julilili42/papers huggingface dataset:
Diagnostic accuracy of hyperbilirubinaemia in anticipating appendicitis and its severity
2014-12-04

Background Hyperbilirubinaemia is reported to be a positive predictor in diagnosing appendicitis and especially appendiceal perforation. We, therefore, analysed the diagnostic accuracy of serum bilirubin in anticipating appendicitis and its severity. Methods All consecutive patients undergoing appendectomy for suspected appendicitis from May 2009 to August 2011 were analysed. Patients were classified based on final histopathological findings into the groups: no appendiceal inflammation, non-perforated appendicitis and perforated appendicitis. Primary outcome was the diagnostic accuracy of serum bilirubin levels in discriminating between no appendiceal inflammation and any appendicitis (perforated and non-perforated appendicitis) and non-perforated and perforated appendicitis. Results Of 493 analysed patients, 125 (25%) had no appendiceal inflammation, 312 (64%) had non-perforated appendicitis and 56 (11%) had perforated appendicitis. The proportion of patients with bilirubin elevation (&gt;1.1 mg/dL) was different between those with no appendiceal inflammation (14%) and any appendicitis (36%) (p&lt;0.0001), and between non-perforated appendicitis and perforated appendicitis 48% (p=0.04). However, the positive and negative likelihood ratios (LRs) for an elevated bilirubin were poor at discriminating the groups: no appendiceal inflammation versus any appendicitis (LR+ 2.62 (95% CI 1.65 to 4.16) and LR− 0.75 (95% CI 0.67 to 0.83)) and non-perforated appendicitis versus perforated appendicitis (LR+ estimate 1.74 (95% CI 1.28 to 2.38) and LR− 0.72 (95% CI 0.55 to 0.93)). Conclusions Hyperbilirubinaemia is present in acute appendicitis but has a low diagnostic accuracy in discriminating between any appendicitis versus no appendiceal inflammation and perforated versus non-perforated appendicitis and is, therefore, of limited value in clinical routine. Trial registration number NCT01698099.
Gas Phase Structures of Peroxides: Experiments and Computational Problems
2014-12-04

Abstract Gas‐phase structures of several organic and inorganic peroxides X‐O‐O‐X and X‐O‐O‐X′, which have been determined experimentally by gas electron diffraction and/or microwave spectroscopy, are discussed. The OO bond length in these peroxides varies from 1.481(8) Å in Me 3 SiOOSiMe 3 to 1.214(2) Å in FOOF and the dihedral angle φ (XO‐OX) between 0° in HC(O)O‐OH and near 180° in Bu t O‐OBu t . Some of the peroxides cause problems for quantum chemistry, since several computational methods fail to reproduce the experimental structures. Extreme examples are MeO‐OMe and FO‐OF. In the case of MeO‐OMe only about half of the more than 100 computational methods reported in the literature reproduce the experimentally determined double‐minimum shape of the torsional potential around the OO bond correctly. For FO‐OF only a small number of close to 200 computational methods reproduce the OO and OF bond lengths better than ±0.02 Å.
Multi-Wavelength View of Supernova Remnants
2014-12-04

This contribution gives a very short overview on the emission of supernova remnants and the processes that are responsible for both the thermal and non-thermal origins of the emission, typically observed in radio, X-rays, and up to gamma-rays. We discuss in particular the case of the Galactic SNR CTB 109. As detailed X-ray studies combined with observations in radio have shown, CTB 109 is interacting with a giant molecular cloud complex. The interaction of the SNR shock with dense interstellar clouds is responsible for both the unusual semi-circular morphology of the SNR and the bright X-ray feature inside the SNR, and, as has been shown recently, seems also to play a major role in the production of gamma-rays.
The exopolysaccharide Psl–eDNA interaction enables the formation of a biofilm skeleton in P seudomonas aeruginosa
2014-12-05

Summary A hallmark of bacterial biofilms is a self‐produced extracellular matrix of exopolysaccharide, extracellular DNA ( eDNA ) and proteins that hold bacterial cells together in the community. However, interactions among matrix components and how the interactions contribute to the formation of matrix remain unclear. Here, we show the physical interaction between exopolysaccharide P sl and eDNA , the two key biofilm matrix components of the opportunistic pathogen P seudomonas aeruginosa . The interaction allows the two components to combine to form a web of eDNA–P sl fibres, which resembles a biofilm skeleton in the centre of pellicles to give bacteria structural support and capability against agents targeted on one matrix component. The web of eDNA–P sl fibres was also found in flow‐cell biofilms at microcolonies initiation stage. The colocalization of eDNA or P sl fibres with bacterial cell membrane stain suggests that fibre‐like eDNA is likely derived from the lysis of dead bacteria in biofilms. Psl can interact with DNA from diverse sources, suggesting that P . aeruginosa has the ability to use DNA of other organisms (such as human neutrophils and other bacterial species) to form its own communities, which might increase the survival of P . aeruginosa in multispecies biofilms or within a human host.
Grassland management intensification weakens the associations among the diversities of multiple plant and animal taxa
2014-12-05

Land‐use intensification is a key driver of biodiversity change. However, little is known about how it alters relationships between the diversities of different taxonomic groups, which are often correlated due to shared environmental drivers and trophic interactions. Using data from 150 grassland sites, we examined how land‐use intensification (increased fertilization, higher livestock densities, and increased mowing frequency) altered correlations between the species richness of 15 plant, invertebrate, and vertebrate taxa. We found that 54% of pairwise correlations between taxonomic groups were significant and positive among all grasslands, while only one was negative. Higher land‐use intensity substantially weakened these correlations (35% decrease in r and 43% fewer significant pairwise correlations at high intensity), a pattern which may emerge as a result of biodiversity declines and the breakdown of specialized relationships in these conditions. Nevertheless, some groups (Coleoptera, Heteroptera, Hymenoptera and Orthoptera) were consistently correlated with multidiversity, an aggregate measure of total biodiversity comprised of the standardized diversities of multiple taxa, at both high and low land‐use intensity. The form of intensification was also important; increased fertilization and mowing frequency typically weakened plant–plant and plant–primary consumer correlations, whereas grazing intensification did not. This may reflect decreased habitat heterogeneity under mowing and fertilization and increased habitat heterogeneity under grazing. While these results urge caution in using certain taxonomic groups to monitor impacts of agricultural management on biodiversity, they also suggest that the diversities of some groups are reasonably robust indicators of total biodiversity across a range of conditions.
Congenital chylothorax: a prospective nationwide epidemiological study in Germany
2014-12-05

Background Congenital chylothorax (CCT) is a rare disease of unknown aetiology. Treatment approaches vary; none has been evaluated prospectively. Objective To prospectively determine incidence, treatment and outcome of infants with CCT born in Germany in 2012. Design CCT was defined as non-traumatic chylous pleural effusion within 28 days after birth. As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of CCT cases, which were analysed based on anonymised questionnaires and discharge summaries. Data are shown as median (range) or n/N. Results Of 37 cases reported, 28 met inclusion criteria. Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT was 1:24 000. Nine infants suffered from proven or suspected syndromal anomalies, most frequently Noonan syndrome (5/9). Postnatally, 23 required mechanical ventilation, 3 continuous positive airway pressure; only 1 had no respiratory support. 17 infants were treated with inotropes/vasopressors, 25 required pleural drainage for 11 (1–36) days. In 13 infants, enteral feeds were withheld initially; 25 received medium-chain triglyceride diet at some time, 9 were treated with octreotide or somatostatin. 18 infants survived without, 6 with sequelae attributable to the underlying disorder; 3 infants died (median age at death 37 (2–144) days). Duration of hospital stay in survivors was 51 (20–127) days. Infants treated with octreotide or somatostatin had similar outcomes compared with those not treated. Conclusions Based on this small observational study, CCT seems to have a favourable prognosis if not associated with genetic disorders.
Site-directed Mutagenesis Switching a Dimethylallyl Tryptophan Synthase to a Specific Tyrosine C3-Prenylating Enzyme
2014-12-05

The tryptophan prenyltransferases FgaPT2 and 7-DMATS (7-dimethylallyl tryptophan synthase) from Aspergillus fumigatus catalyze C(4)- and C(7)-prenylation of the indole ring, respectively. 7-DMATS was found to accept l-tyrosine as substrate as well and converted it to an O-prenylated derivative. An acceptance of l-tyrosine by FgaPT2 was also observed in this study. Interestingly, isolation and structure elucidation revealed the identification of a C(3)-prenylated l-tyrosine as enzyme product. Molecular modeling and site-directed mutagenesis led to creation of a mutant FgaPT2_K174F, which showed much higher specificity toward l-tyrosine than l-tryptophan. Its catalytic efficiency toward l-tyrosine was found to be 4.9-fold in comparison with that of non-mutated FgaPT2, whereas the activity toward l-tryptophan was less than 0.4% of that of the wild-type. To the best of our knowledge, this is the first report on an enzymatic C-prenylation of l-tyrosine as free amino acid and altering the substrate preference of a prenyltransferase by mutagenesis.
Focus Sensitive Operators
2014-12-05

Abstract This chapter investigates operators that evaluate alternatives. An indirect analysis of association with focus (Rooth (1992) is assumed, according to which there is just one focus evaluating operator. In addition to focus, questions and polarity items are considered. Both also involve an operator that evaluates alternatives. The alternative semantic tier is thus used in several types of construction, and the interaction of the respective operators has to be investigated. A compositional semantic analysis of alternatives is argued for that is based on distinguished variables.
Adaptive learning in a compartmental model of visual cortexâ€”how feedback enables stable category learning and refinement
2014-12-05

The categorization of real world objects is often reflected in the similarity of their visual appearances. Such categories of objects do not necessarily form disjunct sets of objects, neither semantically nor visually. The relationship between categories can often be described in terms of a hierarchical structure. For instance, tigers and leopards build two separate mammalian categories, both of which are subcategories of the category Felidae. In the last decades, the unsupervised learning of categories of visual input stimuli has been addressed by numerous approaches in machine learning as well as in computational neuroscience. However, the question of what kind of mechanisms might be involved in the process of subcategory learning, or category refinement, remains a topic of active investigation. We propose a recurrent computational network architecture for the unsupervised learning of categorial and subcategorial visual input representations. During learning, the connection strengths of bottom-up weights from input to higher-level category representations are adapted according to the input activity distribution. In a similar manner, top-down weights learn to encode the characteristics of a specific stimulus category. Feedforward and feedback learning in combination realize an associative memory mechanism, enabling the selective top-down propagation of a category's feedback weight distribution. We suggest that the difference between the expected input encoded in the projective field of a category node and the current input pattern controls the amplification of feedforward-driven representations. Large enough differences trigger the recruitment of new representational resources and the establishment of additional (sub-) category representations. We demonstrate the temporal evolution of such learning and show how the proposed combination of an associative memory with a modulatory feedback integration successfully establishes category and subcategory representations.
Improved Outcome with ATRA-Arsenic Trioxide Compared to ATRA-Chemotherapy in Non-High Risk Acute Promyelocytic Leukemia – Updated Results of the Italian-German APL0406 Trial on the Extended Final Series
2014-12-06

Abstract Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013. Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-&lt;71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10x109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally developed by the MD Anderson Cancer Center group, or the Italian AIDA2000 protocol (Estey et al., Blood 2006 and Lo-Coco et al., Blood 2010). Patients in the ATRA-ATO arm received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in the ATRA-CHT arm received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based consolidation together with ATRA and low dose CHT and ATRA for maintenance. The primary study objective was EFS at 2 years. Results: A total of 254 patients were evaluable for response to induction. CR was achieved in 122/122 (100%) in the ATRA-ATO versus 128/132 (97%) in the ATRA-CHT arm (P=0.12). Four patients died during induction in the ATRA-CHT arm. After a median follow-up of 36 months (range 1-75 months), the 2-year EFS was 98% and 84.9% in the ATRA-ATO and ATRA-CHT groups respectively (P= 0.0002), The 2-year cumulative incidence of relapse (CIR) rate was 1.1% and 9.4%, respectively (P=0.005) and, finally, the 2-year overall survival (OS) rate was 99.1% vs. 94.4% (P=0.01) for ATRA-ATO vs ATRA-CHT, respectively. Conclusions: The data on this extended cohort demonstrate a significantly augmented survival benefit coupled to a higher antileukemic efficacy provided by ATRA-ATO as compared to ATRA-CHT, in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting. Figure 1 Figure 1. Disclosures Platzbecker: Teva: Honoraria. Off Label Use: Presentation includes off-label use of arsenic trioxide (ATO) in front-line management of APL. ATO is currently approved in treatment of relapsed APL in the US and Europe. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Lübbert:Cephalon / TEVA: Travel support Other. Link:TEVA: Consultancy, Speakers Bureau. Radsak:Celgene: Research Funding. Döhner:TEVA: Research Funding. Schlenk:TEVA: Research Funding, Speakers Bureau. Lo-Coco:TEVA: Honoraria; Lundbeck: Honoraria.
Platelet-Derived Proteases ADAM10 and ADAM17 Impair NK Cell Immunosurveillance of Metastasizing Tumor Cells By Diminishing NKG2D Ligand Surface Expression
2014-12-06

Abstract Introduction: NK cells are cytotoxic lymphocytes the reactivity of which is governed by the principles of ‘missing-self’ and “induced-self’ recognition. This implies that cells with low or absent expression of MHC class I and/or stress-induced expression of ligands for activating receptors like NKG2D (NKG2DL) are preferentially eliminated by NK cells. We and others reported previously that NKG2DL undergo proteolytic cleavage (i.e. shedding) which promotes evasion from NKG2D-mediated tumor immunosurveillance. Notably, the reactivity of NK cells is also influenced by various other components of the hematopoietic system, and we and others provided evidence for the involvement of platelets in tumor immune evasion including impairment of NKG2D-mediated immune surveillance (e.g., Kopp et al., Cancer Res 2009, Raab et al., Blood 2013 122:3488). Here we extend our recent findings and provide further data how platelets affect immunostimulatory NKG2D-NKG2DL interaction. Methods: Tumor cells were incubated with platelets from healthy donors or treated with platelet-derived soluble factors (releasate) obtained by stimulation of platelets with known platelet agonists including ADP and thrombin. NKG2DL and ADAM10 as well as ADAM17 surface expression on tumor cells and platelets, respectively, was measured by FACS, while release of NKG2DL was determined by ELISA. ADAM10 and 17 protein levels were assessed by immunoblotting. NK cell lysis of tumor cells in the presence or absence of coating platelets or platelet releasate was determined by chromium release assays. Results: We found that interaction of platelets with tumor cells resulted in substantially reduced NKG2DL expression on the surface of the malignant cells, which was paralleled by enhanced release of soluble NKG2DL. Similar albeit weaker effects were observed upon treatment of tumor cells with platelet releasate, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Notably, ADAM10 and ADAM17, the known sheddases of NKG2DL, were found to be expressed on the platelet surface, and sheddases could also be detected in platelet releasate, pointing to an involvement in platelet-mediated NKG2DL shedding. Diminished NKG2DL surface expression resulted in reduced NKG2D-mediated NK cell cytotoxicity as revealed by blocking experiments using NKG2D antibody and F(ab)2 fragments specific for the modulated NKG2DL. Conclusion: We propose that induction of NKG2DL shedding constitutes a novel mechanism by which the interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance. Disclosures No relevant conflicts of interest to declare.
Development and Preclinical Characterization of an Fc-Optimized CD133 Antibody for Induction of NK Cell Reactivity Against Myeloid Leukemia
2014-12-06

Abstract NK cells are cytotoxic lymphocytes that play a major role in anti-tumor immunity and largely contribute to the efficacy of allogenic stem cell transplantation (SCT) in leukemia. Another clinically important feature of NK cells is their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) upon application of monoclonal antibodies (mAb) like Rituximab, a feature considered critical for the therapeutic success of antibody treament. Modifications of the human IgG1 Fc-part in anti-tumor antibodies lead to markedly improved capability to recruit Fc-receptor bearing effector cells as highlighted by the improved clinical efficacy of the Fc-engineered CD20 antibody Ofatumumab as compared to its unmodified counterpart Rituximab in CLL. So far, no immunotherapeutic antibodies are available for the treatment of myeloid leukemias. Here we report on the development and preclinical characterization of an Fc-optimized mAb directed towards CD133, which is expressed on a wide variety of malignant cell types. As a first step we evaluated binding of three different mouse anti-human CD133 mAbs (clones AC133, W6B3 and 293C3) to 20 primary AML and 6 primary CML samples in order to identify a clone with optimal binding characteristics. AC133 and W6B3 comparably bound to the leukemic cells in 11/20 AML and 5/6 CML samples. In contrast, binding of 293C3 was observed in 18/20 AML cases and 5/6 CML cases. Thus, 293C3 recognizes a different epitope than the other two antibody clones, which is expressed in a high proportion of myeloid leukemia cases. Accordingly, 293C3 was selected for generating chimeric mAbs with either a wildtype Fc part (293C3-WT) or a variant containing distinct modifications (S239D/I332E) to enhance its affinity to the activating Fc receptor CD16 (293C3-SDIE). The binding specificity of 293C3-WT and 293C3-SDIE was validated by FACS in analyses with CD133 transfectants and mock controls. When comparing 293C3-WT and 293C3-SDIE with regard to their immunostimulatory properties, we found that already 293C3-WT induced NK cell ADCC against primary leukemia cells as revealed by analyses of degranulation and target cell lysis. These effects were by far exceeded by treatment with 293C3-SDIE, confirming the functional relevance of the SDIE modification in its Fc part. Notably, treatment with 293C3-SDIE also enhanced the reactivity of NK cells against CD133-positive AML cells in an autologous setting. Considering the expression of CD133, among others, on healthy hematopoietic progenitor cells, we further performed colony forming unit assays with healthy bone marrow cells, which did not reveal any toxicity of 293C3-SDIE at the level of committed hematopoietic progenitor cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound which we envisage in particular for the elimination of minimal residual disease in CD133 bearing leukemia, especially in the context of allogenic SCT. Disclosures No relevant conflicts of interest to declare.