tbuckley/cabot-search huggingface dataset:
Skeletal Muscle Degenerative Diseases and Strategies for Therapeutic Muscle Repair
Authors: Mohammadsharif Tabebordbar, Eric T. Wang, Amy J. Wagers
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Skeletal muscle is a highly specialized, postmitotic tissue that must withstand chronic mechanical and physiological stress throughout life to maintain proper contractile function. Muscle damage or disease leads to progressive weakness and disability, and manifests in more than 100 different human disorders. Current therapies to treat muscle degenerative diseases are limited mostly to the amelioration of symptoms, although promising new therapeutic directions are emerging. In this review, we discuss the pathological basis for the most common muscle degenerative diseases and highlight new and encouraging experimental and clinical opportunities to prevent or reverse these afflictions.
VATS or simple talc poudrage under medical thoracoscopy for recurrent spontaneous pneumothorax
Authors: J-M. Tschopp, J-M. Schnyder, M. Froudarakis, P. Astoul
Journal: European Respiratory Journal (2008)

VATS or simple talc poudrage under medical thoracoscopy for recurrent spontaneous pneumothoraxTo the Editors:,We read with interest the paper by RENA et al. [1] published recently in the European Respiratory Journal.The authors compared two surgical techniques of pleurodesis (i.e., mechanical abrasion and apical pleurectomy).They deliberately selected patients with stage III primary spontaneous pneumothorax (PSP), according to Vanderschueren classification, and showed that mechanical pleural abrasion requiring less time to be performed was safer than apical pleurectomy.It was a well-designed randomised controlled study answering an editorial [2] encouraging more scientific evaluation of videoassisted thoracic surgery (VATS).
Antoine-Laurent de Lavoisier (1743–1794) and the birth of respiratory physiology
Authors: Marianna Karamanou, George Androutsos
Journal: Thorax (2013)

<h3>Background</h3> For more than 1500 years, the status of knowledge concerning the physiology of human respiration has remained almost unchanged. In the 18th century, the French chemist Antoine-Laurent de Lavoisier conducted breathing experiments on human and animal respiration. <h3>Methods</h3> The main bibliographic sources concerning Lavoisier9s life and work on respiration have been investigated and analysed. <h3>Results</h3> Using an ice-calorimeter, Lavoisier proved that combustion and respiration were one and the same. He also measured the oxygen consumed during respiration and concluded that the amount changes depending on human activities: exercise, eating, fasting, and sitting in a warm or cold room. Moreover, he found variations in pulse and breathing rate. <h3>Conclusions</h3> Lavoisier9s work on respiration is of great historical significance as it represents the first effort to measure human respiratory gas metabolism contributing significantly to the development of respiratory physiology.
A Multicentre Cross-Sectional Survey of Allergic Sensitisation to Subtropical and Temperate Grass Pollens
Authors: Janet M. Davies, Graham O. Solley, William B. Smith, Andrew McLean-Tooke, Sheryl A. van Nunen, Peter Kenneth Smith, Victoria L. Timbrell, John W. Upham, Daman Langguth
Journal: Journal of Allergy and Clinical Immunology (2015)
α-MSH causes a small rise in cAMP but has no effect on basal or ultraviolet-stimulated melanogenesis in human melanocytes
Authors: P.S. FRIEDMANN, F. WREN, J. BUFFEY, S. MACNEIL
Journal: British Journal of Dermatology (1990)

The effects of alpha-melanocyte stimulating hormone (alpha-MSH) were studied on levels of cyclic adenosine 3',5'-monophosphate (cAMP), melanin content and response to ultraviolet radiation (UVR) in cultured human melanocytes (HuMC). Foreskin HuMC were cultured in a hormone-supplemented system not dependent on the presence of phorbol esters. Following addition of alpha-MSH (10(-6) M) there was a rise in cAMP levels maximal between 5 and 15 min to 9.4 +/- 3.2 pM/10(5) cells, while control levels were 3.6 +/- 0.7 pM/10(5) cells. After 7 days' culture in the presence of alpha-MSH (10(-8) -10(-6) M) the melanin content increased by only 35%, whereas Forskolin (10(-5) M) induced a 9.5-fold rise in cAMP after 5 min and a 10.9-fold rise in melanin content after 7 days. When HuMC were irradiated daily for 6 days with UVR (Helarium fluorescent lamps emitting 20% UVB, 80% UVA) melanin content rose 2.7-fold (SE 0.3). This was unchanged or slightly reduced in the presence of alpha-MSH (10(-8)-10(-6) M). Parallel observations on Cloudman S91 melanoma cells showed that alpha-MSH caused only an 80% increase in melanin content after 4 days. The rise in melanin content induced by three daily UV-irradiations (2.4-fold, SE 0.5) was unchanged by alpha-MSH (10(-8)-10(-6) M). Although alpha-MSH induces a small rise in cAMP in HuMC this does not result in melanogenesis, and the response to UVR is not affected by alpha-MSH in either HuMC or S91 cells.
Methodology of bronchial responsiveness
Authors: S. Chinn
Journal: Thorax (1998)

Recommendations for the standardisation of bronchial challenge were made in 1985,1 and updated in 1993.2However, neither document recommended a single protocol or even criteria that would recommend the adoption of a particular method. Even the terminology lacks uniformity, bronchial responsiveness being used in this review in the hope that it offends the fewest number of readers. Distinction has been made, but not consistently, between (hyper)responsiveness as a general term,2(hyper)sensitivity as a leftward shift in the dose-response curve, and (hyper)reactivity as an increase in the dose-response slope.3 “Airway” and “bronchial” have been used interchangeably. The prefix “hyper” has connotations of excessive, implying a bimodal distribution in the population. Although this has not been substantiated, the acronyms BHR (bronchial hyperresponsiveness) and AHR (airway hyperresponsiveness) are well established, the former being adopted in this article.

A review of the methodology of BHR might be expected to cover all aspects of bronchial challenge, but one short article cannot provide this. Rather than reproduce recommendations which were comprehensive on most details,2 this paper emphasises variations in protocol that lead to results from different studies being non-comparable, explains how different methods of summary have arisen, and discusses the implications of these.

Whichever term for BHR is used, challenge with a pharmacological agent or with exercise in children, rather than allergen challenge, is usually implied. Subjects are assessed for eligibility, including adequate baseline lung function. Many different provocation agents have been used1; histamine and methacholine now predominate, although a number of others have recently become popular.2The aerosol generated by a nebuliser is inhaled during inspiration or tidal breathing in increasing doubling concentrations until the chosen measure of lung function has fallen by a predetermined amount from its value measured after inhalation of the diluent, the chosen …
Integrin αIIbβ3
Authors: Kamila Bledzka, Susan S. Smyth, Edward F. Plow
Journal: Circulation Research (2013)

From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.
How often do wrong models produce better phylogenies?
Authors: Z. Yang
Journal: Molecular Biology and Evolution (1997)

As phylogenetic analyses find widespread use in various fields of biology, studies on methods of phylogeny reconstruction are becoming ever more important. Although tree reconstruction has been identified as a statistical estimation problem since the pioneering work of Cavalli-Sforza and Edwards (1967), the complexity of the problem does not seem to be well recognized. In this note I report simulation results in which use of a false model in the maximum-likelihood method recovers the correct tree with higher probabilities than use of the true model. Indeed the false model on average recovers the correct tree more often than the true model, and the difference is not due to small sample sizes or restricted to the case of four taxa. The results highlight the complexity of phylogeny reconstruction and the need for more theoretical work on statistical methods for this type of estimation problem. A simulation study was carried out to examine the performance of phylogeny reconstruction by the maximum-likelihood method when either the correct evolutionary model (referred to as the True method) or a wrong model (the False method) is assumed. The correct model used for simulating data, represented as “JC+G,” uses the substitution model of Jukes and Cantor (1969) in combination with a gamma model of rate variation among sites in which the rates at different sites are multiplied by independent gamma variates normalized to have mean one (Yang 1994). The gamma parameter (x is inversely related to the extent of among-site rate variation and is fixed at (x = 0.2. Probabilities of observing all site patterns were calculated under the JC+G model, and the observed numbers of site patterns, which constitute the simulated data, were sampled from these probabilities (Yang 1996). Five sets of branch lengths for a tree of four taxa and 12 sequence lengths were used (fig. 1); for each tree and sequence length combination, 5,000 data sets were generated. Each simulated data set was analyzed by the two methods to recover the correct tree (Felsenstein 198 1; Yang 1994). Although (x could be estimated from the data under the JC+G model, the correct value (0.2) was used in the True method so that the same number of parameters was estimated in both methods. The only difference between the two methods is that True uses the correct value of CY (0.2) while False uses a false value (a). Twice the log-likelihood difference between the two models averaged from 10.0 for tree D to 27.2 for tree A in the simulation for N = 100 nucleotides and was greater for
Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content.
Authors: Penelope R Haddrill, Brian Charlesworth, Daniel L Halligan, Peter Andolfatto
Journal: Genome biology (2005)

Abstract Background Introns comprise a large fraction of eukaryotic genomes, yet little is known about their functional significance. Regulatory elements have been mapped to some introns, though these are believed to account for only a small fraction of genome wide intronic DNA. No consistent patterns have emerged from studies that have investigated general levels of evolutionary constraint in introns. Results We examine the relationship between intron length and levels of evolutionary constraint by analyzing inter-specific divergence at 225 intron fragments in Drosophila melanogaster and Drosophila simulans , sampled from a broad distribution of intron lengths. We document a strongly negative correlation between intron length and divergence. Interestingly, we also find that divergence in introns is negatively correlated with GC content. This relationship does not account for the correlation between intron length and divergence, however, and may simply reflect local variation in mutational rates or biases. Conclusion Short introns make up only a small fraction of total intronic DNA in the genome. Our finding that long introns evolve more slowly than average implies that, while the majority of introns in the Drosophila genome may experience little or no selective constraint, most intronic DNA in the genome is likely to be evolving under considerable constraint. Our results suggest that functional elements may be ubiquitous within longer introns and that these introns may have a more general role in regulating gene expression than previously appreciated. Our finding that GC content and divergence are negatively correlated in introns has important implications for the interpretation of the correlation between divergence and levels of codon bias observed in Drosophila .
Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma
Authors: M.V. Maraldo, N.P. Brodin, M.C. Aznar, I.R. Vogelius, P. Munck af Rosenschöld, P.M. Petersen, L. Specht
Journal: Annals of Oncology (2013)
The Synthetic Compound CC-5079 Is a Potent Inhibitor of Tubulin Polymerization and Tumor Necrosis Factor-α Production with Antitumor Activity
Authors: Ling-Hua Zhang, Lei Wu, Heather K. Raymon, Roger S. Chen, Laura Corral, Michael A. Shirley, Rama Krishna Narla, Jim Gamez, George W. Muller, David I. Stirling, J. Blake Bartlett, Peter H. Schafer, Faribourz Payvandi
Journal: Cancer Research (2006)

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy
Authors: Fan Lin, Mark C. de Gooijer, Eloy Moreno Roig, Levi C.M. Buil, Susan M. Christner, Jan H. Beumer, Thomas Würdinger, Jos H. Beijnen, Olaf van Tellingen
Journal: Clinical Cancer Research (2014)

Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma.We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type (WT) and Abcb1/Abcg2-deficient (KO) recipients.ABT-888/TMZ is not efficacious against p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR allografts in wild-type recipients, indicating inherent resistance. Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier (BBB) causes a 5-fold reduction of ABT-888 brain penetration (P < 0.0001) that was fully reversible by elacridar. Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/Abcg2 at the BBB and in tumor cells impair TMZ/ABT-888 combination treatment efficacy. Elacridar also markedly improved TMZ/ABT-888 combination treatment in the spontaneous p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in Pten deficient glioblastoma allografts and spontaneous tumors, even in Abcb1/Abcg2 proficient wild-type mice. Loss of PTEN occurs frequently in glioblastoma (36%) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, n = 117).The potential of ABT-888 in glioblastoma can best be demonstrated in patients with PTEN null tumors. Therefore, clinical trials with ABT-888 should evaluate these patients as a separate group. Importantly, inhibition of ABCB1 and ABCG2 (by elacridar) may improve the efficacy of TMZ/ABT-888 therapy in all glioblastoma patients.
Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study
Authors: Mark C Genovese, Roy Fleischmann, Daniel Furst, Namieta Janssen, John Carter, Bhaskar Dasgupta, Judy Bryson, Benjamin Duncan, Wei Zhu, Costantino Pitzalis, Patrick Durez, Kosmas Kretsos
Journal: Annals of the Rheumatic Diseases (2014)

The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.NCT01242488.
Reduction in Inappropriate Therapy and Mortality through ICD Programming
Authors: Arthur J. Moss, Claudio Schuger, Christopher A. Beck, Mary W. Brown, David S. Cannom, James P. Daubert, N.A. Mark Estes, Henry Greenberg, W. Jackson Hall, David T. Huang, Josef Kautzner, Helmut Klein, Scott McNitt, Brian Olshansky, Morio Shoda, David Wilber, Wojciech Zareba
Journal: New England Journal of Medicine (2012)

The implantable cardioverter–defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects.
Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity
Authors: Sandra J. Strauss, Lenushka Maharaj, Susan Hoare, Peter W. Johnson, John A. Radford, Sarah Vinnecombe, Lynda Millard, Ama Rohatiner, Anthony Boral, Elizabeth Trehu, David Schenkein, Frances Balkwill, Simon P. Joel, T. Andrew Lister
Journal: Journal of Clinical Oncology (2006)

To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.