Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. Experimental cancer immunology and therap

Deterministic mathematical modelling for cancer chronotherapeutics: cell population dynamics and treatment optimisation

Chronotherapeutics has been designed and used for more than twenty years as an effective treatment against cancer by a few teams around the world, among whom one of the first is Francis Lévi's at Paul-Brousse hospital (Villejuif, France), in application of circadian clock physiology to determine best infusion times within the 24-hour span for anticancer drug delivery. Mathematical models have been called in the last ten years to give a rational basis to such optimised treatments, for use in the laboratory and ultimately in the clinic. While actual clinical applications of the theoretical optimisation principles found have remained elusive so far to improve chronotherapeutic treatments in use, mathematical models provide proofs of concepts and tracks to be explored experimentally, to progress from theory to bedside. Starting from a simple ordinary differential equation model that allowed setting and numerically solving a drug delivery optimisation problem with toxicity constraints, this modelling enterprise has been extended to represent the division cycle in proliferating cell populations with different molecular targets, to allow for the representation of anticancer drug combinations that are used in clinical oncology. The main point to be made precise in such a therapeutic optimisation problem is to establish, here in the frame of circadian chronobiology, physiologically based differences between healthy and cancer cell populations in their responses to drugs. To this aim, clear biological evidence at the molecular level is still lacking, so that, starting from indirect observations at the experimental and clinical levels and from theoretical considerations on the model, speculations have been made, that will be exposed in this review of cancer chronotherapeutics models with the corresponding optimisation problems and their numerical solutions, to represent these differences between the two cell populations, with regard to circadian clock control

Application of a calorimetric thermal converter as a standard of AC-DC voltage and current transfer difference

At the National Research Council of Canada (NRC) the primary standard of AC-DC transfer difference at frequencies from 10 kHz to 100 MHz is a Calorimetric Thermal Voltage Converter (CTVC). Because of a simple design, not unlike a coaxial calorimeter for RF power measurements, its frequency characteristic can be estimated theoretically from a number of mechanical and electrical parameters. An internal Tee, integrated into the CTVC, improves calibration accuracy of working standards. Over the years several of these converters have been manufactured for different operating voltages and with different frequency characteristics, leading to an optimized design with a frequency characteristic practically flat over eight decades of frequency. The paper describes details of construction of the CTVC. Results of RF-DC voltage transfer difference measurements, AC-DC current transfer difference and uncertainty evaluation of the converter are discussed.Peer reviewed: YesNRC publication: Ye

Evaluation of a calorimetric thermal voltage converter for RF-DC difference up to 1 GHz

In this paper, we present a performance evaluation of the RF-DC transfer difference for a calorimetric thermal voltage converter (CTVC) designed by the National Research Council of Canada (NRC) at frequencies up to 1 GHz. In the first part of this paper, we describe a bilateral comparison of the RF-DC difference standards between the NRC and the National Metrology Centre of the Agency for Science, Technology and Research of Singapore, in the frequency band from 1 kHz to 100 MHz. A good agreement is observed between the two laboratories using the CTVC as a traveling standard. In the second part of this paper, we evaluate the performance of the CTVC at higher frequencies up to 1 GHz. In this part, RF-DC difference of the CTVC is mathematically modeled and experimentally evaluated in terms of the calibration factor of a thermistor mount and the reflection coefficients at its type-N input connector. \ua9 2013 IEEE.Peer reviewed: YesNRC publication: Ye