Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer

Constraining forest certificate's market to improve cost-effectiveness of biodiversity conservation in Sao Paulo state, Brazil

The recently launched Brazilian "forest certificates" market is expected to reduce environmental compliance costs for landowners through an offset mechanism, after a long history of conservation laws based in command-and-control and strict rules. In this paper we assessed potential costs and evaluated the cost-effectiveness of the instrument when introducing to this market constraints that aim to address conservation objectives more specifically. Using the conservation planning software Marxan with Zones we simulated different scopes for the "forest certificates" market, and compared their cost-effectiveness with that of existing command-and-control (C&C), i.e. compliance to the Legal Reserve on own property, in the state of Sao Paulo. The simulations showed a clear potential of the constrained "forest certificates" market to improve conservation effectiveness and increase cost-effectiveness on allocation of Legal Reserves. Although the inclusion of an additional constraint of targeting the BIOTA Conservation Priority Areas doubled the cost (+95%) compared with a "free trade" scenario constrained only by biome, this option was still 50% less costly than the Baseline scenario of compliance with Legal Reserve at the property.The recently launched Brazilian "forest certificates" market is expected to reduce environmental compliance costs for landowners through an offset mechanism, after a long history of conservation laws based in command-and-control and strict rules. In this1110118sem informaçãosem informaçã

Field Scanner Design for MUSTANG of the Green Bank Telescope

MUSTANG is a bolometer camera for the Green Bank Telescope (GBT) working at a frequency of 90 GHz. The detector has a field of view of 40 arcseconds. To cancel out random emission change from atmosphere and other sources, requires a fast scanning reflecting system with a few arcminute ranges. In this paper, the aberrations of an off-axis system are reviewed. The condition for an optimized system is provided. In an optimized system, as additional image transfer mirrors are introduced, new aberrations of the off-axis system may be reintroduced, resulting in a limited field of view. In this paper, different scanning mirror arrangements for the GBT system are analyzed through the ray tracing analysis. These include using the subreflector as the scanning mirror, chopping a flat mirror and transferring image with an ellipse mirror, and chopping a flat mirror and transferring image with a pair of face-to-face paraboloid mirrors. The system analysis shows that chopping a flat mirror and using a well aligned pair of paraboloids can generate the required field of view for the MUSTUNG detector system, while other systems all suffer from larger off-axis aberrations added by the system modification. The spot diagrams of the well aligned pair of paraboloids produced is only about one Airy disk size within a scanning angle of about 3 arcmin.Comment: 7 pages, 9 figure

An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers

Finding the best clearing approach: Towards 3D wide-scale multimodal imaging of aged human brain tissue

The accessibility of new wide-scale multimodal imaging techniques led to numerous clearing techniques emerging over the last decade. However, clearing mesoscopic-sized blocks of aged human brain tissue remains an extremely challenging task. Homogenizing refractive indices and reducing light absorption and scattering are the foundation of tissue clearing. Due to its dense and highly myelinated nature, especially in white matter, the human brain poses particular challenges to clearing techniques. Here, we present a comparative study of seven tissue clearing approaches and their impact on aged human brain tissue blocks (> 5 mm). The goal was to identify the most practical and efficient method in regards to macroscopic transparency, brief clearing time, compatibility with immunohistochemical processing and wide-scale multimodal microscopic imaging. We successfully cleared 26 × 26 × 5 mm3-sized human brain samples with two hydrophilic and two hydrophobic clearing techniques. Optical properties as well as light and antibody penetration depths highly vary between these methods. In addition to finding the best clearing approach, we compared three microscopic imaging setups (the Zeiss Laser Scanning Microscope (LSM) 880 , the Miltenyi Biotec Ultramicroscope ll (UM ll) and the 3i Marianas LightSheet microscope) regarding optimal imaging of large-scale tissue samples. We demonstrate that combining the CLARITY technique (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel) with the Zeiss LSM 880 and combining the iDISCO technique (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) with the Miltenyi Biotec UM ll are the most practical and efficient approaches to sufficiently clear aged human brain tissue and generate 3D microscopic images. Our results point out challenges that arise from seven clearing and three imaging techniques applied to non-standardized tissue samples such as aged human brain tissue

embCAB Sequence Variation Among Ethambutol-Resistant Mycobacterium Tuberculosis Isolates Without embB306 Mutation

Mechanisms of resistance to ethambutol in Mycobacterium tuberculosis remain inadequately described. Although there is mounting evidence that mutations of codon 306 in embB play a key role, a significant number of phenotypically ethambutol-resistant strains do not carry mutations in this codon. Here, other mutations in the embCAB operon are suggested to be involved in resistance development

Temperature Dependence of Damping and Frequency Shifts of the Scissors Mode of a trapped Bose-Einstein Condensate

We have studied the properties of the scissors mode of a trapped Bose-Einstein condensate of $^{87}$Rb atoms at finite temperature. We measured a significant shift in the frequency of the mode below the hydrodynamic limit and a strong dependence of the damping rate as the temperature increased. We compared our damping rate results to recent theoretical calculations for other observed collective modes finding a fair agreement. From the frequency measurements we deduce the moment of inertia of the gas and show that it is quenched below the transition point, because of the superfluid nature of the condensed gas.Comment: 5 pages, 4 figure

Assessing ecosystem services from multifunctional trees in pastures using Bayesian belief networks

A Bayesian belief network (BBN) was developed to assess preferred combinations of trees in live fences and on pastures in silvopastoral systems. The BBN was created with information from Rivas, Nicaragua, using local farmer knowledge on tree species, trees' costs and benefits, farmers' expressed needs and aspirations, and scientific knowledge regarding tree functional traits and their contribution to ecosystem services and benefits. The model identifies combinations of trees, which provide multiple ecosystem services from pastures, improving their productivity and contribution to farmer livelihoods. We demonstrate how the identification of portfolios of multifunctional trees can satisfy a profile of desired ecosystem services prioritized by the farmer. Diagnostics using Bayesian inference starts with an identification of farmer needs and ‘works backwards’ to identify a silvopastoral system structure. We conclude that Bayesian belief networks are a promising modeling technique for multi-criteria decisions in farm adaptation processes, where interventions must be adapted to specific contexts and farmer preferences