Evaluación de la hemostasis

We try to explain the coagulation mechanism evaluation through our own clinical experience

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

Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)

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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

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

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

A Phase I Study of Tak-659 and Paclitaxel in Patients With Taxane-Refractory Advanced Solid Tumors

BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response. CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors

ALMA Observations of Asteroid 3 Juno at 60 Kilometer Resolution

We present Atacama Large Millimeter/submillimeter Array (ALMA) 1.3 mm continuum images of the asteroid 3 Juno obtained with an angular resolution of 0.042 arcseconds (60 km at 1.97 AU). The data were obtained over a single 4.4 hr interval, which covers 60% of the 7.2 hr rotation period, approximately centered on local transit. A sequence of ten consecutive images reveals continuous changes in the asteroid's profile and apparent shape, in good agreement with the sky projection of the three-dimensional model of the Database of Asteroid Models from Inversion Techniques. We measure a geometric mean diameter of 259pm4 km, in good agreement with past estimates from a variety of techniques and wavelengths. Due to the viewing angle and inclination of the rotational pole, the southern hemisphere dominates all of the images. The median peak brightness temperature is 215pm13 K, while the median over the whole surface is 197pm15 K. With the unprecedented resolution of ALMA, we find that the brightness temperature varies across the surface with higher values correlated to the subsolar point and afternoon areas, and lower values beyond the evening terminator. The dominance of the subsolar point is accentuated in the final four images, suggesting a reduction in the thermal inertia of the regolith at the corresponding longitudes, which are possibly correlated to the location of the putative large impact crater. These results demonstrate ALMA's potential to resolve thermal emission from the surface of main belt asteroids, and to measure accurately their position, geometric shape, rotational period, and soil characteristics.Comment: 8 pages, 3 figures, 2 tables, accepted for publication in the Astrophysical Journal Letter