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

Evaluation of Heterogenous Oxidation Reaction of Copper Concentrate/Pyrite/Silica Sand Mixture by Preheated Oxygen Gas Blowing

A hand-made apparatus to react copper concentrate (Cc)/pyrite (Py)/silica sand (Ss) mixture was developed for an imitated concentrate burner at laboratory scale. An instantaneous (&lt; 1 s) ignition reaction was macroscopically observed by preheated oxygen gas blowing to Cc/Py/Ss mixture with a Fe/SiO2 mass ratio of 1.1. SEM-EDS analysis was used to observe microstructure and phase distribution in reacted and water-quenched particles. As for the Cc/Ss samples collected at the point close to the gas blowing spot, 70–80 mass% Cu matte phase and heterogeneous slag phase including large amounts of magnetite (Mag) particles were formed. At the lower part from the gas blowing spot with a distance of 275 mm, 60–65 mass% Cu matte phase was confirmed. The area fraction of Mag particles in the slag phase decreased with increasing Py adding concentration in the mixture sample. Our results suggested the concentration and microscopic distribution of Py in the mixture including Cc contributed to control both Cu concentration in matter phase and Mag particle concentration in slag phase

Development of Nd-Doped CaWO₄ Single Crystalline Scintillators Emitting Near-Infrared Light

Nd-doped CaWO4 single crystals with dopant concentrations of 0.1, 0.5, and 1% were synthesized by the floating zone method. The transmission, photoluminescence, and scintillation properties were evaluated from ultraviolet to near-infrared (NIR) ranges. An emission peak due to transitions of the host was observed at 400 nm, and several sharp peaks originating from Nd3+ 4f–4f transitions were confirmed at 900, 1060, and 1300 nm. The quantum yields of 0.1, 0.5, and 1% Nd-doped samples were 70.7, 79.5, and 61.2%, respectively, when monitored, and excited wavelengths were 750–1500 nm and 590 nm. Decay times consistent with typical Nd3+ transitions were obtained when NIR ranges were monitored. Additionally, the energy transfer between the host and Nd3+ occurred according to the decay measurement. The relationship between X-ray irradiated dose rate and intensity in the range of NIR was investigated by combining the crystals with an InGaAs-photodiode. The lowest detectable dose rate retaining the linearity of the present crystals was 0.3–0.06 Gy/h

Development of Nd-Doped CaWO4 Single Crystalline Scintillators Emitting Near-Infrared Light

Nd-doped CaWO4 single crystals with dopant concentrations of 0.1, 0.5, and 1% were synthesized by the floating zone method. The transmission, photoluminescence, and scintillation properties were evaluated from ultraviolet to near-infrared (NIR) ranges. An emission peak due to transitions of the host was observed at 400 nm, and several sharp peaks originating from Nd3+ 4f&ndash;4f transitions were confirmed at 900, 1060, and 1300 nm. The quantum yields of 0.1, 0.5, and 1% Nd-doped samples were 70.7, 79.5, and 61.2%, respectively, when monitored, and excited wavelengths were 750&ndash;1500 nm and 590 nm. Decay times consistent with typical Nd3+ transitions were obtained when NIR ranges were monitored. Additionally, the energy transfer between the host and Nd3+ occurred according to the decay measurement. The relationship between X-ray irradiated dose rate and intensity in the range of NIR was investigated by combining the crystals with an InGaAs-photodiode. The lowest detectable dose rate retaining the linearity of the present crystals was 0.3&ndash;0.06 Gy/h

Er-Doped Mg₄Ta₂O₉ Single-Crystal Scintillators Emitting Near-Infrared Photons for High-Dose Field Monitoring

Mg4Ta2O9 single crystals doped with 0.01, 0.1, and 1% Er were grown using the floating zone method, and their photoluminescence and scintillation properties were studied. X-ray diffraction analysis confirmed that all samples had a hexagonal structure of Mg4Ta2O9. The samples showed that the emission peak at 1550 nm was due to 4f−4f transitions of Er3+ ions, with quantum yields of 32.9, 46.6, and 18.0% for 0.01, 0.1, and 1% doping concentrations, respectively. All samples showed scintillation with a broad emission band at 350 nm due to charge transfer from Ta5+ to O2− ions and emission peak at 1550 nm due to 4f−4f transition of Er3+ ions. The dose rate response functions showed that the detection limit for all samples was 0.06 Gy/h for scintillation detector applications

X-ray-Induced Scintillation Properties of Nd-Doped Bi4Si3O12 Crystals in Visible and Near-Infrared Regions

Undoped, 0.5, 1.0, and 2.0% Nd-doped Bi4Si3O12 (BSO) crystals were synthesized by the floating zone method. Regarding photoluminescence (PL) properties, all samples had emission peaks due to the 6p&ndash;6s transitions of Bi3+ ions. In addition, the Nd-doped samples had emission peaks due to the 4f&ndash;4f transitions of Nd3+ ions as well. The PL quantum yield of the 0.5, 1.0, and 2.0% Nd-doped samples in the near-infrared range were 67.9, 73.0, and 56.6%, respectively. Regarding X-ray-induced scintillation properties, all samples showed emission properties similar to PL. Afterglow levels at 20 ms after X-ray irradiation of the undoped, 0.5, 1.0, and 2.0% Nd-doped samples were 192.3, 205.9, 228.2, and 315.4 ppm, respectively. Dose rate response functions had good linearity from 0.006 to 60 Gy/h for the 1.0% Nd-doped BSO sample and from 0.03 to 60 Gy/h for the other samples

Role of a Water Network around the Mn₄CaO₅ Cluster in Photosynthetic Water Oxidation: A Fourier Transform Infrared Spectroscopy and Quantum Mechanics/Molecular Mechanics Calculation Study

Photosynthetic water oxidation takes place at the Mn₄CaO₅ cluster in photosystem II. Around the Mn₄CaO₅ cluster, a hydrogen bond network is formed by several water molecules, including four water ligands. To clarify the role of this water network in the mechanism of water oxidation, we investigated the effects of the removal of Ca²⁺ and substitution with metal ions on the vibrations of water molecules coupled to the Mn₄CaO₅ cluster by means of Fourier transform infrared (FTIR) difference spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. The OH stretching vibrations of nine water molecules forming a network between D1-D61 and Y_Z were calculated using the QM/MM method. On the the calculated normal modes, a broad positive feature at 3200–2500 cm^–1 in an S₂-minus-S₁ FTIR spectrum was attributed to the vibrations of strongly hydrogen-bonded OH bonds of water involving the vibrations of water ligands to a Mn ion and the in-phase coupled vibration of a water network connected to Y_Z, while bands in the 3700–3500 cm^–1 region were assigned to the coupled vibrations of weakly hydrogen-bonded OH bonds of water. All the water bands were lost upon Ca²⁺ depletion and Ba²⁺ substitution, which inhibit the S₂ → S₃ transition, indicating that a solid water network was broken by these treatments. By contrast, Sr²⁺ substitution slightly altered the water bands around 3600 cm^–1, reflecting minor modification in water interactions, consistent with the retention of water oxidation activity with a decreased efficiency. These results suggest that the water network around the Mn₄CaO₅ cluster plays an essential role in the water oxidation mechanism particularly in a concerted process of proton transfer and water insertion during the S₂ → S₃ transition

Characteristics of limb kinematics in the gait disorders of post-stroke patients

Abstract Post-stroke gait disorders involve altered lower limb kinematics. Recently, the endpoint of the lower limb has been used as a control variable to understand gait kinematics better. In a cross-sectional study of sixty-seven post-stroke patients, the limb extension angle and effective limb length during gait were used as input variables with a mixed Gaussian model-based probabilistic clustering approach to identify five distinct clusters. Each cluster had unique characteristics related to motor paralysis, spasticity, balance ability, and gait strategy. Cluster 1 exhibited high limb extension angle and length values, indicating increased spasticity. Cluster 2 had moderate extension angles and high limb lengths, indicating increased spasticity and reduced balance ability. Cluster 3 had low limb extension angles and high limb length, indicating reduced balance ability, more severe motor paralysis, and increased spasticity. Cluster 4 demonstrated high extension angles and short limb lengths, with a gait strategy that prioritized stride length in the component of gait speed. Cluster 5 had moderate extension angles and short limb lengths, with a gait strategy that prioritized cadence in the component of gait speed. These findings provide valuable insights into post-stroke gait impairment and can guide the development of personalized and effective rehabilitation strategies