The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels

Tissue engineering of the blood-brain barrier (BBB) in vitro has been rapidly expanding to address the challenges of mimicking the native structure and function of the BBB. Most of these models utilize 2D conventional microfluidic techniques. However, 3D microvascular models offer the potential to more closely recapitulate the cytoarchitecture and multicellular arrangement of in vivo microvasculature, and also can recreate branching and network topologies of the vascular bed. In this perspective, we discuss current 3D brain microvessel modeling techniques including templating, printing, and self-assembling capillary networks. Furthermore, we address the use of biological matrices and fluid dynamics. Finally, key challenges are identified along with future directions that will improve development of next generation of brain microvasculature models

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

T cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation

CASPER: Coupled Air-Sea Processes and Electromagnetic Ducting Research

The article of record as published may be found at http://dx.doi.org/10.1175/BAMS-D-16-0046.1The objective of CASPER is to improve our capability to characterize the propagation of radio frequency (RF) signals through the marine atmosphere with coordinated efforts in data collection, data analyses, and modeling of the air–sea interaction processes, refractive environment, and RF propagation.Office of Naval Research (ONR) Multidisciplinary University Research Initiative (MURI) programOffice of Naval Research Multidisciplinary University Research InitiativeUS Naval Research Laboratory (ONR)grant N0001416WX00469program element 61153N (WU BE023-01-41-5461C04)Office of Naval Research Multidisciplinary University Research Initiative grant N0001416WX00469US Naval Research Laboratory program element 61153N (WU BE023-01-41-1C04