Invited Review Meeting Report: SMART Timing-Principles of Single Molecule Techniques Course at the University of Michigan 2014

ABSTRACT: Four days after the announcement of the 2014 Nobe

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

Regenerative cooling analysis of oxygen/methane rocket engines

Methane is a promising propellant for future liquid rocket engines. In the cooling channels of a regeneratively cooled engine, it would be close to the critical point. This results in drastic changes in the fluid properties, which makes cooling analysis a challenge. This thesis describes a two-pronged approach to tackle this problem. Simple and fast engineering tools allow for the development of insight in the design space using rapid iterations and parametric analyses. However, they are often rather inaccurate. In contrast, detailed multi-dimensional tools for numerical analysis are more accurate, but they require more computation time. Both approaches are developed for the analysis of regenerative cooling channels of oxygen/methane engines. Each approach uses complex but accurate models for the thermodynamic and transport properties of methane. OMECA (short for One-dimensional Methane Engine Cooling Analysis) is a one-dimensional tool that was developed in Python from scratch. This tool divides a nozzle into stations and analyses the one-dimensional thermal equilibrium at each station. It makes extensive use of semi-empirical equations to calculate the heat transfer at both the hot gas side and the coolant side. The tool is compared to a coupled multi-physics analysis tool, showing that the accuracy of the wall temperature is rather poor, with discrepancies of up to 150~K. Both at the hot gas and coolant side, large deviations are present. However, if the input heat flux is correct, OMECA predicts the coolant pressure drop and temperature rise with a 10% accuracy. To obtain a higher accuracy at the coolant side, the open-source CFD package OpenFOAM is adapted for analysis of supercritical methane. Of particular note is the custom library that interpolates the fluid property tables at runtime. The selected solver is applicable to steady-state compressible flows. The software is then systematically validated using three validation cases. With experimental validation data obtained through cooperation with CIRA, an accuracy of 15 K for the wall temperature prediction is demonstrated. The pressure drop is predicted within 10%. Traditionally, the launcher industry uses copper alloys as wall material in regeneratively cooled combustion chambers. They offer a high allowable temperature and high thermal conductivity, but are also heavy and expensive. Recently, several companies have demonstrated aluminium combustion chambers. Aluminium alloys have weight and cost advantages, but have lower allowable temperature and thermal conductivity. The developed tools for cooling analysis are therefore employed to compare aluminium and copper for a generic 10~kN combustion chamber. It is discovered that a thermal barrier coating must be employed to protect the hot gas side of an aluminium combustion chamber, otherwise regenerative cooling is not feasible. Even with such a coating, the pressure drop required to cool the coated aluminium chamber is three times higher than the pressure drop required for a copper chamber. A difference in pressure drop has effects on the vehicle level. A larger pressure drop in the cooling channel of a rocket engine necessitates a higher feed pressure. For a pressure fed engine, this means the tank must be stronger and heavier. It is found that even at modest fuel mass, the increase in tank mass is eight times as large as the decrease in engine mass offered by aluminium. This shows that using aluminium for the chamber wall is not advantageous with respect to copper for a pressure fed, regeneratively cooled, oxygen/methane rocket engine.Space Systems EngineeringSpace EngineeringAerospace Engineerin

Analysis of supercritical methane in rocket engine cooling channels

Methane is a promising propellant for liquid rocket engines. As a regenerative coolant, it would be close to its critical point, complicating cooling analysis. This study encompasses the development and validation of a new, open-source computational fluid dynamics (CFD) method for analysis of methane cooling channels. Validation with experimental data has been carried out, showing an accuracy within 20 K for wall temperature and 10% for pressure drop. It is shown that the turbulence model has only a limited impact on the simulation results and that the wall function approach generates valid results. Finally, a cooling analysis is performed to compare two thrust chamber materials. A traditional copper alloy is compared to aluminium as chamber material for a small moderate-pressure oxygen/ methane engine. The analyses show that aluminium is a feasible chamber material only if a thermal barrier coating is applied. In addition, a significantly higher cooling channel pressure drop is incurred for an aluminium chamber than for a copper chamber due to the lower allowable temperature.Space Systems Egineerin

Cryogenic rocket engine development at Delft aerospace rocket engineering

This paper describes the current developments regarding cryogenic rocket engine technology at Delft Aerospace Rocket Engineering (DARE). DARE is a student society based at Delft University of Technology with the goal of being the first student group in the world to launch a rocket into space. After the launch of the hybrid engine powered Stratos II+ sounding rocket in October 2015, DARE decided to investigate highly efficient liquid rocket engine technology . In this context DARE initiated the cryogenic project with the goal of developing a liquid rocket engine using liquid oxygen and liquid methane as propellants with a nominal thrust in the order of 10kN. Eventually this engine shall power a future sounding rocket into space. As an intermediate step, a 3 kN class engine is being developed. Subsystem development tests and possibly a hot-fire test campaign on this engine are planned for 2016 and its development intends to provide DARE with the required experience and knowledge to develop large scale liquid rocket engines. The engine is developed in cooperation with Heliaq Advanced Engineering and is designed to meet the requirements of the second stage engine of the ALV reusable launch vehicle. The design is a pressure-fed engine, regeneratively cooled using the liquid methane fuel. After passing the coolant channels, the methane is injected into the combustion chamber in gaseous state together with the liquid oxygen in a co-axial manner. The engine is ignited by means of a pyrotechnic igniter using an ammonium perchlorate based propellant. During a test sequence, the propellants are stored in insulated run-tanks and are pressurized using helium. This paper describes the project objective, the current progress on the design and production, and finally four proposed research topics that are indented to be conducted at the faculty of Aerospace Engineering of Delft University of Technology.Space Systems Egineerin

In vitro exploration of a myeloid-derived suppressor cell line as vehicle for cancer gene therapy

Recent research indicates that cell-mediated gene therapy can be an interesting method to obtain intratumoral expression of therapeutic proteins. This paper explores the possibility of using transfected myeloid-derived suppressor cells (MDSCs), derived from a murine cell line, as cellular vehicles for transporting plasmid DNA (pDNA) encoding interleukin-12 (IL-12) to tumors. Transfecting these cells via electroporation caused massive cell death. This was not due to electroporation-induced cell damage, but was mainly the result of the intracellular presence of plasmids. In contrast, pDNA transfection using Lipofectamine 2000 (LF2000) did not result in a significant loss of viability. Differences in delivery mechanism may explain the distinctive effects on cell viability. Indeed, electroporation is expected to cause a rapid and massive influx of pDNA resulting in cytosolic pDNA levels that most likely surpass the activation threshold of the intracellular DNA sensors leading to cell death. In contrast, a more sustained intracellular release of the pDNA is expected with LF2000. After lipofection with LF2000, 56% of the MDSCs were transfected and transgene expression lasted for at least 24 h. Moreover, biologically relevant amounts of IL-12 were produced by the MDSCs after lipofection with an IL-12 encoding pDNA. In addition, IL-12 transfection caused a significant upregulation of CD80 and considerably reduced the immunosuppressive capacity of the MDSCs. IL-12-transfected MDSCs were still able to migrate to tumor cells, albeit that lipofection of the MDSCs seemed to slightly decrease their migration capacity

What does research on nicotine and tobacco use have to offer alcohol reseachers?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74420/1/j.1360-0443.1990.tb03079.x.pd