Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study.

BACKGROUND: Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting. METHODS: Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data. RESULTS: Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1-9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1-19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20-31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25-4.3) and 11.2 (95 %CI: 9.3-12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3-4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia. CONCLUSION: EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors

ALMA-IMF IX: Catalog and Physical Properties of 315 SiO Outflow Candidates in 15 Massive Protoclusters

We present a catalog of 315 protostellar outflow candidates detected in SiO J=5-4 in the ALMA-IMF Large Program, observed with ~2000 au spatial resolution, 0.339 km/s velocity resolution, and 2-12 mJy/beam (0.18-0.8 K) sensitivity. We find median outflow masses, momenta, and kinetic energies of ~0.3 M$_{\odot}$, 4 M$_{\odot}$ km/s, and 10$^{45}$ erg, respectively. Median outflow lifetimes are 6,000 years, yielding median mass, momentum, and energy rates of $\dot{M}$ = 10$^{-4.4}$ M$_{\odot}$ yr$^{-1}$, $\dot{P}$ = 10$^{-3.2}$ M$_{\odot}$ km/s yr$^{-1}$, and $\dot{E}$ = 1 L$_{\odot}$. We analyze these outflow properties in the aggregate in each field. We find correlations between field-aggregated SiO outflow properties and total mass in cores (~3$-$5$\sigma$), and no correlations above 3$\sigma$ with clump mass, clump luminosity, or clump luminosity-to-mass ratio. We perform a linear regression analysis and find that the correlation between field-aggregated outflow mass and total clump mass - which has been previously described in the literature - may actually be mediated by the relationship between outflow mass and total mass in cores. We also find that the most massive SiO outflow in each field is typically responsible for only 15-30% of the total outflow mass (60% upper limit). Our data agree well with the established mechanical force-bolometric luminosity relationship in the literature, and our data extend this relationship up to L $\geq$ 10$^6$ L$_{\odot}$ and $\dot{P}$ $\geq$ 1 M$_{\odot}$ km/s yr$^{-1}$. Our lack of correlation with clump L/M is inconsistent with models of protocluster formation in which all protostars start forming at the same time.Comment: 46 pages, 14 figures, 10 tables. This publication has an associated Zenodo entry, which can be found here: https://zenodo.org/records/835059

ALMA-IMF VIII -- Combination of Interferometric Continuum Images with Single-Dish Surveys and Structural Analysis of Six Protoclusters

We present the combination of ALMA-IMF and single-dish continuum images from the Mustang-2 Galactic Plane Survey (MGPS90) at 3 millimeters and the Bolocam Galactic Plane Survey (BGPS) at 1 millimeter. Six and ten out of the fiffteen ALMA-IMF fields are combined with MGPS90 and BGPS, respectively. The combination is made via the feathering technique. We used the dendrogram algorithm throughout the combined images, and performed further analysis in the six fields with combination in both bands (G012.80, W43-MM1, W43-MM2, W43-MM3, W51-E, W51-IRS2). In these fields, we calculated spectral index maps and used them to separate regions dominated by dust or free-free emission, and then performed further structural analysis. We report the basic physical parameters of the dust-dominated (column densities, masses) and ionized (emission measures, hydrogen ionization photon rates) structures. We also searched for multi-scale relations in the dust-dominated structures across the analyzed fields, finding that the fraction of mass in dendrogram leaves (which we label as "Leaf Mass Eficiency", LME) as a function of molecular gas column density follows a similar trend: a rapid, exponential-like growth, with maximum values approaching 100% in most cases. The observed behaviour of the LME with gas column is tentatively interpreted as an indicator of large star formation activity within the ALMA-IMF protoclusters. W51-E and G012.80 stand out as cases with comparatively large and reduced potential for further star formation, respectively.Comment: Accepted to The Astrophysical Journal Supplemen

Effects of a carbohydrate-restricted diet on emerging plasma markers for cardiovascular disease

BACKGROUND: Increasing evidence supports carbohydrate restricted diets (CRD) for weight loss and improvement in traditional markers for cardiovascular disease (CVD); less is known regarding emerging CVD risk factors. We previously reported that a weight loss intervention based on a CRD (% carbohydrate:fat:protein = 13:60:27) led to a mean weight loss of 7.5 kg and a 20% reduction of abdominal fat in 29 overweight men. This group showed reduction in plasma LDL-cholesterol and triglycerides and elevations in HDL-cholesterol as well as reductions in large and medium VLDL particles and increases in LDL particle size. In this study we report on the effect of this intervention with and without fiber supplementation on plasma homocysteine, lipoprotein (a) [Lp(a)], C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). METHODS: Twenty nine overweight men [body mass index (BMI) 25–35 kg/m(2)] aged 20–69 years consumed an ad libitum CRD (% carbohydrate:fat:protein = 13:60:27) including a standard multivitamin every other day for 12 wk. Subjects were matched by age and BMI and randomly assigned to consume 3 g/d of either a soluble fiber supplement (n = 14) or placebo (n = 15). RESULTS: There were no group or interaction (fiber × time) main effects, but significant time effects were observed for several variables. Energy intake was spontaneously reduced (-30.5%). This was accompanied by an increase in protein intake (96.2 ± 29.8 g/d to 107.3 ± 29.7 g/d) and methionine intake (2.25 ± 0.7 g/d, to 2.71 ± 0.78 g/d; P < 0.001). Trans fatty acid intake was significantly reduced (-38.6%) while dietary folate was unchanged, as was plasma homocysteine. Bodyweight (-7.5 ± 2.5 kg) was reduced as was plasma Lp(a) (-11.3%). Changes in plasma Lp(a) correlated with reductions in LDL-cholesterol (r = .436, P < 0.05) and fat loss (r = .385, P < 0,05). At wk 12, both CRP (-8.1%) and TNF-α (-9.3%) were reduced (P < 0.05) independently of weight loss. IL-6 concentrations were unchanged. CONCLUSION: A diet based on restricting carbohydrates leads to spontaneous caloric reduction and subsequent improvement in emerging markers of CVD in overweight/obese men who are otherwise healthy

A TRENCH ISOLATED HIGH SPEED BIPOLAR PROCESS FOR A 10K GATE, 950MHz, VLSI CIRCUIT

Une technologie bipolaire rapide, de dimension critique micronique, utilisant l'isolement par sillons et un émetteur en polysilicium a été évaluée et caractérisée. Une démonstration du rendement de la technologie a été réalisée sur un circuit VLSI de 10000 portes.A one micron bipolar process using trench isolation and polysilicon emitter has been evaluated and characterised. The demonstration of yield was achieved on a 10000 gate VLSI circuit

ALMA-IMF IX: Catalog and Physical Properties of 315 SiO Outflow Candidates in 15 Massive Protoclusters

We present a catalog of 315 protostellar outflow candidates detected in SiO J=5-4 in the ALMA-IMF Large Program, observed with ~2000 au spatial resolution, 0.339 km/s velocity resolution, and 2-12 mJy/beam (0.18-0.8 K) sensitivity. We find median outflow masses, momenta, and kinetic energies of ~0.3 M$_{\odot}$, 4 M$_{\odot}$ km/s, and 10$^{45}$ erg, respectively. Median outflow lifetimes are 6,000 years, yielding median mass, momentum, and energy rates of $\dot{M}$ = 10$^{-4.4}$ M$_{\odot}$ yr$^{-1}$, $\dot{P}$ = 10$^{-3.2}$ M$_{\odot}$ km/s yr$^{-1}$, and $\dot{E}$ = 1 L$_{\odot}$. We analyze these outflow properties in the aggregate in each field. We find correlations between field-aggregated SiO outflow properties and total mass in cores (~3$-$5$σ$), and no correlations above 3$σ$ with clump mass, clump luminosity, or clump luminosity-to-mass ratio. We perform a linear regression analysis and find that the correlation between field-aggregated outflow mass and total clump mass - which has been previously described in the literature - may actually be mediated by the relationship between outflow mass and total mass in cores. We also find that the most massive SiO outflow in each field is typically responsible for only 15-30% of the total outflow mass (60% upper limit). Our data agree well with the established mechanical force-bolometric luminosity relationship in the literature, and our data extend this relationship up to L $\geq$ 10$^6$ L$_{\odot}$ and $\dot{P}$ $\geq$ 1 M$_{\odot}$ km/s yr$^{-1}$. Our lack of correlation with clump L/M is inconsistent with models of protocluster formation in which all protostars start forming at the same time

ALMA-IMF IX: Catalog and Physical Properties of 315 SiO Outflow Candidates in 15 Massive Protoclusters

We present a catalog of 315 protostellar outflow candidates detected in SiO J=5-4 in the ALMA-IMF Large Program, observed with ~2000 au spatial resolution, 0.339 km/s velocity resolution, and 2-12 mJy/beam (0.18-0.8 K) sensitivity. We find median outflow masses, momenta, and kinetic energies of ~0.3 M$_{\odot}$, 4 M$_{\odot}$ km/s, and 10$^{45}$ erg, respectively. Median outflow lifetimes are 6,000 years, yielding median mass, momentum, and energy rates of $\dot{M}$ = 10$^{-4.4}$ M$_{\odot}$ yr$^{-1}$, $\dot{P}$ = 10$^{-3.2}$ M$_{\odot}$ km/s yr$^{-1}$, and $\dot{E}$ = 1 L$_{\odot}$. We analyze these outflow properties in the aggregate in each field. We find correlations between field-aggregated SiO outflow properties and total mass in cores (~3$-$5$σ$), and no correlations above 3$σ$ with clump mass, clump luminosity, or clump luminosity-to-mass ratio. We perform a linear regression analysis and find that the correlation between field-aggregated outflow mass and total clump mass - which has been previously described in the literature - may actually be mediated by the relationship between outflow mass and total mass in cores. We also find that the most massive SiO outflow in each field is typically responsible for only 15-30% of the total outflow mass (60% upper limit). Our data agree well with the established mechanical force-bolometric luminosity relationship in the literature, and our data extend this relationship up to L $\geq$ 10$^6$ L$_{\odot}$ and $\dot{P}$ $\geq$ 1 M$_{\odot}$ km/s yr$^{-1}$. Our lack of correlation with clump L/M is inconsistent with models of protocluster formation in which all protostars start forming at the same time

ALMA-IMF. VI : investigating the origin of stellar masses: Core mass function evolution in the W43-MM2&MM3 mini-starburst

Context. Among the most central open questions regarding the initial mass function (IMF) of stars is the impact of environment on the shape of the core mass function (CMF) and thus potentially on the IMF.Aims: The ALMA-IMF Large Program aims to investigate the variations in the core distributions (CMF and mass segregation) with cloud characteristics, such as the density and kinematic of the gas, as diagnostic observables of the formation process and evolution of clouds. The present study focuses on the W43-MM2&MM3 mini-starburst, whose CMF has recently been found to be top-heavy with respect to the Salpeter slope of the canonical IMF.Methods: W43-MM2&MM3 is a useful test case for environmental studies because it harbors a rich cluster that contains a statistically significant number of cores (specifically, 205 cores), which was previously characterized in Paper III. We applied a multi-scale decomposition technique to the ALMA 1.3 mm and 3 mm continuum images of W43-MM2&MM3 to define six subregions, each 0.5-1 pc in size. For each subregion we characterized the probability distribution function of the high column density gas, η-PDF, using the 1.3 mm images. Using the core catalog, we investigate correlations between the CMF and cloud and core properties, such as the η-PDF and the core mass segregation.Results: We classify the W43-MM2&MM3 subregions into different stages of evolution, from quiescent to burst to post-burst, based on the surface number density of cores, number of outflows, and ultra-compact HII presence. The high-mass end (>1 M⊙) of the subregion CMFs varies from close to the Salpeter slope (quiescent) to top-heavy (burst and post-burst). Moreover, the second tail of the η-PDF varies from steep (quiescent) to flat (burst and post-burst), as observed for high-mass star-forming clouds. We find that subregions with flat second η-PDF tails display top-heavy CMFs.Conclusions: In dynamical environments such as W43-MM2&MM3, the high-mass end of the CMF appears to be rooted in the cloud structure, which is at high column density and surrounds cores. This connection stems from the fact that cores and their immediate surroundings are both determined and shaped by the cloud formation process, the current evolutionary state of the cloud, and, more broadly, the star formation history. The CMF may evolve from Salpeter to top-heavy throughout the star formation process from the quiescent to the burst phase. This scenario raises the question of if the CMF might revert again to Salpeter as the cloud approaches the end of its star formation stage, a hypothesis that remains to be tested.Fil: Pouteau, Y.. Universite Grenoble Alpes; FranciaFil: Motte, F.. Universite Grenoble Alpes; FranciaFil: Nony, T.. Universidad Autónoma de México. Instituto de Radioastronomía y Astrofísica; MéxicoFil: González, M.. Universite Grenoble Alpes; FranciaFil: Joncour, I.. Universite Grenoble Alpes; FranciaFil: Robitaille, J.-F.. Universite Grenoble Alpes; FranciaFil: Busquet, G.. Universidad de Barcelona; EspañaFil: Galván Madrid, R.. Universidad Autónoma de México. Instituto de Radioastronomía y Astrofísica; MéxicoFil: Gusdorf, A.. Universite Paris-Saclay; FranciaFil: Hennebelle, P.. Universite Paris-Saclay; FranciaFil: Ginsburg, A.. University of Virginia; Estados UnidosFil: Csengeri, T.. Universite Paris-Saclay; FranciaFil: Sanhueza, P.. National Astronomical Observatory of Japan; JapónFil: Dell'Ova, P.. Universite Paris-Saclay; FranciaFil: Stutz, A. M.. Universidad de Concepción; ChileFil: Towner, A. P. M.. University of Virginia; Estados UnidosFil: Cunningham, N.. Universite Grenoble Alpes; FranciaFil: Louvet, F.. Universite Grenoble Alpes; FranciaFil: Men?shchikov, A.. Universite Paris-Saclay; FranciaFil: Fernandez Lopez, Manuel. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Schneider, N.. Max Planck Institute For Extraterrestrial Physics; AlemaniaFil: Armante, M.. Universite Paris-Saclay; FranciaFil: Bally, J.. University of Maryland; Estados UnidosFil: Baug, T.. Academia Sinica; ChinaFil: Bonfand, M.. Universite de Bordeaux; FranciaFil: Bontemps, S.. Universite de Bordeaux; FranciaFil: Bronfman, L.. Universidad de Chile; ChileFil: Brouillet, N.. Universite de Bordeaux; FranciaFil: Díaz-González, D.. Universidad Autónoma de méxico. Instituto de Radioastronomía y Astrofísica; MéxicoFil: Herpin, F.. Universite de Bordeaux; FranciaFil: Lefloch, B.. Universite de Bordeaux; FranciaFil: Liu, H.-L.. Academia Sinica; ChinaFil: Lu, X.. Academia Sinica; ChinaFil: Nakamura, F.. National Astronomical Observatory of Japan; JapónFil: Luong, Q. Nguyen. National Tsing Hua University; ChinaFil: Olguin, F.. National Tsing Hua University; ChinaFil: Tatematsu, K.. National Astronomical Observatory Of Japan; JapónFil: Valeille Manet, M.. Universite de Bordeaux; Franci

ALMA-IMF. II. Investigating the origin of stellar masses: Continuum images and data processing

International audienceWe present the first data release of the ALMA-IMF Large Program, which covers the 12m-array continuum calibration and imaging. The ALMA-IMF Large Program is a survey of fifteen dense molecular cloud regions spanning a range of evolutionary stages that aims to measure the core mass function. We describe the data acquisition and calibration done by the Atacama Large Millimeter/submillimeter Array (ALMA) observatory and the subsequent calibration and imaging we performed. The image products are combinations of multiple 12 m array configurations created from a selection of the observed bandwidth using multi-term, multi-frequency synthesis imaging and deconvolution. The data products are self-calibrated and exhibit substantial noise improvements over the images produced from the delivered data. We compare different choices of continuum selection, calibration parameters, and image weighting parameters, demonstrating the utility and necessity of our additional processing work. Two variants of continuum selection are used and will be distributed: the "best-sensitivity" (bsens) data, which include the full bandwidth, including bright emission lines that contaminate the continuum, and "cleanest" (cleanest), which select portions of the spectrum that are unaffected by line emission. We present a preliminary analysis of the spectral indices of the continuum data, showing that the ALMA products are able to clearly distinguish free-free emission from dust emission, and that in some cases we are able to identify optically thick emission sources. The data products are made public with this release. Data are only available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/662/A9</A