Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment. Yet, response rates are still limited, and tumour progression commonly occurs. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity.

Structural Analysis of Breast-Milk α-Casein: An α-Helical Conformation Is Required for TLR4-Stimulation.

Breast-milk α-casein is a Toll-like receptor 4 (TLR4) agonist, whereas phosphorylated α-casein does not bind TLR4. The objective of this study was to analyse the structural requirements for these effects. In silico analysis of α-casein indicated high α-helical content with coiled-coil characteristics.

Data-Driven Prediction and Uncertainty Quantification of Process Parameters for Directed Energy Deposition.

Laser-based directed energy deposition using metal powder (DED-LB/M) offers great potential for a flexible production mainly defined by software. To exploit this potential, knowledge of the process parameters required to achieve a specific track geometry is essential. Existing analytical, numerical, and machine-learning approaches, however, are not yet able to predict the process parameters in a satisfactory way.

An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells.

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients.

Visualization and identification of single meteoritic organic molecules by atomic force microscopy.

Using high-resolution atomic force microscopy (AFM) with CO-functionalized tips, we atomically resolved individual molecules from Murchison meteorite samples. We analyzed powdered Murchison meteorite material directly, as well as processed extracts that we prepared to facilitate characterization by AFM. From the untreated Murchison sample, we resolved very few molecules, as the sample contained mostly small molecules that could not be identified by AFM.

A branching process model for dormancy and seed banks in randomly fluctuating environments.

The goal of this article is to contribute towards the conceptual and quantitative understanding of the evolutionary benefits for (microbial) populations to maintain a seed bank consisting of dormant individuals when facing fluctuating environmental conditions. To this end, we discuss a class of '2-type' branching processes describing populations of individuals that may switch between 'active' and 'dormant' states in a random environment oscillating between a 'healthy' and a 'harsh' state. We incorporate different switching strategies and suggest a method of 'fair comparison' to incorporate potentially varying reproductive costs.

Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma.

In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade. Recent clinical data indicated an improved overall survival for sorafenib in combination with the HDAC inhibitor resminostat in a platelet count dependent manner. Here, the impact of platelets on the sorafenib and resminostat drug effects in HCC cells was explored.

Nanoscale magnonic Fabry-Pérot resonator for low-loss spin-wave manipulation.

Active control of propagating spin waves on the nanoscale is essential for beyond-CMOS magnonic computing. Here, we experimentally demonstrate reconfigurable spin-wave transport in a hybrid YIG-based material structure that operates as a Fabry-Pérot nanoresonator. The magnonic resonator is formed by a local frequency downshift of the spin-wave dispersion relation in a continuous YIG film caused by dynamic dipolar coupling to a ferromagnetic metal nanostripe.

IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells.

Chimeric antigen receptor (CAR) redirected T cells are efficacious in the treatment of leukemia/lymphoma, however, showed less capacities in eliminating solid tumors which is thought to be partly due to the lack of cytokine support in the tumor lesion. In order to deliver supportive cytokines, we took advantage of the inherent ability of mesenchymal stem cells (MSCs) to actively migrate to tumor sites and engineered MSCs to release both IL7 and IL12 to promote homeostatic expansion and Th1 polarization. There is a mutual interaction between engineered MSCs and CAR T cells; in presence of CAR T cell released IFN-γ and TNF-α, chronic inflammatory Th2 MSCs shifted towards a Th17/Th1 pattern with IL2 and IL15 release that mutually activated CAR T cells with extended persistence, amplification, killing and protection from activation induced cell death.

Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma.

Purpose: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response.

Experimental Design: We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSC, Apceth-301).

Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME).

Background: The efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors.

Alpha-1 Antitrypsin-Expressing Mesenchymal Stromal Cells Confer a Long-Term Survival Benefit in a Mouse Model of Lethal GvHD.

Acute graft-versus-host disease is a frequent complication associated with allogeneic hematopoietic stem cell transplantation. Patients that become refractory to initial steroid treatment have a poor prognosis. apceth-201 consists of human allogeneic mesenchymal stromal cells, engineered by lentiviral transduction to express the protease inhibitor alpha-1 antitrypsin, to augment the anti-inflammatory potential of the mesenchymal stromal cells.

p120ctn-Mediated Organ Patterning Precedes and Determines Pancreatic Progenitor Fate.

The mechanism of how organ shape emerges and specifies cell fate is not understood. Pancreatic duct and endocrine lineages arise in a spatially distinct domain from the acinar lineage. Whether these lineages are pre-determined or settle once these niches have been established remains unknown.

Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice.

Background: Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice.

Methods: Human MSCs were obtained by bone marrow aspiration of healthy donors as in a previously described GMP process.

Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies.

Objectives: Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies.

Methods: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD).

MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach.

Purpose: The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response.

Methods: MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study.

VIP changes during daytime in chicken intrinsic choroidal neurons.

Purpose: Ocular autonomic control is mediated by sympathetic and parasympathetic nerve fibres. Their interactions are complemented by primary afferent nerve fibers of and intrinsic choroidal neurons (ICN). As the vasodilatative neuropeptide, vasoactive intestinal peptide (VIP), is expressed in extrinsic and intrinsic ocular neurons, it is of special interest in ophthalmic research.

Cell therapy for lung disease.

Besides cancer and cardiovascular diseases, lung disorders are a leading cause of morbidity and death worldwide. For many disease conditions no effective and curative treatment options are available. Cell therapies offer a novel therapeutic approach due to their inherent anti-inflammatory and anti-fibrotic properties.

IL-3 promotes the development of experimental autoimmune encephalitis.

Little is known about the role of IL-3 in multiple sclerosis (MS) in humans and in experimental autoimmune encephalomyelitis (EAE). Using myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE, we show that CD4 T cells are the main source of IL-3 and that cerebral IL-3 expression correlates with the influx of T cells into the brain. Blockade of IL-3 with monoclonal antibodies, analysis of IL-3 deficient mice, and adoptive transfer of leukocytes demonstrate that IL-3 plays an important role for development of clinical symptoms of EAE, for migration of leukocytes into the brain, and for cerebral expression of adhesion molecules and chemokines.

Noise pollution has limited effects on nocturnal vigilance in peahens.

Natural environments are increasingly exposed to high levels of noise pollution. Noise pollution can alter the behavior of animals but we know little about its effects on antipredator behavior. We therefore investigated the impact of noise pollution on vigilance behavior and roost selection in an avian species, peafowl (), that inhabits urban environments.

Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development.

Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process.

A Review of Clinical Studies and Practical Guide for the Administration of Triplet Chemotherapy Regimens with Bevacizumab in First-line Metastatic Colorectal Cancer.

Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics.

IL-3 contributes to development of lupus nephritis in MRL/lpr mice.

MRL/lpr mice develop a spontaneous autoimmune disease that closely resembles human systemic lupus erythematosus (SLE) with DNA autoantibodies, hypergammaglobulinemia, immune complex glomerulonephritis, and systemic vasculitis. Little is known about the role of IL-3 in SLE. In order to study this we analyzed the expression of IL-3 in murine lupus and determined whether blockade of IL-3 with a monoclonal antibody or injection of recombinant IL-3 affects lupus nephritis in MRL/lpr mice.