Claus Vogelmeier
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) greatly contribute to declining health status and the progression of the disease, thereby incurring significant direct and indirect health care costs. The prevention of exacerbations, therefore, is an important treatment goal.Objectives: To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations.Methods: Randomized, double-blind, parallel-group study. After a 4-wk run-in period, 994 clinically stable patients were randomized to one of two treatment groups: 507 patients received the salmeterol/fluticasone combination 50/500 μg twice daily and 487 received salmeterol 50 μg twice daily for 44 wk.Main Results: The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group (p < 0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 d, p < 0.0001). Other endpoints, including health-related quality of life, peak expiratory flow, and use of rescue medication, were significantly improved in the combination therapy group. Both treatments were well tolerated.Conclusions: This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD.
Increased DNA and protein synthesis in the involved and uninvolved skin of patients with psoriasis
Authors: R. MARKS
Journal: British Journal of Dermatology (1975)

Journal Article Increased DNA and protein synthesis in the involved and uninvolved skin of patients with psoriasis Get access R. MARKS R. MARKS The Welsh National School of Medicine, Cardiff Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 93, Issue s11, 1 July 1975, Page 28, https://doi.org/10.1111/j.1365-2133.1975.tb06781.x Published: 01 July 1975
Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial
Authors: N. B. Klarenbeek, S. M. van der Kooij, T. J. W. Huizinga, Y. P. M. Goekoop-Ruiterman, H. M. J. Hulsmans, M. V. van Krugten, I. Speyer, J. K. de Vries-Bouwstra, P. J. S. M. Kerstens, T. W. J. Huizinga, B. A. C. Dijkmans, C. F. Allaart
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To evaluate the effect of disease activity and antirheumatic treatment on blood pressure (BP) in patients with recent-onset rheumatoid arthritis (RA). <h3>Methods</h3> 508 patients with RA were randomised to receive (1) sequential monotherapy, (2) step-up combination therapy, (3) initial combination with prednisone or (4) with infliximab. Systolic and diastolic BP (SBP, DBP), disease activity score (DAS) and body mass index (BMI) were evaluated every 3 months. A linear mixed model was used to model SBP and DBP in each treatment group during year 1, adjusting for baseline BP, changes in BMI, DAS and cardiovascular medication. <h3>Results</h3> In all groups, mean SBP and DBP were lower for patients with DAS ≤2.4 than for patients with DAS &gt;2.4. In addition, patients initially treated with infliximab (group 4) had a larger decrease in SBP and DBP over time than patients in groups 1–3. The decrease in BP was also observed in patients treated with infliximab after failure on conventional disease-modifying antirheumatic drugs in groups 1–3. The decrease in BP associated with treatment with infliximab occurred irrespective of the DAS response. <h3>Conclusion</h3> A lower DAS is associated with lower BP. An additional decrease in BP was observed in patients treated with infliximab. Further research is needed to confirm the effect of infliximab on BP.
Estrogen Receptor Mutations and Changes in Downstream Gene Expression and Signaling
Authors: Ines Barone, Lauren Brusco, Suzanne A.W. Fuqua
Journal: Clinical Cancer Research (2010)

Estrogens play a crucial role in regulating the growth and differentiation of breast cancers, with approximately two thirds of all breast tumors expressing the estrogen receptor alpha (ERalpha). Therefore, therapeutic strategies directed at inhibiting the action of ERalpha by using anti-estrogens such as tamoxifen, or reducing estrogens levels by using aromatase inhibitors, such as letrozole, anastrozole, or exemestane, are the standard treatments offered to women with ERalpha-positive cancer. However, not all patients respond to endocrine therapies (termed de novo resistance), and a large number of patients who do respond will eventually develop disease progression or recurrence while on therapy (acquired resistance). Recently, variant forms of the receptor have been identified owing to alternative splicing or gene mutation. This article reviews these variant receptors and their clinical relevance in resistance to endocrine therapy, by addressing their molecular cross-talk with growth factor receptors and signaling components. Understanding the complexity of receptor-mediated signaling has promise for new combined therapeutic options that focus on more efficient blockade of receptor cross-talk.
Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract
Authors: A. P. Moran, A. Gupta, L. Joshi
Journal: Gut (2011)

Glycosylation is a key modification of proteins and lipids and is involved in most intermolecular and intercellular interactions. The gastrointestinal mucus gel is continuous and can be divided into two layers: a secreted loosely associated layer and a layer firmly attached to the mucosa. In addition, the membrane-bound glycosylated proteins and lipids create a glycocalyx, which remains adherent on each cell and is dynamic and responsive to the physiological state and environment of the cell. The secreted glycans form a mucus gel layer that serves as a physicochemical sensor and barrier network and is primarily composed of mucins and associated peptides. These glycans protect gut epithelial cells from chemical, biological and physical insults and are continuously renewed. Pathogens colonise and invade the host epithelial cells using protein–protein and glycan–lectin interactions. During the process of colonisation and infection, the glycosylation state of both host and pathogen change in response to the presence of the other. This complex modulation of glycan expression critically determines pathogenesis and the host response in terms of structural changes and immune response. In addition, by influencing host immunity and gut glycosylation, the microbiota can further effect protection against pathogens. In this review, the roles of host glycosylation in interactions with two prevalent bacterial pathogens, <i>Campylobater jejuni</i> and <i>Helicobacter pylori</i>, are discussed to illustrate important concepts in pathogenesis.
Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma.
Authors: D Y Leung, R J Martin, S J Szefler, E R Sher, S Ying, A B Kay, Q Hamid
Journal: The Journal of Experimental Medicine (1995)

In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p &amp;lt; 0.01) and IL-4 mRNA (p &amp;lt; 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p &amp;lt; 0.01) and IL-5 (p &amp;lt; 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p &amp;lt; 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.