Systems biology as a compass to understand cancer-immune interactions in humans

Major achievements in the field of immune oncology have demonstrated the ability of the immune system to induce a response against cancer. The prognostic impact of pre-existing immunity in several cancer types, including breast and colon cancer, demonstrates the influence of the immune system on disease progression. At the same time, immunotherapeutic approaches that aim to enhance antitumor immune reactions have significantly improved the clinical outcome for a subset of patients. However, a large proportion of patients (60-80%) do not respond to immunotherapeutic treatments. To extend the benefit of immunotherapeutic strategies to a larger number of patients, it is imperative to understand the mechanisms associated with immune responsiveness. Different variables have been described to influence the development of antitumor immunity in cancer patients, including the tumor’s genetic program, the genetic makeup of the patients, and environmental factors such as the microbiome. These factors likely act in concert to modulate antitumor immune responses. This thesis aimed to dissect the molecular determinants of cancer immune responsiveness in human tumors. A systems biology approach was used to define underlying factors that shape the tumor microenvironment and reveal potential mechanisms of immune escape.LUMC / Geneeskund

The thermoregulatory and thermal responses of individuals with a spinal cord injury during exercise, acclimation and by using cooling strategies-A systematic review

In individuals with a spinal cord injury thermoregulatory mechanisms are fully or partially interrupted. This could lead to exercise-induced hyperthermia in temperate conditions which can be even more distinct in hot conditions. Hyperthermia has been suggested to impair physiological mechanisms in athletes, which could negatively influence physical performance and subjective well-being or cause mild to severe health issues. The aim was to evaluate the literature on the thermoregulatory and thermal responses of individuals with a spinal cord injury during exercise in temperate and hot conditions taking the effects of cooling techniques and heat acclimation into account. Two electronic databases, PubMed and Web of Science were searched. Studies were eligible if they observed the influence of exercise on various thermoregulatory parameters (e.g., core and skin temperature, sweat rate, thermal sensation) in individuals with a spinal cord injury. In total 32 articles were included of which 26 were of strong, 3 of moderate and 3 of weak quality. Individuals with a high lesion level, especially those with a tetraplegia, reached a higher core and skin temperature with a lower sweat rate. The use of cooling techniques before and during exercise can positively affect the burden of the impaired thermoregulatory system in all individuals with a spinal cord injury. Due to the absence of normal thermoregulatory abilities, individuals with a high-level spinal cord injury need special attention when they are exercising in temperate and hot conditions to prevent them from potential heat related issues. The use of cooling techniques can reduce this risk. [Abstract copyright: Copyright © 2021 Grossmann, Flueck, Perret, Meeusen and Roelands.

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer

Isometries of infinite dimensional Hilbert geometries

In this paper we extend two classical results concerning the isometries of strictly convex Hilbert geometries, and the characterisation of the isometry groups of Hilbert geometries on finite dimensional simplices, to infinite dimensions. The proofs rely on a mix of geometric and functional analytic methods

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

Triple-negative breast cancer (TNBC) accounts for ~15\u201320% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness

Combined assessment of the tumor-stroma ratio and tumor immune cell infiltrate for immune checkpoint inhibitor therapy response prediction in colon cancer

The best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor-stroma ratio (TSR) quantifies intratumoral stromal content and was recently found to be predictive of response to neoadjuvant therapy in multiple cancer types. In the current work, we predicted the likelihood of ICI therapy responsivity of 335 therapy-naive colon adenocarcinoma tumors from The Cancer Genome Atlas, using bioinformatics approaches. The TSR was scored on diagnostic tissue slides, and tumor-infiltrating immune cells (TIICs) were inferred from transcriptomic data. Tumors with high stromal content demonstrated increased T regulatory cell infiltration (p = 0.014) but failed to predict ICI therapy response. Consequently, we devised a hybrid tumor microenvironment classification of four stromal categories, based on histological stromal content and transcriptomic-deconvoluted immune cell infiltration, which was associated with previously established transcriptomic and genomic biomarkers for ICI therapy response. By integrating these biomarkers, stroma-low/immune-high tumors were predicted to be most responsive to ICI therapy. The framework described here provides evidence for expansion of current histological TIIC quantification to include the TSR as a novel, easy-to-use biomarker for the prediction of ICI therapy response.Experimentele farmacotherapi

Optimisation of piston compression ring for improved energy efficiency of high performance race engines

The primary function of the piston compression ring is to seal the combustion chamber from the bottom end of the engine. As a result, its conformance to the cylinder liner surface is of prime importance. This close-contact contiguity results in increased friction, making this contact conjunction responsible for a significant proportion of energy losses. The frictional losses can be as much as 2–6% of the expended fuel energy, which is quite significant for such a diminutive contact. Under these conditions, the geometrical profile, the surface topography and the inertial properties of the ring assume significant importance. The paper presents an integrated mixed-hydrodynamic analysis of the compression ring–cylinder liner contact with multi-parameter optimisation, based on the use of a genetic algorithm. The multi-objective functionality includes minimisation of the parasitic energy loss, reduction in the incidence of asperity level interactions as well as minimisation of the ring mass. Both cold running engine conditions and hot running engine conditions in line with the New European Drive Cycle were considered. Hitherto, such an approach has not been reported in the literature

Consensus statement on placebo effects in sports and exercise: the need for conceptual clarity, methodological rigour, and the elucidation of neurobiological mechanisms.

In June 2017 a group of experts in anthropology, biology, kinesiology, neuroscience, physiology, and psychology convened in Canterbury, UK, to address questions relating to the placebo effect in sport and exercise. The event was supported exclusively by Quality Related (QR) funding from the Higher Education Funding Council for England (HEFCE). The funder did not influence the content or conclusions of the group. No competing interests were declared by any delegate. During the meeting and in follow-up correspondence, all delegates agreed the need to communicate the outcomes of the meeting via a brief consensus statement. The two specific aims of this statement are to encourage researchers in sport and exercise science to: 1. Where possible, adopt research methods that more effectively elucidate the role of the brain in mediating the effects of treatments and interventions. 2. Where possible, adopt methods that factor for and/or quantify placebo effects that could explain a percentage of inter-individual variability in response to treatments and interventio

Physical and Pharmacological Restraints in Hospital Care:Protocol for a Systematic Review

Background: Physical and pharmacological restraints, defined as all measures limiting a person in his or her freedom, are extensively used to handle unsafe or problematic behavior in hospital care. There are increasing concerns as to the extent with which these restraints are being used in hospitals, and whether their benefits outweigh their potential harm. There is currently no comprehensive literature overview on the beneficial and/or adverse effects of the use of physical and pharmacological restraints in the hospital setting. Methods: A systematic review of the existing literature will be performed on the beneficial and/or adverse effects of physical and pharmacological restraints in the hospital setting. Relevant databases will be systematically searched. A dedicated search strategy was composed. A visualization of similarities (VOS) analysis was used to further specify the search. Observational studies, and if available, randomized controlled trials reporting on beneficial and/or adverse effects of physical and/or pharmacological restraints in the general hospital setting will be included. Data from included articles will be extracted and analyzed. If the data is suitable for quantitative analysis, meta-analysis will be applied. Discussion: This review will provide data on the beneficial and/or adverse effects of the use of physical and pharmacological restraints in hospital care. With this review we aim to guide health professionals by providing a critique of the available evidence regarding their choice to either apply or withhold from using restraints. A limitation of the current review will be that we will not specifically address ethical aspects of restraint use. Nevertheless, the outcomes of our systematic review can be used in the composition of a multidisciplinary guideline. Furthermore, our systematic review might determine knowledge gaps in the evidence, and recommendations on how to target these gaps with future research. Systematic Review Registration: PROSPERO registration number: CRD42019116186