Foreground removal from CMB temperature maps using an MLP neural network

One of the main obstacles in extracting the Cosmic Microwave Background (CMB) signal from observations in the mm-submm range is the foreground contamination by emission from galactic components: mainly synchrotron, free-free and thermal dust emission. Due to the statistical nature of the intrinsic CMB signal it is essential to minimize the systematic errors in the CMB temperature determinations. Following the available knowledge of the spectral behavior of the galactic foregrounds simple, power law-like spectra have been assumed. The feasibility of using a simple neural network for extracting the CMB temperature signal from the combined CMB and foreground signals has been investigated. As a specific example, we have analysed simulated data, like that expected from the ESA Planck Surveyor mission. A simple multilayer perceptron neural network with 2 hidden layers can provide temperature estimates, over more than 80 percent of the sky, that are to a high degree uncorrelated with the foreground signals. A single network will be able to cover the dynamic range of the Planck noise level over the entire sky.Comment: Accepted for publication in Astrophysics and Space Scienc

Low-cost inorganic cation exchange membrane for electrodialysis: optimum processing temperature for the cation exchanger

The optimum temperature for fixing zirconium phosphate, obtained by precipitation, on a low-cost ceramic support was determined in order to obtain an inorganic cation exchange membrane for electrodialysis. Zirconium phosphate ion exchange capacity maximised between 450 and 550°C, thus it was considered the optimum processing temperature. The origin of this maximum was investigated by means of X-ray diffraction and termogravimetry and evolved gas analysis. Zirconium phosphate formation by precipitation in the porous network of the support was verified by scanning electron microscopy and energy dispersive X-ray analysis and mercury intrusion porosimetry. The membrane obtained after thermal treatment at 450°C displayed selectivity to the cations present in the spent rinse water of the chromium plating process. This property allows the recovery of chromium by removing the cations through the cation exchange ceramic membrane.The authors wish to express their gratitude to the Spanish Ministry of Science and Innovation for the support given to the research study (National Basic Research Programme, Ref. CTQ2008-06750-C02-02), as well as for the FPU student grant awarded to one of the authors (Ref.: AP2009-4409).Mestre, S.; Sales, S.; Palacios, M.; Lorente, M.; Mallol, G.; Pérez-Herranz, V. (2013). Low-cost inorganic cation exchange membrane for electrodialysis: optimum processing temperature for the cation exchanger. Desalination and Water Treatment. 51(16-18):3317-3324. https://doi.org/10.1080/19443994.2012.749177S331733245116-18Strathmann, H. (2010). Electromembrane Processes: Basic Aspects and Applications. Comprehensive Membrane Science and Engineering, 391-429. doi:10.1016/b978-0-08-093250-7.00048-7Drioli, E., & Fontananova, E. (s. f.). Integrated Membrane Processes. Membrane Operations, 265-283. doi:10.1002/9783527626779.ch12Strathmann, H. (s. f.). Fundamentals in Electromembrane Separation Processes. Membrane Operations, 83-119. doi:10.1002/9783527626779.ch5Alberti, G., Casciola, M., Costantino, U., & Levi, G. (1978). Inorganic ion exchange membranes consisting of microcrystals of zirconium phosphate supported by Kynar®. Journal of Membrane Science, 3(2), 179-190. doi:10.1016/s0376-7388(00)83021-5Semiat, R., & Hasson, D. (s. f.). Seawater and Brackish-Water Desalination with Membrane Operations. Membrane Operations, 221-243. doi:10.1002/9783527626779.ch10Bregman, J. ., & Braman, R. . (1965). Inorganic ion exchange membranes. Journal of Colloid Science, 20(9), 913-922. doi:10.1016/0095-8522(65)90064-4Bishop, H. K., Bittles, J. A., & Guter, G. A. (1969). Investigation of inorganic ion exchange membranes for electrodialysis. Desalination, 6(3), 369-380. doi:10.1016/s0011-9164(00)80226-xRajan, K. S., Boies, D. B., Casolo, A. J., & Bregman, J. . (1966). Inorganic ion-exchange membranes and their application to electrodialysis. Desalination, 1(3), 231-246. doi:10.1016/s0011-9164(00)80255-6INAMUDDIN, KHAN, S., SIDDIQUI, W., & KHAN, A. (2007). Synthesis, characterization and ion-exchange properties of a new and novel ‘organic–inorganic’ hybrid cation-exchanger: Nylon-6,6, Zr(IV) phosphate. Talanta, 71(2), 841-847. doi:10.1016/j.talanta.2006.05.042HELEN, M., VISWANATHAN, B., & MURTHY, S. (2007). Synthesis and characterization of composite membranes based on α-zirconium phosphate and silicotungstic acid. Journal of Membrane Science, 292(1-2), 98-105. doi:10.1016/j.memsci.2007.01.018Yu.S. Dzyaz’ko, V.N. Belyakov, N.V. Stefanyak, S.L. Vasilyuk, Anion-exchange properties of composite ceramic membranes containing hydrated zirconium dioxide, Russ. J. Appl. Chem. 79 (2006) 769–773.Linkov, V. ., & Belyakov, V. . (2001). Novel ceramic membranes for electrodialysis. Separation and Purification Technology, 25(1-3), 57-63. doi:10.1016/s1383-5866(01)00090-9Linkov, V. M., Dzyaz’ko, Y. S., Belyakov, V. N., & Atamanyuk, V. Y. (2007). Inorganic composite membranes for electrodialytic desaltination. Russian Journal of Applied Chemistry, 80(4), 576-581. doi:10.1134/s1070427207040118El-Sourougy, M. R., Zaki, E. E., & Aly, H. F. (1997). Transport characteristics of ceramic supported zirconium phosphate membrane. Journal of Membrane Science, 126(1), 107-113. doi:10.1016/s0376-7388(96)00273-6Sánchez, E., Mestre, S., Pérez-Herranz, V., & García-Gabaldón, M. (2005). Síntesis de membranas cerámicas para la regeneración de baños de cromado agotados. Boletín de la Sociedad Española de Cerámica y Vidrio, 44(6), 409-414. doi:10.3989/cyv.2005.v44.i6.340Sánchez, E., Mestre, S., Pérez-Herranz, V., Reyes, H., & Añó, E. (2006). Membrane electrochemical reactor for continuous regeneration of spent chromium plating baths. Desalination, 200(1-3), 668-670. doi:10.1016/j.desal.2006.03.475Alberti, G., Casciola, M., Costantino, U., & Vivani, R. (1996). Layered and pillared metal(IV) phosphates and phosphonates. Advanced Materials, 8(4), 291-303. doi:10.1002/adma.19960080405Alberti, G., & Torracca, E. (1968). Crystalline insoluble salts of polybasic metals - II. Synthesis of crystalline zirconium or titanium phosphate by direct precipitation. Journal of Inorganic and Nuclear Chemistry, 30(1), 317-318. doi:10.1016/0022-1902(68)80096-xTrobajo, C., Khainakov, S. A., Espina, A., & García, J. R. (2000). On the Synthesis of α-Zirconium Phosphate. Chemistry of Materials, 12(6), 1787-1790. doi:10.1021/cm0010093Alberti, G. (1978). Syntheses, crystalline structure, and ion-exchange properties of insoluble acid salts of tetravalent metals and their salt forms. Accounts of Chemical Research, 11(4), 163-170. doi:10.1021/ar50124a007Rajeh, A. O., & szirtes, L. (1995). Investigations of crystalline structure of gamma-zirconium phosphate. Journal of Radioanalytical and Nuclear Chemistry Articles, 196(2), 319-322. doi:10.1007/bf02038050Krogh Andersen, A. M., Norby, P., Hanson, J. C., & Vogt, T. (1998). Preparation and Characterization of a New 3-Dimensional Zirconium Hydrogen Phosphate, τ-Zr(HPO4)2. Determination of the Complete Crystal Structure Combining Synchrotron X-ray Single-Crystal Diffraction and Neutron Powder Diffraction. Inorganic Chemistry, 37(5), 876-881. doi:10.1021/ic971060hFeng, Y., He, W., Zhang, X., Jia, X., & Zhao, H. (2007). The preparation of nanoparticle zirconium phosphate. Materials Letters, 61(14-15), 3258-3261. doi:10.1016/j.matlet.2006.11.132Clearfield, A. (2000). INORGANIC ION EXCHANGERS, PAST, PRESENT, AND FUTURE. Solvent Extraction and Ion Exchange, 18(4), 655-678. doi:10.1080/07366290008934702Szirtes, L., Shakshooki, S. K., Szeleczky, A. M., & Rajeh, A. O. (1998). Thermoanalyncal Investigation of Some Layered Zirconium Salts and Their Various Derivatives I. Journal of Thermal Analysis and Calorimetry, 51(2), 503-515. doi:10.1007/bf03340188Al-Othman, A., Tremblay, A. Y., Pell, W., Letaief, S., Burchell, T. J., Peppley, B. A., & Ternan, M. (2010). Zirconium phosphate as the proton conducting material in direct hydrocarbon polymer electrolyte membrane fuel cells operating above the boiling point of water. Journal of Power Sources, 195(9), 2520-2525. doi:10.1016/j.jpowsour.2009.11.052Thakkar, R., Patel, H., & Chudasama, U. (2007). A comparative study of proton transport properties of zirconium phosphate and its metal exchanged phases. Bulletin of Materials Science, 30(3), 205-209. doi:10.1007/s12034-007-0036-3Jiang, P., Pan, B., Pan, B., Zhang, W., & Zhang, Q. (2008). A comparative study on lead sorption by amorphous and crystalline zirconium phosphates. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 322(1-3), 108-112. doi:10.1016/j.colsurfa.2008.02.035García-Gabaldón, M., Pérez-Herranz, V., García-Antón, J., & Guiñón, J. L. (2009). Use of ion-exchange membranes for the removal of tin from spent activating solutions. Desalination and Water Treatment, 3(1-3), 150-156. doi:10.5004/dwt.2009.453García-Gabaldón, M., Pérez-Herranz, V., García-Antón, J., & Guiñón, J. L. (2009). Effect of hydrochloric acid on the transport properties of tin through ion-exchange membranes. Desalination and Water Treatment, 10(1-3), 73-79. doi:10.5004/dwt.2009.69

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer