Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls.

Immuno-inflammatory hepatotoxicity models to assess side effects of biologicals exemplified by aldesleukin.

Introduction: Hepatotoxicity induced by immunotherapeutics is an appearing cause for immune-mediated drug-induced liver injury. Such immuno-toxic mechanisms are difficult to assess using current preclinical models and the incidence is too low to detect in clinical trials. As hepatotoxicity is a frequent reason for post-authorisation drug withdrawal, there is an urgent need for immuno-inflammatory models to assess the hepatotoxic potential of immuno-modulatory drug candidates.

Analysis of RBP expression and binding sites identifies PTBP1 as a regulator of CD19 expression in B-ALL.

Despite massive improvements in the treatment of B-ALL through CART-19 immunotherapy, a large number of patients suffer a relapse due to loss of the targeted epitope. Mutations in the locus and aberrant splicing events are known to account for the absence of surface antigen. However, early molecular determinants suggesting therapy resistance as well as the time point when first signs of epitope loss appear to be detectable are not enlightened so far.

Reduction of adhesion formation after gynaecological adhesiolysis surgery with 4DryField PH - a retrospective, controlled study with second look laparoscopies.

Adhesions are a common consequence of abdomino-pelvic surgery. Efficacy of available adhesion prevention agents is discussed controversially. Here, we used the adhesion barrier 4DryField PH: a powder, which is transformed into a barrier gel with saline solution.

Changed inflammatory markers after application of 4DryField PH for adhesion prevention in gynecological surgery.

Introduction: The development of peritoneal adhesions and the effects of different antiadhesion agents on such mechanisms are not fully understood. Temporary rises of the C-reactive protein (CRP) level have been reported after antiadhesion agent application. We present the changes of inflammation markers observed after use of a starch-based polysaccharide certified for adhesion prevention and hemostasis 4DF (4DryField PH).

AMPKβ1 and AMPKβ2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner.

Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice.

Histone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood glucose in type 2 diabetic mice. In the present study, we aimed to evaluate the potential of class IIa HDAC inhibition as a therapeutic opportunity for the treatment +of metabolic diseases.

Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells.

Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells.

Activation of Adenosine Monophosphate-Activated Protein Kinase Reduces the Onset of Diet-Induced Hepatocellular Carcinoma in Mice.

The worldwide obesity and type 2 diabetes epidemics have led to an increase in nonalcoholic fatty liver disease (NAFLD). NAFLD covers a spectrum of hepatic pathologies ranging from simple steatosis to nonalcoholic steatohepatitis, characterized by fibrosis and hepatic inflammation. Nonalcoholic steatohepatitis predisposes to the onset of hepatocellular carcinoma (HCC).

Helix 8 is the essential structural motif of mechanosensitive GPCRs.

G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H receptors (HRs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation.

Low level of exosomal long non-coding RNA is a prognostic biomarker in colorectal cancer.

Molecular risk stratification of colorectal cancer can improve patient outcome. A panel of lncRNAs ( and ) derived from serum exosomes of patients with non-metastatic CRC and healthy donors was analyzed. Exosomes from healthy donors carried significantly more and transcripts in comparison to CRC patients.

Expression of Glypican 3 is an Independent Prognostic Biomarker in Primary Gastro-Esophageal Adenocarcinoma and Corresponding Serum Exosomes.

Exosomes are nano-sized membranous vesicles of endosomal origin that carry nucleic acids, lipids and proteins. The cargo of exosomes is cell origin specific and the release of these exosomes and uptake by an acceptor cell is seen as a vital element of cell-cell communication. Here, we sought to investigate the diagnostic and prognostic value of the expression of glypican 3 () on primary gastro-esophageal adenocarcinoma (GEA) tissue () and corresponding serum exosomes ().

Lack of beta-arrestin signaling in the absence of active G proteins.

G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of "zero functional G" at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o.

A first-in-human, randomized, controlled, subject- and reviewer-blinded multicenter study of Actamax™ Adhesion Barrier.

Purpose: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery.

Methods: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks.

Evaluation of the HystSim™-virtual reality trainer: an essential additional tool to train hysteroscopic skills outside the operation theater.

Background: Minimally invasive surgery is a major pillar of gynecological surgery. However, there are very few training opportunities outside the operation theater (OR) due to the cost and equipment requirements of organ simulators, virtual reality trainers (VRT) are promising tools to fill this gap.

Methods: Experienced and inexperienced participants of a minimally invasive surgery course followed the standardized HystSim™-VRT training program.

Uterine perforation following a fractional curettage successfully treated with the modified polysaccharide 4DryField® PH: a case report.

Background: Uterine perforation is the most common complication of curettage and may result in bleeding. Therefore, urgent control of bleeding from the uterine wall perforation is necessary to avoid an emergency hysterectomy or blood transfusion, to prevent peritoneal adhesion formation, possible chronic pelvic pain, and infertility. In the present case, an active bleeding secondary to a perforation of the uterus during curettage, for diagnosis of endometrial carcinoma, was instantaneously and successfully treated with only the application of a novel modified polysaccharide powder.

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function.

Unlabelled: The canonical Wnt/β-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/β-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in β-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that β-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression.

Long term follow-up concerning safety and efficacy of novel adhesion prophylactic agent for laparoscopic myomectomy in the prospective randomized ADBEE study.

We conducted a prospective randomized single blind - subject study in the University Clinic of Gynecology of Pius-Hospital Oldenburg. The primary objective of the ADBEE study was to assess the safety and manageability of ADBLOCK when used as an adjunct to laparoscopic surgery for the primary of myomas in women wishing to improve pregnancy outcomes. The study population included 32 women aged between 18-45 years, in good general health condition, who have not completed their family planning and who are undergoing primary ('virgin') laparoscopic myomectomy with an aim to improve pregnancy outcomes.

Use of Modified Polysaccharide 4DryField (®) PH for Adhesion Prevention and Hemostasis in Gynecological Surgery: A Two-Center Observational Study by Second-Look Laparoscopy.

Purpose. This study evaluates both scopes of 4DryField PH, certified for adhesion prevention and hemostasis, in patients undergoing surgery for various and severe gynecological disorders. Methods.

How to avoid risks for patients in minimal-access trials: Avoiding complications in clinical first-in-human studies by example of the ADBEE study.

A clinical trial is a prospective study designed to establish the safety and efficacy of investigational devices in humans, in accordance with the strict guidelines of the Food and Drug Administration (FDA; USA) or European Medicines Agency (EMA; Europe). Before a clinical first-in-human study is initiated, preclinical studies of the investigational product are mandatory, and the results should be sufficient to indicate that the investigational device is acceptably safe for the proposed evaluation in human subjects. The present paper describes an experience of clinical trials, highlighting ways of avoiding possible complications in clinical first-in-human studies.

β-Catenin-Gli1 interaction regulates proliferation and tumor growth in medulloblastoma.

Background: The Wnt/beta-catenin and the Hedgehog (Hh) pathway interact in various cell types while eliciting opposing or synergistic cellular effects. Both pathways are known as exclusive drivers of two distinct molecular subtypes of medulloblastoma (MB). In sonic hedgehog (Shh)-driven MB, activation of Wnt signaling has been shown to suppress tumor growth by either beta-catenin-dependent or -independent inhibition of Shh signaling.

Analysis of angiogenesis in the developing mouse central nervous system.

In order to study basic mechanisms of sprouting angiogenesis, researchers worldwide rely on the use of model tissues such as rodent retina, which becomes vascularized postnatally, to study the growth of blood vessels. By definition, models have to be simple, recapitulating angiogenic processes in a stereotyped and relatively easy accessible manner, allowing the application of standardized analyses. These criteria also apply in an ideal manner to the embryonic mouse hindbrain, which becomes vascularized by sprouting angiogenesis from a preformed perineural vascular plexus, leading to the stereotypical formation of a capillary subventricular plexus.

Sulfated glycosaminoglycans support osteoblast functions and concurrently suppress osteoclasts.

In order to improve bone regeneration, development and evaluation of new adaptive biomaterials is warranted. Glycosaminoglycans (GAGs) such as hyaluronan (HA) and chondroitin sulfate (CS) are major extracellular matrix (ECM) components of bone, and display osteogenic properties that are potentially useful for biomaterial applications. Using native and synthetic sulfate-modified GAGs, we manufactured artificial collagen/GAG ECM (aECMs) coatings, and evaluated how the presence of GAGs and their degree of sulfation affects the differentiation of murine mesenchymal stem cells to osteoblasts (OB) cultivated on these aECMs.