First-line palliative HER2-targeted therapy in HER2-positive metastatic breast cancer is less effective after previous adjuvant trastuzumab-based therapy

Background. Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-näive patients (TN-group) in order to investigate the possibility of trastuzumab resistance. Patients and Methods. Patients treated with first-line HER2-targeted- containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves andmultivariable Cox proportional hazards models. Results. Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p5.01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p5.03) after adjustment for age, year of diagnosis, diseasefree interval, hormone receptor status, metastatic site, and cytotoxic regimens. Conclusion. First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-näive patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.</p

The optimal choice of privatizing state-owned enterprises: A political economic model

We study the choices of two types of maximizing Public Servants over how far to carry privatization of industries and in what order to privatize. Two stylizations of the Public Servant's objectives are considered, a Niskanen-style Bureaucrat who maximizes a surplus budget subject to the constraint of staying in office, and a Populist who maximizes popularity/consumer welfare subject to the constraint of a balanced budget. Other things being equal, the Bureaucrat will privatize the sector (firms) with the least market power and the largest subsidy first. The Populist will adopt the same policy, if the marginal costs of products in the private sectors are not too high with respect to the marginal utilities. If the marginal costs are too high, however, the Populist will privatize the sector with the largest market power first. We also show that privatization is easier and faster in less democratic societies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45520/1/11127_2004_Article_BF00136520.pd

Interactieve ontwerpmethodieken voor integrale duurzaamheid Toepassing van RIO in een aantal niet-veehouderij-gebonden cases

RIO (Reflexief Interactief Ontwerpen) bestaat uit drie hoofdonderdelen: de (systeem)analysefase, de ontwerpfase en de verankeringsfase. RIO is ontstaan in een veehouderijcontext. Die context heeft een aantal specifieke eigenschappen, die toepassing van RIO in andere sectoren niet volledig vanzelfsprekend maakt. In een drietal projecten in de tuinbouw en biobased research is onderzocht in hoeverre (onderdelen van) RIO toepasbaar zijn in deze contexten. Gemeenschappelijk kenmerk van de cases die daarbij aan de orde waren was dat een technologisch kernidee het startpunt voor het ontwerpproces vormde, met een min of meer impliciete maatschappelijke problematiek die daarachter werd voorondersteld. De drie cases zijn: grasraffinage, Teelt de Grond Uit: bloembollen en appel, Teelt de grond uit: vinicultuur en aquaponics

Nutrición infantil y salud ósea

Producción CientíficaMantener un adecuado estado nutricional en todas las etapas de la vida es decisivo para lograr un metabolismo óseo que favorezca la salud. La osteoporosis se caracteriza por una alteración en la cantidad y calidad de la mineralización ósea, lo que origina una fragilidad del esqueleto con riesgo aumentado de fracturas, especialmente vertebrales y de cadera. Es un problema público a nivel mundial, que afecta a una proporción elevada de hombres y mujeres, y que se desarrolla de forma asintomática hasta que se manifiesta de forma imprevista y causa una fractura del esqueleto. Estudios en niños han demostrado que el desarrollo de osteoporosis en la edad adulta puede verse condicionada por el estado nutricional durante la infancia, especialmente en lo referente a los aportes de calcio y vitamina D. No obstante, existen aún muchas cuestiones abiertas, tanto en lo referente a su patogenia y diagnóstico como a su tratamiento; algunas de éstas se revisan en este trabajo

Differences in Trial and Real-world Populations in the Dutch Castration-resistant Prostate Cancer Registry

__Background:__ Trials in castration-resistant prostate cancer (CRPC) treatment have shown improved outcomes, including survival. However, as trial populations are selected, results may not be representative for the real-world population. The aim of this study was to assess the differences between patients treated in a clinical trial versus standard care during the course of CRPC in a real-world CRPC population. __Design, setting, and participants:__ Castration-resistant Prostate Cancer Registry is a population-based, observational, retrospective registry. CRPC patients from 20 hospitals in the Netherlands have been included from 2010 to 2013. __Outcome measurements and statistical analysis:__ Baseline characteristics, systemic treatment, and overall survival were the main outcomes. Descriptive statistics, multivariate Cox regression, and multiple imputations with the Monte Carlo Markov Chain method were used. __Results and limitations:__ In total, 1524 patients were enrolled of which 203 patients had participated in trials at any time. The median follow-up period was 23 mo. Patients in the trial group were significantly younger and had less comorbidities. Docetaxel treatment was more freque

Multifaceted Activities of Seven Nanobodies against Complement C4b

Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama (Lama glama) immunization, that bind to human C4b (Homo sapiens) with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined singleparticle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications

Measurement of the p-pbar -> Wgamma + X cross section at sqrt(s) = 1.96 TeV and WWgamma anomalous coupling limits

The WWgamma triple gauge boson coupling parameters are studied using p-pbar -> l nu gamma + X (l = e,mu) events at sqrt(s) = 1.96 TeV. The data were collected with the DO detector from an integrated luminosity of 162 pb^{-1} delivered by the Fermilab Tevatron Collider. The cross section times branching fraction for p-pbar -> W(gamma) + X -> l nu gamma + X with E_T^{gamma} > 8 GeV and Delta R_{l gamma} > 0.7 is 14.8 +/- 1.6 (stat) +/- 1.0 (syst) +/- 1.0 (lum) pb. The one-dimensional 95% confidence level limits on anomalous couplings are -0.88 < Delta kappa_{gamma} < 0.96 and -0.20 < lambda_{gamma} < 0.20.Comment: Submitted to Phys. Rev. D Rapid Communication

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s} = 1.96 TeV using Kinematic Characteristics of Lepton + Jets Events

We present a measurement of the top quark pair ttbar production cross section in ppbar collisions at a center-of-mass energy of 1.96 TeV using 230 pb**{-1} of data collected by the DO detector at the Fermilab Tevatron Collider. We select events with one charged lepton (electron or muon), large missing transverse energy, and at least four jets, and extract the ttbar content of the sample based on the kinematic characteristics of the events. For a top quark mass of 175 GeV, we measure sigma(ttbar) = 6.7 {+1.4-1.3} (stat) {+1.6- 1.1} (syst) +/-0.4 (lumi) pb, in good agreement with the standard model prediction.Comment: submitted to Phys.Rev.Let