Molecular line emissions from pre main sequence objects

We present some preliminary results obtained with the LWS G.T. programme on the study of young objects driving molecular outflows. In particular, we discuss the importance of molecular emission in these sources and address the role of the H20 cooling

Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m−2, cisplatin 75 mg m−2 on day 1 and fluorouracil 750 mg m−2 day−1 on days 2–5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m−2 week−1 for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week−1). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2–66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1–12.4), and the 1- and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3–4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified

A Cooperative Interaction between Nontranslated RNA Sequences and NS5A Protein Promotes In Vivo Fitness of a Chimeric Hepatitis C/GB Virus B

GB virus B (GBV-B) is closely related to hepatitis C virus (HCV), infects small non-human primates, and is thus a valuable surrogate for studying HCV. Despite significant differences, the 5′ nontranslated RNAs (NTRs) of these viruses fold into four similar structured domains (I-IV), with domains II-III-IV comprising the viral internal ribosomal entry site (IRES). We previously reported the in vivo rescue of a chimeric GBV-B (vGB/IIIHC) containing HCV sequence in domain III, an essential segment of the IRES. We show here that three mutations identified within the vGB/IIIHC genome (within the 3′NTR, upstream of the poly(U) tract, and NS5A coding sequence) are necessary and sufficient for production of this chimeric virus following intrahepatic inoculation of synthetic RNA in tamarins, and thus apparently compensate for the presence of HCV sequence in domain III. To assess the mechanism(s) underlying these compensatory mutations, and to determine whether 5′NTR subdomains participating in genome replication do so in a virus-specific fashion, we constructed and evaluated a series of chimeric subgenomic GBV-B replicons in which various 5′NTR subdomains were substituted with their HCV homologs. Domains I and II of the GBV-B 5′NTR could not be replaced with HCV sequence, indicating that they contain essential, virus-specific RNA replication elements. In contrast, domain III could be swapped with minimal loss of genome replication capacity in cell culture. The 3′NTR and NS5A mutations required for rescue of the related chimeric virus in vivo had no effect on replication of the subgenomic GBneoD/IIIHC RNA in vitro. The data suggest that in vivo fitness of the domain III chimeric virus is dependent on a cooperative interaction between the 5′NTR, 3′NTR and NS5A at a step in the viral life cycle subsequent to genome replication, most likely during particle assembly. Such a mechanism may be common to all hepaciviruses

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Enantioselective synthesis and selective monofunctionalization of (4R,6R)-4,6-dihydroxy-2,8-dioxabicyclo[3.3.0]octane

An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol unit

Methodology of 3D structure modelling of sedimentary stratiform mineral deposits-a case of the Mechelinki Zechstein salt deposit at the Puck Bay

Construction of a data base structure and resulted 3D structure images of sedimentary stratiform deposits was exemplified in a case of rock salt deposit at the Puck Bay (northern Poland). Analysis of 3D models of deposit structure (lithological and facies ones) and distribution models of selected chemical (resource) parameters evidenced a high correlation between the distinguished salt facies types and resource features. The imaged facies and chemical patterns indicated that the middle and western parts of the deposit are the most prospective for future management for both underground salt exploitation and cavern solution (gas/oil storage). Another area for future prospecting and management is located towards NW and NNW from the actual salt deposit area. The presented methodology could be applied to other sedimentary deposits, e.g. raw minerals and lignites, simplifying the resource calculation and projecting their proper and economic management

Bromine geochemistry and characteristics of Zechstein salt rocks in selected core materials from the Góra salt diapir near Inowrocław (Central Poland)

Kompleksowe badania wykształcenia i zmian zawartości bromu w materiałach rdzeniowych z trzech profili solnych utworów cechsztynu, odwierconych na terenie wysadu solnego Góra, umożliwiły przedstawienie charakterystyki poszczególnych ogniw litostratygraficznych solnych oraz skonstruowanie syntetycznych ich sukcesji w profilu pionowym. Obserwacje tendencji zmian zawartości bromu okazały się pomocne w wyznaczeniu kierunku stropu ogniw solonych i wskazaniu położenia osi przypuszczalnych wielkoskalowych deformacji fałdowych w obrębie kompleksów soli kamiennej.Detailed macroscopic profiling of salt cores from selected wells drilled in the Góra salt diapir (central Poland), supported with bromine content analyses, enabled to define and characterize the succession of Zechstein (Upper Permian) lithostratigraphic units in each well. The study results allowed also to define better the type of tectonic macrodeformations (as folds) within studied salt series, being so common in any salt diapir, but difficult to observe in well sections

Characteristics and tectonics of Zechstein salt rocks of the Góra salt diapir near Inowrocław on the basis of geochemical-lithological study of selected borehole sections

Detailed macroscopic profiling of salt cores from selected wells drilled in the Góra salt diapir (central Poland; Fig. 1, 2) and analyses of bromine content made it possible to define and characterize lithostratigraphic units of the Zechstein (Upper Permian) succession (Fig. 3, 4). Interpretation of relations between the units identified in the studied well sections allowed the first schematic reconstruction of internal structure of top part of the salt trunk (Fig. 5). The principal idea of this reconstruction is probable origin of the Góra diapir as a salt trunk with a recumbent fold at the top (Fig. 6A). Subsequent uplift of the diapir and erosion resulted in removal of significant part of younger salt deposits so only those squeezed into the salt trunk interior escaped the erosion (Fig. 6B). Models of internal structure of salt diapirs are of remarkable practical value as they facilitate proper location of the mining works (e.g. leaching wells, galleries, chambers and caverns) and prediction of possible gas and water hazards