Pre-operative chemotherapy in early stage resectable non-small-cell lung cancer: a randomized feasibility study justifying a multicentre phase III trial

Surgical resection offers the best chance for cure for early stage non-small-cell lung cancer (NSCLC, stage I, II, IIIA), but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage (IB, II, IIIA) resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m−2, vinblastine 6 mg m−2 and cisplatin 50 mg m−2 (MVP)] followed by surgery (n = 11), or to surgery alone. Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III–IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial. © 1999 Cancer Research Campaig

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family

<p>Abstract</p> <p>Background</p> <p>The androgen insensitivity syndrome may cause developmental failure of normal male external genitalia in individuals with 46,XY karyotype. It results from the diminished or absent biological action of androgens, which is mediated by the androgen receptor in both embryo and secondary sex development. Mutations in the androgen receptor gene, located on the X chromosome, are responsible for the disease. Almost 70% of 46,XY affected individuals inherited mutations from their carrier mothers.</p> <p>Findings</p> <p>Molecular abnormalities in the androgen receptor gene in individuals of a Brazilian family with clinical features of severe forms of partial androgen insensitivity syndrome were evaluated. Seven members (five 46,XY females and two healthy mothers) of the family were included in the investigation. The coding exons and exon-intron junctions of androgen receptor gene were sequenced. Five 46,XY members of the family have been found to be hemizygous for the c.3015C>T nucleotide change in exon 7 of the androgen receptor gene, whereas the two 46,XX mothers were heterozygote carriers. This nucleotide substitution leads to the p.L830F mutation in the androgen receptor.</p> <p>Conclusions</p> <p>The novel p.L830F mutation is responsible for grades 5 and 6 of partial androgen insensitivity syndrome in two generations of a Brazilian family.</p

Hot gas flows on global and nuclear galactic scales

Since its discovery as an X-ray source with the Einstein Observatory, the hot X-ray emitting interstellar medium of early-type galaxies has been studied intensively, with observations of improving quality, and with extensive modeling by means of numerical simulations. The main features of the hot gas evolution are outlined here, focussing on the mass and energy input rates, the relationship between the hot gas flow and the main properties characterizing its host galaxy, the flow behavior on the nuclear and global galactic scales, and the sensitivity of the flow to the shape of the stellar mass distribution and the mean rotation velocity of the stars.Comment: 22 pages. Abbreviated version of chapter 2 of the book "Hot Interstellar Matter in Elliptical Galaxies", Springer 201

Proactive and integrated primary care for frail older people: design and methodological challenges of the Utrecht primary care PROactive frailty intervention trial (U-PROFIT)

<p>Abstract</p> <p>Background</p> <p>Currently, primary care for frail older people is reactive, time consuming and does not meet patients' needs. A transition is needed towards proactive and integrated care, so that daily functioning and a good quality of life can be preserved. To work towards these goals, two interventions were developed to enhance the care of frail older patients in general practice: a screening and monitoring intervention using routine healthcare data (U-PRIM) and a nurse-led multidisciplinary intervention program (U-CARE). The U-PROFIT trial was designed to evaluate the effectiveness of these interventions. The aim of this paper is to describe the U-PROFIT trial design and to discuss methodological issues and challenges.</p> <p>Methods/Design</p> <p>The effectiveness of U-PRIM and U-CARE is being tested in a three-armed, cluster randomized trial in 58 general practices in the Netherlands, with approximately 5000 elderly individuals expected to participate. The primary outcome is the effect on activities of daily living as measured with the Katz ADL index. Secondary outcomes are quality of life, mortality, nursing home admission, emergency department and out-of-hours General Practice (GP), surgery visits, and caregiver burden.</p> <p>Discussion</p> <p>In a large, pragmatic trial conducted in daily clinical practice with frail older patients, several challenges and methodological issues will occur. Recruitment and retention of patients and feasibility of the interventions are important issues. To enable broad generalizability of results, careful choices of the design and outcome measures are required. Taking this into account, the U-PROFIT trial aims to provide robust evidence for a structured and integrated approach to provide care for frail older people in primary care.</p> <p>Trial registration</p> <p><a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2288">NTR2288</a></p

How to evaluate the risk/benefit of trimodality therapy in locally advanced non-small-cell lung cancer

The trimodality approach represented by concurrent chemoradiotherapy followed by surgical resection is a highly effective, but potentially toxic therapy for locally advanced non-small-cell lung cancer (NSCLC). In this review, we discuss the current status of this therapy in patients with mediastinal node-positive (N2) stage III NSCLC or superior sulcus tumor, and present an overview of the principles for optimisation of the risk/benefit. Numerous clinical questions remain, and enrolment of patients into well-designed clinical trials should be encouraged

Treating frailty-a practical guide

Frailty is a common syndrome that is associated with vulnerability to poor health outcomes. Frail older people have increased risk of morbidity, institutionalization and death, resulting in burden to individuals, their families, health care services and society. Assessment and treatment of the frail individual provide many challenges to clinicians working with older people. Despite frailty being increasingly recognized in the literature, there is a paucity of direct evidence to guide interventions to reduce frailty. In this paper we review methods for identification of frailty in the clinical setting, propose a model for assessment of the frail older person and summarize the current best evidence for treating the frail older person. We provide an evidence-based framework that can be used to guide the diagnosis, assessment and treatment of frail older people

The Toll→NFκB Signaling Pathway Mediates the Neuropathological Effects of the Human Alzheimer's Aβ42 Polypeptide in Drosophila

Alzheimer's (AD) is a progressive neurodegenerative disease that afflicts a significant fraction of older individuals. Although a proteolytic product of the Amyloid precursor protein, the Αβ42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of Αβ42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated Αβ42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human Αβ42 polypeptide induces cell death and tissue degeneration in the compound eye. One of the genes identified in our genetic screen is Toll (Tl). It encodes the receptor for the highly conserved Tl→NFkB innate immunity/inflammatory pathway and is a fly homolog of the mammalian Interleukin-1 (Ilk-1) receptor. We found that Tl loss-of-function mutations dominantly suppress the neuropathological effects of the Αβ42 polypeptide while gain-of-function mutations that increase receptor activity dominantly enhance them. Furthermore, we present evidence demonstrating that Tl and key downstream components of the innate immunity/inflammatory pathway play a central role in mediating the neuropathological activities of Αβ42. We show that the deleterious effects of Αβ42 can be suppressed by genetic manipulations of the Tl→NFkB pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of Aβ42. Since postmortem studies have shown that the Ilk-1→NFkB innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl→NFkB signaling actively promotes the process of Αβ42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies