6 research outputs found
Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer
Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.Pattern Recognition and Bioinformatic
Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition
In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I–IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A-, B- and C-type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A-type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C-type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A-type and B-type tumors have a more proliferative and epithelial phenotype and B-types benefit from adjuvant chemotherapy. B-type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.Intelligent SystemsElectrical Engineering, Mathematics and Computer Scienc
Search for anomaly-mediated supersymmetry breaking with the ATLAS detector based on a disappearing-track signature in pp collisions at sqrt(s) = 7TeV$
none3019G. Aad;B. Abbott;J. Abdallah;A. A. Abdelalim;A. Abdesselam;O. Abdinov;B. Abi;M. Abolins;H. Abramowicz;H. Abreu;E. Acerbi;B. S. Acharya;D. L. Adams;T. N. Addy;J. Adelman;M. Aderholz;S. Adomeit;P. Adragna;T. Adye;S. Aefsky;J. A. Aguilar-Saavedra;M. Aharrouche;S. P. Ahlen;F. Ahles;A. Ahmad;M. Ahsan;G. Aielli;T. Akdogan;T. P. A. Åkesson;G. Akimoto;A. V. Akimov;A. Akiyama;M. S. Alam;M. A. Alam;J. Albert;S. Albrand;M. Aleksa;I. N. Aleksandrov;F. Alessandria;C. Alexa;G. Alexander;G. Alexandre;T. Alexopoulos;M. Alhroob;M. Aliev;G. Alimonti;J. Alison;M. Aliyev;P. P. Allport;S. E. Allwood-Spiers;J. Almond;A. Aloisio;R. Alon;A. Alonso;B. Alvarez Gonzalez;M. G. Alviggi;K. Amako;P. Amaral;C. Amelung;V. V. Ammosov;A. Amorim;G. Amorós;N. Amram;C. Anastopoulos;L. S. Ancu;N. Andari;T. Andeen;C. F. Anders;G. Anders;K. J. Anderson;A. Andreazza;V. Andrei;M-L. Andrieux;X. S. Anduaga;A. Angerami;F. Anghinolfi;A. Anisenkov;N. Anjos;A. Annovi;A. Antonaki;M. Antonelli;A. Antonov;J. Antos;F. Anulli;S. 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Jussel;A. Juste Rozas;V. V. Kabachenko;S. Kabana;M. Kaci;A. Kaczmarska;P. Kadlecik;M. Kado;H. Kagan;M. Kagan;S. Kaiser;E. Kajomovitz;S. Kalinin;L. V. Kalinovskaya;S. Kama;N. Kanaya;M. Kaneda;T. Kanno;V. A. Kantserov;J. Kanzaki;B. Kaplan;A. Kapliy;J. Kaplon;D. Kar;M. Karagounis;M. Karagoz;M. Karnevskiy;K. Karr;V. Kartvelishvili;A. N. Karyukhin;L. Kashif;G. Kasieczka;R. D. Kass;A. Kastanas;M. Kataoka;Y. Kataoka;E. Katsoufis;J. Katzy;V. Kaushik;K. Kawagoe;T. Kawamoto;G. Kawamura;M. S. Kayl;V. A. Kazanin;M. Y. Kazarinov;J. R. Keates;R. Keeler;R. Kehoe;M. Keil;G. D. Kekelidze;J. Kennedy;C. J. Kenney;M. Kenyon;O. Kepka;N. Kerschen;B. P. Kerševan;S. Kersten;K. Kessoku;J. Keung;F. Khalil-zada;H. Khandanyan;A. Khanov;D. Kharchenko;A. Khodinov;A. G. Kholodenko;A. Khomich;T. J. Khoo;G. Khoriauli;A. Khoroshilov;N. Khovanskiy;V. Khovanskiy;E. Khramov;J. Khubua;H. Kim;M. S. Kim;P. C. Kim;S. H. Kim;N. Kimura;O. Kind;B. T. King;M. King;R. S. B. King;J. Kirk;L. E. Kirsch;A. E. Kiryunin;T. Kishimoto;D. 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Lee;S. C. Lee;L. Lee;M. Lefebvre;M. Legendre;A. Leger;B. C. LeGeyt;F. Legger;C. Leggett;M. Lehmacher;G. Lehmann Miotto;X. Lei;M. A. L. Leite;R. Leitner;D. Lellouch;M. Leltchouk;B. Lemmer;V. Lendermann;K. J. C. Leney;T. Lenz;G. Lenzen;B. Lenzi;K. Leonhardt;S. Leontsinis;C. Leroy;J-R. Lessard;J. Lesser;C. G. Lester;A. Leung Fook Cheong;J. Levêque;D. Levin;L. J. Levinson;M. S. Levitski;A. Lewis;G. H. Lewis;A. M. Leyko;M. Leyton;B. Li;H. Li;S. Li;X. Li;Z. Liang;H. Liao;B. Liberti;P. Lichard;M. Lichtnecker;K. Lie;W. Liebig;R. Lifshitz;C. Limbach;A. Limosani;M. Limper;S. C. Lin;F. Linde;J. T. Linnemann;E. Lipeles;L. Lipinsky;A. Lipniacka;T. M. Liss;D. Lissauer;A. Lister;A. M. Litke;C. Liu;D. Liu;H. Liu;J. B. Liu;M. Liu;S. Liu;Y. Liu;M. Livan;S. S. A. Livermore;A. Lleres;J. Llorente Merino;S. L. Lloyd;E. Lobodzinska;P. Loch;W. S. Lockman;T. Loddenkoetter;F. K. Loebinger;A. Loginov;C. W. Loh;T. Lohse;K. Lohwasser;M. Lokajicek;J. Loken;V. P. Lombardo;R. E. Long;L. Lopes;D. Lopez Mateos;J. 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Marchiori;M. Marcisovsky;A. Marin;C. P. Marino;F. Marroquim;R. Marshall;Z. Marshall;F. K. Martens;S. Marti-Garcia;A. J. Martin;B. Martin;B. Martin;F. F. Martin;J. P. Martin;Ph. Martin;T. A. Martin;V. J. Martin;B. Ma
Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study
Background Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications.Methods We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged >= 18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients' preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARR(adj)). This study is registered with ClinicalTrials. gov, number NCT01865513.Findings Between June 16, 2014, and April 29, 2015, data from 22 803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7.6%] of 21 694); ORadj 1.86, 95% CI 1.53-2.26; ARR(adj) -4.4%, 95% CI -5.5 to -3.2). Only 2.3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1.31, 95% CI 1.15-1.49; ARR(adj) -2.6%, 95% CI -3.9 to -1.4) and the administration of reversal agents (1.23, 1.07-1.41; -1.9%, -3.2 to -0.7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1.03, 95% CI 0.85-1 center dot 25; ARR(adj) -0.3%, 95% CI -2.4 to 1.5) nor extubation at a train-of-four ratio of 0.9 or more (1.03, 0.82-1.31; -0.4%, -3.5 to 2.2) was associated with better pulmonary outcomes.Interpretation We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications