julilili42/papers huggingface dataset:
On the Analysis of Echo Questions
2017-03-31

Echo questions are first and foremost questions, i.e. the speaker tries to get the hearer to close an informational gap. But unlike normal questions they convey the impression that the speaker reopens a gap that both speaker and hearer know has already been closed before. This ‘echo’ effect correlates with likewise distinctive formal features: Thus, in (German) echo wh-questions, on which I concentrate, the wh-phrase is positionally free, always bears the nuclear accent, the final contour is typically a rise, and these formal features may combine with all clause types to yield bona fide echo wh-questions. So far, the standard mode of analyzing echo (wh-) questions has been discourse- based, i.e. their particular form and the echo effect are taken to be derivable from their being ‘quotes’ of a previous utterance, with a wh-phrase and/or prosodic features added to mark the re-questioned aspect. The main aim of this paper is to show that this approach is mistaken, and that an analysis is feasible whereby the pragmatic properties of echo (wh) questions are derived from their formal properties, notably their focusing properties, in a non-ad hoc way.
A Module-System Discipline for Model-Driven Software Development
2017-03-31

Model-driven development is a pragmatic approach to software development that embraces domain-specific languages (DSLs), where models correspond to DSL programs. A distinguishing feature of model-driven development is that clients of a model can select from an open set of alternative semantics of the model by applying different model transformation. However, in existing model-driven frameworks, dependencies between models, model transformations, and generated code artifacts are either implicit or globally declared in build scripts, which impedes modular reasoning, separate compilation, and programmability in general.&lt;br/&gt;We propose the design of a new module system that incorporates models and model transformations as modules. A programmer can apply transformations in import statements, thus declaring a dependency on generated code artifacts. Our design enables modular reasoning and separate compilation by preventing hidden dependencies, and it supports mixing modeling artifacts with conventional code artifacts as well as higher-order transformations. We have formalized our design and the aforementioned properties and have validated it by an implementation and case studies that show that our module system successfully integrates model-driven development into conventional programming languages.
OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143
2017-04-01

\\nBACKGROUND: Despite available treatment options for patients (pts) with recurrent glioblastoma (GBM), &lt; 5% of pts survive 5 years beyond initial diagnosis, and no single-agent therapy has demonstrated a survival benefit in the second-line setting, including bevacizumab (bev), which is approved for the treatment of recurrent disease. Nivolumab (nivo), a fully human IgG4 monoclonal antibody that inhibits the programmed death 1 receptor, has provided clinical benefit in multiple cancer types. In cohort 2 of the open-label, phase 3 CheckMate 143 study (NCT02017717), the efficacy and safety of nivo was compared with that of bev in pts with GBM experiencing their first recurrence after prior radiotherapy (RT) and temozolomide (TMZ). METHODS: Pts with no prior VEGF therapy were randomized 1:1 to receive nivo 3 mg/kg Q2W or bev 10 mg/kg Q2W until confirmed disease progression; pts were stratified by the presence/absence of measurable disease. The primary endpoint was overall survival (OS); secondary endpoints were 12-mo OS rate and investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Assessment in Neuro-Oncology criteria. RESULTS: At the time of final analyses (Jan 20, 2017), 369 pts were randomized to the nivo (n = 184) or bev (n = 185) treatment arms; of these pts, 182 received nivo and 165 received bev. At baseline, most pts in the nivo (83%) and bev (84%) arms had measurable disease, and 40% (nivo) and 43% (bev) of pts required corticosteroids, with 14% (nivo) and 15% (bev) receiving â¥ 4 mg/day. Deaths were reported in 154 (nivo) and 147 (bev) pts; median OS was 9.8 mo with nivo and 10.0 mo with bev, and the 12-mo OS rate was 42% in both arms. PFS medians were 1.5 mo (nivo) and 3.5 mo (bev). Among evaluable pts treated with nivo (n = 153) or bev (n = 156), ORRs were 8% (nivo) and 23% (bev); duration of response medians were 11.1 mo (nivo) and 5.3 mo (bev). Treatment-related AEs (TRAEs) occurred in 57% (nivo) and 58% (bev) of pts; the most common TRAEs (â¥ 10% of pts in either arm; nivo vs bev) were fatigue (21% vs 14%) and hypertension (1% vs 22%). Grade 3â4 TRAEs were reported in 18% (nivo) and 15% (bev) of pts. Serious AEs (all causality) were reported in 46% (nivo) and 35% (bev) of pts; seizure (8% vs 6%) and malignant neoplasm progression (11% vs 7%) were the only serious AEs reported in â¥ 5% of pts in either arm. AEs leading to discontinuation occurred in 10% (nivo) and 15% (bev) of pts. CONCLUSIONS: Nivo did not demonstrate an improved OS compared with bev in pts with recurrent GBM. The ORR was lower with nivo than bev; however, responses with nivo were more durable. The safety profile of nivo was consistent with that observed in other tumor types. Studies of nivo in combination with RT Â± TMZ in pts with newly diagnosed GBM are ongoing.
The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo
2017-04-01

Influenza viruses (IV) continue to pose an imminent threat to human welfare. Yearly re-occurring seasonal epidemic outbreaks and pandemics with high mortality can occur. Besides vaccination against a limited number of viral strains only a few antiviral drugs are available, which are losing their effectiveness as more and more IV strains become resistant. Thus, new antiviral approaches that omit IV resistance are urgently needed. Here, the dependency on the cellular Raf/MEK/ERK signaling pathway for IV replication opens a new perspective. In consequence, we studied the antiviral potential of the MEK inhibitor Cl-1040 (PD184352). We show that Cl-1040 significantly reduces virus titers in vitro via retention of viral RNP complexes in the cell nucleus. Furthermore, Cl-1040 is effective against a broad range of IV strains, including highly pathogenic avian IV, as well as against a Tamiflu<sup>®</sup>-resistant IV strain. Using a mouse model, we demonstrate that Cl-1040 can reduce IV lung titers in vivo. Importantly, the treatment window for Cl-1040 expands up to 48 h post infection when Tamiflu<sup>®</sup> treatment has no effect. In conclusion, Cl-1040 offers an interesting perspective for anti-IV approaches.
Blindfolding during wakefulness causes decrease in sleep slow wave activity
2017-04-01

Slow wave activity (SWA, 0.5-4 Hz) represents the predominant EEG oscillatory activity during slow wave sleep (SWS). Its amplitude is considered in part a reflection of synaptic potentiation in cortical networks due to encoding of information during prior waking, with higher amplitude indicating stronger potentiation. Previous studies showed that increasing and diminishing specific motor behaviors produced corresponding changes in SWA in the respective motor cortical areas during subsequent SWS Here, we tested whether this relationship can be generalized to the visual system, that is, whether diminishing encoding of visual information likewise leads to a localized decrease in SWA over the visual cortex. Experiments were performed in healthy men whose eyes on two different days were or were not covered for 10.5 h before bedtime. The subject's EEG was recorded during sleep and, after sleep, visual evoked potentials (VEPs) were recorded. SWA during nonrapid eye movement sleep (NonREM sleep) was lower after blindfolding than after eyes open (<i>P</i> < 0.01). The decrease in SWA that was most consistent during the first 20 min of NonREM sleep, did not remain restricted to visual cortex regions, with changes over frontal and parietal cortical regions being even more pronounced. In the morning after sleep, the N75-P100 peak-to-peak-amplitude of the VEP was significantly diminished in the blindfolded condition. Our findings confirm a link between reduced wake encoding and diminished SWA during ensuing NonREM sleep, although this link appears not to be restricted to sensory cortical areas.
Digital Space Systems Engineering through Semantic Data Models
2017-04-01

Model-based Systems Engineering requires an intuitive semantically strong data model to enable precise data specification and provide the foundation for fruitful data analyses during data evolution. This paper presents an approach to use the Web Ontology Language (OWL) for specifying a Conceptual Data Model (CDM) being transformed into a format understandable by the Eclipse Modeling Framework (EMF) to profit from powerful data handling and knowledge management functions during runtime. Coalescing OWL with EMF brings up the strength of both approaches leading to considerably better data models with less failure potential and reveal notably more analysis potential by using a common data model specification. This approach also enables the direct application of reasoning functionality for automatic inference of several pieces of knowledge and automatic checks as illustrated by examples from aerospace industry.
Resilient Integration of Distributed High-Performance Zones into the BelWue Network Using OpenFlow
2017-04-01

BelWue is the Internet service provider for higher education and research institutions in Baden-Wuerttemberg, Germany. Recently, high-performance zones (HPZs) have been established on major university campuses and interconnected with a high-speed network for innovation and research (NeIF). This work presents the SDN-NeIF architecture, a resilient integration of the HPZs into the NeIF and the legacy infrastructure of BelWue and its connected universities, leveraging OpenFlow and BGP. The concept is validated by a prototype, results from a field trial are provided, and additional benefits of using SDN are discussed.
An easy-to-use image labeling platform for automatic magnetic resonance image quality assessment
2017-04-01

In medical imaging, images are usually evaluated by a human observer (HO) depending on the underlying diagnostic question which can be a time-demanding and cost-intensive process. Model observers (MO) which mimic the human visual system can help to support the HO during this reading process or can provide feedback to the MR scanner and/or HO about the derived image quality. For this purpose MOs are trained on HO-derived image labels with respect to a certain diagnostic task. We propose a non-reference image quality assessment system based on a machine-learning approach with a deep neural network and active learning to keep the amount of needed labeled training data small. A labeling platform is developed as a web application with accounted data security and confidentiality to facilitate the HO labeling procedure. The platform is made publicly available.
The unfinished Reformation
2017-04-01

In this article Jürgen Moltmann offers a clarion call to the whole church at the eve of the 500th anniversary of the Protestant Reformation to be semper reformanda. Moltmann discusses five major points: the theological implications of the contemporary move from a culture of dispute to a culture of dialogue; the unity of the Christian church under what he terms “the papacy of all believers”; the only true “reformation by faith alone” initiated by the Anabaptists; the ecumenical importance of celebrating the Lord’s Supper together; and, finally, the idea that a reformation of hope needs to follow a reformation of faith.
P06.05 The natural HLA ligandome of glioblastoma stem-like cells: Antigen discovery for T-cell based immunotherapy
2017-04-01

\\nIntroduction: Glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Materials and Methods: HLA classÂ IÂ and classÂ II ligands of culture-expanded GSC lines (GS-2, GS-5, GS-9) and snap frozen freshly resected glioblastoma samples (n=9) were isolated by immunoprecipitation and characterized using liquid chromatography and tandem mass spectrometry (LC-MS/MS). HLA ligandomes of GSC and freshly resected patient samples were compared to a comprehensive HLA ligandome database of human normal tissues including human brain. Immunogenicity of top-ranking candidates was shown by T-cell priming followed by intracellular cytokine staining and HLA multimer staining. Results: We identified 15 antigens represented by 38 different HLA ligands showing natural presentation both on GSC and patient samples. Importantly, in vitro immunogenicity assays clearly suggest these peptides to be epitopes of functional CD8 T-cell responses thus rendering them prime candidates for immunotherapy. Conclusions: We present an antigen discovery approach based on the comparative analysis of the HLA classÂ IÂ and HLA classÂ II peptidomes of GSC and patient samples. The characterization of the natural GSC-immunopeptidome is an important step towards the informed design of highly specific T-cell immunotherapy targeting the glioblastoma stem cell niche.
Determination of protein turnover in E. coli cells during exit from persistence
2017-04-01

Chronic infections that can relapse even after recurrent courses of antibiotic therapy are a major challenge in treatment of infectious diseases. In a number of bacterial pathogens, a very small subpopulation of cells, known as persisters, can become transiently tolerant to multiple antibiotics by restraining their growth and entering a dormant‐like state termed persistence. Key players in persistence are toxin‐antitoxin (TA) modules that encode a toxin, that inhibits cell growth, and antitoxin that regulates toxin activity. In E. coli , toxic activity of a Ser/Thr kinase HipA is responsible for growth inhibition and increased levels of persisters. In stress conditions, HipA phosphorylates and inhibits glutamate‐tRNA ligase (GltX) causing strong inhibition of translation. Such dormant cells are able to sense when conditions have improved, re‐initiate their growth and exit persistent state (resuscitate). Since the molecular mechanisms that govern the switch between persistence and resuscitation are largely unknown, we aimed to study early protein synthesis and turnover during resuscitation by performing a time‐resolved analysis of protein translation during the exit from persistent state. To that end, we employed pulse labeling with stable isotope‐labeled amino acids in cell culture (SILAC), in combination with high resolution mass spectrometry‐based proteomics. We enriched the low‐frequency persister cells by inducing the hipA gene , which caused immediate growth arrest, and treated the culture with a high dose of ampicillin to lyse and remove non‐persister cells. To trigger cell growth and resuscitation we induced the antitoxin‐encoding hipB gene. Resuscitating cells were pulse‐labeled with isotopically labeled lysine and harvested in regular intervals. In this experimental setup, only the newly synthesized proteins from resuscitated persister cells could incorporate lysine, enabling the quantification of the protein turnover during resuscitation. Within the first five hours after initiation of resuscitation we were able to measure SILAC label incorporation in up to 500 proteins and estimate their turnover rates. Intriguingly, most of the quantified proteins were involved in the regulation of transcription, translation and response to stress. We are currently setting up follow up experiments to investigate the role of several high‐turnover proteins in resuscitation. To our knowledge, this is the first application of a pulse‐chase SILAC‐based proteomic approach to study protein synthesis in the field of bacterial persistence. This study can largely help in understanding of the molecular basis of the exit from persistence, a state that is greatly responsible for reactivation of disease.
Abstract B44: Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer
2017-04-01

Abstract Introduction: One of the major mechanisms of radioresistance in solid tumors is the activa-tion of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through stimulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). As it is known that the PI3K/Akt pathway is hyperactivated in K-RAS mutated (K-RASmut), we investigated if targeting PI3K would be a potential approach for enhancing radiosensitivity of K-RASmut cells non-small lung cancer (NSCLC). Methods: The K-RASmut NSCLC cell lines A549 and H460 were utilized to examine the effect of PI3K inhibition on Akt signaling, non-homologous end joining (NHEJ) repair of DSBs, and post-irradiation cell survival. Results: Short-term (1-2 h) pre-treatment of K-RASmut cells with the PI3K inhibitor PI-103 (1 μM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect in K-RASmut cells after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with PI-103 together MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through NHEJ leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts in vivo. Akt and P-DNA-PKcs activity was inhibited 30 min post-irradiation in xenografts, which were pre-treated by PI-103 30 min before irradiation. However, after a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Conclusion: Due to ERK-dependent reactivation of Akt in K-RAS mutated NSCLC cells, dual targeting of PI3K and MEK is an effective approach to induce radiosensitization. Acknowledgement: This work was supported by grants from the Deutsche Forschungsge-meinschaft (DFG, RO 527/7-1) awarded to HPR /MT and GRK 1302/2 (T11) awarded to MT/HPR. Citation Format: Mahmoud Toulany, Mari Ilda, Deric L. Wheeler, H. Peter Rodemann. Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B44.
P14.10 Secondary CNS involvement in malignant lymphoma: Data from a multicenter prospective international registry
2017-04-01

In systemic lymphoma, a secondary CNS involvement (secondary CNS lymphoma, SCNSL) occurs in 2-5% of patients. With conventional therapy the prognosis of SCNSL is poor with median overall survival (OS) in most series of approx. 6 months. The optimal therapeutic management has not been established; long-term control seems possible only with intensive chemotherapy including high-dose chemotherapy with autologous stem-cell transplantation (HD-ASCT). Since 2011, data on SCNSL patients have been prospectively collected in a multicenter international registry. Thus far, 173 immunocompetent patients with CNS involvement at diagnosis (cohort I, n=30) or at progression/relapse (cohort II, n=143) from 41 centers have been included. The median age was 63 years (26-86), 111 (64%) were male. The median time to CNS involvement in cohort II was 10.6 months Of 155 patients with data available, 122 (79%) had aggressive B-cell lymphoma, 25 (16%) indolent lymphoma, 5 (3%) mantle cell lymphoma and 3 (2%) T-cell lymphoma. Lymphoma localization in the CNS was brain parenchyma in 84 (54%), meningeal compartment in 37 (24%), spinal cord in 2 (1%) and a combination of these compartments in 32 (21%). Simultaneous systemic involvement was found in 42% of patients in cohort II. Therapy for CNS involvement and outcome was analyzed in 99 patients thus far (16 in cohort I and 83 in cohort II). Systemic therapy alone was given to 48 (49%), systemic + intrathecal therapy to 43 (43%), intrathecal therapy alone to 5 (5%), radiotherapy alone to 2 (2%); one patient did not receive any treatment. Systemic chemotherapy was high-dose methotrexate-based in 81 (89%) and high-dose cytarabine-based in 53 (58%); 61 (61% of all) patients received rituximab systemically. Liposomal cytarabine was the most frequent intrathecal therapy given in 30 out of 48 patients (63%). HD-ASCT was performed in 25 (25%) patients. The median progression-free survival (PFS) was 5.9 months (95% CI 3.1-8.7), the median OS 18.6 months (95% CI 10.3-26.9). On univariate analysis, CNS lymphoma at diagnosis, no meningeal involvement, better ECOG performance status, treatment with rituximab, HD-ASCT and response to therapy were associated with better outcome. Multivariate analysis was done using blockwise variable selection, starting with demographic data and findings at first diagnosis, and subsequently enlarging the model by findings at CNS involvement, therapy of CNS involvement and outcome of CNS therapy. Here, a probable prognostic role for cohort I and HD-ASCT (for OS) and no meningeal involvement (for both PFS and OS) was found with response to CNS therapy being the dominating prognostic factor (for both OS and PFS). This is the largest prospective series on SCNSL in the era of modern lymphoma therapies. The results underscore the role of intensive therapy for long-term control of SCNSL. At the meeting, an updated analysis will be presented.
P03.21 Casp9 germline mutation in a family with multiple brain tumors
2017-04-01

We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which four brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry demonstrated the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.