Drug-perturbation-based stratification of blood cancer

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.Peer reviewe

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Comparative Analysis of American and Spanish Cruise Passenger's Behavioral Intentions

[EN] Earlier studies of cross-national differences in consumer behavior in different consumption sectors have verified that cultural differences have a strong influence on consumers. Despite the importance of cross-national analysis, no studies in the literature examine the moderating effects of nationality on the construction of behavioral intentions and their antecedents among cruise line passengers. This study investigates the moderating effects of nationality on the relationships between perceived value, satisfaction, trust and behavioral intentions among Spanish and (U.S.) American passengers of cruise lines that use Barcelona as home port and port-of-call. A theoretical model was tested with a total of 968 surveys. Structural equation models (SEMs) were used, by means of a multigroup analysis. Results of this study indicated that Spaniards showed stronger relationships between trust and behavioral intentions, and between emotional value and satisfaction. Americans presented stronger relations.[PT] Estudos em distintos setores de consumo verificaram que as diferenças culturais têm uma forte influência sobre os consumidores. Apesar da importância da análise transnacional, não há estudos na literatura que examinem os efeitos da nacionalidade na construção das intenções de comportamento e seus antecedentes entre os passageiros de cruzeiros. Esta pesquisa investiga os efeitos moderadores da nacionalidade nas relações entre valor percebido, satisfação, confiança e intenções de comportamento entre passageiros espanhóis e norte-americanos. Realizaram-se 968 enquetes para provar o modelo teórico, que foi analisado com modelos de equações estruturais, mediante uma análise multigrupo. Os resultados indicam que os espanhóis mostraram relações mais fortes entre confiança e intenções de comportamento, e entre valor emocional e satisfação. Ao contrário dos norte-americanos, que apresentaram relações mais fortes entre qualidade de serviço e satisfação, e entre qualidade de serviço e intenções de comportamento.[ES] Algunos estudios anteriores de diferencias observadas entre países respecto de las conductas de los consumidores de diferentes sectores de consumo verificaron que las diferencias culturales ejercen una poderosa influencia sobre los consumidores. A pesar de la importancia de los análisis transnacionales, no hay en la literatura estudios que analicen los efectos moderadores de la nacionalidad sobre la construcción de intenciones de conducta y sus antecedentes entre pasajeros de cruceros. Este estudio investiga los efectos moderadores de la nacionalidad sobre las relaciones entre el valor percibido, la satisfacción, la confianza y las intenciones de conducta entre los pasajeros españoles y norteamericanos (EE. UU.) de cruceros, que utilizan a Barcelona como puerto de origen y puerto de escala. Se probó un modelo teórico con un total de 968 encuestas. Se emplearon modelos de ecuaciones estructurales (SEM por su sigla en inglés), a través de un análisis multigrupo. Los resultados de este estudio indicaron que los españoles mostraron relaciones más sólidas entre la confianza y las intenciones de comportamiento y entre el valor emocional y la satisfacción. Los americanos evidenciaron relaciones más sólidas entre la calidad del servicio y la satisfacción y entre la calidad del servicio y las intenciones de conducta.Forgas-Coll, S.; Palau-Saumell, R.; Sanchez-Garcia, J.; Garrigós Simón, FJ. (2016). Comparative Analysis of American and Spanish Cruise Passenger's Behavioral Intentions. RAE-Revista de Administração de Empresas. 56(1):87-100. doi:10.1590/S0034-759020160108S8710056

A gravitational-wave standard siren measurement of the Hubble constant

The detection of GW170817 (ref. 1) heralds the age of gravitational-wave multi-messenger astronomy, with the observations of gravitational-wave and electromagnetic emission from the same transient source. On 17 August 2017 the network of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)2 and Virgo3 detectors observed GW170817, a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst event, GRB 170817A, was detected consistent with the LIGO–Virgo sky localization region4–6). The sky region was subsequently observed by optical astronomy facilities7, resulting in the identification of an optical transient signal within about 10 arcseconds of the galaxy NGC 4993 (refs 8–13). GW170817 can be used as a standard siren14–18, combining the distance inferred purely from the gravitational-wave signal with the recession velocity arising from the electromagnetic data to determine the Hubble constant. This quantity, representing the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Our measurements do not require any form of cosmic ‘distance ladder’19; the gravitational-wave analysis directly estimates the luminosity distance out to cosmological scales. Here we report H0 = kilometres per second per megaparsec, which is consistent with existing measurements20,21, while being completely independent of them

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p