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Transcutaneous point‐shear wave elastography (p‐SWE) performed using an acoustic radiation force impulse can be used to quantify pancreatic stiffness in chronic pancreatitis (CP). We aimed to evaluate its usefulness to diagnose and monitor CP. 175 participants were included in this prospective study including patients with CP (n= 65), liver cirrhosis (LC; n= 60), alcohol abuse (n= 10) and healthy controls (n= 40). Point‐shear wave elastography of the pancreas was performed and quantified as median shear wave velocity (SWV). In the same way, p‐SWE of the spleen served as a marker of portal hypertension. The M‐ANNHEIM Severity score was used as global marker for disease activity in CP. Compared to healthy controls, pancreatic SWV was significantly elevated in CP (1.38 vs. 0.96 m/s; p< 0.0001, MWU‐test). Pancreatic SWV was increased in alcoholic CP but not in hereditary CP. Receiver operating characteristic analysis revealed 1.2 m/s as the optimal cut‐off to identify non‐heredity‐CP subjects (90% specificity; 81% sensitivity; 92% positive predictive value). Pancreatic SWV correlated significantly with the M‐ANNHEIM Severity score, severity of CP‐typical complications (both p< 0.05, linear regression analysis), morphological changes of the pancreas and need for hospital treatment (both p< 0.05, MWU‐test) but not with exocrine or endocrine insufficiency. Pancreatic SWV >1.7 m/s was identified to predict M‐ANNHEIM Severity score ≥11 points. Pancreatic SWV was also elevated in LC (1.42 m/s; p< 0.001), correlating with increased splenic SWV. Transcutaneous pancreatic p‐SWE represents a bedside, cost‐effective and non‐invasive tool which adds valuable information to the process of diagnosing and monitoring CP. By portal hypertension, an increased pancreatic SWV must be expected.

Ein exaktes Tumorstaging ist erforderlich, um die Patienten nach der Diagnose eines Ösophaguskarzinoms einer stadiengerechten Therapie zuführen zu können. Bei hochgradigen intraepithelialen Neoplasien oder Mukosakarzinomen soll eine endoskopische Resektion erfolgen. Die Ösophagektomie sollte minimal-invasiv oder in Kombination mit offenen Verfahren (Hybridtechnik) durchgeführt werden. Da die Prognose beim lokal fortgeschrittenen Ösophaguskarzinom bei alleiniger Operation schlecht ist, wird eine multimodale Therapie empfohlen. Bei lokal fortgeschrittenen Adenokarzinomen des Ösophagus oder des ösophagogastralen Übergangs wird eine perioperative Chemotherapie oder eine präoperative Radiochemotherapie durchgeführt. Bei lokal fortgeschrittenen Plattenepithelkarzinomen des Ösophagus wird eine präoperative Radiochemotherapie mit anschließender vollständiger Resektion oder eine definitive Radiochemotherapie ohne Operation empfohlen. Bei Resttumor im Resektionspräparat nach neoadjuvanter Radiochemotherapie und R0-Resektion von Plattenepithelkarzinomen oder Adenokarzinomen sollte eine adjuvante Immuntherapie mit Nivolumab durchgeführt werden. Systemische palliative Behandlungsoptionen (Chemotherapie, Chemotherapie plus Immuntherapie, Immuntherapie allein) bei inoperablem oder metastasiertem Speiseröhrenkrebs hängen von der Histologie ab und werden nach PD-L1- und/oder Her2-Expression stratifiziert.

Diagnosis and therapy of esophageal carcinoma is challenging and requires a multidisciplinary approach. The purpose of the updated German guideline “Diagnosis and Treatment of Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus—version 3.1” is to provide practical and evidence‐based advice for the management of patients with esophageal cancer. Recommendations were developed by a multidisciplinary expert panel based on an extensive and systematic evaluation of the published medical literature and the application of well‐established methodologies (e.g. Oxford evidence grading scheme, grading of recommendations). Accurate diagnostic evaluation of the primary tumor as well as lymph node and distant metastases is required in order to guide patients to a stage‐appropriate therapy after the initial diagnosis of esophageal cancer. In high‐grade intraepithelial neoplasia or mucosal carcinoma endoscopic resection shall be performed. Whether endoscopic resection is the definitive therapeutic measure depends on the histopathological evaluation of the resection specimen. Esophagectomy should be performed minimally invasive or in combination with open procedures (hybrid technique). Because the prognosis in locally advanced esophageal carcinoma is poor with surgery alone, multimodality therapy is recommended. In locally advanced adenocarcinomas of the esophagus or esophagogastric junction, perioperative chemotherapy or preoperative radiochemotherapy should be administered. In locally advanced squamous cell carcinomas of the esophagus, preoperative radiochemotherapy followed by complete resection or definitive radiochemotherapy without surgery should be performed. In the case of residual tumor in the resection specimen after neoadjuvant radiochemotherapy and R0 resection of squamous cell carcinoma or adenocarcinoma, adjuvant immunotherapy with nivolumab should be given. Systemic palliative treatment options (chemotherapy, chemotherapy plus immunotherapy, immunotherapy alone) in unresectable or metastastic esophageal cancer depend on histology and are stratified according to PD‐L1 and/or Her2 expression.

Introduction:Mobile Health (mHealth) applications allow for new possibilities and opportunities in patient care. Their potential throughout the whole patient journey is undisputed. However, the eventual adoption by patients depends on their acceptance of and motivation to use mHealth applications as well as their adherence. Therefore, we investigated the motivation and drivers of acceptance for mHealth and developed an adapted model of the Unified Theory of Acceptance and Use of Technology (UTAUT2). Methods:We evaluated 215 patients with chronic gastroenterological diseases who answered a questionnaire including all model constructs with 7-point Likert scale items. Our model was adapted from the Unified Theory of Acceptance and Use in Technology 2 and includes influencing factors such as facilitating conditions, performance expectancy, hedonic motivation, social influence factors, effort expectancy, as well as personal empowerment and data protection concerns. Model evaluation was performed with structural equation modelling with PLS-SEM. Bootstrapping was performed for hypothesis testing. Results and Conclusion:Patients had a median age of 55.5 years, and the gender ratio was equally distributed. Forty percent received a degree from a university, college, technical academy, or engineering school. The majority of patients suffered from chronic liver disease, but patients with inflammatory bowel diseases, GI cancers, and pancreatic diseases were also included. Patients considered their general technology knowledge as medium to good or very good (78%). Actual usage of mHealth applications in general was rare, while the intention to use them was high. The leading acceptance factor for mHealth applications in our patient group was feasibility, both in terms of technical requirements and the intuitiveness and manageability of the application. Concerns about data privacy did not significantly impact the intention to use mobile devices. Neither the gamification aspect nor social influence factors played a significant role in the intention to use mHealth applications. Interpretation:Most of our patients were willing to spend time on a mHealth application specific to their disease on a regular basis. Acceptance and adherence are ensured by efficient utilization that requires minimum effort and compatible technologies as well as support in case of difficulties. Social influence and hedonic motivation, which were part of UTAUT2, as well as data security concerns, were not significantly influencing our patients’ intention to use mHealth applications. A literature review revealed that drivers of acceptance vary considerably among different population and patient groups. Therefore, healthcare and mHealth providers should put effort into understanding their specific target groups’ drivers of acceptance. We provided those for a cohort of patients from gastroenterology in this project.

Autoimmune liver diseases (AILDs) are rare and require precise evaluation, which is often challenging for medical providers. Chatbots are innovative solutions to assist healthcare professionals in clinical management. In our study, ten liver specialists systematically evaluated four chatbots to determine their utility as clinical decision support tools in the field of AILDs.

The assessment of adverse events from endoscopic procedures is essential for successful interventions, ensuring accurate follow-up, adverse event management, and processing for quality control. Despite the critical need for structured documentation, the current practice often relies on free-text recordings, which poses challenges for scalable intervention analysis; however, the introduction of large language models (LLMs) offers a promising solution by enabling the automatic extraction of adverse event details from procedural reports without altering existing documentation practices.

ObjectiveMultidrug resistance protein 2 (MRP2) is a bottleneck in bilirubin excretion. Its loss is sufficient to induce hyperbilirubinaemia, a prevailing characteristic of acute liver failure (ALF) that is closely associated with clinical outcome. This study scrutinises the transcriptional regulation of MRP2 under different pathophysiological conditions.DesignHepatic MRP2, farnesoid X receptor (FXR) and Forkhead box A2 (FOXA2) expression and clinicopathologic associations were examined by immunohistochemistry in 14 patients with cirrhosis and 22 patients with ALF. MRP2 regulatory mechanisms were investigated in primary hepatocytes, Fxr−/−mice and lipopolysaccharide (LPS)-treated mice.ResultsPhysiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. Fxr−/−mice lack apical MRP2 expression and rapidly progress into hyperbilirubinaemia. In patients with ALF, hepatic FXR expression is undetectable, however, patients without infection maintain apical MRP2 expression and do not suffer from hyperbilirubinaemia. These patients express FOXA2 in hepatocytes. FOXA2 upregulates MRP2 transcription through binding to its promoter. Physiologically, nuclear FOXA2 translocation is inhibited by insulin. In ALF, high levels of glucagon and tumour necrosis factor α induce FOXA2 expression and nuclear translocation in hepatocytes. Impressively, ALF patients with sepsis express low levels of FOXA2, lose MRP2 expression and develop severe hyperbilirubinaemia. In this case, LPS inhibits FXR expression, induces FOXA2 nuclear exclusion and thus abrogates the compensatory MRP2 upregulation. In both Fxr−/−and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels.ConclusionFOXA2 replaces FXR to maintain MRP2 expression in ALF without sepsis. Ectopic FOXA2 expression to maintain MRP2 represents a potential strategy to prevent hyperbilirubinaemia in septic ALF.

ABSTRACTLung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivospheroids obtained from the patient’s liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.

A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab.

Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents.

Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis.

Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis.

Pancreatic acinar cell carcinoma (ACC) is a rare malignant disease that displays distinct differences to pancreatic ductal adenocarcinoma. Here, we report the case of a patient with ACC and underlying breast cancer susceptibility gene 2 (BRCA2) germline mutation that developed severe pancreatic panniculitis (PP) during the course of the disease. The patient received a multimodal therapy including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib, resulting in an overall survival of 47 months. Findings from this case are compared to the current knowledge on management of ACC and paraneoplastic PP.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+T cells or TNF neutralization, suggesting that CD8+T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Die aktuelle COVID-19-Pandemie zeigt, wie sehr wir von Infektionskrankheiten bedroht sein können. Effektive Impfungen werden aber häufig nicht ausreichend durchgeführt. Im März 2020 wurde in Deutschland das Masernschutzgesetz eingeführt, um die Immunität in der Bevölkerung auf über 95 % zu steigern.

Two impact experiments were carried out on blocks of Maggia gneiss to assess the influence of mechanical target anisotropies on the cratering process. The experiments were done within the framework of Multidisciplinary Experimental and Modeling Impact Research Network. In one experiment the metamorphic foliation was vertical, that is, oriented perpendicular to the target surface, and in the other horizontal, that is, parallel to the target surface. This study reveals that due to preferred spallation along the foliation, the cratering efficiency is higher if the foliation is horizontal. The study further presents a comprehensive quantitative strain analysis in the subsurface of these craters. We use biotite kink bands as strain markers. The distribution of strain differs strongly in both experiments. If the foliation is vertical, the area beneath the central crater floor shows a high compressive strain. This is attributed to the ability of biotite to kink more easily when shortened parallel to its basal plane. If the foliation is horizontal, surface kinking is reduced and tensile failure along the foliation deepens the crater during unloading. Kinked bioites are appropriate strain markers to quantify the strain in the target rocksLayering in the target causes mechanical heterogeneity and affects the cratering processesOrientation of the layering with respect to the target surface affects the crater morphology and the distribution of strain in subsurface

Aufgrund der stark ansteigenden und häufig inadäquaten Verordnung von Antibiotika nimmt die Anzahl resistenter Keime zu.

The prevalence of metabolic-dysfunction-associated steatotic liver disease (MASLD) is alarmingly high; it is estimated to affect up to a quarter of the global population, making it the most common liver disorder worldwide. MASLD is characterized by excessive hepatic fat accumulation and is commonly associated with comorbidities such as obesity, dyslipidemia, and insulin resistance; however, it can also manifest in lean individuals. Therefore, it is crucial to develop effective therapies for this complex condition. Currently, there are no approved medications for MASLD treatment, so there is a pressing need to investigate alternative approaches. Extensive research has characterized MASLD as a multifaceted disease, frequently linked to metabolic disorders that stem from dietary habits. Evidence suggests that changes in the gut microbiome play a fundamental role in the development and progression of MASLD from simple steatosis to steatohepatitis and even hepatocellular carcinoma (HCC). In this review, we critically examine the literature on the emerging field of gut-microbiota-based therapies for MASLD and metabolic-dysfunction-associated steatohepatitis (MASH), including interventions such as fecal microbiota transplantation (FMT), probiotics, prebiotics, short-chain fatty acids, antibiotics, metabolic pathway targeting, and immune checkpoint kinase blockade.

ABSTRACTThe world is witnessing a global increase in the urban population, particularly in developing Asian and African countries. Concomitantly, the global burden of non-communicable diseases (NCDs) is rising, markedly associated with the changing landscape of lifestyle and environment during urbanization. Accumulating studies have revealed the role of the gut microbiome in regulating the immune and metabolic homeostasis of the host, which potentially bridges external factors to the host (patho-)physiology. In this review, we discuss the rising incidences of NCDs during urbanization and their links to the compositional and functional dysbiosis of the gut microbiome. In particular, we elucidate the effects of urbanization-associated factors (hygiene/pollution, urbanized diet, lifestyles, the use of antibiotics, and early life exposure) on the gut microbiome underlying the pathogenesis of NCDs. We also discuss the potential and feasibility of microbiome-inspired and microbiome-targeted approaches as novel avenues to counteract NCDs, including fecal microbiota transplantation, diet modulation, probiotics, postbiotics, synbiotics, celobiotics, and precision antibiotics.

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction. Co-inhibitory ‘checkpoint molecules’ are tightly connected to T cell activation and balance excessive or prolonged immune activation by suppressing clonal expansion. Previous studies have suggested that NK cells might also suppress lymphocyte expansion, but the specific ligands enabling T cell recognition by natural cytotoxicity receptors (NCRs) remain unknown.

This sample preparation workflow enables the spatially-resolved monitoring of tissue protease activity in frozen tissue slices using MALDI MS Imaging. It measures the decrease of a general tracer substrate, substance P, and the increase in digestion products in a time-dependent manner. Attenuation of tracer degradation by protease inhibitor mix is concentration-dependent. In a mouse model, we visualized high protease activity in gastric tumor compared to surrounding tissue, and differential protease expression in these tissues was confirmed using quantitative bottom-up proteomics.

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Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure-associated liver disease. The aim of this study was therefore to determine the direct influence of DEHP on different liver cell types. HepG2, human upcyte hepatocytes, primary murine hepatocytes, LX-2, human upcyte hepatic stellate cells, and liver organoids were cultured with DEHP (0.5–500 µmol/L) and parameters including cytotoxicity, cell–cell interactions, and expression of metabolizing enzymes were investigated. DEHP modulated the expression of xenobiotic metabolizing enzymes, reduced the formation of bile canaliculi and cell polarity, and inhibited Cyp-activity in hepatocytes. DEHP had a toxic effect on LX-2 and induced the fibrogenic activation of hepatic stellate cells. The mode of action of DEHP was different in monolayer cultures compared to 3D-liver organoids, which were more sensitive to DEHP. This study suggests that DEHP modulates expression and activity of drug-detoxifying liver enzymes in humans at a clinically relevant concentration. Furthermore, it may contribute to the development of cholestasis and fibrosis. These findings strongly support the opinion, that there is a significant potential for serious adverse effects of DEHP derived from medical devices on human health, especially in very young infants with immature livers.

•Listeria monocytogenesis a rare cause of spontaneous bacterial peritonitis. 1% of humans are asymptomatic carriers of Listeria monocytogenes, which can lead to endogenous infection in cirrhosis.•In case of high leukocyte count in peritoneal fluid, Listeria-induced SBP is an important differential diagnosis to intestinal perforation in patients with cirrhosis.•Listeria is not covered by empiric therapy with cephalosporins. A combination of aminopenicillin and aminoglycoside is recommended. Early and correct antimicrobial therapy reduces the mortality significantly.

ObjectiveBone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease.DesignLevels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice.ResultsQuiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis.ConclusionsConstitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.

Planetary collisions in the solar system typically induce melting and vaporization of the impactor and a certain volume of the target. To study the dynamics of quasi‐instantaneous melting and subsequent quenching under postshock P‐Tconditions of impact melting, we used continuous‐wave laser irradiation to melt and vaporize sandstone, iron meteorite, and basalt. Using high‐speed imaging, temperature measurements, and petrologic investigations of the irradiation targets, we show that laser‐generated melts exhibit typical characteristics of impact melts (particularly ballistic ejecta). We then calculate the entropy gains of the laser‐generated melts and compare them with the entropy gains associated with the thermodynamic states produced in hypervelocity impacts at various velocities. In conclusion, our experiments extend currently attainable postshock temperatures in impact experiments to ranges commensurate with impacts in the velocity range of 4–20 km s–1and allow to study timescales and magnitudes of petrogenetic processes in impact melts. Laser melting of planetary materials forms melts with thermodynamic properties of impact melts originating from adiabatic decompressionLaser‐generated melts are petrologically similar to impact melts and allow for estimating time scales of impact melt formation and coolingDirect laser irradiation of planetary materials simulates effectively the formation of impact melts and vapors in the 4–20 km s–1range

Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride– and bile duct ligation–challenged mouse models in vivoand evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure.

Loss of hepatic HNF4α expression is frequently observed in end-stage liver disease (ESLD) and associated with loss of vital liver functions and thus increases mortality. Loss of HNF4α expression is mediated by inflammatory cytokines such as TGF-β. However, details of how HNF4α is suppressed are largely unknown to date. This study reports that TGF-β does not directly inhibit HNF4α, but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CBP/p300 to the HNF4α promoter. The recruitment of CBP/p300 is indispensable for C/EBPα binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitroobservation, 67 out of 98 patients positive for hepatic HNF4α express both p-SMAD2 and C/EBPα, whereas 22 patients negative for HNF4α expression lack either p-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibits C/EBPα transcription. Therefore, long-term TGF-β incubation results in C/EBPα depletion, which abrogates HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter is abolished by insulin. Two thirds of patients negative for C/EBPα lack membrane GLUT2 expression in hepatocytes, indicating insulin resistance. Taken together, hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.

Primary hepatocytes are a versatile tool to investigate all aspects of liver function, and frequently used in drug development and testing. Upon TGF-β challenge, hepatocytes either undergo an epithelial to mesenchymal transition (EMT) or apoptosis: culture on stiff collagen (monolayer) results in EMT whereas hepatocytes in a soft collagen matrix (sandwich) undergo programmed cell death. In this study, we analyzed the transcriptional programs triggered by TGF-β under different culture conditions.

AbstractBackground:Gastric cancer is the second most common cause of cancer-related deaths worldwide. There are large geographic variations in the incidence of these tumors, with 60 occurring in East Asia. For patients with resectable disease, surgery and perioperative treatment can be effective. For patients with advanced gastric cancer, chemotherapy regimens result in a median survival of 9-11 months. In general, the prognosis for advanced disease is poor and 5-year overall survival rates are around 15. Combination therapies yield better survival rates, albeit with increased toxicity. Therefore, more effective and less toxic treatment regimens are needed. Summary:The molecular aberrations that characterize the different subgroups of gastric cancer have been used as therapeutic targets. However, the heterogeneity and complexity of gastric cancers is a major challenge for the development of effective targeted therapies. This review examines the main molecular targets in the treatment of gastric cancer, namely the vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor (HGF)/c-Met, epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Key Message:The molecular aberrations characteristic of gastric cancer are being explored for the development of targeted therapies, including the VEGF, HER2, HGF/c-Met, EGFR and PI3K/Akt signaling pathways. Practical Implications:Trastuzumab, an antibody which targets HER2, is the first approved targeted therapy for the treatment of gastric cancer. However, trastuzumab is only effective in HER2-positive tumors (about 10-20 of all gastric cancers). Ramucirumab, which targets the VEGF receptor 2, has yielded benefits with respect to overall survival in a phase III trial and is an effective treatment for advanced gastric cancer with approval in second-line treatment. Apatinib and rilotumumab are another two promising new agents currently under development.© 2015 S. Karger AG, Basel