First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma.

PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.Patients and methodsGDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.ResultsForty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.ConclusionsGDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier

Star formation triggered by the Galactic HII region RCW 120: First results from the Herschel Space Observatory

By means of different physical mechanisms, the expansion of HII regions can promote the formation of new stars of all masses. RCW 120 is a nearby Galactic HII region where triggered star formation occurs. This region is well-studied - there being a wealth of existing data - and is nearby. However, it is surrounded by dense regions for which far infrared data is essential to obtain an unbiased view of the star formation process and in particular to establish whether very young protostars are present. We attempt to identify all Young Stellar Objects (YSOs), especially those previously undetected at shorter wavelengths, to derive their physical properties and obtain insight into the star formation history in this region. We use Herschel-PACS and -SPIRE images to determine the distribution of YSOs observed in the field. We use a spectral energy distribution fitting tool to derive the YSOs physical properties. Herschel-PACS and -SPIRE images confirm the existence of a young source and allow us to determine its nature as a high-mass (8-10 MSun) Class 0 object (whose emission is dominated by a massive envelope) towards the massive condensation 1 observed at (sub)-millimeter wavelengths. This source was not detected at 24 micron and only barely seen in the MISPGAL 70 micron data. Several other red sources are detected at Herschel wavelengths and coincide with the peaks of the millimeter condensations. SED fitting results for the brightest Herschel sources indicate that, apart from the massive Class 0 that forms in condensation 1, young low mass stars are forming around RCW 120. The YSOs observed on the borders of RCW 120 are younger than its ionizing star, which has an age of about 2.5 Myr.Comment: 5 pqges, 3 figures, accepted by A&A (Special issue on the Herschel first results

Procés d’integració dels programes de formació permanent de Postgrau de la Universitat Politècnica de Catalunya a l'Espai Europeu d'Educació Superior

Projecte presentat al 3r Premi a la Qualitat de la Gestió Universitària, convocat pel Consell Social de la UP

Gastropatía hipertrófica de píloro : resolución quirúrgica de tres casos clínicos mediante la técnica de píloroplastia Y-U

Descripción de la técnica de piloroplastia en colgajo antral y-U en la resolución de 3 casos clínicos de gastropatía por hipertrofia crónica del píloro.Description of the y-U antral flap advancement pyloroplasty to the resolution of 3 clinic cases of chronic hypertrophic pyloric gastropathy

Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor

CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation

Probing the Early Evolution of Young High-Mass Stars

Near-infrared imaging surveys of high-mass star-forming regions reveal an amazingly complex interplay between star formation and the environment (Churchwell et al. 2006; Alvarez et al. 2004). By means of near-IR spectroscopy the embedded massive young stars can be characterized and placed in the context of their birth site. However, so far spectroscopic surveys have been hopelessly incomplete, hampering any systematic study of these very young massive stars. New integral field instrumentation available at ESO has opened the possibility to take a huge step forward by obtaining a full spectral inventory of the youngest massive stellar populations in star-forming regions currently accessible. Simultaneously, the analysis of the extended emission allows the characterization of the environmental conditions. The Formation and Early Evolution of Massive Stars (FEMS) collaboration aims at setting up a large observing campaign to obtain a full census of the stellar content, ionized material, outflows and PDR's over a sample of regions that covers a large parameter space. Complementary radio, mm and infrared observations will be used for the characterization of the deeply embedded population. For the first eight regions we have obtained 40 hours of SINFONI observations. In this contribution, we present the first results on three regions that illustrate the potential of this strategy.Comment: To appear in ASP Conf. Proceedings of "Massive Star Formation: Observations confront Theory", H. Beuther et al. (eds.), held in Heidelberg, September 200

La recerca a Catalunya en el context europeu. L’exit d’una anomalia feta model

En el número 50 de la revista L'Espill trobaràs un dossier monogràfic sobre "La crisi europea. Europa com a idea i com a projecte, avui", amb contribucions d'Adam Zagajewski, Joan F. Mira, Antoni Mora, Marina Garcés, Simona Škrabec, Andrei Kurkov, Antoni Martí Monterde, Enzo Traverso, Wolf Lepenies, Robert Menasse, Josep Maria Terricabras, Manuel Sanchis, Estanislau Vidal-Folch, Sebastian Landschbauer, Étienne Balibar, Ulrike Guérot, Josep Maria Martorell, Montserrat Daban, Francesc Xavier Grau i Josep Lluís Gómez Mompart. A més, una enquesta d'Adolf Beltran sobre el present i el futur d'Europa i dos documents, de Joan Fuster i de Vicent Ventura

Herschel Observations of the W43 "mini-starburst"

Aims: To explore the infrared and radio properties of one of the closest Galactic starburst regions. Methods: Images obtained with the Herschel Space Observatory at wavelengths of 70, 160, 250, 350, and 500 microns using the PACS and SPIRE arrays are analyzed and compared with radio continuum VLA data and 8 micron images from the Spitzer Space Telescope. The morphology of the far-infrared emission is combined with radial velocity measurements of millimeter and centimeter wavelength transitions to identify features likely to be associated with the W43 complex. Results: The W43 star-forming complex is resolved into a dense cluster of protostars, infrared dark clouds, and ridges of warm dust heated by massive stars. The 4 brightest compact sources with L > 1.5 x 10^4 Lsun embedded within the Z-shaped ridge of bright dust emission in W43 remain single at 4" (0.1 pc) resolution. These objects, likely to be massive protostars or compact clusters in early stages of evolution are embedded in clumps with masses of 10^3 to 10^4 Msun, but contribute only 2% to the 3.6 x 10^6 Lsun far-IR luminosity of W43 measured in a 16 by 16 pc box. The total mass of gas derived from the far-IR dust emission inside this region is ~10^6 Msun. Cometary dust clouds, compact 6 cm radio sources, and warm dust mark the locations of older populations of massive stars. Energy release has created a cavity blowing-out below the Galactic plane. Compression of molecular gas in the plane by the older HII region near G30.684-0.260 and the bipolar structure of the resulting younger W43 HII region may have triggered the current mini-star burst.Comment: 5 pages, 3 figures, accepted for A&A Special Issu

Trends in the use of electrical cardioversion for atrial fibrillation: influence of major trials and guidelines on clinical practice

Background: The purpose of the present study was to assess the trends in the use of ECV following published studies that had compared rhythm and rate control strategies on atrial fibrillation (AF), and the recommendations included in the current clinical practice guidelines. Methods: The REVERCAT is a population-based assessment of the use of electrical cardioversion (ECV) in treating persistent AF in Catalonia (Spain). The initial survey was conducted in 2003 and the follow-up in 2010. Results: We observed a decrease of 9% in the absolute numbers of ECV performed (436 in 2003 vs. 397 in 2010). This is equivalent to 27% when considering population increases over this period. The patients treated with ECV in 2010 were younger, had a lower prevalence of previous embolism, a higher prevalence of diabetes, and increased body weight. Underlying heart disease factors indicated, in 2010, a higher proportion of NYHA >= II and left ventricular ejection fraction <30%. We observed a reduction in the number of ECV performed in 16 of the 27 (67%) participating hospitals. However, there was an increase of 14% in the number of procedures performed in tertiary hospitals, and was related to the increasing use of ECV as a bridge to AF ablation. Considering the initial number of patients treated with ECV, the rate of sinus rhythm at 3 months was almost unchanged (58% in 2003 vs. 57% in 2010; p = 0.9) despite the greater use of biphasic energy in 2010 and a similar prescription of anti-arrhythmic drugs. Conclusions: Although we observed a decrease in the number of ECVs performed over the 7 year period between the two studies, this technique remains a common option for treating patients with persistent AF. The change in the characteristics of candidate patients did not translate into better outcomes