Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40.

Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.Experimental Design: We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.Results: The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4+ T-cell proliferation at day 13, but at day 19, both CD4+ and CD8+ T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in approximately 30% of treated animals.Conclusions: These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. Clin Cancer Res; 23(20); 6165-77. ©2017 AACRSee related commentary by Colombo, p. 5999

Estimates for practical quantum cryptography

In this article I present a protocol for quantum cryptography which is secure against attacks on individual signals. It is based on the Bennett-Brassard protocol of 1984 (BB84). The security proof is complete as far as the use of single photons as signal states is concerned. Emphasis is given to the practicability of the resulting protocol. For each run of the quantum key distribution the security statement gives the probability of a successful key generation and the probability for an eavesdropper's knowledge, measured as change in Shannon entropy, to be below a specified maximal value.Comment: Authentication scheme corrected. Other improvements of presentatio

The Dutch resolution variant of the classical resolution of racemates by formation of diastereomeric salts:Family behaviour in nucleation inhibition

The resolution of racemates through their diastereomeric salts can be positively affected by the addition of small amounts of suitable nucleation inhibitors. This discovery is a logical extension of “Dutch Resolution”, in which equimolar amounts of resolving agents that are members of the same family (i.e., structurally related) are used. We conducted a systematic search for nucleation inhibitors of the resolving agent 1-phenylethylamine. A wide range of amines that bear possible family resemblances to 1-phenylethylamine was investigated. It was found that (R)-1-phenylbutylamine is a good inhibitor of (R)-1-phenylethylamine. Results of turbidity measurements showed that, for the model case of mandelic acid resolution, the chief effect of this inhibitor was to widen the metastable zone for the more soluble diastereomer. This observation is in accordance with previous experience. Further scouting for possible family members revealed a wide variation in the effectiveness of inhibitors, dependent on their structure. By far the most effective inhibitors are bifunctional 1-phenylethylamine and/or 1-phenylbutylamine analogues. The effect of racemic inhibitors was found to approach that of enantiomerically pure inhibitors of the same absolute configuration of the 1-phenylethylamine used for resolution. The most effective inhibitors were tested for the resolution of a structural variety of racemates, and were shown to be broadly applicable.

IPCP: Immersive Parallel Coordinates Plots for Engineering Design Processes

Computational engineering design methods and tools are common practice in modern industry. Such approaches are integral in enabling designers to efficiently explore larger and more complex design spaces. However, at the same time, computational engineering design methods tend to dramatically increase the number of candidate solutions that decision-makers must interpret in order to make appropriate choices within a set of solutions. Since all candidate solutions can be represented in digital form together with their assessment criteria, evaluated according to some sort of simulation model, a natural way to explore and understand the complexities of the design problem is to visualize their multidimensional nature. The task now involves the discovery of patterns and trends within the multidimensional design space. In this work, we aim to enhance the design decision-making process by embedding visual analytics into an immersive virtual reality environment. To this end, we present a system called IPCP: immersive parallel coordinates plots. IPCP combines the well-established parallel coordinates visualization technique for high-dimensional data with immersive virtual reality. We propose this approach in order to exploit and discover efficient means to use new technology within a conventional decision-making process. The aim is to provide benefits by enhancing visualizations of 3D geometry and other physical quantities with scientific information. We present the design of this system, which allows the representation and exploration of multidimensional scientific datasets. A qualitative evaluation with two surrogate expert users, knowledgeable in multidimensional data analysis, demonstrate that the system can be used successfully to detect both known and previously unknown patterns in a real-world test dataset, producing an early indicative validation of its suitability for decision support in engineering design processes.Cambridge European and Trinity Hall; Engineering and Physical Sciences Research Council (EPSRC-1788814

Quantum Nonlocality without Entanglement

We exhibit an orthogonal set of product states of two three-state particles that nevertheless cannot be reliably distinguished by a pair of separated observers ignorant of which of the states has been presented to them, even if the observers are allowed any sequence of local operations and classical communication between the separate observers. It is proved that there is a finite gap between the mutual information obtainable by a joint measurement on these states and a measurement in which only local actions are permitted. This result implies the existence of separable superoperators that cannot be implemented locally. A set of states are found involving three two-state particles which also appear to be nonmeasurable locally. These and other multipartite states are classified according to the entropy and entanglement costs of preparing and measuring them by local operations.Comment: 27 pages, Latex, 6 ps figures. To be submitted to Phys. Rev. A. Version 2: 30 pages, many small revisions and extensions, author added. Version 3: Proof in Appendix D corrected, many small changes; final version for Phys. Rev. A Version 4: Report of Popescu conjecture modifie

The work–recovery cycle of kidney strain and inflammation in sugarcane workers following repeat heat exposure at work and at home

PurposeTo examine heat exposure at work and home and the work–recovery cycle and temporal variation of kidney strain, muscle injury and inflammation biomarkers in sugarcane workers.Methods20 male sugarcane workers (age: 33 ± 7 years) with a workplace Rest.Shade.Hydration (RSH) intervention were observed over 4 days, at the end (18 h post-shift recovery) and beginning of a work week (42 h post-shift recovery). Measures included work intensity (heart rate), gastro-intestinal temperature, estimated body core temperature (using heart rate), fluid consumption, pre- and post-work blood and urine samples, physical activity (accelerometery) away from work, plus ambient heat exposure at work and home.ResultsOn workdays, workers awakened at approx. 02:40 after 5 h sleep in ~ 30 °C. Across work shifts, daily average WBGT ranged from 26 to 29 °C (cooler than normal) and average workload intensity ranged from 55 to 58%HRmax. Workers reported consuming ~ 8 L of water and ~ 4 × 300 mL bags of electrolyte fluid each day. Serum creatinine, cystatin C and creatine phosphokinase markedly increased post-work and decreased during recovery; serum potassium did the opposite (all p &lt; 0.01). Biomarker concentration changes were similar between recovery periods (18 h vs. 42 h; all p &gt; 0.27). C-reactive protein was the highest at the end of the work week (p = 0.01).ConclusionDespite RSH intervention, cross-shift kidney strain was marked (recovering overnight) and systemic inflammation increased over the work week. Thus, biomonitoring of kidney function in occupational populations should be performed before a work shift at any point in the work week. This is essential knowledge for field studies and surveillance.<br/

Author correction : a global database for metacommunity ecology, integrating species, traits, environment and space

Correction to: Scientific Data https://doi.org/10.1038/s41597-019-0344-7, published online 08 January 202

Author correction : a global database for metacommunity ecology, integrating species, traits, environment and space

Correction to: Scientific Data https://doi.org/10.1038/s41597-019-0344-7, published online 08 January 202