Reverting immune suppression to enhance cancer immunotherapy

Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD8+T cells. These dynamic immunosuppressive networks prevent tumor rejection at several levels, limiting also the success of immunotherapies. Nevertheless, the recent clinical development of immune checkpoint inhibitors or of molecules modulating cellular targets and immunosuppressive enzymes highlights the great potential of approaches based on the selective disruption of immunosuppressive networks. Currently, the administration of different categories of immunotherapy in combination regimens is the ultimate modality for impacting the survival of cancer patients. With the advent of immune checkpoint inhibitors, designed to mount an effective antitumor immune response, profound changes occurred in cancer immunotherapy: from a global stimulation of the immune system to a specific targeting of an immune component. This review will specifically highlight the players, the mechanisms limiting an efficient antitumor response and the current immunotherapy modalities tailored to target immune suppressive pathways. We also discuss the ongoing challenges encountered by these strategies and provide suggestions for circumventing hurdles to new immunotherapeutic approaches, including the use of relevant biomarkers in the optimization of immunotherapy regimens and the identification of patients who can benefit from defined immune-based approaches

Blockade of TGF-β signaling to enhance the antitumor response is accompanied by dysregulation of the functional activity of CD4

BACKGROUND: The pleiotropic cytokine, transforming growth factor (TGF)-β, and CD4 METHODS: Using BALB/c, FoxP3eGFP and Rag RESULTS: SM16 abrogates TGF-β-induced Treg generation in vitro but does not prevent global homeostatic expansion of CD4 CONCLUSIONS: These findings suggest that blockade of TGF-β signaling is a potentially useful strategy for blunting Treg function to enhance the anti-tumor response. Our data further suggest that the overall dampening of Treg function may involve the expansion of a quiescent Treg precursor population, which is CD

Reverting Immune Suppression to Enhance Cancer Immunotherapy.

Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD

Biofuels from waste to road transport

Biofuels from Waste to Road (WASTE2ROAD) is an EU funded project under the Grant Agreement No. 818120 within the LC-SC3-RES-21-2018 call, “Development of next generation biofuels and alternative renewable fuel technologies for road transport”, as a Research and Innovation Action of the European Union’s Horizon 2020 Programme. The project started in the fall 2018 and will run for 4 years. In 2014, total waste production in the EU amounted to 2.5 billion tons. From this total only a limited (albeit increasing) share (36%) was recycled, while the rest was landfilled or burned, of which some 600 million tons could have been recycled or reused. Conversion of all sustainably available biogenic wastes and residues to biofuels could provide 27% of total transport fuel by 2050, achieving around 2.1 gigatons of CO2 emission reductions per year. The increasing demand for biofuels[1] implies the need for the transformation of diverse bio-resources into liquid fuels, and includes transformation of the biogenic part of municipal and industrial wastes into such biofuels. This clearly is a stepping stone to achieve the European goals[2] but it also poses challenges, such as 1) diversity and inhomogeneity of wastes throughout Europe (variable composition depending on the type of waste and geographical location), 2) the complexity of the conversion of wastes compared to fossil oils, 3) the technological aspects of co-refining and 4) high overall costs with moderate process performance. [1] https://www.iea.org/publications/freepublications/publication/Biofuels_Roadmap_WEB.pdf [2] https://europeanclimate.org/wp-content/uploads/2014/02/WASTED-final.pdf Please click Additional Files below to see the full abstract

Library Design in Combinatorial Chemistry by Monte Carlo Methods

Strategies for searching the space of variables in combinatorial chemistry experiments are presented, and a random energy model of combinatorial chemistry experiments is introduced. The search strategies, derived by analogy with the computer modeling technique of Monte Carlo, effectively search the variable space even in combinatorial chemistry experiments of modest size. Efficient implementations of the library design and redesign strategies are feasible with current experimental capabilities.Comment: 5 pages, 3 figure

Predicting crystal growth via a unified kinetic three-dimensional partition model

Understanding and predicting crystal growth is fundamental to the control of functionality in modern materials. Despite investigations for more than one hundred years1, 2, 3, 4, 5, it is only recently that the molecular intricacies of these processes have been revealed by scanning probe microscopy6, 7, 8. To organize and understand this large amount of new information, new rules for crystal growth need to be developed and tested. However, because of the complexity and variety of different crystal systems, attempts to understand crystal growth in detail have so far relied on developing models that are usually applicable to only one system9, 10, 11. Such models cannot be used to achieve the wide scope of understanding that is required to create a unified model across crystal types and crystal structures. Here we describe a general approach to understanding and, in theory, predicting the growth of a wide range of crystal types, including the incorporation of defect structures, by simultaneous molecular-scale simulation of crystal habit and surface topology using a unified kinetic three-dimensional partition model. This entails dividing the structure into ‘natural tiles’ or Voronoi polyhedra that are metastable and, consequently, temporally persistent. As such, these units are then suitable for re-construction of the crystal via a Monte Carlo algorithm. We demonstrate our approach by predicting the crystal growth of a diverse set of crystal types, including zeolites, metal–organic frameworks, calcite, urea and L-cystine

Synthesis of ‘unfeasible’ zeolites

R.E.M. thanks the Royal Society and the E.P.S.R.C. (Grants EP/L014475/1, EP/K025112/1 and EP/K005499/1) for funding work in this area. J.Č. and P.N. acknowledge the Czech Science Foundation for the project of the Centre of Excellence (P106/12/G015) and the European Union Seventh Framework Programme (FP7/ 2007-­‐2013) under grant agreement n°604307. The research leading to these results has received funding from the European Union Seventh Framework Programme under Grant Agreement 312483 – ESTEEM2 (Integrated Infrastructure Initiative–I3). We thank Professor Wuzong Zhou and Dr. Fengjiao Yu for their expertise in TEM and Daniel Dawson for help with NMR.Zeolites are porous aluminosilicate materials that have found applications in many different technologies. However, although simulations suggest that there are millions of possible zeolite topologies, only a little over 200 zeolite frameworks of all compositions are currently known, of which about 50 are pure silica materials. This is known as the zeolite conundrum - why have only so few of all the possible structures been made? Several criteria have been formulated to explain why most zeolites are unfeasible synthesis targets. Here we demonstrate the synthesis of two such 'unfeasible' zeolites, IPC-9 and IPC-10, through the assembly-disassembly-organization-reassembly mechanism. These new high-silica zeolites have rare characteristics, such as windows that comprise odd-membered rings. Their synthesis opens up the possibility of preparing other zeolites that have not been accessible by traditional solvothermal synthetic methods. We envisage that these findings may lead to a step change in the number and types of zeolites available for future applications.PostprintPeer reviewe