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We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
This paper reports on the SYN-RA (SYNtax-based Reference Annotation) project, an on-going project of annotating German newspaper texts with referential relations. The project has developed an inventory of anaphoric and coreference relations for German in the context of a unified, XML-based annotation scheme for combining morphological, syntactic, semantic, and anaphoric information. The paper discusses how this unified annotation scheme relates to other formats currently discussed in the literature, in particular the annotation graph model of Bird and Liberman (2001) and the pie-in-thesky scheme for semantic annotation.
The purpose of this paper is to describe recent developments in the morphological, syntactic, and semantic annotation of the TüBa-D/Z treebank of German. The TüBa-D/Z annotation scheme is derived from the Verbmobil treebank of spoken German [4, 10], but has been extended along various dimensions to accommodate the characteristics of written texts. TüBa-D/Z uses as its data source the "die tageszeitung" (taz) newspaper corpus. The Verbmobil treebank annotation scheme distinguishes four levels of syntactic constituency: the lexical level, the phrasal level, the level of topological fields, and the clausal level. The primary ordering principle of a clause is the inventory of topological fields, which characterize the word order regularities among different clause types of German, and which are widely accepted among descriptive linguists of German [3, 6]. The TüBa-D/Z annotation relies on a context-free backbone (i.e. proper trees without crossing branches) of phrase structure combined with edge labels that specify the grammatical function of the phrase in question. The syntactic annotation scheme of the TüBa-D/Z is described in more detail in [12, 11]. TüBa-D/Z currently comprises approximately 15 000 sentences, with approximately 7 000 sentences being in the correction phase. The latter will be released along with an updated version of the existing treebank before the end of this year. The treebank is available in an XML format, in the NEGRA export format [1] and in the Penn treebank bracketing format. The XML format contains all types of information as described above, the NEGRA export format contains all sentenceinternal information while the Penn treebank format includes only those layers of information that can be expressed as pure tree structures. Over the course of the last year, more fine grained linguistic annotations have been added along the following dimensions: 1. the basic Stuttgart-Tübingen tagset, STTS, [9] labels have been enriched by relevant features of inflectional morphology, 2. named entity information has been encoded as part of the syntactic annotation, and 3. a set of anaphoric and coreference relations has been added to link referentially dependent noun phrases. In the following sections, we will describe each of these innovations in turn and will demonstrate how the additional annotations can be incorporated into one comprehensive annotation scheme.
Inhibition of the proteasome is considered as a promising strategy to sensitize cancer cells to apoptosis. Recently, we demonstrated that the proteasome inhibitor Bortezomib primes neuroblastoma cells to TRAIL-induced apoptosis. In the present study, we investigated whether Bortezomib increases chemosensitivity of neuroblastoma cells. Unexpectedly, we discover an antagonistic interaction of Bortezomib and microtubule-interfering drugs. Bortezomib significantly attenuates the loss of cell viability and induction of apoptosis on treatment with Taxol and different vinca alkaloids but not with other chemotherapeutics, that is, Doxorubicin and Cisplatinum. Importantly, Bortezomib inhibits G2/M transition by inhibiting proteasomal degradation of cell cycle regulatory proteins such as p21, thereby preventing cells to enter mitosis, the cell cycle phase in which they are most vulnerable to antitubulin chemotherapeutics. Consequently, Bortezomib counteracts Taxol-induced mitotic arrest and polyploidy, as shown by reduced expression of PLK1 and phosphorylated histone H3. In addition, Bortezomib antagonizes Taxol-mediated degradation of MCL-1 during mitotic arrest by preventing cells to enter mitosis and by inhibiting the proteasome. Downregulation of MCL-1 is critically required for Taxol-induced apoptosis, as overexpression of a phosphomutant MCL-1 variant, which is resistant to degradation, significantly diminishes Taxol-triggered apoptosis. Vice versa, attenuation of Bortezomib-mediated accumulation of MCL-1 by knockdown of MCL-1 significantly enhances Taxol/Bortezomib-induced apoptosis. Thus, Bortezomib rescues Taxol-induced apoptosis by inhibiting G2/M transition and mitigating MCL-1 degradation. The identification of this antagonistic interaction of Bortezomib and microtubule-targeted drugs has important implications for the design of Bortezomib-based combination therapies.
Objectives. To assess interreader agreements and a learning curve between three (senior, junior, and beginner) different experienced musculoskeletal ultrasonographers. Senior served as the imaging "gold standard".
Methods. Clinically dominant joints (finger, shoulder, knee, tibiotalar, and talonavicular) of 15 rheumatoid arthritis (RA) patients were examined by three different experienced ultrasonographers (senior 10 years, junior 10 months, and beginner one month). Each patient's ultrasonographic findings were reported unaware of the other investigators' results. coefficients, percentage agreements, sensitivities, and specificities were calculated.
Results. 120 joints of 15 RA patients were evaluated. Comparing junior's and beginner's results each to the senior's findings, the overall for all examined joints was 0.83 (93%) for junior and 0.43 (76%) for beginner. Regarding the different joints, junior's findings correlate very well with the senior's findings (finger joints: ; shoulder: ; knee: ; tibiotalar joint: ; talonavicular joint: ) while beginner's findings just showed fair to moderate agreements (finger joints: ; shoulder: ; knee: ; tibiotalar joint: ; talonavicular joint: ). In total, beginner's results clearly improved from (agreement of 67%) at baseline to (agreement of 89%) at the end of the evaluation period.
Conclusions. Ultrasonographic evaluation of a ten-month-experienced investigator in comparison to a senior ultrasonographer was of substantial agreement. Agreements between a beginner and a highly experienced ultrasonographer were only fair at the beginning, but during the study including ultrasonographical sessions of 15 RA patients, the beginner clearly improved in musculoskeletal ultrasonography.
The wild silkmoth genus Sinobirma Bryk, 1944 is a poorly known monotypic taxon from the eastern end of the Himalaya Range. It was convincingly proposed to be closely related to some members of an exclusively Afro-tropical group of Saturniidae, but its biogeographical and evolutionary history remains enigmatic. After examining recently collected material from Tibet, northern India, and northeastern Myanmar, we realized that this unique species, S. malaisei Bryk, 1944 only known so far from a few specimens and from a very restricted area near the border between north-eastern Myanmar and the Yunnan province of China, may in fact belong to a group of closely related cryptic species. In this work, we combined morphological comparative study, DNA barcoding, and the sequences of a nuclear marker (D2 expansion segment of the 28S rRNA gene) to unequivocally delimit three distinct species in the genus Sinobirma, of which two are described as new to science: S. myanmarensis sp. n. and S. bouyeri sp. n. An informative DNA barcode sequence was obtained from the female holotype of S. malaisei—collected in 1934—ensuring the proper assignation of this name to the newly collected and studied specimens. Our findings represent another example of the potential of coupling traditional taxonomy and DNA barcoding for revealing and solving difficult cases of cryptic diversity. This approach is now being generalized to the world fauna of Saturniidae, with the participation of most of the taxonomists studying these moths.
The verb ‘rise’ can be used both with property-denoting nouns like ‘temperature’ but also with NPs like ‘a Titan’ or ‘China’. Whereas in the former case the change triggered by a rising event is directly related to the subject (its current value increases), this does not hold for ‘a titan’ or ‘China’. In this case it is a property of these objects, say their height or their political power, which increases in value. Furthermore, ‘rise’ does not target a particular property as the examples above show. This data has led Cooper (2010) to the conclusion that it is presumably not possible (i) “to extract a single general meaning of words which covers all the particular meanings of the word in context”, and (ii) “to determine once and for all the set of particular contextually determined meanings of a word”. In this article we present a solution to the two problems raised by ‘rise’ in a frame theory. ‘Rise’ is analyzed as a scalar verb which does not lexicalize a complete scale in its meaning. Rather, it shows underspecification relative to the dimension (property) parameter of a scale. The set of admissible properties is determined by a constraint on the value ranges of properties. If the property is not uniquely determined by the subject, the comprehender uses probabilistic reasoning based on world knowledge and discourse information to defeasibly infer the most likely candidates from this set (2nd problem).
The first problem is solved not by simply introducing objects into the representation of a discourse but instead by pairs consisting of an object and an associated frame component which collects the object information contributed by the discourse. Changes triggered by events like the one denoted by ‘rise’ are modelled as update operations on the frame component while the object component is left unchanged.
This software demonstration presents the possibilities for the construction, administration, and evaluation of criterion- referenced, computerized adaptive and nonadaptive tests with the R-based open-source KAT-HS app. This app enables users to apply the continuous item calibration strategy of Fink, Born, Spoden, and Frey (2018).