A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence. METHODS AND FINDINGS: In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK). CONCLUSIONS: Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions

The CHEOPS mission

The CHaracterising ExOPlanet Satellite (CHEOPS) was selected in 2012, as the first small mission in the ESA Science Programme and successfully launched in December 2019. CHEOPS is a partnership between ESA and Switzerland with important contributions by ten additional ESA Member States. CHEOPS is the first mission dedicated to search for transits of exoplanets using ultrahigh precision photometry on bright stars already known to host planets. As a follow-up mission, CHEOPS is mainly dedicated to improving, whenever possible, existing radii measurements or provide first accurate measurements for a subset of those planets for which the mass has already been estimated from ground-based spectroscopic surveys and to following phase curves. CHEOPS will provide prime targets for future spectroscopic atmospheric characterisation. Requirements on the photometric precision and stability have been derived for stars with magnitudes ranging from 6 to 12 in the V band. In particular, CHEOPS shall be able to detect Earth-size planets transiting G5 dwarf stars in the magnitude range between 6 and 9 by achieving a photometric precision of 20 ppm in 6 hours of integration. For K stars in the magnitude range between 9 and 12, CHEOPS shall be able to detect transiting Neptune-size planets achieving a photometric precision of 85 ppm in 3 hours of integration. This is achieved by using a single, frame-transfer, back-illuminated CCD detector at the focal plane assembly of a 33.5 cm diameter telescope. The 280 kg spacecraft has a pointing accuracy of about 1 arcsec rms and orbits on a sun-synchronous dusk-dawn orbit at 700 km altitude. The nominal mission lifetime is 3.5 years. During this period, 20% of the observing time is available to the community through a yearly call and a discretionary time programme managed by ESA.Comment: Submitted to Experimental Astronom

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Comparison of the Prediction Accuracy of Lung Cancer Survival Using Our 64-Gene Signature and a Different 50-Gene Signature

<div><p>(A and B) Kaplan-Meier survival curves for dataset 6 under our 64-gene signature (A) and the 50-gene signature from Beer et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030467#pmed-0030467-b005" target="_blank">5</a>] (B). Scores were estimated using two principle components.</p> <p>(C and D) Kaplan-Meier survival curves for dataset 7 using our 64-gene signature (C) and the 50-gene signature from Beer et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030467#pmed-0030467-b005" target="_blank">5</a>] (D). Scores were estimated using eight principle components.</p></div

Gene Expression Patterns of 64 Top Survival Genes for 197 NSCLC Patients from Datasets 1 to 5

<p>Patients were generally classified into two groups (short-term versus long-term survival) with distinct expression patterns. The first column on the left represents patient status: 0, alive; 1, dead; the second column on the left represents follow-up time (days).</p

Validation Analyses of Gene Expression Profiling

<div><p>(A) QRT-PCR validations of several candidate survival-related genes. Bars represent fold changes for the selected genes with differential expression between long- (>5 y) and short-term survival (<2 y) patients. Positive fold change represents up-regulated, and negative fold change represents down-regulated in short-term survival patients. * <i>p</i> ≤ 0.05; ** <i>p</i> ≤ 0.01; *** <i>p</i> ≤ 0.005.</p> <p>(B and C) Immunostaining analysis of CRABP1 and ABCC1 expression in long- and short- term survival lung cancer patients. Low magnification (B) and 40× (C). Positive CRABP1 immunoreactivity was observed in cytoplasm of an acinar ADC (lower left photomicrographs of B and C) from short-term survival patients, and no CRABP1 reactivity was seen in a lung ADC from a long-term survival patient (upper left). Strong ABCC1 membranous staining (lower right) in tumor cells from short-term survival patients was observed, and weak ABCC1 reactivity was seen in a lung ADC from a long-term survival patient (upper right).</p> <p>(D) Distribution of CRABP1 and ABCC1 protein levels in short- and long-term survival patients.</p></div

Survival Analyses of Stage I NSCLC

<div><p>(A) Kaplan-Meier survival curves for patients with stage IA and with IB NSCLC.</p> <p>(B) Kaplan-Meier survival curves for stage IA and IB patients defined by having positive (high-risk) or negative (low-risk) risk scores of overall survival. The risk scores were estimated with seven principle components based on the model built by 64 survival-related genes identified in five datasets.</p> <p>(C) Area under the ROC curve for survival models based on stage information or expression data, respectively.</p></div

The structural basis of cephalosporin formation in a mononuclear ferrous enzyme

Deacetoxycephalosporin-C synthase (DAOCS) is a mononuclear ferrous enzyme that transforms penicillins into cephalosporins by inserting a carbon atom into the penicillin nucleus. In the first half-reaction, dioxygen and 2-oxoglutarate produce a reactive iron-oxygen species, succinate and CO2. The oxidizing iron species subsequently reacts with penicillin to give cephalosporin and water. Here we describe high-resolution structures for ferrous DAOCS in complex with penicillins, the cephalosporin product, the cosubstrate and the coproduct. Steady-state kinetic data, quantum-chemical calculations and the new structures indicate a reaction sequence in which a ‘booby-trapped’ oxidizing species is formed. This species is stabilized by the negative charge of succinate on the iron. The binding sites of succinate and penicillin overlap, and when penicillin replaces succinate, it removes the stabilizing charge, eliciting oxidative attack on itself. Requisite groups of penicillin are within 1 Å of the expected position of a ferryl oxygen in the enzyme–penicillin complex.