bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B18: Development of human STING agonists for prostate cancer immunotherapy
Authors: Wu Jian Hui 
Published: January 2017

Abstract
Recent studies have identified the host STING pathway as a critical mechanism of innate immune sensing of cancer, that drives type-I interferons (IFNs) production and promotes aggressive antitumor responses. Thus, STING agonists could be candidates for testing as stimulants for anticancer immune activity. Although DMXAA binds and activates mouse STING, it cannot activate human STING (hSTING). This species specificity is thought to be the reason that DMXAA showed dramatic effect against solid tumor in rodent models, but failed in human clinical trials. In this project, we aim to identify novel chemical compounds as agonists of hSTING.
By combining in silico screening and in vitro assays, we have discovered two novel chemical compounds that activate hSTING. Direct binding of our compounds with hSTING was confirmed by Surface plasmon resonance (SPR) analysis. We demonstrated that our hSTING agonist activated interferon signaling pathway in monocytic human THP-1 cells, which express endogenous hSTING. Further, our compound itself is not cytotoxic to 22Rv1 prostate cancer cells, but the spent supernatants of the THP-1 cells exposed to our compound are cytotoxic to 22Rv1 cells. Chemical optimization of initial active compounds is in progress. We aim to generate compound candidates as potent hSTING agonists for in vivo evaluation in rodent models.
Note: This abstract was not presented at the conference.
Citation Format: Jian Hui Wu. Development of human STING agonists for prostate cancer immunotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B18.
Abstract B30: Inhibition of eIF4E/MNK axis by novel MNKDAs reduces breast cancer tumor growth, migration, invasion and metastasis
Authors: Ramalingam Senthilmurugan , Gediya Lalji , Ramamurthy Vidya , Choi Yong , Lapidus Rena , Vincent Njar 
Published: January 2017

Abstract
Triple-negative breast cancer (TNBC) represents a molecularly heterogeneous subgrouping of high-risk breast tumors characterized by aggressive behavior, poor prognosis and lack of targeted therapeutic options. The translation initiation factor eIF4E, an oncogene essential for cap-dependent translation of specific mRNAs critical for cell division, cell survival, angiogenesis, and metastasis is commonly overexpressed in primary breast cancers including TNBC. eIF4E therapeutic targeting is considered novel and significant because tumor cells specifically overexpress eIF4E and develop an oncogene addiction to eIF4E, rendering the cells vulnerable to eIF4E inhibition, whereas normal cells are relatively insensitive. Phosphorylation of eIF4E at serine-209 is critical for the oncogenic activity of eIF4E, and it has been suggested that chemical compounds that prevent the phosphorylation of eIF4E could act as effective anticancer drugs. Herein, we report that a novel inhibitor of peIF4E function (Novel Retinamides, NRs), safely and potently suppresses breast tumor formation. Administration of novel retinamides (mnk degrading agents: MNKDAs) blocked the growth of primary breast tumors in MDA-MB-231 xenograft model, TNBC patient derived xenografts (PDX), and reduced the development of lung metastases in an invasive model. Mechanistically, NRs resulted in the degradation of MNKs (MNK1 and MNK2), a key kinase chiefly responsible for phosphorylating and activating eIF4E. This in turn hampered peIF4E involved translation initiation and activation of genes associated with cell proliferation and survival. Furthermore, MNK degradation by NRs also suppressed epithelial-to-mesenchymal transition, a process crucial for metastasis as evident by increased expression of E-cadherin and reduced expression of N-cadherin, fibronectin and vimentin; snail, slug, twist, fibronectin, claudin, lamin, TCF/ZEB-1, beta catenin, MMPs and vimentin. Taken together, the preclinical evidence of tumor regression and metastasis in TNBC models suggest that NRs offers considerable promise as new therapeutic candidate to target TNBC and metastatic breast cancer.
Citation Format: Senthilmurugan Ramalingam, Lalji Gediya, Vidya Ramamurthy, Yong Choi, Rena Lapidus, Njar Vincent. Inhibition of eIF4E/MNK axis by novel MNKDAs reduces breast cancer tumor growth, migration, invasion and metastasis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B30.
Abstract B33: Persistent activation of ERK and SMAD4 nuclear retention by high free fatty acids promote breast cancer metastasis
Authors: Wu Yong , Yu Xiaoting , Bhat Kruttika , Dwabe Sami , Atefi Mohammad , Vadgama Jay 
Published: January 2017

Abstract
Obesity increases the risk of developing distant metastatic recurrence, and diminishes overall and breast cancer-specific survival; however, the mechanisms behind this correlation and relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are usually elevated in obese individuals. Here, using human breast cancer cell lines, we found that TGF-β transiently activates the extracellular signal-regulated kinase (ERK) and subsequently marks SMAD4 for phosphorylation, which facilitates SMAD4-ubiquitin specific peptidase 9, X-linked (USP9x) interaction, SMAD4 nuclear retention, SMAD3-SMAD4 complex nuclear accumulation, and stimulated TGF-β/SMAD3–mediated transcriptional activity of Twist and Snail. USP9x competitively inhibited the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding and monoubiquitinating SMAD4. This process maintained SMAD4 nuclear retention and stabilized the SMAD3/SMAD4 complex in the nucleus. Inhibition of ERK resulted in SMAD4 de-phosphorylation, USP9x-SMAD4 disassociation and SMAD4-TIF1γ interaction, which ultimately marks SMAD4 for mono-ubiquitination, leading to SMAD4 nuclear export and termination of the transcription of Twist and Snail. In addition, loss of USP9x abolished TGF-β–induced SMAD4 nuclear retention and SMAD3/SMAD4 formation, leading to inhibition of Twist and Snail expression. We also found that ERK-induced SMAD4 T277 phosphorylation and SMAD4-USP9x interaction was required for TGF-β–induced breast cancer invasion, which was attributed to SMAD3/SMAD4-dependent up-regulation of the transcription factors, Twist and Snail. Importantly, FFA further facilitates TGF-β–induced ERK activation, SMAD4 phosphorylation, SMAD4 nuclear retention and SMAD3/SMAD4 formation, thus promoting TGF-β–dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. Additionally, phospho-ERK and -SMAD4 levels correlated with activated TGF-β signaling and metastasis in obese patient breast cancer specimens. Altogether, we demonstrated that USP9x promotes breast cancer invasion by promoting nuclear retention of SMAD4 and identified crosstalk between USP9x and TGF-β/ERK/SMAD4/SMAD3 pathways. Our study highlights the vital interaction of USP9x and SMAD4 for governing TGF-β signaling and dyslipidemia-induced aberrant TGF-β activation during breast cancer metastasis.
Citation Format: Yong Wu, Xiaoting Yu, Kruttika Bhat, Sami Dwabe, Mohammad Atefi, Jay Vadgama. Persistent activation of ERK and SMAD4 nuclear retention by high free fatty acids promote breast cancer metastasis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B33.
Abstract B41: Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors
Authors: Single Andrew , Chen Augustine , Telford Bryony , Beetham Henry , Guilford Parry 
Published: January 2017

Abstract
E-cadherin (CDH1) is a cell-cell adhesion protein implicated in the epithelial-mesenchymal transition and frequently dysregulated in diffuse gastric cancer (DGC) and invasive lobular breast cancer (ILBC). Germline CDH1 mutations define hereditary diffuse gastric cancer (HDGC), a rare cancer syndrome characterised by highly penetrant DGC and an elevated rate of ILBC in females. There is a strong need to develop specific chemopreventative strategies for CDH1 germline mutation carriers which are capable of reducing the viability of early stage CDH1-deficient cancers whilst minimizing side effects.
We have previously applied a synthetic lethal approach to an isogenic pair of MCF10A breast cell lines, one with and one without functional CDH1 expression (MCF10A CDH1-/-), to screen for drugs which preferentially reduce the viability of CDH1-deficient cells. This led to our finding that histone deacetylase inhibitors (HDACi; entinostat and vorinostat) and SRC inhibitors (SRCi; saracatinib) are involved in synthetic lethal interactions with MCF10A CDH1-/- cells. Single agent therapy, however, only produces a modest synthetic lethal effect, leading to our interest in developing synergistic drug combinations.
We have now shown that statins, inhibitors of the HMG-CoA reductase enzyme, also show a synthetic lethal phenotype in the MCF10A isogenic cell line pair. This result suggests that survival of E-cadherin-deficient cells may be enhanced by the mevalonate pathway, a metabolic pathway responsible for synthesizing prenyl groups and subsequently activating the small GTPase proteins Rho, Rac, and Cdc42. SRC is also a known activator of GTPase proteins and combined statin and saracatinib treatment caused an enhanced reduction in cell viability in the isogenic MCF10A cells whilst maintaining the synthetic lethal phenotype. This drug combination was shown to be synergistic in both cell lines using the Chou-Talalay median effect analysis and is the first known example of synergy between a statin and SRC inhibitor. Combined statin and HDACi treatment also enhanced cell viability inhibition and was synthetic lethal in the MCF10A pair. This effect was observed using both class-I specific (entinostat) and pan- (vorinostat) HDACi and was synergistic in both cell lines using median effect analysis. These are the first known examples of synergistic drug combinations being used in the field of synthetic lethality and serve as a foundation for novel DGC and ILBC treatment options.
Citation Format: Andrew Single, Augustine Chen, Bryony Telford, Henry Beetham, Parry Guilford. Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B41.
SYNAMET - A Microcorpus of Synesthetic Metaphors. Preliminary Premises of the Description of Metaphor in Discourse
Authors: Zawisławska Magdalena Anna 
Published: January 2017

SYNAMET - A Microcorpus of Synesthetic Metaphors. Preliminary Premises of the Description of Metaphor in DiscourseThis article describes the preliminary premises of metaphor annotation in SYNAMET - the developing microcorpus of synesthetic metaphors. The analysis is based on the CLST theory (Context-Limited Simulation Theory) put forward by D. Ritchie. According to this theory, the metaphor’s vehicle may activate various types of associations between words: semantic relations, perceptual sensations, or emotional simulations. The range of potential associations evoked by the vehicle is limited by the topic, i.e. the lexical context in which the metaphor appears. The relations between the vehicle and the topic may be presented in the form of a semantic frame.To reconstruct the frames within the project, linguistic works devoted to sensory perception- vision, hearing, smell and taste- will be utilized. The corpus annotation will consist of the following stages: 1) metaphor identification, 2) indication of the metaphor cluster (CM) - a phrase or a passage of the text, centered around one referent, 3) isolation of the metaphorical units (MU) - word forms or phrases combining lexemes primarily belonging to different perceptual frames.The outcome of the MU analysis will include: a general metaphorical scheme of the MU, lexical items activating the frame of the MU (together with their grammatical description), a detailed metaphor scheme of the MU, and the semantic and grammatical categorization of the MU. SYNAMET – mikrokorpus metafor synestezyjnych. Wstępne założenia opisu metafory w dyskursieArtykuł opisuje wstępne założenia anotacji metafor w powstającym mikrokorpusie metafor synestezyjnych SYNAMET. Podstawą metody opisu będzie teoria CLST (Context-Limited Simulation Theory) D. Ritchie’go. W myśl tej teorii nośnik metafory (vehicle) może aktywować różne typy powiązania między wyrazami: semantyczne, zmysłowe lub emocjonalne. Potencjalny zakres powiązań nośnika ogranicza topik (topic), czyli kontekst, w którym metafora się pojawia. Powiązania nośnika oraz topiku przedstawia się w postaci ram interpretacyjnych.W rekonstrukcji ram na potrzeby korpusu wykorzystane zostaną prace językoznawcze poświęcone percepcji zmysłowej: wzrokowi, słuchowi, zapachowi, smakowi. Anotacja korpusu będzie przebiegać według następującego schematu: 1) identyfikacja metafor, 2) wyodrębnienie w tekście układu metaforycznego (UM) – frazy lub fragmentu tekstu, zorganizowanego wokół jednego referenta, 3) wyodrębnienie jednostek metaforycznych (JM) – form wyrazowych lub fraz, w których występuje połączenie leksemów przynależnych prymarnie do różnych ram percepcyjnych.Wyniki analizy JM zostaną przestawione w postaci: ogólnego schematu metaforycznego, zestawu wyrazów aktywujących ramy (wraz z ich opisem gramatycznym), szczegółowego schematu metaforycznego, kategoryzacji semantycznej i gramatycznej metafor.
Technical Features of the Architecture of an Electronic Trilingual Dictionary
Authors: Chetverikov Grygorii , Vechirska Iryna , Puzik Oleksii 
Published: January 2017

Technical Features of the Architecture of an Electronic Trilingual DictionaryThis article is devoted to the development of the software system used to create an English-Russian-Ukrainian terminological dictionary. Scanned and recognized documents in MSWord format were the input data for the dictionary. Issues which appeared during the parsing of the input data are analyzed and solutions using regular expressions are identified. This article also describes the scheme of the dictionary’s lexicographical database, and its classes of models, views and view models.In addition, a detailed description of the software system from a user’s perspective is included, the prospects for the usage of the dictionary are discussed, and the methods used during the development of the system are described.The software system is built using the design pattern Model-View-View-Model. Through the use of this pattern, internal logic is separated from user interface, thus changes made in different parts of the software may be independent. The developed software system allows users to edit, to fill, and thus to create new thematic transferable electronic dictionaries. The main advantage of the system is the equality of languages, i.e. each user can decide which language is to be major. Opracowanie oprogramowania trzyjęzycznego słownika elektronicznegoArtykuł jest poświęcony opracowaniu oprogramowania rosyjsko-ukraińsko-angielskiego słownika terminologicznego. Za wejściowe dane autorzy przyjęli zeskanowane i rozpoznane dokumenty w formacie MSWord. Błędy powstałe w czasie analizy składniowej wejściowych danych zostały przeanalizowane, a autorzy wskazali drogę ich likwidacji za pomocą regularnych wyrażeń.W pracy została dokładnie opisana baza leksykograficzna danych słownika, zostały opisane klasy modelu danych i klasy modelu prezentacji systemu. Oprogramowanie jest zbudowane w taki sposób, aby można było wykorzystać szablon projektowania Model-View-ViewModel. Dzięki wykorzystaniu tego szablonu interfejs użytkowania jest oddzielony od logiki programu, co pozwala wprowadzać niezależne zmiany poszczególnych części oprogramowania.Sporządzone oprogramowanie pozwala na redagowanie, uzupełnienie i tym samym tworzenie nowych tematycznych słowników przekładowych. Zaletą systemu jest równorzędność języków. Autorzy nakreślili zarówno sposoby wykorzystania samego słownika, jak i metody jego budowania.
Between Galileo and Darwin, or Towards a Unified Mode of Idealization in Cognitive Linguistics
Authors: Strugielska Ariadna 
Published: January 2017

Between Galileo and Darwin, or Towards a Unified Mode of Idealization in Cognitive LinguisticsThe aim of this paper is to demonstrate that Cognitive Linguistics is in need of a coherent model through which the meaning of symbolic units can be represented. Departing from the premise that scientific theorizing requires taking a stance on the nature of idealization, the current discussion concentrates on cognitive linguists’ perspectives on the process, and reveals a lack of uniformity in the models proposed.On the whole, generalizations in Cognitive Linguistics are conducted in a manner reflecting the basic commitments of the approach, and hence the idealized models discussed strive to capture the embodied nature of cognition reflected in the semantic poles of symbolic units.However, a detailed analysis shows that a number of significant choices underlying the process of abstraction are random. Consequently, the modes of idealization revealed through semantic frames and cognitive domains lead to the emergence of barely compatible semantic categories which are assumed to represent the meaning of the same symbolic unit.It is thus postulated that if Cognitive Linguistics aspires to become a mature scientific theory, whose constructs and hypotheses can be operationalized and falsified, it needs to develop a more unified framework in which the situated and distributed natures of meaning are accounted for in a motivated manner. Między Galileuszeam a Aarwinem albo o spójnym modelu idealizacji w językoznawstwie kognitywnymCelem niniejszego artykułu jest wskazanie konieczności stworzenia spójnego modelu reprezentacji znaczeniowej jednostek symbolicznych w obrębie językoznawstwa kognitywnego. Przyjmując jako punkt wyjścia założenie, że podstawą budowania teorii naukowych jest idealizacja, dokonany zostaje przegląd modeli reprezentacji semantycznej, proponowanych przez czołowych językoznawców kognitywnych.Analiza wyidealizowanych modeli kognitywnych w ujęciu Fillmore’a (1985), Lakoffa (1987) i Langackera (1987) wskazuje na zbieżności na poziomie ogólnym, czyli na zgodność, iż biegun semantyczny jednostki symbolicznej winien odzwierciedlać ucieleśnioną naturę poznania. Na poziomie szczegółowym jednakże można zauważyć szereg rozbieżności między omawianymi modelami, wynikających z nieuzasadnionych wyborów badaczy dotyczących sposobu abstrahowania.W rezultacie wykazano, że znaczenie tej samej jednostki symbolicznej jest w językoznawstwie kognitywnym definiowane odmiennie, w zależności od przyjętej procedury idealizacji. Zaobserwowane niekonsekwencje metodologiczne podają w wątpliwość dojrzałość językoznawstwa kognitywnego jako teorii naukowej.
On the Dynamical Control of the Mesosphere–Lower Thermosphere by the Lower and Middle Atmosphere
Authors: Smith Anne K. , Pedatella Nicholas M. , Marsh Daniel R. , Matsuo Tomoko 
Published: January 2017

Abstract
The NCAR Whole Atmosphere Community Climate Model (WACCM) is used to investigate the dynamical influence of the lower and middle atmosphere on the upper mesosphere and lower thermosphere. In simulations using a methodology adapted from the “specified dynamics” (nudged) version of the model, horizontal winds and temperature over part of the vertical range of the atmosphere are relaxed toward results from a previous simulation that serves as the true simulation, equivalent to meteorological analysis. In the upper mesosphere, the magnitude of the divergence of the constrained simulations from the true simulation depends on the vertical extent and frequency of the data used for nudging the model and grows with altitude. The simulations quantify the error growth of the model dynamical fields when data and forcing terms are known exactly and there are no model biases. The error growth rate and the ultimate discrepancy between the nudged and true fields depend strongly on the method used for representing gravity wave drag. The largest error growth occurs when the gravity wave parameterization uses interactive wave sources that depend on convective activity or fronts. Errors are reduced when the same parameterization is used with smoothly varying specified wave sources. The smallest errors are seen when the parameterized gravity wave drag is replaced by linear Rayleigh friction damping on the wind speed. These comparisons demonstrate the role of gravity waves in transporting the variability of the troposphere into the mesosphere and lower thermosphere.
Cloud-Base Height Estimation from VIIRS. Part I: Operational Algorithm Validation against CloudSat
Authors: Seaman Curtis J. , Noh Yoo-Jeong , Miller Steven D. , Heidinger Andrew K. , Lindsey Daniel T. 
Published: January 2017

AbstractThe operational VIIRS cloud-base height (CBH) product from the Suomi–National Polar-Orbiting Partnership (SNPP) satellite is compared against observations of CBH from the cloud profiling radar (CPR) on board CloudSat. Because of the orbits of SNPP and CloudSat, these instruments provide nearly simultaneous observations of the same locations on Earth for a ~4.5-h period every 2–3 days. The methodology by which VIIRS and CloudSat observations are spatially and temporally matched is outlined. Based on four 1-month evaluation periods representing each season from June 2014 to April 2015, statistics related to the VIIRS CBH retrieval performance have been collected. Results indicate that when compared against CloudSat, the VIIRS CBH retrieval does not meet the error specifications set by the Joint Polar Satellite System (JPSS) program, with a root-mean-square error (RMSE) of 3.7 km for all clouds globally. More than half of all matching VIIRS pixels and CloudSat profiles have CBH errors exceeding the 2-km error requirement. Underscoring the significance of these statistics, it is shown that a simple estimate based on a constant cloud geometric thickness of 2 km outperforms the current operational CBH algorithm. It was found that the performance of the CBH product is impacted by the accuracy of upstream retrievals [primarily cloud-top height (CTH)] and the a priori information used by the CBH retrieval algorithm. However, even when CTH errors were small, CBH errors still exceed the JPSS program error specifications with an RMSE of 2.3 km.
Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment
Authors: Shafat Manar S. , Oellerich Thomas , Mohr Sebastian , Robinson Stephen D. , Edwards Dylan R. , Marlein Christopher R. , Piddock Rachel E. , Fenech Matthew , Zaitseva Lyubov , Abdul-Aziz Amina , Turner Jeremy , Watkins Johnathan A. , Lawes Matthew , Bowles Kristian M. , Rushworth Stuart A. 
Published: January 2017

Key PointsBone marrow adipocytes support AML survival. AML induces adipocyte lipolysis of triglyceride to free fatty acids and subsequent transport by FABP4.
TCR-based therapy for multiple myeloma and other B-cell malignancies targeting intracellular transcription factor BOB1
Authors: Jahn Lorenz , Hombrink Pleun , Hagedoorn Renate S. , Kester Michel G. D. , van der Steen Dirk M. , Rodriguez Tania , Pentcheva-Hoang Tsvetelina , de Ru Arnoud H. , Schoonakker Marjolein P. , Meeuwsen Miranda H. , Griffioen Marieke , van Veelen Peter A. , Falkenburg J. H. Frederik , Heemskerk Mirjam H. M. 
Published: January 2017

Key Points
Isolation and characterization of a high-affinity TCR targeting the intracellular B cell–specific transcription factor BOB1. T cells expressing a BOB1-specific TCR lysed and eradicated primary multiple myeloma and other B-cell malignancies in vitro and in vivo.