20 research outputs found

    Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

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    Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm

    Four Dimensions of Journalistic Convergence: A preliminary approach to current media trends at Spain

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    Convergence is a very polysemous concept that has been used to describe various trends in journalism that have something in common: the blurring of the limits between different media, professional skills and roles. This paper proposes to analytically structure convergence into four dimensions: integrated production, multiskilled professionals, multiplatform delivery and active audience. This analytical grid can help in exploring convergence avoiding deterministic assumptions and allowing to map its development in different media companies as an open process with diverse outcomes. A sample of 58 Spanish cases is studied using the conceptual framework. Multiplatform delivery is the most popular convergence strategy, and in any given dimension developments tend not to radically change established professional routines and values. Integration and multiskilling dimensions seem to be closely related and mainly developed in local and regional media with small staffs. Delivery and audience strategies are more complex in national media

    New insights into the genetic etiology of Alzheimer's disease and related dementias

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    Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

    Measurement of the double-differential high-mass Drell-Yan cross section in pp collisions at √s = 8 TeV with the ATLAS detector

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    This paper presents a measurement of the double-differential cross section for the Drell-Yan Z/γ∗ → ℓ+ℓ− and photon-induced γγ → ℓ+ℓ− processes where ℓ is an electron or muon. The measurement is performed for invariant masses of the lepton pairs, mℓℓ, between 116 GeV and 1500 GeV using a sample of 20.3 fb−1 of pp collisions data at centre-of-mass energy of √s = 8 TeV collected by the ATLAS detector at the LHC in 2012. The data are presented double differentially in invariant mass and absolute dilepton rapidity as well as in invariant mass and absolute pseudorapidity separation of the lepton pair. The single-differential cross section as a function of mℓℓ is also reported. The electron and muon channel measurements are combined and a total experimental precision of better than 1% is achieved at low mℓℓ. A comparison to next-to-next-to-leading order perturbative QCD predictions using several recent parton distribution functions and including next-to-leading order electroweak effects indicates the potential of the data to constrain parton distribution functions. In particular, a large impact of the data on the photon PDF is demonstrated

    Seguimiento de las guías españolas para el manejo del asma por el médico de atención primaria: un estudio observacional ambispectivo

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    Objetivo Evaluar el grado de seguimiento de las recomendaciones de las versiones de la Guía española para el manejo del asma (GEMA 2009 y 2015) y su repercusión en el control de la enfermedad. Material y métodos Estudio observacional y ambispectivo realizado entre septiembre del 2015 y abril del 2016, en el que participaron 314 médicos de atención primaria y 2.864 pacientes. Resultados Utilizando datos retrospectivos, 81 de los 314 médicos (25, 8% [IC del 95%, 21, 3 a 30, 9]) comunicaron seguir las recomendaciones de la GEMA 2009. Al inicio del estudio, 88 de los 314 médicos (28, 0% [IC del 95%, 23, 4 a 33, 2]) seguían las recomendaciones de la GEMA 2015. El tener un asma mal controlada (OR 0, 19, IC del 95%, 0, 13 a 0, 28) y presentar un asma persistente grave al inicio del estudio (OR 0, 20, IC del 95%, 0, 12 a 0, 34) se asociaron negativamente con tener un asma bien controlada al final del seguimiento. Por el contrario, el seguimiento de las recomendaciones de la GEMA 2015 se asoció de manera positiva con una mayor posibilidad de que el paciente tuviera un asma bien controlada al final del periodo de seguimiento (OR 1, 70, IC del 95%, 1, 40 a 2, 06). Conclusiones El escaso seguimiento de las guías clínicas para el manejo del asma constituye un problema común entre los médicos de atención primaria. Un seguimiento de estas guías se asocia con un control mejor del asma. Existe la necesidad de actuaciones que puedan mejorar el seguimiento por parte de los médicos de atención primaria de las guías para el manejo del asma. Objective: To assess the degree of compliance with the recommendations of the 2009 and 2015 versions of the Spanish guidelines for managing asthma (Guía Española para el Manejo del Asma [GEMA]) and the effect of this compliance on controlling the disease. Material and methods: We conducted an observational ambispective study between September 2015 and April 2016 in which 314 primary care physicians and 2864 patients participated. Results: Using retrospective data, we found that 81 of the 314 physicians (25.8%; 95% CI 21.3–30.9) stated that they complied with the GEMA2009 recommendations. At the start of the study, 88 of the 314 physicians (28.0%; 95% CI 23.4–33.2) complied with the GEMA2015 recommendations. Poorly controlled asthma (OR, 0.19; 95% CI 0.13–0.28) and persistent severe asthma at the start of the study (OR, 0.20; 95% CI 0.12–0.34) were negatively associated with having well-controlled asthma by the end of the follow-up. In contrast, compliance with the GEMA2015 recommendations was positively associated with a greater likelihood that the patient would have well-controlled asthma by the end of the follow-up (OR, 1.70; 95% CI 1.40–2.06). Conclusions: Low compliance with the clinical guidelines for managing asthma is a common problem among primary care physicians. Compliance with these guidelines is associated with better asthma control. Actions need to be taken to improve primary care physician compliance with the asthma management guidelines

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    (1,3,4-Oxadiazole)copper(II) compounds: Dimensionality, magnetism and nuclease activity

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    The work presented here describes the synthesis of new copper(II) complexes derived from 2-amino-5-(pyridin-2-yl)-1,3,4-oxadiazole (L1) and 2-methylamino-5-(pyridin-2-yl)-1,3,4-oxadiazole (L2) which also incorporate azido (N3 -), thiocyanato (NCS-), cyanato (NCO-), dicyanamido [N(CN)2 -, dca] and malonato (C3H2O4 2-, mal) coligands. Structures of the [Cu(L2)(mal)(H2O)]·2H 2O(1), [{Cu(L2)(mal)}2] (2), [Cu(L 2)2-(NCS)2] (3), [Cu(L1)(NCS) 2]n (4) and [{Cu(L2)}2(dca) 2](ClO4)2·2H2O (5) compounds show the dependence of the dimensionality on parameters such as the type of oxadiazole and coligand utilised, solvents or reaction times. In this sense, 1 and 3 are mononuclear complexes, 2 contains centrosymmetric dinuclear entities, 4 is a 1D compound in which thiocyanato groups act as end-to-end bridges and 5 shows a 2D arrangement of dinuclear motifs linked through dicyanamido spacers. The copper(II) ions acquire distorted octahedral (3 and 4), square-pyramidal (1 and 2) and trigonal bipyramidal (5) geometries. Stacking π-π interactions and hydrogen bonds stabilise the crystal frameworks. Water tetramers are present in 1. Spectroscopic (infrared, UV/Vis absorption and electron spin resonance) studies have also been developed for 1-5 and for the Cu(L2)(dca) 2(H2O) (6), Cu(L2)(NCO)2 (7) and Cu(L2)2(N3)2(H2O) 2 (8) complexes. The studies suggest the coordination of oxadiazole and coligands in all cases. Magnetic measurements show antiferromagnetic coupling for compound 5, ferromagnetic interactions for compound 2 and paramagnetic behaviour in compound 4. The susceptibility data were fitted by using the Bleaney-Bowers' equation for the copper(II) dimers derived from H = -2JS1S2. The resultant J/k values are +2.15 and -38.3 K for compounds 2 and 5, respectively. Magneto-structural correlations are discussed and extended to more than 30 published dinuclear Cu(NN) 2Cu′ diazole-only bridged compounds. All these systems show J values close to or greater than those given by the expression J ≈ -90 + 3 Δβ (where Δβ is the difference between the Cu-N-N and Cu-N′-N′ angles). The artificial nuclease activity of 1, 2, 3 and 5 in the presence of mercaptopropionic acid or glutathione has also been analysed and compared with that exhibited by [Cu(L2)2(H 2O)2](NO3)2 and CuSO4. © Wiley-VCH Verlag GmbH & Co. KGaA, 2009.We thank Dr. J. J. Delgado (SCAI, Universidad de Burgos, Spain) for the elemental analyses and Prof. R. Olazcuaga and Dr. F. Guillen (CNRS, Pessac, France) for the reflectance measurements. This work was financially supported by the Junta de Castilla y Leon (BU033A06) and Ministerio de Ciencia y Tecnologia (MCYT) [CTQ2007-63690 (ERDF(EU)-DGI-MCYT)]. P. G.-S. thanks the Universidad de Burgos for a Doctoral Fellowship.Peer Reviewe
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