Challenges and Opportunities for Immunotherapeutic Intervention against Myeloid Immunosuppression in Glioblastoma

Glioblastoma multiforme (GBM), the most common and deadly brain cancer, exemplifies the paradigm that cancers grow with help from an immunosuppressive tumor microenvironment (TME). In general, TME includes a large contribution from various myeloid lineage-derived cell types, including (in the brain) altered pathogenic microglia as well as monocyte-macrophages (Macs), myeloid-derived suppressor cells (MDSC) and dendritic cell (DC) populations. Each can have protective roles, but has, by definition, been coopted by the tumor in patients with progressive disease. However, evidence demonstrates that myeloid immunosuppressive activities can be reversed in different ways, leading to enthusiasm for this therapeutic approach, both alone and in combination with potentially synergistic immunotherapeutic and other strategies. Here, we review the current understanding of myeloid cell immunosuppression of anti-tumor responses as well as potential targets, challenges, and developing means to reverse immunosuppression with various therapeutics and their status. Targets include myeloid cell colony stimulating factors (CSFs), insulin-like growth factor 1 (IGF1), several cytokines and chemokines, as well as CD40 activation and COX2 inhibition. Approaches in clinical development include antibodies, antisense RNA-based drugs, cell-based combinations, polarizing cytokines, and utilizing Macs as a platform for Chimeric Antigen Receptors (CAR)-based tumor targeting, like with CAR-T cells. To date, promising clinical results have been reported with several of these approaches

SDSS-IV MaNGA: Spatially resolved star formation in barred galaxies

A novel wave-energy device is presented. Both a preliminary proof-of-principle of a working, scaled laboratory version of the energy device is shown as well as the derivation and analysis of a comprehensive mathematical and numerical model of the new device. The wave-energy device includes a convergence in which the waves are amplified, a constrained wave buoy with a (curved) mast and direct energy conversion of the buoy motion into electrical power via an electro-magnetic generator. The device is designed for use in breakwaters and it is possible to be taken out of action during severe weather. The new design is a deconstruction of elements of existing wave-energy devices, such as the TapChan, IP wave-buoy and the Berkeley Wedge, put together in a different manner to enhance energy conversion and, hence, efficiency. The idea of wave-focusing in a contraction emerged from our work on creating and simulating rogue waves in crossing seas, including a “bore-soliton-splash”. Such crossing seas have been recreated and modelled in the laboratory and in simulations by using a geometric channel convergence. The mathematical and numerical modelling is also novel. One monolithic variational principle governs the dynamics including the combined (potential-flow) hydrodynamics, the buoy motion and the power generation, to which the dissipative elements such as the electrical resistance of the circuits, coils and loads have been added a posteriori. The numerical model is a direct and consistent discretisation of this comprehensive variational principle. Preliminary numerical calculations are shown for the case of linearised dynamics; optimisation of efficiency is a target of future work

SDSS-IV MaNGA: spatially resolved dust attenuation in spiral galaxies

Dust attenuation in star-forming spiral galaxies affects stars and gas in different ways due to local variations in dust geometry. We present spatially resolved measurements of dust attenuation for a sample of 232 such star-forming spiral galaxies, derived from spectra acquired by the SDSS-IV MaNGA survey. The dust attenuation affecting the stellar populations of these galaxies (obtained using full spectrum stellar population fitting methods) is compared with the dust attenuation in the gas (derived from the Balmer decrement). Both of these attenuation measures increase for local regions of galaxies with higher star formation rates; the dust attenuation affecting the stellar populations increases more so than the dust attenuation in the gas, causing the ratio of the dust attenuation affecting the stellar populations to the dust attenuation in the gas to decrease for local regions of galaxies with higher star formation rate densities. No systematic difference is discernible in any of these dust attenuation quantities between the spiral arm and inter-arm regions of the galaxies. While both the dust attenuation in the gas and the dust attenuation affecting the stellar populations decrease with galactocentric radius, the ratio of the two quantities does not vary with radius. This ratio does, however, decrease systematically as the stellar mass of the galaxy increases. Analysis of the radial profiles of the two dust attenuation measures suggests that there is a disproportionately high concentration of birth clouds (incorporating gas, young stars and clumpy dust) nearer to the centres of star-forming spiral galaxies.Comment: 17 pages, 8 figures, accepted for publication in Monthly Notices of the Royal Astronomical Societ

A Biologic-Device Combination Product Delivering Tumor-Derived Antigens Elicits Immunogenic Cell Death-Associated Immune Responses Against Glioblastoma

Background IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5–6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients. Methods Mouse (m) or human (h) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or mIGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1–6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving mIGV-001 were immunophenotyped. mIGV-001 and hIGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting. Results IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1–6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice. Conclusions These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM

SDSS-IV MaNGA: Stellar Population Gradients Within Barred Galaxies

Bars in galaxies are thought to stimulate both inflow of material and radial mixing along them. Observational evidence for this mixing has been inconclusive so far however, limiting the evaluation of the impact of bars on galaxy evolution. We now use results from the MaNGA integral field spectroscopic survey to characterise radial stellar age and metallicity gradients along the bar and outside the bar in 128 strongly barred galaxies. We find that age and metallicity gradients are flatter in the barred regions of almost all barred galaxies when compared to corresponding disk regions at the same radii. Our results re-emphasize the key fact that by azimuthally averaging integral field spectroscopic data one loses important information from non-axisymmetric galaxy components such as bars and spiral arms. We interpret our results as observational evidence that bars are radially mixing material in galaxies of all stellar masses, and for all bar morphologies and evolutionary stages

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure