Growth/differentiation factor 15 causes TGFβ activated kinase 1 dependent muscle atrophy in pulmonary arterial hypertension

Introduction Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target. Methods GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo. Results Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment. Conclusions Circulating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH

Rotary-Wing Aeroelasticity: Current Status and Future Trends

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76177/1/AIAA-9022-592.pd

The Vehicle, Fall 1984

Vol. 26, No. 1 Table of Contents Thoughts on I-57Jim Caldwellpage 3 A Night Between Lonely and BlindJennifer K. Soulepage 4 What is Unnatural is Sometimes MagicAngelique Jenningspage 4 Cutting ClosenessBecky Lawsonpage 5 PhotoBrian Ormistonpage 6 The Sensuality of Corn One Week in AugustMichelle Mitchellpage 7 American MusicJim Caldwellpage 7 Water is WaitingMichael Kuopage 8 WhereJennifer K. Soulepage 8 The Fishing HoleJan Kowalskipage 9 Miller\u27s PondSue Gradypage 9 PhotoCathy Stonerpage 11 Young Man Reading To His LoverMaggie Kennedypage 11 ShellsChristopher R. Albinpage 12 In The ShadeJohn Fehrmannpage 12 FallLynanne Feilenpage 13 IndecisionDave L. Brydenpage 13 Dark Falls SoftlyAngelique Jenningspage 14 Not a Parked \u2757 Chevy in the Summer in the CountryMichelle Mitchellpage 20 BirdAnnie Heisepage 20 Clouds Created Only For Poets And Certain WomenJennifer K. Soulepage 21 SandGraham Lewispage 22 PhotoFred Zwickypage 23 Judgment CallCathy Moepage 23 I was hip that night Dan Hintzpage 24 A Sight Of WindDan Von Holtenpage 25 Tillard Isabel M. Parrottpage 26 The WidowMaggie Kennedypage 27 The SeparationMichelle Mitchellpage 27 The Garden Hose TrialMaggie Kennedypage 28 InterruptionsJennifer K. Soulepage 28 On Happening Across Jesus While Cleaning the BasementMaggie Kennedypage 29 GileonMichelle Mitchellpage 30 If My Father Were A Writer, He Would Still BuildAngelique Jenningspage 36 A Visit to Grandpa Gib\u27s HouseTammy Veachpage 37 For Having SeenAngelique Jenningspage 38 PhotoJudy Klancicpage 39 The Earth in BlueSusan J. Bielskypage 39 Things I Could Have SaidAngelique Jenningspage 40 AcrosticsAnnie Heisepage 40https://thekeep.eiu.edu/vehicle/1044/thumbnail.jp

The Vehicle, Fall 1984

Vol. 26, No. 1 Table of Contents Thoughts on I-57Jim Caldwellpage 3 A Night Between Lonely and BlindJennifer K. Soulepage 4 What is Unnatural is Sometimes MagicAngelique Jenningspage 4 Cutting ClosenessBecky Lawsonpage 5 PhotoBrian Ormistonpage 6 The Sensuality of Corn One Week in AugustMichelle Mitchellpage 7 American MusicJim Caldwellpage 7 Water is WaitingMichael Kuopage 8 WhereJennifer K. Soulepage 8 The Fishing HoleJan Kowalskipage 9 Miller\u27s PondSue Gradypage 9 PhotoCathy Stonerpage 11 Young Man Reading To His LoverMaggie Kennedypage 11 ShellsChristopher R. Albinpage 12 In The ShadeJohn Fehrmannpage 12 FallLynanne Feilenpage 13 IndecisionDave L. Brydenpage 13 Dark Falls SoftlyAngelique Jenningspage 14 Not a Parked \u2757 Chevy in the Summer in the CountryMichelle Mitchellpage 20 BirdAnnie Heisepage 20 Clouds Created Only For Poets And Certain WomenJennifer K. Soulepage 21 SandGraham Lewispage 22 PhotoFred Zwickypage 23 Judgment CallCathy Moepage 23 I was hip that night Dan Hintzpage 24 A Sight Of WindDan Von Holtenpage 25 Tillard Isabel M. Parrottpage 26 The WidowMaggie Kennedypage 27 The SeparationMichelle Mitchellpage 27 The Garden Hose TrialMaggie Kennedypage 28 InterruptionsJennifer K. Soulepage 28 On Happening Across Jesus While Cleaning the BasementMaggie Kennedypage 29 GileonMichelle Mitchellpage 30 If My Father Were A Writer, He Would Still BuildAngelique Jenningspage 36 A Visit to Grandpa Gib\u27s HouseTammy Veachpage 37 For Having SeenAngelique Jenningspage 38 PhotoJudy Klancicpage 39 The Earth in BlueSusan J. Bielskypage 39 Things I Could Have SaidAngelique Jenningspage 40 AcrosticsAnnie Heisepage 40https://thekeep.eiu.edu/vehicle/1044/thumbnail.jp

A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

<p>Abstract</p> <p>Background</p> <p>Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials.</p> <p>Methods/Design</p> <p>The PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1), single-blind, non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express²paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to <2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control.</p> <p>Discussion</p> <p>The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at <url>http://www.clinicaltrials.gov</url>, identification numbers NCT00484315 and NCT00489541.</p

Estimating the potential survival gains by eliminating socioeconomic and sex inequalities in stage at diagnosis of melanoma.

BACKGROUND: Although inequalities in cancer survival are thought to reflect inequalities in stage at diagnosis, little evidence exists about the size of potential survival gains from eliminating inequalities in stage at diagnosis. METHODS: We used data on patients diagnosed with malignant melanoma in the East of England (2006-2010) to estimate the number of deaths that could be postponed by completely eliminating socioeconomic and sex differences in stage at diagnosis after fitting a flexible parametric excess mortality model. RESULTS: Stage was a strong predictor of survival. There were pronounced socioeconomic and sex inequalities in the proportion of patients diagnosed at stages III-IV (12 and 8% for least deprived men and women and 25 and 18% for most deprived men and women, respectively). For an annual cohort of 1025 incident cases in the East of England, eliminating sex and deprivation differences in stage at diagnosis would postpone approximately 24 deaths to beyond 5 years from diagnosis. Using appropriate weighting, the equivalent estimate for England would be around 215 deaths, representing 11% of all deaths observed within 5 years from diagnosis in this population. CONCLUSIONS: Reducing socioeconomic and sex inequalities in stage at diagnosis would result in substantial reductions in deaths within 5 years of a melanoma diagnosis.This article is an independent research supported by different funding bodies, beyond the authors’ own employing organisations. MJR was partially funded by a Cancer Research UK Postdoctoral Fellowship (CRUK_A13275). GL is supported by a Postdoctoral Fellowship award by the National Institute for Health Research (NIHR PDF-2011-04-047) to end of 2014 and a Cancer Research UK Clinician Scientist Fellowship award (A18180) from January 2015. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the National Institute for Health Research, the Department of Health, Cancer Research UK, or any other organisation. We thank all staff at the National Cancer Registration Service, Public Health England, Eastern Office, who helped collect and code data used in this study. We particularly acknowledge the help of Dr Clement H Brown and Dr Brian A Rous who were responsible for staging.This is the final published version. It first appeared at http://www.nature.com/bjc/journal/v112/n1s/full/bjc201550a.html

Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations

Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138-45