Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small ...and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.
Abstract Mutations in leucine-rich repeat kinase 2 (LRRK2) have been causally linked to neuronal cell death in Parkinson's disease. LRRK2 expression has also been detected in B lymphocytes and ...macrophages, suggesting a role in immune responses. In the present study, we demonstrate that LRRK2 is expressed in primary microglial cells isolated from brains of adult mice. Moreover, lipopolysaccharide (LPS)-activated microglial cells from mice overexpressing the Parkinson's disease-linked LRRK2(R1441G) mutation exhibit increased expression and secretion of proinflammatory cytokines compared with wild-type control microglia. Expression of the LPS receptor Toll-like receptor 4 (TLR4) and downstream signaling proteins did not differ between LRRK2(R1441G) transgenic microglia and wild-type controls. Consistently, conditioned medium from LPS-stimulated LRRK2(R1441G) transgenic microglia induced significant cell death when added to neuronal cultures. These findings indicate that enhanced neuroinflammation may contribute to neurodegeneration in Parkinson's disease patients carrying LRRK2 mutations.
The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of ...antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The growth restriction factor
Q is the key quantity in current descriptions of the solutal effect on grain growth and grain refinement during solidification of alloys. A rigorous treatment for the ...evaluation of
Q in multicomponent alloys based on consistent thermodynamic descriptions of the alloy phase equilibria is presented. On closer inspection the conventional approach to calculate
Q in multicomponent alloys from liquidus gradient
m
i and partition coefficient
k
i must fail for a wide range of common alloys exhibiting minute amounts of primary crystallizing intermetallic phase, exemplified for Mg–Al–Mn and Al–Si–Ti alloys. The rigorous approach provides an extension of the applicability range of the concept of
Q. The qualitative similarity of inoculant particles and primary intermetallic phases is verified by calculations for Al–Si–Ti–B alloys.
On 17 April 2011, all analysis centers (ACs) of the International GNSS Service (IGS) adopted the reference frame realization IGS08 and the corresponding absolute antenna phase center model igs08.atx ...for their routine analyses. The latter consists of an updated set of receiver and satellite antenna phase center offsets and variations (PCOs and PCVs). An update of the model was necessary due to the difference of about 1 ppb in the terrestrial scale between two consecutive realizations of the International Terrestrial Reference Frame (ITRF2008 vs. ITRF2005), as that parameter is highly correlated with the GNSS satellite antenna PCO components in the radial direction.
For the receiver antennas, more individual calibrations could be considered and GLONASS-specific correction values were added. For the satellite antennas, all correction values except for the GPS PCVs were newly estimated considering more data than for the former model. Satellite-specific PCOs for all GPS satellites active since 1994 could be derived from reprocessed solutions of five ACs generated within the scope of the first IGS reprocessing campaign. Two ACs separately derived a full set of corrections for all GLONASS satellites active since 2003.
Ignoring scale-related biases, the accuracy of the satellite antenna PCOs is on the level of a few cm. With the new phase center model, orbit discontinuities at day boundaries can be reduced, and the consistency between GPS and GLONASS results is improved. To support the analysis of low Earth orbiter (LEO) data, igs08.atx was extended with LEO-derived PCV estimates for big nadir angles in June 2013.
Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR ...inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.
FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).
The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.
FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.
We demonstrate a plasmonic Mach-Zehnder (MZ) modulator with a flat frequency response exceeding 170 GHz. The modulator comprises two phase modulators exploiting the Pockels effect of an organic ...electro-optic material in plasmonic slot waveguides. We further show modulation at 100 GBd NRZ and 60 GBd PAM-4. The electrical drive signals were generated using a 100 GSa/s digital to analog converter (DAC). The high-speed and small-scale devices are relevant for next-generation optical interconnects.
This article discusses the attitude modes employed by present Global (and Regional) Navigation Satellite Systems (GNSSs) and the models used to describe them along with definitions of the ...constellation-specific spacecraft body frames. A uniform convention for the labeling of the principal spacecraft axes is proposed by the International GNSS Service (IGS), which results in a common formulation of the nominal attitude of all GNSS satellites in yaw-steering mode irrespective of their specific orbit and constellation. The conventions defined within this document provide the basis for the specification of antenna phase center offsets and variations in a multi-GNSS version of the IGS absolute phase center model in the ANTEX (antenna exchange) format. To facilitate the joint analysis of GNSS observations and satellite laser ranging measurements, laser retroreflector array coordinates consistent with the IGS-specific spacecraft frame conventions are provided in addition to representative antenna offset values for all GNSS constellations.
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