tbuckley/cabot-search huggingface dataset:
Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants
Authors: KF Rabe, H Magnussen, G Dent
Journal: European Respiratory Journal (1995)

In addition to its emerging immunodulatory properties, theophylline is a bronchodilator and also decreases mean pulmonary arterial pressure in vivo. The mechanism of action of this drug remains controversial; adenosine antagonism, phosphodiesterase (PDE) inhibition and other actions have been advanced to explain its effectiveness in asthma. Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) are involved in the regulation of smooth muscle tone, and the breakdown of these nucleotides is catalysed by multiple PDE isoenzymes. The PDE isoenzymes present in human bronchus and pulmonary artery have been identified, and the pharmacological actions of inhibitors of these enzymes have been investigated. Human bronchus and pulmonary arteries are relaxed by theophylline and by selective inhibitors of PDE III, while PDE IV inhibitors also relax precontracted bronchus and PDE V/I inhibitors relax pulmonary artery. There appears to be some synergy between inhibitors of PDE III and PDE IV in relaxing bronchus, and a pronounced synergy between PDE III and PDE V inhibitors in relaxing pulmonary artery. In neither tissue does 8-phenyltheophylline, a xanthine exhibiting adenosine antagonism but not PDE inhibition, cause any significant relaxation, implying that theophylline does not exert its actions through adenosine antagonism. The close correspondence of theophylline concentrations inhibiting bronchus or pulmonary artery PDE and those causing relaxation points towards PDE inhibition as the major mechanism of action of theophylline in smooth muscle relaxation.
How to stabilize unstable plaque
Authors: R. Hirschberg
Journal: Cardiovascular Research (2011)

This editorial refers to ‘Inhibition of rupture of established atherosclerotic plaques by treatment with apolipoprotein A-I’ by G.J. Reimers et al. , doi:10.1093/cvr/cvr057 

Association studies and epidemiological observations have shown that high plasma levels of high-density lipoprotein-cholesterol (HDL-C) provide cardiovascular protection.1 The anti-atherosclerosis activity of HDL is multifaceted and may include anti-thrombotic, anti-oxidative, and anti-inflammatory mechanisms. However, reverse cholesterol transport through which cholesterol is removed from tissues and plaques and shuttled to the liver for excretion with bile is thought to be the major action of HDL in its atheroma-preventing effort.

These observations and experimental findings gave rise to studies in experimental animals and phase I and II trials of short-term infusions of reconstituted HDL with the aim of accelerating reverse cholesterol transport.2–4 In the ERASE clinical trial reconstituted HDL (made of human apolipoprotein A-1, Apo A-1, and soybean phosphatidylcholine) that was administered beginning shortly after an acute coronary syndrome tended to reduce …
Alternative Promoter Usage at the Notch1 Locus Supports Ligand-Independent Signaling in T Cell Development and Leukemogenesis
Authors: Pablo Gómez-del Arco, Mariko Kashiwagi, Audrey F. Jackson, Taku Naito, Jiangwen Zhang, Feifei Liu, Barbara Kee, Marc Vooijs, Freddy Radtke, Juan Miguel Redondo, Katia Georgopoulos
Journal: Immunity (2010)
Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management?
Authors: S Nattel
Journal: Cardiovascular Research (2002)

Atrial fibrillation (AF) is a very common clinical problem, and presently available treatment options are suboptimal. A tremendous amount has been learned over the past 10 years about the atrial substrates that support sustained AF at the tissue, ionic and molecular levels. This understanding of the fundamental mechanisms underlying AF has opened up a variety of new, rationally-based therapeutic approaches. The present paper reviews what is known about the mechanistic substrates that lead to AF and discusses the potential therapeutic consequences.
Gene regulatory network inference: evaluation and application to ovarian cancer allows the prioritization of drug targets
Authors: Piyush B Madhamshettiwar, Stefan R Maetschke, Melissa J Davis, Antonio Reverter, Mark A Ragan
Journal: Genome Medicine (2012)

Altered networks of gene regulation underlie many complex conditions, including cancer. Inferring gene regulatory networks from high-throughput microarray expression data is a fundamental but challenging task in computational systems biology and its translation to genomic medicine. Although diverse computational and statistical approaches have been brought to bear on the gene regulatory network inference problem, their relative strengths and disadvantages remain poorly understood, largely because comparative analyses usually consider only small subsets of methods, use only synthetic data, and/or fail to adopt a common measure of inference quality.We report a comprehensive comparative evaluation of nine state-of-the art gene regulatory network inference methods encompassing the main algorithmic approaches (mutual information, correlation, partial correlation, random forests, support vector machines) using 38 simulated datasets and empirical serous papillary ovarian adenocarcinoma expression-microarray data. We then apply the best-performing method to infer normal and cancer networks. We assess the druggability of the proteins encoded by our predicted target genes using the CancerResource and PharmGKB webtools and databases.We observe large differences in the accuracy with which these methods predict the underlying gene regulatory network depending on features of the data, network size, topology, experiment type, and parameter settings. Applying the best-performing method (the supervised method SIRENE) to the serous papillary ovarian adenocarcinoma dataset, we infer and rank regulatory interactions, some previously reported and others novel. For selected novel interactions we propose testable mechanistic models linking gene regulation to cancer. Using network analysis and visualization, we uncover cross-regulation of angiogenesis-specific genes through three key transcription factors in normal and cancer conditions. Druggabilty analysis of proteins encoded by the 10 highest-confidence target genes, and by 15 genes with differential regulation in normal and cancer conditions, reveals 75% to be potential drug targets.Our study represents a concrete application of gene regulatory network inference to ovarian cancer, demonstrating the complete cycle of computational systems biology research, from genome-scale data analysis via network inference, evaluation of methods, to the generation of novel testable hypotheses, their prioritization for experimental validation, and discovery of potential drug targets.
MET-Independent Lung Cancer Cells Evading EGFR Kinase Inhibitors Are Therapeutically Susceptible to BH3 Mimetic Agents
Authors: Weiwen Fan, Zhe Tang, Lihong Yin, Bei Morrison, Said Hafez-Khayyata, Pingfu Fu, Honglian Huang, Rakesh Bagai, Shan Jiang, Adam Kresak, Scott Howell, Amit Vasanji, Chris A. Flask, Balazs Halmos, Henry Koon, Patrick C. Ma
Journal: Cancer Research (2011)

Targeted therapies for cancer are inherently limited by the inevitable recurrence of resistant disease after initial responses. To define early molecular changes within residual tumor cells that persist after treatment, we analyzed drug-sensitive lung adenocarcinoma cell lines exposed to reversible or irreversible epidermal growth factor receptor (EGFR) inhibitors, alone or in combination with MET-kinase inhibitors, to characterize the adaptive response that engenders drug resistance. Tumor cells displaying early resistance exhibited dependence on MET-independent activation of BCL-2/BCL-XL survival signaling. Further, such cells displayed a quiescence-like state associated with greatly retarded cell proliferation and cytoskeletal functions that were readily reversed after withdrawal of targeted inhibitors. Findings were validated in a xenograft model, showing BCL-2 induction and p-STAT3[Y705] activation within the residual tumor cells surviving the initial antitumor response to targeted therapies. Disrupting the mitochondrial BCL-2/BCL-XL antiapoptotic machinery in early survivor cells using BCL-2 Homology Domain 3 (BH3) mimetic agents such as ABT-737, or by dual RNAi-mediated knockdown of BCL-2/BCL-XL, was sufficient to eradicate the early-resistant lung-tumor-cells evading targeted inhibitors. Similarly, in a xenograft model the preemptive cotreatment of lung tumor cells with an EGFR inhibitor and a BH3 mimetic eradicated early TKI-resistant evaders and ultimately achieved a more durable response with prolonged remission. Our findings prompt prospective clinical investigations using BH3-mimetics combined with targeted receptor kinase inhibitors to optimize and improve clinical outcomes in lung-cancer treatment.
Complete inclusion of adaptive rowing only 1000 m ahead
Authors: Tomislav Smoljanovic, Ivan Bojanic, Jo A Hannafin, Axel Urhausen, Daniel Theisen, Romain Seil, Alain Lacoste
Journal: British Journal of Sports Medicine (2013)

Adaptive rowing (AR) at the Paralympic level is accessible for rowers with physical disability. AR was included for the first time in the Beijing 2008 Paralympic Games. Racing distance for all AR events is currently 1000 m, which impedes public recognition of this sport and leads to many organisational challenges during the inclusive World Rowing Championships. The aim of this report was to discuss the feasibility of increasing AR race distance to 2000 m from a sports injury and athletic health perspective. As limited data on injury and illness risks exist in AR, knowledge and experiences had to be taken from other Paralympic sports. The anticipated duration of 2000 m AR competitions is either comparable or considerably lower than that of the other Paralympic disciplines with similar characteristics. AR has inherent injury and health risks especially within thorax, shoulders and low back region, but they are not expected to be significantly modified by increased racing times. Specific considerations need to be taken into account for athletes with a spinal cord injury, like in other sport disciplines. There are no distinctive contra-indications for AR events of 2000 m based on the current literature review and a 10-year experience in this sport. Long-term follow-ups are needed to understand fully the injury and health risk associated with AR and to develop appropriate prevention strategies.
Epstein-Barr Virus and Cancer
Authors: Matthew P. Thompson, Razelle Kurzrock
Journal: Clinical Cancer Research (2004)

Abstract EBV was the first human virus to be directly implicated in carcinogenesis. It infects &amp;gt;90% of the world’s population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt’s lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
Molecular analysis of sequence variants in the Fcɛ receptor I β gene and IL‐4 gene promoter in Italian atopic families
Authors: L. Rigoli, C. Di Bella, V. Procopio, G. Barberio, I. Barberi, L. Caminiti, S. La Grutta, S. Briuglia, C. D. Salpietro, G. B. Pajno
Journal: Allergy (2004)

The genetic variants in the Fcepsilon receptor I beta gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)-4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another.A group of 25 Italian nuclear families were studied. In each family at least two allergic subjects were present. The allergic children were 65 and the allergic relatives were 35. One hundred and three nonallergic unrelated controls included outpatiens with no history of atopy. The (C590T) promoter polymorphism of the IL-4 and the genetic variant Glu237Gly of Fcepsilon RI beta genes were analysed by the polymerase chain reaction-restriction fragment length polymorphism method.A significant difference was observed in the genotype frequency at codon 237 of the Fcepsilon RI beta gene between allergic children and nonatopic control (P < 0.01) and in the allergic relatives (P < 0.001). In the children, the Glu237Gly polymorphism was also associated with elevated circulating levels of immunoglobulin E. The -590C/T allele of IL-4 promoter gene showed no association with atopy.In our study, the Glu237Gly polymorphism of the Fcepsilon RI beta gene was associated with atopy. Our results have not pointed out an association between the (C590T) promoter polymorphism of the IL-4 gene and atopy. These data suggest the potential role of the Fc RI beta gene in the development of the allergy.
Association of <i>Megalin</i> Genetic Polymorphisms with Prostate Cancer Risk and Prognosis
Authors: Sarah K. Holt, Danielle M. Karyadi, Erika M. Kwon, Janet L. Stanford, Peter S. Nelson, Elaine A. Ostrander
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Megalin, an endocytic receptor expressed by prostate epithelial cells, can internalize biologically active androgens bound to sex hormone binding globulin. Genetic variation within megalin could potentially influence levels of steroid hormone uptake. Experimental Design: Forty haplotype-tagging single-nucleotide polymorphisms (htSNP) were analyzed in a population-based, case-control study of 553 Caucasian men who were diagnosed with prostate cancer between the ages of 40 and 64 years from the Seattle-Puget Sound region and 534 control men. Prostate cancer risk was estimated using adjusted unconditional logistic regression for both individual SNPs and haplotypes. Risks of disease recurrence/progression and prostate-specific cancer mortality were estimated using Cox proportional hazards regression. Results: We found no strong evidence of altered risk of developing prostate cancer for any of the htSNPs when they were assessed individually or in haplotypes. However, three htSNPs were significantly associated with both disease recurrence/progression and mortality. Risk of recurrence/progression alone was also associated with five additional htSNPs, and six other htSNPS showed evidence of modification by primary androgen deprivation therapy. Two additional htSNPs were significantly associated with altered risk of death from prostate cancer. Conclusions: Preliminary results suggest that common genetic variation within the megalin gene could alter both risk of recurrence/progression and prostate-specific cancer mortality. In addition, androgen deprivation therapy effectiveness may be modified by the activity of this gene. To our knowledge, this is the first study that has examined polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes.
Vav1/2/3-null Mice Define an Essential Role for Vav Family Proteins in Lymphocyte Development and Activation but a Differential Requirement in MAPK Signaling in T and B Cells
Authors: Keiko Fujikawa, Ana V. Miletic, Frederick W. Alt, Roberta Faccio, Tracie Brown, Jeremy Hoog, Jessica Fredericks, Shinzo Nishi, Shirly Mildiner, Sheri L. Moores, Joan Brugge, Fred S. Rosen, Wojciech Swat
Journal: The Journal of Experimental Medicine (2003)

The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far by the expression of three highly related family members. We generated mice lacking all Vav family proteins and show that Vav-null mice produce no functional T or B cells and completely fail to mount both T-dependent and T-independent humoral responses. Whereas T cell development is blocked at an early stage in the thymus, immature B lineage cells accumulate in the periphery but arrest at a late “transitional” stage. Mechanistically, we show that the Vav family is crucial for both TCR and B cell receptor (BCR)–induced Ca2+ signaling and, surprisingly, is only required for mitogen-activated protein kinase (MAPK) activation in developing and mature T cells but not in B cells. Thus, the abundance of immature B cells generated in Vav-null mice may be due to intact Ras/MAPK signaling in this lineage. Although the expression of Vav1 alone is sufficient for normal lymphocyte development, our data also reveal lineage-specific roles for Vav2 and Vav3, with the first demonstration that Vav3 plays a critical compensatory function in T cells. Together, we define an essential role for the entire Vav protein family in lymphocyte development and activation and establish the limits of functional redundancy both within this family and between Vav and other Rho–guanine nucleotide exchange factors.
Long-term Clinical Outcome of Phase IIb Clinical Trial of Percutaneous Injection with Holmium-166/Chitosan Complex (Milican) for the Treatment of Small Hepatocellular Carcinoma
Authors: Ja Kyung Kim, Kwang-Hyub Han, Jong Tae Lee, Yong Han Paik, Sang Hoon Ahn, Jong Doo Lee, Kwan Sik Lee, Chae Yoon Chon, Young Myoung Moon
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The purpose of this study was to evaluate the long-term tumor response after phase IIb clinical study and the safety of percutaneous holmium-166 (166Ho)/chitosan complex injection (PHI) therapy for small hepatocellular carcinoma as a local ablative treatment. 166Ho is a radioactive isotope derived from natural holmium-165. We developed a 166Ho/chitosan complex (Milican, Dong Wha Pharmaceutical Co., Seoul, Korea) using chitosan as a vehicle to retain the radioactive material within the tumor. Experimental Design: Forty patients with single hepatocellular carcinoma &amp;lt;3 cm in maximal diameter were enrolled in this study. The patients either had refused surgery or were poor surgical candidates and were treated with only single session of PHI. Results: Two months after PHI, complete tumor necrosis was achieved in 31 of 40 patients (77.5%) with hepatocellular carcinoma lesions &amp;lt;3 cm and in 11 of 12 patients (91.7%) with hepatocellular carcinoma &amp;lt;2 cm. Tumors recurred in 28 patients during the long-term follow-up period, of which 24 recurred at another intrahepatic site. The 1-year and 2-year cumulative local recurrence rates were 18.5% and 34.9%, respectively. The survival rates at 1, 2, and 3 years were 87.2%, 71.8%, and 65.3%, respectively. Transient bone marrow depression was serious adverse event requiring hospitalization in two patients. Conclusions: PHI was found to be a safe and novel local ablative procedure for the treatment of small hepatocellular carcinoma and could be used as a bridge to transplantation. A phase III randomized active control trial is clearly warranted among a larger study population.
Sedation of critically ill patients during mechanical ventilation. A comparison of propofol and midazolam.
Authors: J P Kress, M F O'Connor, A S Pohlman, D Olson, A Lavoie, A Toledano, J B Hall
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Propofol (P) and midazolam (M) are frequently given by continuous infusion for sedation in critically ill, mechanically ventilated patients. We compared these drugs with regard to: (1) time-to-awaken; (2) reproducibility of bedside assessments of level of sedation; (3) time-to-sedation; and (4) change in oxygen consumption (V O2) from awake to sedated state. Seventy-three patients were prospectively randomized to receive either P (n=37) or M (n=36). Wake-up times after stopping the drug were assessed by blinded and unblinded observers, by asking patients to perform simple tasks. Times to sedate were assessed by consensus agreement among nurses and investigators. Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min. Blinded versus unblinded observations had excellent correlation. Average time to sedate and decrease in V O2 were not different. We conclude that in this patient population: (1) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocols; (2) P had a faster, more reliable, wake-up time; (3) assessments of time-to-awaken were objective and reproducible; (4) time to sedation was not significantly different; (5) V O2 decreased similarly with both.
Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer
Authors: William J. Gradishar, Sergei Tjulandin, Neville Davidson, Heather Shaw, Neil Desai, Paul Bhar, Michael Hawkins, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2005)

ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel.Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225).ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time.ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.
Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?
Authors: M.M. Regan, O. Pagani, B. Walley, R. Torrisi, E.A. Perez, P. Francis, G.F. Fleming, K.N. Price, B. Thürlimann, R. Maibach, M. Castiglione-Gertsch, A.S. Coates, A. Goldhirsch, R.D. Gelber
Journal: Annals of Oncology (2008)