julilili42/papers huggingface dataset:
Modulated Fourier Expansions for Continuous and Discrete Oscillatory Systems
2012-11-15

This article reviews some of the phenomena and theoretical results on the long-time energy behaviour of continuous and discretized oscillatory systems that can be explained by modulated Fourier expansions: longtime preservation of total and oscillatory energies in oscillatory Hamiltonian systems and their numerical discretizations, near-conservation of energy and angular momentum of symmetric multistep methods for celestial mechanics, metastable energy strata in nonlinear wave equations. We describe what modulated Fourier expansions are and what they are good for.
LaSr3F5(CN2)2: A Prototype Structure for Mixed-Valent Eu4F5(CN2)2
2012-11-15

The new compound LaSr(3)F(5)(CN(2))(2) was prepared and structurally characterized as a prototype structure for the remarkably distorted mixed-valent compound Eu(4)F(5)(CN(2))(2), which contains four distinct europium ions in the structure: one Eu(3+) and three Eu(2+). Instead of repeating the given distorted structural pattern, LaSr(3)F(5)(CN(2))(2) forms a structure which can be considered as an ideal high-symmetry structure for Eu(4)F(5)(CN(2))(2), due to the occupation of La(3+) and Sr(2+) ions on one and the same crystallographic position. The crystal symmetry of this structure is an interesting issue to compare with what has been previously proposed.
Color Coulomb potential in Yang-Mills theory from Hamiltonian flows
2012-11-15

We consider the Hamiltonian formulation of Yang-Mills theory in the Coulomb gauge and apply the recently developed technique of Hamiltonian flows. We formulate a flow equation for the color Coulomb potential which allows for a scaling solution that results in an almost linearly rising confining potential.
Dynamic electromagnetic response of three-dimensional Josephson junction arrays
2012-11-15

Abstract—We present a theoretical study on the dynamical properties of three-dimensional arrays of Josephson junctions. Our results indicate that such superconducting networks represent highly sensitive 3D-SQUIDs having some major advantages in comparison with conventional planar SQUIDs. The voltage response function of 3D-SQUIDs is directly related to the vector-character of external electromagnetic fields. The theory developed here allows the three-dimensional reconstruction of a detected external field including phase information about the field variables. Applications include the design of novel magnetometers, gradiometers and particle detectors. I.
Whole-Body Vibration Improves Functional Recovery in Spinal Cord Injured Rats
2012-11-16

Whole-body vibration (WBV) is a relatively novel form of exercise used to improve neuromuscular performance in healthy individuals. Its usefulness as a therapy for patients with neurological disorders, in particular spinal cord injury (SCI), has received little attention in clinical settings and, surprisingly, even less in animal SCI models. We performed severe compression SCI at a low-thoracic level in Wistar rats followed by daily WBV starting 7 (10 rats) or 14 (10 rats) days after injury (WBV7 and WBV14, respectively) and continued over a 12-week post-injury period. Rats with SCI but no WBV training (sham, 10 rats) and intact animals (10 rats) served as controls. Compared to sham-treated rats, WBV did not improve BBB score, plantar stepping, or ladder stepping during the 12-week period. Accordingly, WBV did not significantly alter plantar H-reflex, lesion volume, serotonergic input to the lumbar spinal cord, nor cholinergic or glutamatergic inputs to lumbar motoneurons at 12 weeks after SCI. However, compared to sham, WBV14, but not WBV7, significantly improved body weight support (rump-height index) during overground locomotion and overall recovery between 6-12 weeks and also restored the density of synaptic terminals in the lumbar spinal cord at 12 weeks. Most remarkably, WBV14 led to a significant improvement of bladder function at 6-12 weeks after injury. These findings provide the first evidence for functional benefits of WBV in an animal SCI model and warrant further preclinical investigations to determine mechanisms underpinning this noninvasive, inexpensive, and easily delivered potential rehabilitation therapy for SCI.
Synthesis and characterization of pH-sensitive, biotinylated MRI contrast agents and their conjugates with avidin
2012-11-16

Responsive or smart contrast agents (SCAs) provide new opportunities in magnetic resonance imaging (MRI) to examine a number of physiological and pathological events. However, their application in vivo remains challenging. Therefore, much research is focused on the optimization of their properties, to enable their use in additional imaging modalities, pre-targeted delivery, or to increase the local concentration of the agent. The key feature in the SCA synthetic modification is the retention of their physicochemical properties related to the specific MR response. Here, we report the preparation and characterization of pH sensitive SCAs appended with a phosphonate pendant arm and either an aliphatic (GdL(1)) or aromatic linker (GdL(2)). The longitudinal relaxivity of GdL(1) and GdL(2) increases by 146% and 31%, respectively, while the pH decreases from 9 to 5. These two SCAs were converted to the biotinylated systems GdL(3) and GdL(4) and their interaction with avidin was investigated. The binding affinity with avidin was assessed with a fluorescence displacement assay and with MRI phantom experiments in a 3T MRI scanner. The fluorometric assay and MRI E-titrations revealed a 3 : 1 binding mode of GdL(3-4) to avidin with the binding affinity as high as that of the parent avidin-biotin complex. The high binding affinity was confirmed with MRI by a competitive assay. The avidin-GdL(3-4) complexes thus obtained exhibit changes in both r(1) and r(2) that are pH dependent. The results reveal a new pathway for the modification and improvement of SCAs to make them more suitable for in vivo application.
Accelerated evaluation of the robustness of treatment plans against geometric uncertainties by Gaussian processes
2012-11-16

In order to provide a consistently high quality treatment, it is of great interest to assess the robustness of a treatment plan under the influence of geometric uncertainties. One possible method to implement this is to run treatment simulations for all scenarios that may arise from these uncertainties. These simulations may be evaluated in terms of the statistical distribution of the outcomes (as given by various dosimetric quality metrics) or statistical moments thereof, e.g. mean and/or variance. This paper introduces a method to compute the outcome distribution and all associated values of interest in a very efficient manner. This is accomplished by substituting the original patient model with a surrogate provided by a machine learning algorithm. This Gaussian process (GP) is trained to mimic the behavior of the patient model based on only very few samples. Once trained, the GP surrogate takes the place of the patient model in all subsequent calculations.The approach is demonstrated on two examples. The achieved computational speedup is more than one order of magnitude.
Efficacy Analysis of the Novel Dual PI3K-MTORC1/2 Inhibitors NVP-BGT226 and NVP-BEZ235 in Acute Leukemia.
2012-11-16

Abstract Abstract 2474 Introduction: Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. Constitutive phosphorylation of AKT is frequently found in acute leukemia but the underlying molecular mechanisms remain unclear and mutations in the PI3K/AKT pathway are uncommon in leukemia. In some cases, constitutive AKT activation can be linked to gain-of function tyrosine kinase mutations upstream of the PI3K/AKT pathway. While inhibitors of the PI3K/AKT pathway appear attractive for tumor therapy, so far response rates to PI3K inhibitor treatment of various neoplasms are moderate. Furthermore, MTORC1 inhibitors, targeting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We here comparatively studied two novel dual PI3K-MTORC1/2 inhibitors, NVP-BEZ235 and NVP-BGT226, with regard to their ability to inhibit proliferation and to induce apoptosis in different leukemia cell models as well as in primary leukemia samples. Methods: Expression of phospho-AKT protein levels was determined in 74 leukemia patient blood and bone marrow samples by flow cytometry. Protein and functional viability assays evaluating the effects of NVP-BEZ235 and NVP-BGT226 were performed in several leukemia cell lines, mutant-tyrosine kinase cell models and with primary leukemia blasts and bone marrow cells. Antineoplastic activity was assessed in proliferation and apoptosis experiments. Immunoblots were performed to confirm consecutive suppression of AKT signaling. Results: AKT is generally expressed in acute leukemia at significantly higher levels as compared to healthy donor samples (p &lt; 0.05, students t-test). Dual targeting of the PI3K-AKT-MTOR pathway profoundly inhibited AKT signaling, leading to antiproliferative effects in vitro and ex vivo. Moreover, both agents potently induced apoptosis in a subset of leukemia samples with BGT226 being the more effective agent and displaying IC50s at the low nanomolar level. Cell cycle analyses revealed that NVP-BGT226 overrides the G1-arrest observed with NVP-BEZ235-treated cells. Importantly, normal mononuclear cells revealed lower phospho-AKT expression levels and relative insensitivity towards dual PI3K-MTORC1/2 inhibition. Conclusion: Our data provide a strong rationale for clinical evaluation of the tested dual PI3K-MTORC1/2 inhibitors in acute leukemias. Disclosures: No relevant conflicts of interest to declare.
Monocyte-Derived Dendritic Cells Induce Functionally Active Regulatory T Cells Upon Exposure to BCR-ABL Tyrosine Kinase Inhibitors.
2012-11-16

Abstract Abstract 2156 Multiple approaches for treatment of malignant disease presently aim to combine targeted therapy with tyrosine kinase inhibitors (TKI) with immunotherapy. Dendritic cells (DC) are frequently used in such strategies due to their unique ability to initiate potent T cell anti-tumor immunity. Unfortunately, DC may also activate suppressive CD25+FOXP3+ regulatory T cells (Treg), which depends on the stimuli that influence DC in immature state and/or during development from precursor cells. High frequencies of Treg have been described in several types of tumors within the tumor microenvironment, which is associated with poor prognosis and reduced survival. DC development and function are moreover governed by various tyrosine kinases of which some are also inhibited by clinically used TKI. TKI thus may cause immunoinhibitory side effects, and we previously demonstrated that exposure of monocyte-derived DC to the BCR-ABL inhibitor imatinib causes up-regulation of the immunosuppressive type I transmembrane glycoprotein osteoactivin (GPNMB, DC-HIL) and reduces expression of activating surface antigens as well as T cell-stimulatory capacity of DC in vitro (Schwarzbich et al., 2012). Other investigators reported that imatinib induces functionally Treg in CML patients, but the underlying mechanisms are so far unknown. (Bachy et al., 2011). On the other hand, TKI may inhibit proliferation and suppressive capacity of regulatory T cells in vitro (Chen et al., 2007). Here we tried to solve this apparent discrepancy by analyzing the influence of TKI on DC-Treg interaction. Monocyte-derived DC (moDC) were generated over 7 days by exposing blood monocytes to GM-CSF and IL-4. TNF was added on day 6 of culture in case of maturation, and imatinib or nilotinib (3μM each) were added to the culture medium every second day starting from the first day of culture. Induction and functionality of Treg was determined by FACS and so called effector T cell suppression assays upon culture of moDC with autologous PBMC. We found that exposure of moDC to imatinib or nilotinib only slightly increased the frequency of Treg as compared to controls. However, these Treg strongly inhibited autologous T cell proliferation as assessed by T cell suppression assays. This was mediated by direct cellular interaction, as culture supernatants of TKI-treated DC did not alter Treg function and also did not contain elevated levels of the immunosuppressive (and Treg inducing) cytokines TGF-β and IL-10. Thus, our data indicate that the seemingly contradictory results of the in vivo and in vitro studies described above may be explained by the effects caused by exposure of moDC to BCR-ABL TKI which results in the induction of functionally active Treg. These findings are of special importance for future combinatory approaches using TKI and DC-based immunotherapy. Disclosures: No relevant conflicts of interest to declare.
Inhibition of PI3K/Akt and Erk Signaling Pathways by BCR-ABL Tyrosine Kinase Inhibitors up-Regulates the Immunosuppressive Receptor Osteoactivin in Monocyte-Derived Dendritic Cells
2012-11-16

Abstract Abstract 1050 Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is expressed in dendritic cells (DC). Osteoactivin/syndecan-4 (SD-4) interaction was previously shown to inhibit T cell activation by antigen-presenting cells. We recently demonstrated that exposure of human peripheral blood monocytes to IL-10 or pharmacological levels of the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib or nilotinib during differentiation into monocyte-derived DC (moDC) causes up-regulation of osteoactivin at the transcript and protein level in vitro (Schwarzbich et al., 2012). Here we aimed to elucidate the molecular mechanisms responsible for osteoactivin up-regulation in moDC upon exposure to IL-10 or TKI (imatinib, nilotinib). moDC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Every second day, starting from the first day of culture, IL-10 or TKI were added to the culture medium. Alternatively, specific inhibitors of PI3K, Akt, Erk and/or C-Raf signal transduction pathways were added to the cell cultures. Cells were harvested on day 7 of culture for immunophenotyping and osteoactivin expression analysis using FACS, western-blotting and real-time qRT-PCR. The expression and activity of signal transduction molecules was monitored by western-blotting and pathway protein arrays. Analysis of moDC function was performed using mixed lymphocyte reactions (MLR). Our in vitro analysis revealed that IL-10 and BCR-ABL TKI inhibit the PI3K/Akt and, to a lesser extent, the Erk pathway in moDC. Specific inhibition of these signal transduction cascades resulted in profound up-regulation of osteoactivin expression in moDC confirming the involvement of PI3K/Akt and Erk in the regulation of osteoactivin expression. In line, TKI treatment and inhibition of PI3K/Akt and Erk comparably affected the phenotype of moDC. Moreover, the inhibition of these signalling cascades resulted in reduced stimulatory capacity of moDC in MLR with allogenic T cells, and this could be restored by addition of blocking osteoactivin antibody. Our data reveal that TKI exert immunosuppressive effects in moDC by interfering with pathways involved in IL-10 receptor signaling. Inhibition of osteoactivin expression or function may thus constitute a promising strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.
Bimodal Induction of NK Cell Reactivity Against Acute Myeloid (AML) and Chronic Lymphoid Leukemia (CLL) by Fc-Engineered GITR-Fc Fusion Proteins.
2012-11-16

Abstract Abstract 2143 NK cells play an important role in anti-tumor immunity and largely contribute to the efficacy of therapeutic strategies like allogenic stem cell transplantation in AML and application of Rituximab that induces antibody-dependent cellular cytotoxicity (ADCC) in CLL. Recently, we demonstrated that the TNF family member GITR ligand (GITRL) is expressed on leukemia cells in a high proportion of AML and CLL patients and impairs direct and Rituximab-induced reactivity of NK cells which constitutively express its counterpart GITR (e.g., Buechele et al., Leukemia 2012). Here we developed a strategy to reinforce NK anti-leukemia reactivity by combining disruption of NK-inhibitory GITR-GITRL interaction with induction of ADCC against the GITRL-expressing leukemia cells using GITR-Ig fusion proteins with modified Fc moieties. Fc parts were engineered by amino acid exchange as previously described (Lazar et al., PNAS 2006; Armour et al., Eur. J. Immunol. 1999). Compared to wild type GITR-Ig (GITR-Fc-WT), our mutants (S239D/I332E and E233P/L234V/L235A/deltaG236/A327G/A330S) displayed highly enhanced (GITR-Fc-ADCC) and abrogated (GITR-Fc-KO) affinity to the Fc(gamma)RIIIa receptor (CD16) expressed on NK cells, respectively. In functional analyses of NK cells and primary leukemia cells, GITR-Fc-KO, which does not induce ADCC, already increased NK reactivity due to disruption of GITR-GITRL interaction. Treatment with GITR-Fc-WT further enhanced NK reactivity due to modest induction of ADCC, while GITR-Fc-ADCC induced highly increased NK-mediated target cell lysis, degranulation and cytokine production in a target-antigen dependent manner. With CLL cells, combined treatment with GITR-Fc-ADCC fusion protein and Rituximab caused additive effects, resulting in significantly enhanced NK cell ADCC. Notably, the effects of our fusion proteins were observed both in an allogenic setting and when employing NK cells of patients with autologous leukemia cells as targets. Our results demonstrate that Fc-engineered GITR-Fc-ADCC fusion protein may combine both neutralization of the NK-inhibitoryeffects of GITR-GITRL interaction and targeting GITRL-expressing malignant cells for NK anti-tumor reactivity and thus constitute an attractive immunotherapeutic means for the treatment of AML and CLL. Disclosures: No relevant conflicts of interest to declare.
The Role of OX40 and Its Ligand in Acute Myeloid Leukemia: Expression, Function and Modulation of NK Cell Anti-Leukemia Reactivity
2012-11-16

Abstract Abstract 3548 The TNF/TNF receptor (TNFR) family comprises various molecules that substantially influence cellular functions of both tumor and immune effector cells. The TNFR family member OX40 has been shown to influence proliferation and differentiation of T cells in autoimmune diseases. Here we studied the yet unknown role of OX40 in acute myeloid leukemia (AML). Substantial surface expression of OX40 was detected on malignant cells of AML patients in 24 of 60 (40%) investigated cases. Expression of OX40 mRNA and protein by leukemic cells was confirmed by analysis of AML cells lines, which displayed substantial surface levels in 6 of 7 investigated cases. Induction of OX40 signaling into AML cells by recombinant OX40L or agonistic antibodies lead to the release of cytokines like IL-10 and TNF which contribute to AML pathophysiology and stimulated metabolic activity (WST test) of the leukemia cells. Moreover, we found that NK cells, which play an important role in anti-tumor immunity and largely contribute to the clinical success of allogeneic stem cell transplantation (SCT) in AML, express OX40 ligand (OX40L) following activation, and OX40L triggering stimulated NK cell reactivity. Functional analyses with OX40 transfectants and OX40-negative controls confirmed that OX40L signaling promotes NK cell cytotoxicity and IFN-γ production. Furthermore, disruption of OX40-OX40L interaction by blocking OX40 F(ab)2 fragments resulted in reduced cytotoxicity and cytokine production of allogenic NK cells, thereby further confirming the stimulatory effect of OX40L on NK cell anti-leukemia reactivity when interacting with its AML-expressed counterpart. Our data suggest that OX40 is involved in disease pathophysiology of AML and identify OX40-OX40L interaction as previously unknown modulator of NK cell immunosurveillance in AML. Disclosures: No relevant conflicts of interest to declare.
AML1-ETO Collaborates with the TALE Homeobox Genes MEIS1 and MEIS2 in Inducing AML.
2012-11-16

Abstract Abstract 2387 AML1-ETO (AE) is the most frequent fusion gene in human AML. Previously, we and others have demonstrated that the fusion is not able to cause leukemia on its own in experimental murine models, but that it needs collaborative partners. Following the ‘two-hit model’ hypothesis that class I and class II mutations have to collaborate to induce leukemia, we could previously demonstrate that AE (class II) collaborates with FLT3-length mutation (class I) to generate AML in the murine bone marrow transplantation model (BMT model). We now demonstrate that AE can collaborate with mutations of its own class in inducing AML. We focussed our analyses on the TALE homeobox gene family, namely Meis1 and Meis2, as already known in the case of Meis1 to be a potent co-factor for Hox gene associated leukemias and being classified as other homeobox genes as a class II mutation. First, real-time RT - PCR confirmed that MEIS1 is expressed at high levels in a subgroup of AE positive AML patients. Furthermore, MEIS2 was highly and aberrantly expressed virtually in all AE patients (n=70) compared to normal bone marrow. Expression patterns of both MEIS genes correlated with their promoter methylation in the t(8;21) patients and cell lines. To test the functional relevance of MEIS expression in human AE patients, we analysed collaboration of AE with Meis genes in the BMT model: Meis1 and Meis2 were retrovirally expressed alone or in combination with AE in 5-FU treated primary murine bone marrow and injected into lethally irradiated recipients (AML1-ETO alone, n=10; EGFP control, n=7; AE+Meis1, n=14; AE+Meis2, n=4). None of the mice in the AE as well as in the control group developed disease. In contrast, mice transplanted with BM co-expressing AE+Meis1 and AE+Meis2 developed lethal disease after a median latency of 102 and 255 days respectively. AE+Meis1 induced MPS in three, AML in seven and ALL in three cases, whereas AE+Meis2 induced AML in all cases. Functional relevance of MEIS expression was further confirmed in human AML cell lines as shRNA mediated depletion of MEIS1 as well as MEIS2 impaired cell growth in AE positive AML cell lines and so far one primary AE AML sample. To understand the mechanisms of AE/MEIS collaboration co-immunoprecipitation assays were performed documenting weak binding of Meis1, but strong interaction of Meis2 with AE. ChIP-Seq is currently being performed to test whether DNA binding of MEIS genes alter in collaboration with AE. Taken together, we could demonstrate that AE collaborates with Meis genes in AML. It furthermore shows that a class II mutation can be converted into an overt oncogene by a mutation of its own class. Disclosures: No relevant conflicts of interest to declare.