Explaining in-vitro to in-vivo efficacy correlations in oncology pre-clinical development via a semi-mechanistic mathematical model.

In-vitro to in-vivo correlations (IVIVC), relating in-vitro parameters like IC50 to in-vivo drug exposure in plasma and tumour growth, are widely used in oncology for experimental design and dose decisions. However, they lack a deeper understanding of the underlying mechanisms. Our paper therefore focuses on linking empirical IVIVC relations for small-molecule kinase inhibitors with a semi-mechanistic tumour-growth model.

Decreased eukaryotic initiation factors expression upon temozolomide treatment-potential novel implications for eIFs in glioma therapy.

Purpose: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment.

Radius additivity score: a novel combination index for tumour growth inhibition in fixed-dose xenograft studies.

The effect of combination therapies in many cancers has often been shown to be superior to that of monotherapies. This success is commonly attributed to drug synergies. Combinations of two (or more) drugs in xenograft tumor growth inhibition (TGI) studies are typically designed at fixed doses for each compound.

Complementary CRISPR screen highlights the contrasting role of membrane-bound and soluble ICAM-1 in regulating antigen-specific tumor cell killing by cytotoxic T cells.

Cytotoxic CD8 +T lymphocytes (CTLs) are key players of adaptive anti-tumor immunity based on their ability to specifically recognize and destroy tumor cells. Many cancer immunotherapies rely on unleashing CTL function. However, tumors can evade killing through strategies which are not yet fully elucidated.

Transcriptomic and Proteomic Changes Driving Pulmonary Fibrosis Resolution in Young and Old Mice.

Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis. Yet in this model, it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging.

Antifibrotic Drug Nintedanib Inhibits CSF1R to Promote IL-4-associated Tissue Repair Macrophages.

Profibrotic and prohomeostatic macrophage phenotypes remain ill-defined, both and , impeding the successful development of drugs that reprogram macrophages as an attractive therapeutic approach to manage fibrotic disease. The goal of this study was to reveal profibrotic and prohomeostatic macrophage phenotypes that could guide the design of new therapeutic approaches targeting macrophages to treat fibrotic disease. This study used nintedanib, a broad kinase inhibitor approved for idiopathic pulmonary fibrosis, to dissect lung macrophage phenotypes during fibrosis-linked inflammation by combining and bulk and single-cell RNA-sequencing approaches.

Graft-Versus-Host Disease Prevention by -Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells that dampen overwhelming adaptive immune responses through multiple mechanisms and are recognized as an attractive novel immune intervention therapy for counteracting the destructive effects of graft- -host disease (GVHD) developing after allogeneic bone marrow transplantation (BMT). MDSCs can be produced in great numbers for cellular therapy, but they present a mixture of subsets whose functions in GVHD prevention are undefined. Here, we generated MDSCs from murine BM cells in the presence of GM-CSF and defined the integrin CD11c as a marker to subdivide MDSCs into two functional subgroups: CD11b+CD11c+ and CD11b+CD11c- MDSCs.

CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1.

More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7-H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes.

High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells.

Macrophages are pivotal effectors of host immunity and regulators of tissue homeostasis. Understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (hiPSC)-derived monocytes and macrophages, as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of macrophage biology and implication in human diseases.

Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling.

Background: Interleukin-6 is a pleiotropic cytokine with high clinical relevance and an important mediator of cellular communication, orchestrating both pro- and anti-inflammatory processes. Interleukin-6-induced signalling is initiated by binding of IL-6 to the IL-6 receptor α and subsequent binding to the signal transducing receptor subunit gp130. This active receptor complex initiates signalling through the Janus kinase/signal transducer and activator of transcription pathway.

Sub-femtomolar detection of DNA and discrimination of mutant strands using microwell-array assisted digital enzyme-linked oligonucleotide assay.

Detection methods that do not rely on the amplification of DNA but can reach sensitivity, specificity and throughput of gold standard methods, such as qPCR, have been extensively explored in recent years. Here, we present a hydrophilic-in-hydrophobic (HIH)-microwell array platform that empowers a panel of different amplification-free DNA bioassays: digital enzyme-linked oligonucleotide assay (ELONA), ligation-assisted (LA) digital ELONA and so-called 'analog' bioassays. We developed all three bioassays by using magnetic beads for capturing DNA target, followed by hybridization of enzyme-labelled detection probes and sealing of the built complexes into the femtoliter HIH microwells to achieve the fluorescent readout of single DNA molecules.

Stable IL- 1β-Activation in an Inflammasome Signalling Model Depends on Positive and Negative Feedbacks and Tight Regulation of Protein Production.

Introduction: NLRP3-dependent inflammasome signalling is a key pathway during inflammatory processes and its deregulation is implicated in several diseases. NLRP3-inflammasome pathway activation leads to the rapid, phosphorylation-driven NF$\kappa$κB-pathway signalling, subsequently proceeds via slower transcription/translation process for producing pro-enzymes, and finally leads to the medium-speed enzymatic activation of the central inflammatory mediator IL-$1\beta$1β[1] . We here were interested in how the timing of the rate-limiting step of transcription/translation and the presence of a positive and negative auto-regulation would pose conditions for meaningful and stable IL-$1\beta$1β-activation.

The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling.

Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range.

Defining external factors that determine neuronal survival, apoptosis and necrosis during excitotoxic injury using a high content screening imaging platform.

Cell death induced by excessive glutamate receptor overactivation, excitotoxicity, has been implicated in several acute and chronic neurological disorders. While numerous studies have demonstrated the contribution of biochemically and genetically activated cell death pathways in excitotoxic injury, the factors mediating passive, excitotoxic necrosis are less thoroughly investigated. To address this question, we developed a high content screening (HCS) based assay to collect high volumes of quantitative cellular imaging data and elucidated the effects of intrinsic and external factors on excitotoxic necrosis and apoptosis.

Identifying differential miR and gene consensus patterns in peripheral blood of patients with cardiovascular diseases from literature data.

Background: Numerous recent studies suggest the potential of circulating MicroRNAs (miRs) in peripheral blood samples as diagnostic or prognostic markers for coronary artery disease (CAD), acute coronary syndrome (ACS) and heart failure (HF). However, literature often remains inconclusive regarding as to which markers are most indicative for which of the above diseases. This shortcoming is mainly due to the lack of a systematic analyses and absence of information on the functional pathophysiological role of these miRs and their target genes.

Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation.

Activation of the NLRP3-inflammasome pathway and production of the inflammatory cytokine IL-1B after cellular damage caused by infarct or infection is a key process in several diseases such as acute myocardial infarction and inflammatory bowel disease. However, while the molecular triggers of the NLRP3-pathway after cellular damage are well known, the mechanisms that sustain or confine its activity are currently under investigation. We present here an Ordinary Differential Equation-based model that investigates the mechanisms of inflammasome activation and regulation in monocytes to predict IL-1β activation kinetics upon a two-step activation by Damage-Associate-Molecular-Particles (DAMP) and extracellular ATP.

Doxorubicin-induced chronic dilated cardiomyopathy-the apoptosis hypothesis revisited.

The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10-20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation.

Modelling tumour cell proliferation from vascular structure using tissue decomposition into avascular elements.

Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other.

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions.

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity.

Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis.

Purpose Of Review: Microvesicles, in general, and exosomes together with their delivered content in particular, are now being widely recognized as key players in atherosclerosis. We have previously reviewed the role of microvesicles in atherosclerosis pathogenesis, diagnosis and therapy. Here, we focus on the roles of exosomes and discuss their emergent role in mediating activation and response to inflammation, vessel infiltration and induction of coagulation.

Single-cell imaging of bioenergetic responses to neuronal excitotoxicity and oxygen and glucose deprivation.

Excitotoxicity is a condition occurring during cerebral ischemia, seizures, and chronic neurodegeneration. It is characterized by overactivation of glutamate receptors, leading to excessive Ca(2+)/Na(+) influx into neurons, energetic stress, and subsequent neuronal injury. We and others have previously investigated neuronal populations to study how bioenergetic parameters determine neuronal injury; however, such experiments are often confounded by population-based heterogeneity and the contribution of effects of non-neuronal cells.

Harnessing system models of cell death signalling for cytotoxic chemotherapy: towards personalised medicine approaches?

Most cytotoxic chemotherapeutics are believed to kill cancer cells by inducing apoptosis. Understanding the factors that contribute to impairment of apoptosis in cancer cells is therefore critical for the development of novel therapies that circumvent the widespread chemoresistance. Apoptosis, however, is a complex and tightly controlled process that can be induced by different classes of chemotherapeutics targeting different signalling nodes and pathways.

The indirect activation model of mitochondrial outer membrane permeabilisation (MOMP) initiation requires a trade-off between robustness in the absence of and sensitivity in the presence of stress.

Mitochondrial outer membrane permeabilisation (MOMP) is a hallmark of apoptosis and is controlled by antagonising members of the BCL 2 protein family. However, whether the effector proteins for MOMP, BAX and BAK, require a separate activation step (direct activation model) or if the sole inhibition of otherwise active effectors by anti-apoptotic BCL 2 proteins suffices (indirect activation model) is controversial. To address this question, we recently identified that, in most cells, effector proteins were more abundant than their inhibitors.