julilili42/papers huggingface dataset:
Adenosine Receptor Adora2b Plays a Mechanistic Role in the Protective Effect of the Volatile Anesthetic Sevoflurane during Liver Ischemia/Reperfusion
2016-07-14

Abstract Background Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet–neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR. Methods Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a −/− , and Adora2b −/− mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction. Results Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type ( P &lt; 0.05) but not in Adora2b −/− mice (n ≥ 5). Sevoflurane reduced PNC sequestration 1.9-fold ( P &lt; 0.05) and alanine aminotransferase release 3.5-fold ( P &lt; 0.05) in wild-type but not in Adora2b −/− mice (n = 5). In Adora2a −/− mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n ≥ 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4). Conclusions Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients.
A Quasi-Free-Standing Single Layer of a B3N3-Doped Nanographene Molecule Deposited on Au(111) Single Crystals
2016-07-14

We investigate the electronic structure of a quasi-free-standing single layer of a B3N3-doped nanographene molecule deposited on Au(111) single crystals. The single layer shows very high orientational order, as well as high chemical and vacuum stability. We demonstrate that the borazine doping is an alternative way to design a material having electronic properties similar to doped graphene/h-BN. Specifically, borazine doping of nanographenes leads to tuning the gap in the same energy range of carbon-doped h-BN, in agreement with the expected doping effect of graphene quantum dots in h-BN. We support our experimental findings by first-principles calculations.
Second harmonic generation properties of Ca3(O3C3N3)2 ‐Sr3(O3C3N3)2 solid solutions
2016-07-14

Solid solutions of the second harmonic generation (SHG) materials Ca 3 (O 3 C 3 N 3 ) 2 (CCY) and Sr 3 (O 3 C 3 N 3 ) 2 (SCY) were prepared via exothermic solid state metathesis reactions from appropriate amounts of the corresponding metal chlorides and potassium cyanate at 525 °C. The change in SHG intensity caused by the successive cation substitution is reported. Differential thermal analyses are used to explore the SCY–K(OCN) phase diagram as a medium for the growth of SCY crystals.
High-Resolution Three-Dimensional ComputedTomography for Assessing ComplicationsRelated to Intrathecal Drug Delivery
2016-07-14

Background: The assessment of the functionality of intrathecal drug delivery (IDD) systems remains difficult and time-consuming. Catheter-related problems are still very common, and sometimes difficult to diagnose. Objectives: The aim of the present study is to investigate the accuracy of high-resolution three-dimensional computed tomography (CT) in order to detect catheter-related pump dysfunction. Study Design: An observational, retrospective investigation. Setting: Academic medical center in Germany. Methods: We used high-resolution three dimensional (3D) computed tomography with volume rendering technique (VRT) or fluoroscopy and conventional axial-CT to assess IDDrelated complications in 51 patients from our institution who had IDD systems implanted for the treatment of chronic pain or spasticity. Results: Twelve patients (23.5%) presented a total of 22 complications. The main type of complication in our series was catheter-related (50%), followed by pump failure, infection, and inappropriate refilling. Fluoroscopy and conventional CT were used in 12 cases. High-resolution 3D CT VRT scan was used in 35 instances with suspected yet unclear complications. Using 3D-CT (VRT) the sensitivity was 58.93% – 100% (CI 95%) and the specificity 87.54% – 100% (CI 95%).The positive predictive value was 58.93% – 100% (CI 95%) and the negative predictive value: 87.54% – 100% (CI 95%). Fluoroscopy and axial CT as a combined diagnostic tool had a sensitivity of 8.3% – 91.7% (CI 95%) and a specificity of 62.9% – 100% (CI 95%). The positive predictive value was 19.29% – 100% (CI 95%) and the negative predictive value: 44.43% – 96.89% (CI 95%). Limitations: This study is limited by its observational design and the small number of cases. Conclusion: High-resolution 3D CT VRT is a non- invasive method that can identify IDDrelated complications with more precision than axial CT and fluoroscopy. Key words: Volume rendering technique (VRT), intrathecal drug delivery systems, highresolution 3D computed tomography, complications, spasticity, chronic pain, cost effectiveness, fluoroscopy
Large Observatory for x-ray Timing (LOFT-P): a Probe-class mission concept study
2016-07-14

LOFT-P is a mission concept for a NASA Astrophysics Probe-Class (&lt;$1B) X-ray timing mission, based on the LOFT M-class concept originally proposed to ESAs M3 and M4 calls. LOFT-P requires very large collecting area, high time resolution, good spectral resolution, broad-band spectral coverage (2-30 keV), highly flexible scheduling, and an ability to detect and respond promptly to time-critical targets of opportunity. It addresses science questions such as: What is the equation of state of ultra dense matter? What are the effects of strong gravity on matter spiraling into black holes? It would be optimized for sub-millisecond timing of bright Galactic X-ray sources including X-ray bursters, black hole binaries, and magnetars to study phenomena at the natural timescales of neutron star surfaces and black hole event horizons and to measure mass and spin of black holes. These measurements are synergistic to imaging and high-resolution spectroscopy instruments, addressing much smaller distance scales than are possible without very long baseline X-ray interferometry, and using complementary techniques to address the geometry and dynamics of emission regions. LOFT-P would have an effective area of &gt;6 m2, &gt; 10x that of the highly successful Rossi X-ray Timing Explorer (RXTE). A sky monitor (2-50 keV) acts as a trigger for pointed observations, providing high duty cycle, high time resolution monitoring of the X-ray sky with ∼20 times the sensitivity of the RXTE All-Sky Monitor, enabling multi-wavelength and multimessenger studies. A probe-class mission concept would employ lightweight collimator technology and large-area solid-state detectors, segmented into pixels or strips, technologies which have been recently greatly advanced during the ESA M3 Phase A study of LOFT. Given the large community interested in LOFT (&gt;800 supporters∗, the scientific productivity of this mission is expected to be very high, similar to or greater than RXTE (∼ 2000 refereed publications). We describe the results of a study, recently completed by the MSFC Advanced Concepts Office, that demonstrates that such a mission is feasible within a NASA probe-class mission budget.
SXP 214: AN X-RAY PULSAR IN THE SMALL MAGELLANIC CLOUD, CROSSING THE CIRCUMSTELLAR DISK OF THE COMPANION
2016-07-14

ABSTRACT Located in the Small Magellanic Cloud (SMC), SXP 214 is an X-ray pulsar in a high mass X-ray binary system with a Be-star companion. A recent survey of the SMC under a Chandra X-ray Visionary program found that the source was in a transition when the X-ray flux was on a steady rise. The Lomb–Scargle periodogram revealed a pulse period of 211.49 ± 0.42 s, which is significantly (&gt;5 σ ) shorter than the previous measurements made with XMM-Newton and RXTE . This implies that the system has gone through sudden spin-up episodes recently. The pulse profile shows a sharp eclipse-like feature with a modulation amplitude of &gt;95%. The linear rise of the observed X-ray luminosity from ≲2× to erg s −1 is correlated with a steady softening of the X-ray spectrum, which can be described by the changes in the local absorption from N H ∼ 10 24 to ≲10 20 cm −2 for an absorbed power-law model. The soft X-ray emission below 2 keV was absent in the early part of the observation when only the pulsating hard X-ray component was observed, whereas at later times, both soft and hard X-ray components were observed to be pulsating. A likely explanation is that the neutron star was initially hidden in the circumstellar disk of the companion, and later came out of the disk with the accreted material that continued fueling the observed pulsation.
The on-board calibration system of the X-ray Imaging Polarimetry Explorer (XIPE)
2016-07-14

The calibration system for XIPE is aimed at providing a way to check and correct possible variations of performance of the Gas Pixel Detector during the three years of operation in orbit (plus two years of possible extended operation), while facilitating the observation of the celestial sources. This will be performed by using a filter wheel with a large heritage having a set of positions for the calibration and the observation systems. In particular, it will allow for correcting possible gain variation, for measuring the modulation factor using a polarized source, for removing non interesting bright sources in the field of view and for observing very bright celestial sources. The on-board calibration system is composed of three filter wheels, one for each detector and it is expected to operate for a small number of times during the year. Moreover, since it operates once at a time, within the observation mode, it allows for simultaneous calibration and acquisition from celestial sources on different detectors. In this paper we present the scope and the requirements of the on-board calibration system, its design, and a description of its possible use in space.
The asymptotic behavior of the monodromy representation of the associated family of a compact CMC surface
2016-07-14

Constant mean curvature (CMC) surfaces in space forms can be described by\\ntheir associated -family of flat -connections\\n . In this paper we consider the asymptotic behavior (for\\n ) of the gauge equivalence classes of for compact\\nCMC surfaces of genus We prove (under the assumption of simple\\numbilics) that the asymptotic behavior of the traces of the monodromy\\nrepresentation of determines the conformal type as well as\\nthe Hopf differential locally in the Teichm\\\\"uller space.\\n
The VanRS Homologous Two-Component System VnlRSAbof the Glycopeptide ProducerAmycolatopsis balhimycinaActivates Transcription of thevanHAXScGenes inStreptomyces coelicolor, but not inA. balhimycina
2016-07-15

In enterococci and in Streptomyces coelicolor, a glycopeptide nonproducer, the glycopeptide resistance genes vanHAX are colocalized with vanRS. The two-component system (TCS) VanRS activates vanHAX transcription upon sensing the presence of glycopeptides. Amycolatopsis balhimycina, the producer of the vancomycin-like glycopeptide balhimycin, also possesses vanHAXAb genes. The genes for the VanRS-like TCS VnlRSAb, together with the carboxypeptidase gene vanYAb, are part of the balhimycin biosynthetic gene cluster, which is located 2 Mb separate from the vanHAXAb. The deletion of vnlRSAb did not affect glycopeptide resistance or balhimycin production. In the A. balhimycina vnlRAb deletion mutant, the vanHAXAb genes were expressed at the same level as in the wild type, and peptidoglycan (PG) analyses proved the synthesis of resistant PG precursors. Whereas vanHAXAb expression in A. balhimycina does not depend on VnlRAb, a VnlRAb-depending regulation of vanYAb was demonstrated by reverse transcriptase polymerase chain reaction (RT-PCR) and RNA-seq analyses. Although VnlRAb does not regulate the vanHAXAb genes in A. balhimycina, its heterologous expression in the glycopeptide-sensitive S. coelicolor ΔvanRSSc deletion mutant restored glycopeptide resistance. VnlRAb activates the vanHAXSc genes even in the absence of VanS. In addition, expression of vnlRAb increases actinorhodin production and influences morphological differentiation in S. coelicolor.
Abstract 2354: Cancer vaccine development for hepatocellular carcinoma - HEPAVAC
2016-07-15

Abstract The HEPAVAC Consortium aims to develop a highly innovative, novel cancer vaccine approach for hepatocellular carcinoma (HCC). The international project consortium consists of 9 European Partners from academia and the biotech industry with complementary and substantial expertise in developing immunotherapeutic strategies to treat cancer. The project has started in September 2013 and is supported by the European Commission's 7th Framework Program (www.hepavac.eu). HCC/normal adjacent tissue matched samples have been collected for HLA immunopeptidome analysis. 17 HCC samples from HLA-A*02+ patients and 15 samples from HLA-A*24+ patients have been analysed by mass spectrometry (LC-MS/MS). RNA-expression profiles have been established for 12 HCC samples. HLA-presentation/expression of peptides and mRNA on primary HCC samples are compared to &amp;gt;140 normal tissue samples from relevant organs (including heart, brain, lung, kidney, liver, nerve, skin etc.) from Immatics’ database. A total of 9051 HLA-A*02-restricted different tumor-associated peptides (TUMAPs) have been identified from HLA-A*02+ samples, while a total of 3286 different HLA-A*24-restricted TUMAPs have been identified from HLA-A*24+ samples. Of these, 33 HLA-A*02+ TUMAPS and 33 HLA-A*24+ TUMAPs have been validated, including peptide synthesis, immunogenicity testing and pharmaceutical evaluation. Most promising TUMAP candidates show selective expression only in HCC samples and no expression in normal tissues. In parallel, more than 6600 HLA-DR TUMAPs have been identified in Hep3B cells transfected with CIITA as well as an average of 1500 HLA-DR TUMAPs have been identified in HCC samples. A total of 16 newly identified HCC-specific epitopes have been selected for the HEPAVAC vaccine cocktail and are currently synthesized according to GMP standard. Of these, 7 are restricted to HLA- class I A*02; 5 HLA-A*24 and 4 HLA class II. In parallel, preclinical studies assessing the formulation and combination of the immunological RNA-based adjuvant (RNAdjuvant®) with peptide cocktails are underway. A multi Center phase I/II clinical trial in early HCC patients is predicted to start in July 2016. Citation Format: Sarah Kutscher, Roberto Accolla, Yuk T. Ma, Regina Heidenreich, Francesco Izzo, Alfred Koenigsrainer, Markus Loeffler, Phillip Mueller, Andrea Mayer, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Danila Valmori, Toni Weinschenk, Harpreet Singh-Jasuja, Luigi Buonaguro. Cancer vaccine development for hepatocellular carcinoma - HEPAVAC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2354.
Abstract 257: Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib
2016-07-15

Abstract The multikinase inhibitor sorafenib is approved for the treatment of advanced clear-cell renal and hepatocellular carcinomas, yet, patients’ survival is prolonged for only several months (Wilhelm et al., Mol Cancer Ther 2008). The understanding of this poor efficacy remains incomplete. One reason for treatment failure may be the high interindividual variability in pharmacokinetics of the orally-given sorafenib. Membrane transporters may contribute to pharmacokinetics of sorafenib and its metabolites as recently reported for the hepatic solute carrier (SLC) organic anion transporter family member 1B1 (OATP1B1) and OATP1B3 (Zimmerman et al, Clin Cancer Res 2013). In contrast, the role of organic cation transporter 1 (OCT1), which is also a major hepatic uptake transporter (Nies et al, Handb Exp Pharmacol 2011), for cellular uptake of sorafenib is controversial (Hu et al, Clin Cancer Res 2009; Swift et al, Drug Metab Dispos 2013; Herraez et al, Hepatology 2013). We therefore sought to comprehensively elucidate the impact of OCT1 on cellular sorafenib uptake by using a combination of different in vitro cell culture models and in vivo approaches involving experiments with Oct1 knockout (-/-) mice. Firstly, we analyzed cellular accumulation of radiolabeled sorafenib by the mammalian cell line HEK293 stably expressing OCT1. Despite overexpression of a functional OCT1 transporter, cellular uptake of neither sorafenib nor its active metabolite sorafenib N-oxide was increased. Next, we studied sorafenib and sorafenib N-oxide pharmacokinetics in mice with a homozygous genetic deletion of the Oct1 transporter. The deficiency of Oct1 had no influence on plasma and hepatic sorafenib and sorafenib N-oxide concentrations. Finally, we investigated sorafenib transport into the human hepatocellular carcinoma cell lines HepG2 and HuH7. Although neither OCT1 mRNA nor protein was detected, a considerable cellular accumulation of sorafenib was observed in both cell lines. Expression profiling of a panel of 55 relevant SLC drug uptake transporters identified several potential novel candidates mediating sorafenib accumulation. We conclude from these findings that cellular uptake of sorafenib and sorafenib N-oxide is independent of OCT1 and that other, as yet unidentified, transport mechanisms are responsible for cellular sorafenib uptake. Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany. Citation Format: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies. Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 257.
Abstract 3820: Epigenetic re-expression of fetal IGF2 as therapeutic target in hepatocellular carcinoma
2016-07-15

Abstract Background and aims Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is the multi-kinase inhibitor sorafenib. Consequently, there is a great need for the development of new effective treatments. IGF signaling pathway is aberrantly activated in HCC; however, its contribution to HCC pathogenesis is still unclear. Since IGF2 is overexpressed in HCC, we aimed to elucidate the oncogenic potential and mechanism of dis-regulation of this protein and determine the antitumoral efficacy of molecular abrogation of this ligand by targeted therapies. Methods Transcriptomic profiling, miRNAs expression, RNA- and whole exome- sequencing and methylation were analyzed in 228 HCCs with a focus on IGF-pathway. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out in IGF2-overexpressing tumors. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and two genetically-engineered mosaic mouse models (GEMM) overexpressing IGF2 specifically in the liver were generated to assess IGF2 oncogenicity in hepatocarcinogenesis. The therapeutic potential of a monoclonal-antibody against IGF-ligands (IGF1/2-mAb) alone or in combination with sorafenib was tested in a xenograft model of HCC. Results Here, IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoters methylation (53% of cases) and deregulation of miR-216b, miR-483-5p and miR-let7-d (35% of cases). Re-expression of IGF2 was associated with a progenitor cell-like, poorly differentiated and aggressive subtype of HCC, and poor prognosis (p&amp;lt;0.0001). In a GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p = 0.02). Conversely, IGF2-blockage using an IGF1/2-monoclonal antibody (mAb) or specific shRNAs against IGF2 reduced viability and proliferation in vitro (p&amp;lt;0.05), and inhibited IGF-Insulin pathway activation without disturbing insulin metabolism. IGF1/2-mAb delayed tumor growth and increased survival in vivo compared to placebo or sorafenib (p&amp;lt;0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions IGF2 is the first validated epidriver in HCC and has a key role in the hepatocarcinogenic process. These results provide the rationale for testing IGF1/2-mAb in a selected subset of HCC patients. Citation Format: Iris Martinez-Quetglas, Roser Pinyol, Daniel Dauch, Sara Torrecilla, Victoria Tovar, Agrin Moeini, Clara Alsinet, Anna Portela, Augusto Villanueva, Manel Esteller, Lars Zender, Josep M Llovet. Epigenetic re-expression of fetal IGF2 as therapeutic target in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3820.
Abstract 1257: A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer
2016-07-15

Abstract Myc oncoproteins are causally involved in the genesis of a large fraction of human tumors. Three closely related Myc proteins, c-myc, N-myc and L-myc, have been implicated in cancer, whereas c-myc was identified as an important oncogenic driver in frequent solid tumors.Applying transposon-based mosaic liver cancer mouse models and direct in vivo shRNA screening technology, we found that bypassing a latent p19Arf- and Aurka mediated G2/M cell cycle arrest is required for development of p53 altered liver carcinomas with activated Ras/MAPK signalling. The resulting tumors depend on high MYC levels for survival. A direct interaction of Aurka and MYC was identified in p53 altered liver cancer cells, which could be efficiently disrupted by conformation changing Aurka inhibitors, resulting in MYC degradation and cell death specifically of p53 altered human and murine hepatoma cells. Treatment studies in mouse models of p53 deficient therapy resistant liver cancer revealed marked therapeutic efficacy of conformation changing Aurka inhibitors, thus suggesting a new therapeutic strategy against this major lethal cancer. Citation Format: Dauch Daniel, Ramona Rudalska, Giacomo Cossa, Jean Charles Nault, Sandrine Imbeaud, Nisar P. Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender. A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1257.