Development of a new therapeutic regime for the treatment of glioblastoma multiforme (GBM)

Glioblastoma multiforme is the most frequently occurring primary brain tumour and it carries a dismal prognosis. Despite surgical intervention and aggressive chemo-radiotherapy the median survival of patients is just under 15 months. Very little progress has been made with regards to improving patient survival therefore novel therapeutic interventions are required. Vaccination offers an attractive option for the therapeutic treatment of GBM, with activated T-cells previously being shown to access tumours located within the brain resulting in improved survival in pre-clinical murine models of GBM. Several vaccine platforms have been developed and tested in GBM patients, however many of these therapies fail during clinical trials and as of 2019 no immunotherapeutic treatments have been approved for use in the GBM setting. One major obstacle to overcome when using the immune system to treat GBMs is the highly immunosuppressive phenotype these cancers have. GBMs frequently express immunosuppressive checkpoints that prevent anti-tumour T-cell activity. Immune checkpoint blockade has recently gained approval for the treatment of malignant melanoma, lung cancer, head and neck cancer, lymphoma, bladder cancer and kidney cancer. The utilisation of immune checkpoint blockade as a monotherapy improves survival in small subsets of patients however it is not a completely curative treatment modality. Therefore it is of great interest to see if combining immune checkpoint blockade with vaccine therapy can boost anti-tumour immunity by stimulating T-cells and preventing the inhibitory signals from tumour cells that prevent T-cell killing. Examination of GBM tumour tissues and cell lines revealed that a large proportion of GBMs express the immunogenic antigens Tyrosinase-related protein-2 (TRP-2) and Wilms’ tumour 1 (WT-1). It was also revealed that these tumours expressed several immunosuppressive proteins with PD-L1, HLA E and HLA-G expression being observed in tissues and cell lines studied. It was also revealed that when GBM cell lines were treated with the immune stimulating cytokine IFNγ they up-regulated the immunosuppressive proteins PD-L1 and IDO. The ImmunoBody® DNA plasmid vaccination encodes an IgG antibody molecule that acts as a carrier protein for the peptide targets of interest, these peptides are engrafted into the complementarity determining regions of the antibody. This method of vaccination generates a strong-immune response via direct and cross-presentation. Pre-clinical testing using the humanised HHDII/DR1 C57BL/6 mouse model revealed that a HLA-A2 specific TRP-2 and a HLA-A2 specific WT-1 directed ImmunoBody® vaccine generated a strong peptide specific immune response. When both vaccinations were given simultaneously this strong TRP-2 and WT-1 directed immune response was equivalent to when each vaccine was given alone meaning that epitope dominance is not a factor when targeting these two antigens. Using the HHDII/DR1 humanised mouse the effects of this dual ImmunoBody® vaccination regime was tested both prophylactically and therapeutically. In these proof of concept experiments the B16 HHDII/DR1 Luc2 cell line was utilised. This cell line expresses both TRP-2 and WT-1 antigens and it has the chimeric HLA-A2 HHDII/DR1 MHC molecule meaning it presents HLA-A2 specific peptides. When the dual ImmunoBody® vaccination regime was used prophylactically it significantly improved the survival of mice intracranially implanted with B16 HHDII/DR1 Luc2 cells compared to sham vaccinated mice. In the therapeutic setting the addition of an anti-PD-1 blocking antibody to the dual vaccination regime improved survival of B16 HHDII/DR1 Luc1 tumour bearing mice when compared to dual vaccinated mice receiving PD-1 isotype control antibody and control sham vaccinated mice that received PD-1 isotype antibody. Analysis of tumour infiltrating lymphocyte populations revealed that dual vaccination increases CD8+ T-cell infiltrate into these intracranial tumours with these cells showing increased cell surface expression of the activation markers CD25 and CD69. The dipeptide carnosine was also used to treat GBM cells in vitro, this molecule has previously been shown to have anti-tumour activity. When carnosine was used to treat GBM cells it led to reduced mitochondrial metabolism and migration of these cells. These properties make carnosine an attractive adjunct to immunotherapy. Overall these results provide promise for the use of ImmunoBody® vaccination with immune checkpoint blockade for the treatment of GBM. Whilst immune cells can actively access tumours systemically administered checkpoint antibodies don't cross the blood-brain-barrier freely, therefore in order for these therapies to be further developed methods for improving brain penetrance of checkpoint inhibitors needs to be explored

Targeting cellular pathways in glioblastoma multiforme

Glioblastoma multiforme (GBM) is a debilitating disease that is associated with poor prognosis, short median patient survival and a very limited response to therapies. GBM has a very complex pathogenesis that involves mutations and alterations of several key cellular pathways that are involved in cell proliferation, survival, migration and angiogenesis. Therefore, efforts that are directed toward better understanding of GBM pathogenesis are essential to the development of efficient therapies that provide hope and extent patient survival. In this review, we outline the alterations commonly associated with GBM pathogenesis and summarize therapeutic strategies that are aimed at targeting aberrant cellular pathways in GBM

A light clustering model predictive control approach to maximize thermal power in solar parabolic-trough plants

This article shows how coalitional model predictive control (MPC) can be used to maximize thermal power of large-scale solar parabolic-trough plants. This strategy dynamically generates clusters of loops of collectors according to a given criterion, thus dividing the plant into loosely coupled subsystems that are locally controlled by their corresponding loop valves to gain performance and speed up the computation of control inputs. The proposed strategy is assessed with decentralized and centralized MPC in two simulated solar parabolic-trough fields. Finally, results regarding scalability are also given using these case studies

Sustainable Microalgal Harvesting Process Applying Opuntia cochenillifera: Process Parameters Optimization

Microalgae harvesting by coagulation can use coagulant agents such as alum, synthetic polymers or biocoagulants. Biocoagulants have attracted the attention of researchers because they are natural, biodegradable, and promote high microalgal harvesting efficiencies. This study aims to optimize the harvesting of Chlorella vulgaris based on the dosage of the Opuntia cochenillifera extract and the choice of eluent for biopolymer extraction. The outdoor cultivation of C. vulgaris achieved a specific growth rate of 0.455 d(-1) and a maximum biomass concentration of 1.28 g(DW) L-1. In order to harvest the microalgal biomass, the polymer present in the mucilage of O. cochenillifera was extracted using NaOH and HCl. Coagulation and sedimentation assays were performed with different coagulant dosages: 3.5, 5.9, and 8.2 g L-1. The maximum harvesting efficiencies using the acid and alkaline extract coagulant solutions were 80.8% and 99.5%, respectively, with a dosage of 3.5 g L-1. According to the results, the C. vulgaris biomass can be harvested with the mucilage from O. cochenillifera in acid and alkaline eluents. The application of this biocoagulant constitutes a sustainable solution for microalgal harvesting

Development of a peer-led, network mapping intervention to improve the health of individuals with severe mental illnesses: protocol for a pilot study.

INTRODUCTION: Adults with severe mental illness (SMI) have reduced life expectancy and many have comorbid physical health conditions. Primary care providers are experiencing increased demands for care for people with SMI. Barriers to accessing physical healthcare have been identified which negatively affect quality of care. We propose that peer support workers (PSWs) could deliver an intervention to service users to promote their physical health by drawing on existing social support. The aim of this research was to pilot a novel PSW-led intervention, including personal well-being network mapping, to improve access to primary care for physical health needs. METHODS AND ANALYSIS: Twenty-four participants will be recruited from community-based mental health teams in two boroughs of London. Each participant will be offered a six-session intervention. Quantitative data will be collected before and after intervention (at 4-month follow-up). Qualitative interviews will be conducted with PSWs after completion of the intervention and with participants at a 4-month follow-up. Some intervention sessions will be observed by a member of the research team. This is a pilot study with a small sample aiming to assess acceptability and feasibility of an intervention. We aim to use the results to refine the existing theory of change and to optimise the intervention and its evaluation in a future randomised controlled trial. This study is strengthened by its potential clinical importance and origin in previous research where service users engaged with well-being network mapping. ETHICS AND DISSEMINATION: This study has been approved by the London-Chelsea Regional Ethics Committee (ref: 17/LO/0585). The findings will be disseminated to participants, the National Health Service trusts that we recruited from, primary care mental health leads, commissioners and in peer-reviewed journals and academic conferences

Comments on the quantum Monte Carlo method and the density matrix theory

Density matrix theory is implemented in a variational quantum Monte Carlo computation of electronic properties of atoms and molecules. Differences between electronic densities from conventional and density matrix methods are detected. However, calculated properties present similar behavior and partial antisymmetry can be ignored in the cases studied. (C) 2003 American Institute of Physics.118114781478

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles

Temperature dependence of the refractive index near the reentrant-isotropic-calamitic-nematic phase transition

The laser-induced nonlinear optical response of a lyotropic liquid crystal system in the reentrant-isotropic and calamitic-nematic phases is investigated by the use of the thermal lens technique. The occurrence of an inversion in the temperature coefficient of the ordinary refractive index, dn(perpendicular to)/dT, near the reentrant-isotropic-calamitic-nematic phase transition, is discussed. This effect is attributed to the behavior of the electronic polarizability due to the change in micelle shape near the isotropic-nematic transition, and correlated with the results obtained near the nematic-isotropic transition, previously reported.641

Velocity Correlations in Driven Two-Dimensional Granular Media

Simulations of volumetrically forced granular media in two dimensions produce s tates with nearly homogeneous density. In these states, long-range velocity correlations with a characteristic vortex structure develop; given sufficient time, the correlations fill the entire simulated area. These velocity correlations reduce the rate and violence of collisions, so that pressure is smaller for driven inelastic particles than for undriven elastic particles in the same thermodynamic state. As the simulation box size increases, the effects of veloc ity correlations on the pressure are enhanced rather than reduced.Comment: 12 pages, 6 figures, 21 reference

The phonon theory of liquid thermodynamics

Heat capacity of matter is considered to be its most important property because it holds information about system's degrees of freedom as well as the regime in which the system operates, classical or quantum. Heat capacity is well understood in gases and solids but not in the third state of matter, liquids, and is not discussed in physics textbooks as a result. The perceived difficulty is that interactions in a liquid are both strong and system-specific, implying that the energy strongly depends on the liquid type and that, therefore, liquid energy can not be calculated in general form. Here, we develop a phonon theory of liquids where this problem is avoided. The theory covers both classical and quantum regimes. We demonstrate good agreement of calculated and experimental heat capacity of 21 liquids, including noble, metallic, molecular and hydrogen-bonded network liquids in a wide range of temperature and pressure.Comment: 7 pages, 4 figure