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Early dissemination, metastasis and therapy resistance are central hallmarks of aggressive cancer types and the leading cause of cancer-associated deaths. The EMT-inducing transcriptional repressor ZEB1 is a crucial stimulator of these processes, particularly by coupling the activation of cellular motility with stemness and survival properties. ZEB1 expression is associated with aggressive behaviour in many tumour types, but the potent effects cannot be solely explained by its proven function as a transcriptional repressor of epithelial genes. Here we describe a direct interaction of ZEB1 with the Hippo pathway effector YAP, but notably not with its paralogue TAZ. In consequence, ZEB1 switches its function to a transcriptional co-activator of a ‘common ZEB1/YAP target gene set’, thereby linking two pathways with similar cancer promoting effects. This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in breast cancer, indicating the clinical relevance of our findings. The transcription factors ZEB1 and YAP function in different pathways yet both activate aggressive behaviour in cancer cells. Here, the authors describe that the proteins physically interact and that this changes the transcriptional activity of ZEB1 from a repressor to an activator.

Purpose To evaluate clinical characteristics, quality of life (QoL) and effectiveness in patients with menstrual cycle disorders (MCDs) including abnormal uterine bleeding, dysmenorrhea and mastodynia/mastalgia related to premenstrual syndrome taking the Vitex agnus-castus (VAC) products Cyclodynon® or Mastodynon® in a real-world setting. Methods A single-center retrospective longitudinal cohort study (3 ± 1 months), using data obtained from healthcare data archive and telephone interviews. The main study variables were changes in bleeding, menstrual pain, breast tenderness and patients’ QoL. Results Data from 1700 women with a mean age of 30.2 years (± 6.3) were analyzed. The most common MCDs were dysmenorrhea (43.8%) and mastodynia/mastalgia (21.1%). Three-month treatment with VAC extract substantially decreased the percentage of patients with irregular cycle (from 9.1% to 0.1%) and breast tenderness (from 39.9% to 0.8%). Improvement in bleeding intensity, frequency and menstrual pain was experienced by 83.4%, 79.2%, and 85.2% of the patients, respectively. When analyzed by disease category, these parameters improved in almost all dysmenorrhea patients, while they improved to a lesser extent in mastodynia/mastalgia patients. QoL improved in all aspects, but was reported by a higher proportion of dysmenorrhea patients compared to mastodynia/mastalgia patients. Treatment was overall well tolerated with a favorable safety profile. Conclusion These real-world data demonstrate the effectiveness of the VAC-containing products Cyclodynon® and Mastodynon® in the three-month treatment of MCDs, with a pronounced improvement in key disease symptoms and QoL. Intriguingly, while QoL was generally greatly improved, the response to VAC therapy varied depending on the type of underlying MCD.

The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi - and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo , Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.

BackgroundThe incidence of severe immune-related hepatitis (irHepatitis) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 under combination therapy with ipilimumab and nivolumab ranges from 15% to 20%. Current clinical guidelines recommend initiating treatment with systemic corticosteroids, followed by second-line immunosuppressants such as mycophenolate mofetil. In contrast, the use of the tumor necrosis factor-α antibody infliximab—commonly administered for other immune-related adverse events such as colitis—is generally not recommended for irHepatitis. A recent single-center study, however, reported the use of infliximab for steroid-refractory irHepatitis in 10 patients without signs of infliximab-associated hepatotoxicity and overall favorable efficacy.This multicenter retrospective analysis aimed to evaluate the safety and efficacy of infliximab in patients with steroid-refractory irHepatitis.MethodsA total of 28 patients with advanced cutaneous melanoma and irHepatitis during immune checkpoint inhibitor (ICI) therapy were included from five university hospitals in Germany and one in Belgium. Of these, 27 patients were in American Joint Committee on Cancer stage IV (8th edition).ResultsAll patients received ipilimumab plus nivolumab. The Eastern Cooperative Oncology Group performance status was 0 in 75.0% of patients, and nearly all (27/28) developed severe irHepatitis of CTCAE grade 3 or 4 (V.5.0). The median time to onset of irHepatitis was 46 days after first ICI administration. 96.4% of patients were initially treated with systemic corticosteroids. The median interval between onset of irHepatitis and the first dose of infliximab was 23 days. Infliximab was administered intravenously at a dose of 5 mg/kg. 22 patients received one dose, while 6 patients received two doses. In 82.1% of patients, corticosteroids were tapered to less than 5 mg prednisolone equivalent within a median period of 75 days. Clinical remission for irHepatitis (≤CTCAE grade 1) was achieved in 92.9% of patients and was reached after a median time of 21 days following the first infliximab administration. During a median follow-up of 349 days, no deaths or drug-induced liver injury attributable to infliximab were observed.ConclusionIn this retrospective analysis, infliximab appeared to be effective and safe for the treatment of steroid-refractory irHepatitis, with no evidence of hepatotoxicity.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD.

Anastomotic failure remains one of the most severe complications in gastrointestinal surgery. Despite continuous advancements in stapler technologies and surgical techniques, it continues to be a leading cause of postoperative morbidity and mortality. It contributes substantially to prolonged hospitalization and increased healthcare expenditures. Currently, diagnosis is based on secondary systemic signs, such as inflammatory response or changes in drain fluid, followed by a multimodal diagnostic approach. However, reliable early detection of local alterations is still lacking. Here, the implantation of a bioresorbable is investigated, intra-anastomotically placed sensor device. By performing real-time intra-anastomotic bioimpedance measurements, ischemia-related changes are identified at an early, potentially reversible stage, prior to the onset of clinical or systemic manifestations. Furthermore, the sensor device offers the potential for future integration of pattern-recognition algorithms and the possibility of direct measurement of different markers in the anastomotic microenvironment.

Noonan syndrome (NS), the most common among RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1 S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770 C > T missense change. We characterize the molecular, structural, and functional consequences of aberrant RAF1–associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1 S257L cardiomyocytes and myocardial tissue biopsies. The aforementioned changes correlated with the isoform shift of titin from a longer (N2BA) to a shorter isoform (N2B) that also affected the active force generation and contractile tensions. The genotype-phenotype correlation was confirmed using cardiomyocyte progeny of an isogenic gene-corrected RAF1 S257L -iPSC line and was mainly reversed by MEK inhibition. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. Studies on 3D bioartificial cardiac tissues reveal the impacts of hypertrophic cardiomyopathy-associated RAF1 mutations on sarcomere structure, contractile behavior, Ca 2+ handling, and intracellular signaling.

Background Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPARα and δ activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPARα and δ agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells. Results We found that PPARα and PPARδ agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPARδ induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPARα failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPARδ, but not PPARα agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPARα and PPARδ agonists increased ICAM-1 mRNA stability. Conclusion Therefore, our data provide the first evidence that PPARα and PPARδ agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.

The markets for organic and fair trade certified commodities are growing rapidly, with environmentally sound and more equitable certification systems likely to offer benefits for both small-scale farmers and society at large. Despite much debate about their contribution to sustainability, there has been little scientific analysis, so it is vital to assess if it is technically and economically feasible to meet growing consumer demands regarding food safety, quality and ethics through smallholder and marginal producers. Overall, there is a need to explore the potential of these certification systems as emerging areas in research and development cooperation. This book includes: - Worldwide case studies (from the supply side in Asia, Africa, and Latin America; and from the demand side in Europe and North America) to put theory into practice.- Analyses of sustainable development and poverty reduction through organic and fair trade markets.- Insights into the conditions where it is beneficial for developing country smallholder producers to adopt fair trade and organic certification systems.- Investigation into whether consumers will pay more for a product that is both organic and fair trade certified.This book is an important read for researchers and students in agricultural and development economics, and it is also a useful resource for policy makers and practitioners involved in organic and fair trade agriculture.

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we hypothesized that inhibition of the PRR would prevent the development of diet-induced hepatic steatosis and fibrosis. To test our hypothesis, we fed wild-type mice on a C57Bl/6J background either a high-fat diet (HFD; 60% calories from fat) or normal fat diet (NFD; 10% calories from fat) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis in C57BL/6J mice. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either PRO20, a peptide PRR antagonist, or scrambled peptide (700 μg/kg/d) for 4 or 6 weeks. We found that a 6-week HFD significantly increased liver lipid accumulation, as detected by Oil Red O staining, and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment significantly reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or glucose levels. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area detected by Sirius Red staining was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase (ALT), an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the mechanism by which PRR regulates lipid metabolism in the liver and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis development in NAFLD.