julilili42/papers huggingface dataset:
Abstract 649: Development and preclinical characterization of an Fc-optimized CD133 antibody for improved induction of NK cell reactivity against myeloid leukemia
2014-10-01

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 anti-tumor antibodies (mAb) such as Rituximab. Modifications of the human IgG1 Fc-part of anti-tumor antibodies may lead to markedly improved capability to recruit Fc-receptor bearing effector cells. Here we report on the development and preclinical characterization of an Fc-optimized mAb directed towards CD133, a molecule expressed on a wide variety of malignant cell types. Initially we evaluated binding of three different mouse anti-human CD133 mAbs (clones AC133, W6B3 and 293C3) to 20 AML and 6 CML samples to identify a clone with optimal binding characteristics. Binding of AC133 and W6B3 to the leukemic cells in 11/20 AML and 5/6 CML samples was comparable. In contrast, binding of 293C3 was observed in 18/20 AML cases and 5/6 CML cases. This indicates that 293C3 recognizes a particular epitope, which is expressed in a high proportion of AML cases. Therefore mAb 293C3 was selected for generation of chimeric mAbs with either a wildtype Fc part (293C3-WT) or a variant containing distinct modifications (S239D/I332E) to enhance its affinity to the Fc receptor CD16 (293C3-SDIE). The binding specificity of 293C3-WT and 293C3-SDIE was validated in analyses with CD133 transfectants and the respective mock controls. In cytotoxicity assays and analyses of NK cell degranulation, 293C3-WT clearly induced NK cell ADCC against primary leukemia cells. However, ADCC activity of the Fc-optimized mAb 293C3-SDIE markedly exceeded that of its counterpart containing the wild type Fc part. Considering the expression of CD133 on healthy hematopoietic progenitor cells, we presently evaluate potential toxicity of the antibodies towards these cells and other healthy tissue. We envisage that 293C3-SDIE might be an attractive immunotherapeutic reagent for the elimination of minimal residual disease in CD133 expressing leukemia, particularly in the context of allogenic SCT. Citation Format: Samuel Koerner, Julia Leibold, Ludger Grosse-Hovest, Hans-Jörg Bühring, Helmut R. Salih, Gundram Jung. Development and preclinical characterization of an Fc-optimized CD133 antibody for improved induction of NK cell reactivity against myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2014-649
Abstract 3652: Surface expression and shedding of NKG2D ligands by (metastasizing) tumor cells is altered by platelets leading to impaired NK cell immunosurveillance
2014-10-01

Abstract NK cells play an important role in anti-tumor immunity. The mechanisms leading to NK cell activation are described by the ‘missing-self’ and ‘induced-self' hypotheses, implying that cells with low or absent expression of MHC class I and stress-induced expression of ligands for activating receptors such as NKG2D (NKG2DL), are targeted by NK cells. Besides the direct interaction with their target cells, NK activity is also influenced by various other hematopoietic cells. In mouse models, thrombocytopenia impairs metastasis, and this is reversed by additional depletion of NK cells. Hence, the knowledge of the underlying molecular mechanisms by which platelets influence NK cells is still fragmentary. We already showed that release of TGF-β by platelets upon their interaction with (metastasizing) tumor cells downmodulates the activating receptor NKG2D on NK cells (Kopp et al, Cancer Res. 2009; Placke, J Innate Immun. 2011). Moreover, platelets transfer ́healthy ́ MHC class I to the tumor cell surface. Thus, platelets may facilitate metastasis by interfering with both, ‘induced and missing self' NK cell recognition. Here we provide evidence for a yet unknown mechanism by which platelets further impair NKG2D-mediated immunosurveillance. Tumor cells were incubated with platelets from healthy donors resulting in coating of tumor cells and activation of the platelets, or treated with platelet-derived soluble factors (releasate) obtained either by tumor cell-induced platelet activation (TCIPA) or the platelet agonist thrombin. Presence of platelet derived factors derived either from coating of tumor cells or contained in platelet releasate substantially reduced surface expression of NKG2DL on tumor cells. This was paralleled by enhanced levels of soluble NKG2DL in culture supernatants, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Diminished NKG2DL surface expression resulted in diminished NKG2D-dependent natural cytotoxicity of NK cells, as revealed by blocking experiments using NKG2D antibody and NKG2DL-specific F(ab)2 fragments targeting the specifically modulated NKG2DL. Our data thus identify induction of NKG2DL shedding as novel mechanism by which interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance. Citation Format: Stefanie Raab, Korbinian Nepomuk Kropp, Alexander Steinle, Gerd Klein, Hans-Georg Kopp, Helmut R. Salih. Surface expression and shedding of NKG2D ligands by (metastasizing) tumor cells is altered by platelets leading to impaired NK cell immunosurveillance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3652. doi:10.1158/1538-7445.AM2014-3652
Abstract LB-215: The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab
2014-10-01

Abstract Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that has shown efficacy in metastatic colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Clinical data suggests that patients whom initially respond to cetuximab eventually acquire resistance, highlighting the importance of understanding resistant mechanisms for the development of better treatment regimes for cancer patients. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, and more specifically the Axl receptor as playing a key role in promoting tumor growth and metastasis. In the current study, we utilized NSCLC and HNSCC models of acquired resistance to cetuximab and found that Axl was overexpressed, activated, and highly associated with EGFR as compared parental controls. Further, using siRNA technology and novel Axl targeting agents (antibody and tyrosine kinase inhibitor), Axl was found to regulate proliferation, EGFR activation, and MAPK signaling in cetuximab resistant clones (CtxR). Additionally, Axl mRNA expression was regulated by EGFR induced MAPK activation in resistant cells. To investigate the role of Axl in in vivo models of acquired resistance to cetuximab, de novo acquired resistance was created by prolonged treatment of cetuximab sensitive (CtxS) tumor xenografts with cetuximab. Analysis of resultant CtxR tumors demonstrated that Axl was hyperactivated and highly associated with EGFR as compared to vehicle treated tumors. In addition, CtxR tumors expressing the highest levels of phosphorylated Axl also expressed hyperactivated EGFR, supporting the role of Axl in EGFR activation. Finally, to expand these findings to other members of the TAM family, Tyro, Axl, or Mer were stably overexpressed in CtxS parental NSCLC cells and tested for cetuximab response. The results of this experimentation indicated that stable overexpression of each TAM receptor rendered CtxS cells resistant to cetuximab therapy. Collectively, the studies presented herein identify the TAM family of receptors as key players in acquired resistance to cetuximab and provide rationale for the clinical evaluation of anti-TAM receptor therapeutics in the resistant setting. Citation Format: Toni Michel Brand, Mari Iida, Kelsey L. Corrigan, Neha Luthar, Megan Hornung, Mahmoud Toulany, Parkash Gill, Ravi Salgia, Deric L. Wheeler. The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2014-LB-215
Abstract 148: Release of the TNF-family member BAFF by NK cells contributes to the resistance of chronic lymphoid leukemia cells to direct and Rituximab-induced NK reactivity
2014-10-01

Abstract NK cells are cytotoxic lymphocytes that are particularly important for the immunosurveillance of leukemia. Due to their ability to mediate antibody-dependent cellular cytotoxicity (ADCC), NK cells substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, which is a crucial component in the treatment of B cell malignancies. Available data indicate that the ability of NK cells to target malignant cells and to mediate ADCC is compromised in Chronic Lymphoid Leukemia (CLL), but the underlying mechanisms are still unclear (Jaglowski et al., Blood 2010). With the TNF family member B cell activating factor (BAFF) that regulates, among others, the proliferation and survival of B cells, we believe to have identified a factor which contributes to these clinical observations. We report that NK cells express BAFF on the mRNA level and release the protein in a soluble form with the levels depending on activation state. Notably, relevant BAFF surface expression was neither detected on resting nor activated NK cells. Using a tetrazolium salt based colorimetric assay we found that NK cell-derived BAFF enhances the metabolic activity of primary CLL cells. In addition, BAFF protects CLL cells from chemotherapy-induced cell death e.g. upon treatment with Fludarabine and Cyclophosphamide. Notably, the BAFF-specific antibody Belimumab, which is approved for the treatment of systemic lupus erythematosus, was found to block the leukemia cell-protective effects of BAFF and to restore the sensitivity of the leukemia cells to chemotherapy. Furthermore, BAFF was found to substantially reduce direct NK cell lysis and also Rituximab-mediated ADCC in cultures with primary CLL cells as measured by Europium cytotoxicity assays. Our data on the capacity of BAFF to enhance the metabolic activity of B-CLL cells and their resistance to NK cell cytotoxicity suggest its involvement in the compromised ability of NK cells to combat lymphoid as compared to myeloid leukemias (Pende et al., Blood 2005) and the reportedly impaired ability of NK cells to mediate ADCC upon Rituximab treatment in CLL. Furthermore, our findings point to a possible benefit of combinatory approaches employing Rituximab and Belimumab for immunotherapy of B cell malignancies. Citation Format: Julia Wild, Benjamin J. Schmiedel, Andreas Maurer, Stefanie Raab, Pascal Schneider, Helmut R. Salih. Release of the TNF-family member BAFF by NK cells contributes to the resistance of chronic lymphoid leukemia cells to direct and Rituximab-induced NK reactivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2014-148
Abstract 2974: RNAi mouse models: Revolutionizing drug discovery in vivo
2014-10-01

Abstract RNA interference is a powerful tool for studying gene function, however, the reproducible generation of RNAi tools including RNAi transgenic mice remains a significant limitation. One main hurdle is the identification of potent RNAi triggers, or short hairpin RNAs (shRNAs), that will induce stable and regulated gene silencing. Due to the lack of understanding of the requirements for shRNA biogenesis and target suppression, many predicted shRNAs fail to efficiently induce gene suppression. We have developed a “Sensor assay” that enables the biological identification of effective shRNAs at large scale and show that our assay reliably identifies potent shRNAs that are surprisingly rare and predominantly missed by existing algorithms. In addition, we have engineered a new miRNA scaffold, miR-E, that is more efficiently processed and thus produces more potent knockdown of target genes than our previous miR30 system. By combining our sensored miR-E based shRNAs with high efficiency ES cell targeting, we have developed a fast, scalable pipeline for the production of shRNA transgenic mice with reversible gene silencing. We show that RNAi can cause sufficient knockdown to recapitulate the phenotypes of knockout mice, particularly in cancer models. More importantly, unlike traditional knockout models, RNAi has the powerful advantage of reversibility, since the endogenous gene remains intact. Using this system, we generated a number of inducible RNAi transgenic lines and demonstrate how this approach can identify predicted phenotypes and also unknown functions for well-studied genes. In addition, through regulated gene silencing we are able to mimic drug therapy in mice without the actual drug molecule, allowing us to determine the therapeutic value and/or toxic effects associated with systemic gene suppression. Using this approach, we have been able to pinpoint potential toxicities associated with gene inhibition, results that will guide drug development to avoid target failures which will likely cause harmful and intolerable effects in patients. In a model of hepatocellular carcinoma, we demonstrate that short-term inhibition of a ribosomal protein is sufficient to induce stable cell cycle arrest of liver tumor cells. This system provides a cost-effective and scalable platform for the production of RNAi transgenic mice targeting any mammalian gene - mice with enormous predictive power that will shape our development of better tolerated therapies. Citation Format: Prem K. Premsrirut, BoYoung Yoon, Marina Pesic, Lukas E. Dow, Johannes Zuber, Scott W. Lowe, Gregory J. Hannon, Lars Zender, Christof Fellmann. RNAi mouse models: Revolutionizing drug discovery in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2974. doi:10.1158/1538-7445.AM2014-2974
Live demonstration: Transverse stimulation or artefact?
2014-10-01

Electric properties of the human tongue are experimentally compared with the properties of a purely ohmic resistor. The tongue shows short and strong displacement currents near voltage steps, which are not present in case of the ohmic resistor. They are not artefacts.
O-037 Short-term Effects Of Red Blood Cell Tranfsusion On Hepcidin Concentration In Preterm Infants
2014-10-01

&lt;sec&gt;&lt;st&gt;Background and aims&lt;/st&gt; Hepcidin, which acts as a negative feedback regulator of iron homeostasis, may in future serve as a non-invasive iron status parameter to monitor iron supplementation in preterm infants. For this, coexisting influencing factors should be taken into account. Our objective was to evaluate in preterm infants whether red blood cell (RBC) transfusions have a short-term effect on hepcidin concentrations in serum (Hep&lt;inf&gt;(S)&lt;/inf&gt;) and urine (Hep&lt;inf&gt;(U)&lt;/inf&gt;). &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Prospective observational study including very preterm infants receiving RBC transfusions. The concentration of the mature, 25 amino-acid form of hepcidin was determined in serum und urine by enzyme-linked immunosorbent assay together with cellular indices before and after RBC transfusion. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; The study was conducted between May 2009 and September 2010 at Tübingen University Hospital. 20 preterm infants born at a mean gestational age of 26.0 (interquartile range: 24.9–27.4) weeks and with a mean postnatal age of 30.8 (interquartile range 29.9–32.1) daysreceived 27 RBC transfusions. When measured shortly after transfusion (mean 10 h), hematocrit values increased from a median of 26.6% (SD 2.8) to 40.9% (SD 3.2; p &lt; 0.0001); Hep&lt;inf&gt;(S) &lt;/inf&gt;also increased (geometric mean: 44.3 ng/mL (95% confidence interval: 30.8–63.8) vs. 58.0 ng/mL (95% confidence interval: 35.7–94.3; p &lt; 0.05) but Hep&lt;inf&gt;(U)&lt;/inf&gt; remained unaffected. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusion&lt;/st&gt; These data indicate a short-term effect of RBC transfusions on serum hepcidin concentrations in preterm infants. Further longer-term observational studies are needed to understand the dynamics of hepcidin regulation in preterm infants. &lt;/sec&gt;
Slowly rotating neutron and strange stars inR2gravity
2014-10-02

In the present paper we investigate self-consistently slowly rotating neutron\\nand strange stars in R-squared gravity. For this purpose we first derive the\\nequations describing the structure of the slowly rotating compact stars in\\n -gravity and then simultaneously solve the exterior and the interior\\nproblem. The structure of the slowly rotating neutron stars is studied for two\\ndifferent hadronic equations of state and a strange matter equation of state.\\nThe moment of inertia and its dependence on the stellar mass and the\\n -squared gravity parameter is also examined in details. We find that the\\nneutron star moment of inertia for large values of the parameter can be up\\nto larger compared to the corresponding general relativistic models.\\nThis is much higher than the change in the maximum mass induced by -squared\\ngravity and is beyond the EOS uncertainty. In this way the future observations\\nof the moment of inertia of compact stars could allow us to distinguish between\\ngeneral relativity and gravity, and more generally to test the strong\\nfield regime of gravity.\\n
Personal security since 1820
2014-10-02

Personal security reflects a crucial component of well-being. This chapter relies on homicide rates (the number of intentional deaths per 100 000 inhabitants) to trace changes of violence in time and space. It finds that Western Europe was already quite peaceful from the 19th century onwards, but homicide rates in the United States have been high by comparison. Large parts of Latin America and Africa are also violent crime "hotspots", and so is the former Soviet Union (especially since the fall of communism), while large parts of Asia show low homicide rates. Homicide rates are in general negatively correlated with GDP per capita – the richer a country, the lower the level, but there are important exceptions. In addition, the chapter describes changes in the probability that a random individual lives in a country experiencing an armed internal or external conflict.
Mr Light and people's everyday energy struggles in Central Asia and the Caucasus: an introduction
2014-10-02

The perception of Central Asia and its place in the world has come to be shaped by its large oil and gas reserves. Literature on energy in the region has thus largely focused on related geopolitical issues and national policies. However, little is known about citizens' needs within this broader context of commodities that connect the energy networks of China, Russia and the West. This multidisciplinary special issue brings together anthropologists, economists, geographers and political scientists to examine the role of all forms of energy (here: oil, gas, hydropower and solar power) and their products (especially electricity) in people's daily lives throughout Central Asia and the Caucasus. The papers in this issue ask how energy is understood as an everyday resource, as a necessity and a source of opportunity, a challenge or even as an indicator of exclusionary practices. We enquire into the role and views of energy sector workers, rural consumers and urban communities, and their experiences of energy companies' and national policies. We further examine the legacy of Soviet and more recent domestic energy policies, the environmental of energy use as well as the political impact of citizens' energy grievances.
A Multivariate Analysis of Genetic Constraints to Life History Evolution in a Wild Population of Red Deer
2014-10-02

Abstract Evolutionary theory predicts that genetic constraints should be widespread, but empirical support for their existence is surprisingly rare. Commonly applied univariate and bivariate approaches to detecting genetic constraints can underestimate their prevalence, with important aspects potentially tractable only within a multivariate framework. However, multivariate genetic analyses of data from natural populations are challenging because of modest sample sizes, incomplete pedigrees, and missing data. Here we present results from a study of a comprehensive set of life history traits (juvenile survival, age at first breeding, annual fecundity, and longevity) for both males and females in a wild, pedigreed, population of red deer (Cervus elaphus). We use factor analytic modeling of the genetic variance–covariance matrix (G) to reduce the dimensionality of the problem and take a multivariate approach to estimating genetic constraints. We consider a range of metrics designed to assess the effect of G on the deflection of a predicted response to selection away from the direction of fastest adaptation and on the evolvability of the traits. We found limited support for genetic constraint through genetic covariances between traits, both within sex and between sexes. We discuss these results with respect to other recent findings and to the problems of estimating these parameters for natural populations.
Income inequality since 1820
2014-10-02

This chapter focuses on income inequality as measured by gross (i.e. pre-tax) household income across individuals within a country. It builds upon a number of large-scale initiatives to chart income inequality trends over time, supplementing them with data on wages and heights for the earlier period. Income inequality trends follow a U-shape in most Western European countries and the Western Offshoots. It declined between the end of the 19th century until about 1970, followed by a rise. In Eastern Europe, communism resulted in strong declines in income inequality, followed by a sharp increase after its disintegration in the 1980s. In other parts of the world (China in particular) income inequality is on the rise recently. The chapter also provides evidence on the global income distribution, i.e. assuming all people belong to the same community. This distribution was unimodal in the 19th century, became increasingly bi-modal between 1910 and 1970 and suddenly reverted back into a unimodal distribution between 1980 and 2000.
Human height since 1820
2014-10-02

Average height is an important indicator of people's well-being. It is also a relatively undistorted and easy-to-measure indicator, which makes it particularly suitable for comparisons across time and space. Drawing upon an extensive body of research, the chapter describes the strengths and weaknesses of this indicator. It finds that during the 19th century, average height in Western Offshoots was much higher than elsewhere. Differences between Western Europe and the rest of the world (Eastern Europe, East Asia) were marginal, in spite of the much higher real incomes in the former region. This changed after about 1870, when people's height began to increase in Western Europe, whereas this lagged behind elsewhere. Africans were relatively tall during much of the period studied, but experienced declining height in many countries after the 1960s. People in Southeast Asia stayed relatively short throughout the period.