FLAMINGOS-2: The Facility Near-Infrared Wide-field Imager & Multi-Object Spectrograph for Gemini

We report on the design and status of the FLAMINGOS-2 instrument - a fully-cryogenic facility near-infrared imager and multi-object spectrograph for the Gemini 8-meter telescopes. FLAMINGOS-2 has a refractive all-spherical optical system providing 0.18-arcsecond pixels and a 6.2-arcminute circular field-of-view on a 2048x2048-pixel HAWAII-2 0.9-2.4 mm detector array. A slit/decker wheel mechanism allows the selection of up to 9 multi-object laser-machined plates or 3 long slits for spectroscopy over a 6x2-arcminute field of view, and selectable grisms provide resolutions from $\sim$ 1300 to $\sim$3000 over the entire spectrograph bandpass. FLAMINGOS-2 is also compatible with the Gemini Multi-Conjugate Adaptive Optics system, providing multi-object spectroscopic capabilities over a 3x1-arcminute field with high spatial resolution (0.09-arcsec/pixel). We review the designs of optical, mechanical, electronics, software, and On-Instrument WaveFront Sensor subsystems. We also present the current status of the project, currently in final testing in mid-2006.Comment: Submitted to SPIE Astronomical Telescopes & Instrumentation; 12 pages, incl. color figure

A bootstrap approach for assessing the uncertainty of outcome probabilities when using a scoring system

Background: Scoring systems are a very attractive family of clinical predictive models, because the patient score can be calculated without using any data processing system. Their weakness lies in the difficulty of associating a reliable prognostic probability with each score. In this study a bootstrap approach for estimating confidence intervals of outcome probabilities is described and applied to design and optimize the performance of a scoring system for morbidity in intensive care units after heart surgery. Methods: The bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals of outcome probabilities associated with a scoring system. These confidence intervals were calculated for each score and each step of the scoring-system design by means of one thousand bootstrapped samples. 1090 consecutive adult patients who underwent coronary artery bypass graft were assigned at random to two groups of equal size, so as to define random training and testing sets with equal percentage morbidities. A collection of 78 preoperative, intraoperative and postoperative variables were considered as likely morbidity predictors. Results: Several competing scoring systems were compared on the basis of discrimination, generalization and uncertainty associated with the prognostic probabilities. The results showed that confidence intervals corresponding to different scores often overlapped, making it convenient to unite and thus reduce the score classes. After uniting two adjacent classes, a model with six score groups not only gave a satisfactory trade-off between discrimination and generalization, but also enabled patients to be allocated to classes, most of which were characterized by well separated confidence intervals of prognostic probabilities. Conclusions: Scoring systems are often designed solely on the basis of discrimination and generalization characteristics, to the detriment of prediction of a trustworthy outcome probability. The present example demonstrates that using a bootstrap method for the estimation of outcome-probability confidence intervals provides useful additional information about score-class statistics, guiding physicians towards the most convenient model for predicting morbidity outcomes in their clinical context

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis

Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 – 0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 – 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden

International audienceBackground Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. Methods To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. Results The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. Conclusions This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development

“Una opalescente claridad de celuloide”: El estridentismo y el cine

El estridentismo, movimiento de vanguardia iniciado por Manuel Maples Arce en 1921, buscó transformar no sólo la literatura, sino también la vida cotidiana, por medio de la creación de nuevos espacios culturales y nuevos acercamientos al contexto urbano. En ese proyecto, el cine jugó un papel significativo. Los estridentistas apoyaron al cine más innovador de la época, utilizaron recursos fílmicos como base de nuevas estructuras poéticas y narrativas, y privilegiaron el cine como escenario clave de una modernidad urbana emergente. Este ensayo analiza las relaciones multifacéticas entre el estridentismo y el cine, terminando con una mirada a dos películas neoestridentistas realizadas por el documentalista Jesse Lerner en 2004 y 2006.  “An Opalescent Clarity of Celluloid”: Stridentism and the CinemaStridentism, an avant-garde movement founded by Manuel Maples Arce in 1921, sought to transform not only literature, but also everyday life, through the creation of new aesthetic spaces and new approaches to the urban environment. In that project, cinema played a central role. The Stridentists expressed support for innovative filmmaking, used filmic strategies as the basis for new poetic and narrative structures, and privileged the cinema as a key scenario of an emergent urban modernity. This essay analyzes the multifaceted relations between Stridentism and the cinema, including a look at two neo-Stridentist films made by documentary filmmaker Jesse Lerner in 2004 and 2006.