5PMICROTUBULE-DEPOLYMERIZING AGENTS USED IN ANTIBODY-DRUG-CONJUGATES INDUCE ANTITUMOR ACTIVITY BY STIMULATION OF DENDRITIC CELLS

Antibody drug conjugates (ADCs) are emerging as powerful treatment strategies with outstanding target specificity and high therapeutic activity in cancer patients. While >30 ADCs are currently being investigated in clinical trials, brentuximabvedotin and T-DM1 represent clinically approved ADCs in cancer patients. We hypothesized that their sustained clinical responses could be related to the stimulation of an antitumor immune response. Indeed, the two microtubule-destabilizing agents Dolastatin 10 and Ansamitocin P3, from which the cytotoxic components of brentuximabvedotin and T-DM1 are derived, may serve as prototypes for a class of agents that induce tumor cell death and convert tumor resident, tolerogenic dendritic cells (DCs) into efficient antigen presenting cells (APCs). The two drugs induced phenotypic and functional maturation of murine splenic as well as human monocyte-derived DCs. In contrast, microtubule-stabilizing agents such as taxanes did not display this feature. In tumor models, both Dolastatin 10 and Ansamitocin P3 efficiently promoted antigen uptake and migration of tumor-resident DCs to tumor-draining lymph nodes, thereby potentiating tumor-specific T cell responses. Underlining the requirement of an intact host immune system for the full therapeutic benefit of these two compounds, their antitumor effect was far less pronounced in mice lacking adaptive immunity or dendritic cells. Combinations with immune checkpoint inhibition (anti-CTLA-4/-PD-1) did further augment antitumor immunity and tumor rejection, which was reflected by reduced Treg numbers and elevated effector function of tumor resident T cells. Ultimately, we were able to demonstrate peripheral immune cell activation and brisk T cell infiltration into tumors in patients previously treated with BrentuximabVedotin. Experiments are currently ongoing to investigate the immunological mode of action of T-DM1 using orthotopic breast cancer models and patients undergoing treatment. Our data reveal a novel mode of action for microtubule-depolymerizing agents and provide a strong rationale for clinical treatment regimens combining these with immune-based therapies. Disclosure: All authors have declared no conflicts of interes

Orbital Dependent Phase Control in Ca2-xSrxRuO4

We present first-principles studies on the orbital states of the layered perovskites Ca$_{2-x}$Sr$_x$RuO$_4$. The crossover from antiferromagnetic (AF) Mott insulator for $x < 0.2$ to nearly ferromagnetic (FM) metal at $x=0.5$ is characterized by the systematic change of the $xy$ orbital occupation. For the AF side ($x < 0.2$), we present firm evidence for the $xy$ ferro-orbital ordering. It is found that the degeneracy of $t_{2g}$ (or $e_g$) states is lifted robustly due to the two-dimensional (2D) crystal-structure, even without the Jahn-Teller distortion of RuO$_6$. This effect dominates, and the cooperative occupation of $xy$ orbital is concluded. In contrast to recent proposals, the resulting electronic structure explains well both the observed X-ray absorption spectra and the double peak structure of optical conductivity. For the FM side ($x=0.5$), however, the $xy$ orbital with half filling opens a pseudo-gap in the FM state and contributes to the spin $S$=1/2 moment (rather than $S$=1 for $x$=0.0 case) dominantly, while $yz,zx$ states are itinerant with very small spin polarization, explaining the recent neutron data consistently.Comment: 17 pages, 5 figure

Thermal diffusivity, effusivity and conductivity of CdMnTe mixed crystals

Cd1-xMnxTe mixed crystals belong to a class of materials called ‘‘semimagnetic semiconductor’’ or diluted magnetic semiconductor (DMS) with addition of magnetic ions like Mn2+ implemented into crystal structure. The crystals under investigation were grown from the melt by the high pressure high temperature modified Bridgman method in the range of composition 0 < x < 0.7. Thermal properties of these compounds have been investigated by means of photopyroelectric (PPE) calorimetry in both, back and front detection configuration. The values of the thermal diffusivity and effusivity were derived from experimental data. Thermal conductivity of the specimens was calculated from the simple theoretical dependencies between thermal parameters. The influence of Mn concentration on thermal properties of Cd1-xMnxTe crystals have been presented and discussed

CD40-activated B cells induce anti-tumor immunity in vivo

The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naïve and memory CD4 + and CD8 + and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T-cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy

The Earth System Prediction Suite: Toward a Coordinated U.S. Modeling Capability

The Earth System Prediction Suite (ESPS) is a collection of flagship U.S. weather and climate models and model components that are being instrumented to conform to interoperability conventions, documented to follow metadata standards, and made available either under open source terms or to credentialed users.The ESPS represents a culmination of efforts to create a common Earth system model architecture, and the advent of increasingly coordinated model development activities in the U.S. ESPS component interfaces are based on the Earth System Modeling Framework (ESMF), community-developed software for building and coupling models, and the National Unified Operational Prediction Capability (NUOPC) Layer, a set of ESMF-based component templates and interoperability conventions. This shared infrastructure simplifies the process of model coupling by guaranteeing that components conform to a set of technical and semantic behaviors. The ESPS encourages distributed, multi-agency development of coupled modeling systems, controlled experimentation and testing, and exploration of novel model configurations, such as those motivated by research involving managed and interactive ensembles. ESPS codes include the Navy Global Environmental Model (NavGEM), HYbrid Coordinate Ocean Model (HYCOM), and Coupled Ocean Atmosphere Mesoscale Prediction System (COAMPS); the NOAA Environmental Modeling System (NEMS) and the Modular Ocean Model (MOM); the Community Earth System Model (CESM); and the NASA ModelE climate model and GEOS-5 atmospheric general circulation model

First-principles quantum transport modeling of spin-transfer and spin-orbit torques in magnetic multilayers

We review a unified approach for computing: (i) spin-transfer torque in magnetic trilayers like spin-valves and magnetic tunnel junction, where injected charge current flows perpendicularly to interfaces; and (ii) spin-orbit torque in magnetic bilayers of the type ferromagnet/spin-orbit-coupled-material, where injected charge current flows parallel to the interface. Our approach requires to construct the torque operator for a given Hamiltonian of the device and the steady-state nonequilibrium density matrix, where the latter is expressed in terms of the nonequilibrium Green's functions and split into three contributions. Tracing these contributions with the torque operator automatically yields field-like and damping-like components of spin-transfer torque or spin-orbit torque vector, which is particularly advantageous for spin-orbit torque where the direction of these components depends on the unknown-in-advance orientation of the current-driven nonequilibrium spin density in the presence of spin-orbit coupling. We provide illustrative examples by computing spin-transfer torque in a one-dimensional toy model of a magnetic tunnel junction and realistic Co/Cu/Co spin-valve, both of which are described by first-principles Hamiltonians obtained from noncollinear density functional theory calculations; as well as spin-orbit torque in a ferromagnetic layer described by a tight-binding Hamiltonian which includes spin-orbit proximity effect within ferromagnetic monolayers assumed to be generated by the adjacent monolayer transition metal dichalcogenide.Comment: 22 pages, 9 figures, PDFLaTeX; prepared for Springer Handbook of Materials Modeling, Volume 2 Applications: Current and Emerging Material

The Multi-Scale Infrastructure for Chemistry and Aerosols (MUSICA)

To explore the various couplings across space and time and between ecosystems in a consistent manner, atmospheric modeling is moving away from the fractured limited-scale modeling strategy of the past toward a unification of the range of scales inherent in the Earth system. This paper describes the forward-looking Multi-Scale Infrastructure for Chemistry and Aerosols (MUSICA), which is intended to become the next-generation community infrastructure for research involving atmospheric chemistry and aerosols. MUSICA will be developed collaboratively by the National Center for Atmospheric Research (NCAR) and university and government researchers, with the goal of serving the international research and applications communities. The capability of unifying various spatiotemporal scales, coupling to other Earth system components, and process-level modularization will allow advances in both fundamental and applied research in atmospheric composition, air quality, and climate and is also envisioned to become a platform that addresses the needs of policy makers and stakeholders

Factors associated with sugar intake and sugar sources in European children from 1 to 8 years of age

Background/Objectives:The World Health Organization recommends to limit intake of free sugars to 5% of total energy per day because of the great impact of high sugar intake on body fat deposition, adiposity and dental caries. However, little data exist about total intake and sources of sugar in European children. Therefore, this paper aims to describe sugar intake and dietary sugar sources and associated factors.Subjects/Methods:Three-day weighed dietary records were obtained at eight time points from children 1 to 8 years of age (n=995) in five European countries. Food items were classified into subgroups according to food composition. Linear mixed models were used to examine associated factors.Results:Total sugar intake increased from 65 g/day (30.0% of energy intake (E%)) at 12 months of age to 83 g/day (20.9 E%) at 96 months of age. Around 80% of children's sugar intake was derived from the following sources: milk and dairy products, fruits and fruit products, confectionary and sugar sweetened beverages (SSB). Total sugar intake and dietary sugar sources varied significantly by country of residence. Boys had a significantly (P=0.003) higher total sugar consumption than girls.SSB consumption was significantly higher in children from young mothers while sugar intake from fruit products was lower in children from mothers with lower educational status and those with higher birth order.Conclusions:Sugar intake in our population was lower than in other studies. Total sugar intake was associated with country of residence and gender, while dietary sugar sources varied by country of residence, maternal age, education and birth order