Abstract Background Many persons with Crohn’s Disease (CD) suffer from symptoms not directly linked to the gastrointestinal tract. Among these extraintestinal symptoms (EIS), fatigue, depression and anxiety are the most prevalent, especially during active disease. Growing evidence links disturbed brain-gut-interactions to EIS. We examined intrinsic brain activity in patients with active and remitted CD using a multivariate MRI data fusion approach, evaluated the relationship of functional joint components with EIS and inflammatory markers, and explored the components’ associated neurotransmitter systems. Methods Patients (n=71) with active (aCD, n=47) or remitted disease (rCD, n=24) and healthy controls (HC, n=35) underwent resting-state functional magnetic resonance imaging and completed questionnaires for symptoms of fatigue, depression and anxiety. Patients provided stool samples for faecal calprotectin (fC) analysis. A joint independent component analysis (jICA) of intrinsic brain function (ALFF and ReHo) was conducted to detect convergent neural activity patterns in functionally distinct neural networks (components) that differ between aCD, rCD, and HC. Functional connectivity strength (FCS) in networks with disease state-dependent changes were correlated with EIS and fC, and we performed cross-modal correlations between MRI components and specific PET/SPECT receptor probability maps. Results JICA identified two components that differed between aCD and rCD. One showed a pattern of predominantly orbitofrontal-cingulate cortex connectivity, with lower FCS in aCD vs rCD and HC (Fig. 1A top). This component related to serotonergic and dopaminergic transmission with significant associations between FCS and fatigue as well as fC (Fig. 1B). The other component revealed lower FCS in a sensorimotor network (Fig. 1A middle) with predominantly dopaminergic neurotransmission in rCD vs aCD and HC that was associated with anxiety and depression (Fig. 1B). A third component, predominantly involving cortical midline regions attributed to the so-called “default mode network” was found to differ between HC and CD irrespective of disease status (Fig. 1A bottom). Here, FCS was not associated with EIS (Fig 1B). Conclusion Functional connectivity of distinct resting-state networks differs between disease states and differentially relates to EIS. A sensorimotor network is associated with symptoms of depression and anxiety and dopaminergic neurotransmission, while an affective network correlates with fatigue and serotonergic/dopaminergic neurotransmission. The latter shows the relationship with fatigue only in rCD, suggesting a contribution of disturbed brain-gut-interactions especially in fatigue during remission.

Abstract Background Nutrition plays a crucial role in the development and course of disease in patients with inflammatory bowel disease (IBD). However, standardized nutritional assessments are often lengthy and require the expertise of professional nutritionists, leading to a significant gap in the ability to screen for important dietary factors. As a result, these aspects are frequently overlooked in both clinical practice and scientific research. To address this issue, we aim to develop a short screening instrument that can effectively assess dietary and nutritional aspects in patients with IBD. This tool is not intended to replace, but complement standardized assessments, and to enable clinicians and researchers to address dietary and nutritional aspects in situations where these are otherwise disregarded. Methods A comprehensive literature review was conducted to identify nutritional factors with regard to their pro- and antiinflammatory characteristics in the context of IBD. Based on this research, a prototype screening tool was developed in collaboration with nutritional experts from 3 German University Hospitals (Mannheim, Munich, and Hannover). The first phase of validation involved an evaluation of the prototype screener by consecutive outpatients at the University Medical Center Mannheim (UMM) to assess its feasibility and acceptance. Results Our screening tool contains 28 questions and asks about the frequency of consumption of certain food groups as well as the type of preparation and eating habits with regard to vegetarian or vegan diet, the frequency of meals and the balance and variety of the diet. In the patient evaluation phase, we received feedback from 52 patients (n=37 female, n=36 with Crohn’s Disease, n=51 with remitted or mild disease (1 moderate, none severe). Mean time to complete the screening tool was 9.3 min (SD 7.8). The vast majority of patients stated that they found the screener somewhat or very important (n=47) and somewhat or very easy to understand (n=48), see fig. 1. Seven patients reported that they found at least one question difficult to understand. Ten patients stated that the screener was missing at least one aspect of their dietary habits. No patients reported any unpleasant questions. A global evaluation of the screener according to the German school grading system (from 1 = very good, 6 = very bad) was rated with a mean grade of 1.6. Conclusion This newly developed screening tool to semi-quantitatively assess dietary habits and relevant nutritional aspects in IBD was well-accepted and positively evaluated by patients. In the next step, we will adapt the questionnaire according to patient feedback and then initiate the next phase of the validation process in a multicentric setting.

Abstract Background In IBD, extraintestinal symptoms (EIS) such as fatigue, depression and anxiety are a major burden on the patients’ quality of life (QoL). These EIS are more prevalent in active disease but can persist in remission. A deleterious effect of depression and anxiety on the course of disease has already been confirmed in longitudinal studies, but to our knowledge the relevance and nature of fatigue symptoms in this regard have not been addressed longitudinally. We examined patients with Crohn’s disease (CD) in an active disease state and followed them up after 3-6 months to evaluate the presence, course and relationships of EIS. Methods We recruited patients with CD in active disease and healthy controls (HC). Patients were instructed to complete self-report questionnaires to measure clinical activity (HBI), fatigue (WEIMuS), anxiety and depressive symptoms (HADS-A, -D) and QoL (IBDQ) before a change of therapy (T1, n=49) and 3-6 months later (T2, n=46). HCs (n=25) answered the same questionnaires except IBDQ. We compared EIS scores between PAT and HC, as well as between T1 and T2, and evaluated EIS changes in PAT with regard to response vs. non-response at T2. Finally, we explored the influence of EIS on clinical activity at T2. Results At both visits and in each of the questionnaires analysed, patients showed higher scores for EIS compared to HC (all pcorr<0.004, FDR 0.05). In patients, fatigue scores were significantly lower at T2 compared to T1 (pcorr=0.034). Patients’ QoL improved (pcorr=0.003), while depression and anxiety didn’t change significantly between T1 and T2. When comparing remitted vs non-remitted CD at T2 (see Table 1), remitted patients had larger differences in EIS scores from T1 to T2 (all pcorr=0.012). Also, remitted patients showed significantly higher and more positive changes in QoL compared to non-remitted patients (pcorr=0.005). In multiple regression analysis, BMI, HADS-D and WEIMuS at T1 were positive predictors for the HBI at T2 (all pcorr<0.019). In contrast, HADS-A at T1 was a negative predictor for HBI at T2 with pcorr=0.002 (see Figure 1). Conclusion As expected, EIS were higher in CD compared to HC. Patients who responded to therapy changes showed higher decrease of fatigue, depression and anxiety and higher increases of QoL compared to non-responders. Higher BMI, depressive and fatigue symptoms at T1 were associated with non-response, higher anxiety at T1 could be associated with response. These findings need to be confirmed in larger studies but indicate the importance of successful induction of remission to improve not only intestinal inflammation and QoL, but also fatigue and affective symptoms.

Einleitung Die chemotherapeutische Behandlung von metastasierten Adenokarzinomen des gastroösophagealen Übergangs (AEG) und des Magens verlängert die Lebensdauer von Patienten oft nur um einige Monate. Zielgerichtete Therapien und Biomarker, die das Ansprechen von Patienten auf diese vorhersagen lassen, könnten die Behandlung verbessern. Aus Tumorbiopsien isolierte Organoide (‚patient-derived organoids‘) können genutzt werden, um das Therapieansprechen in vitro zu untersuchen und somit zur Wahl der Behandlung beitragen.

Background Wir untersuchten die Wirksamkeit und Sicherheit einer erneuten Behandlung mit Immun-Checkpoint-Inhibitoren (ICI) bei PatientInnen mit hepatozellulärem Karzinom (HCC), die in einer vorangegangenen systemischen Linie eine ICI-basierte Therapie erhalten hatten.

Introduction Albumin is indispensable for systemic homeostasis. In healthy humans, only hepatocytes synthesize albumin. Impressively, the serum albumin level in patients suffering from liver failure are nearly normal. In this study, we delineate a hierarchically transcriptional regulatory network that controls albumin expression in response to different pathophysiological challenges.

Background We recently provided the first evidence that ECM1 (extracellular matrix protein 1) plays a crucial role in liver homeostasis by attenuating TGF-β activation. ECM1 is often downregulated in liver diseases, including liver cancer and non-alcoholic fatty liver disease. Here we examined the dynamic genomic profile of ECM1 knockout mice liver to define the global molecular changes accompanying its expression depletion.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and its incidence is rising. The introduction of new systemic therapies, including immune-based therapies and biomarker driven therapies, has improved survival in patients at advanced stages. However, overall survival is still poor, and recent advances in understanding of the molecular alterations of HCC have not translated yet into novel biomarkers. Over the past decade, major advancements in ‘omic’ technologies have enabled monitoring of a variety of molecular and organismal processes. A comprehensive analysis of single gene mutations in HCC might lead to detect biomarkers that improve our prognosis and treatment. We developed a bioinformatics pipeline capable of analyzing genomic data to identify key regulatory molecular changes in HCC development and their influence in patient”s prognosis. By looking at genetically determined subgroups of HCC in the TCGA Liver Cancer dataset, we managed to obtain 15 genes frequently affected by oncogenic mutations and analyzed their influence in patient”s survival, identifying CSMD1 as a prognostic biomarker candidate. Nevertheless, the validation in the ICGC HCC database showed that it did not have any statistically significant influence in overall survival. This work reveals that the most frequent single gene mutations are not enough for significant survival changes in HCC and that we should focus our efforts in integrative analysis of clinical information and multi-omics to maximize our clinical benefits in this devastating disease.

Einleitung Neurotransmitter von Schmerzfasern und Nervenfasern des sympathischen Nervensystems fördern Tumorzellwachstum, perineurale Invasion, Angiogenese und Immunevasion im duktalen Adenokarzinom des Pankreas (PDAC). Im Rahmen der Schmerztherapie des Pankreaskarzinoms ist die Ablation der gemeinsam verlaufenden sensiblen Afferenzen und der sympathischen Nervenfasern im Rahmen einer Neurolyse des Plexus coeliacus (CPN) eine etablierte Intervention. Die Datenlage bezüglich der schmerztherapeutischen Effekte ist positiv, bezüglich des Einflusses auf das Gesamtüberleben widersprüchlich. Eine Analyse bezüglich der Beeinflussung des Tumorwachstums erfolgte bisher nicht.

Einleitung Die onkogene Aktivierung des Wnt Signalwegs ist charakteristisch für kolorektale Karzinome (KRK). Trotz häufig vorkommender, aktivierender Mutationen in Genen des Wnt Signalwegs benötigen KRK-Zellen sekretierte Wnt-Liganden (WNTs) für das Tumorwachstum. Die spezifische Wirkung dieser sekretierten WNTs auf onkogene Signalwege im KRK wurde bisher wenig untersucht.

Einleitung Der Peroxisomen-Proliferator-Aktivierte-Rezeptor-Gamma (PPARy) ist ein durch Antidiabetika gesteuerter Transkriptionsfaktor, der onkogene „driver“ Signalwege (RAS/Wnt) des Kolorektalen Karzinoms (KRK) sowie die Differenzierung und Aktivität von Immunzellen im Tumormikromillieu reguliert.

Einleitung Kolonadenome sind Vorläufer von kolorektalen Karzinomen. Neben der traditionellen Adenom-Karzinom-Sequenz, ausgehend von tubulären, villösen und tubulovillösen Adenomen, gibt es eine serratierte Karzinogenese. Diese beinhaltet hyperplastische Polypen und serratierte Adenome. DOK1 ist ein Adapterprotein, das u.a. mit dem EGFR-Signalweg interagiert, als Tumorsuppressor gilt und im kolorektalen Karzinom oft verloren geht. Für Funktion und Prognose ist auch die subzelluläre Lokalisation relevant, so kann zytosolisches DOK1 die Proliferation von Tumorzellen hemmen und geht mit einer besseren Prognose einher, nukleäres DOK1 verliert diese Funktionen.

Hepatocellular carcinoma (HCC) is the most common liver cancer with poor prognosis. Paired related homeobox 1 (PRRX1) is a transcriptional co-activator, which regulates cell growth and differentiation. PRRX1 was linked to epithelial to mesenchymal transition (EMT). To date, it is unknown whether PRRX1 has a functional relevance in HCC. We performed an in-depth analysis of PRRX1 expression, its co-expressed genes and functions in HCC.

Submassive hepatic necrosis (SMHN) is the defining histological feature of acute-on-chronic liver failure (ACLF). In the condition of SMHN, liver progenitor cells (LPC)-mediated regeneration is crucial for survival and recovery of ACLF patients. LPC-mediated liver regeneration comprises three consecutive steps: formation of reactive ducts by activated LPC, LPC differentiation towards hepatocytes, and functional bile canaliculi formation by newly generated hepatocytes. In this study, we examined which steps play crucial roles in ACLF recovery.

In liver diseases with severe parenchymal loss, e.g. acute-on-chronic liver failure (ACLF), liver progenitor cells (LPC) are the main cell source to replenish lost hepatocytes through cell reprogramming. The molecular mechanisms underlying LPC towards hepatocytes differentiation in ACLF largely remain unknown to date. Activation of LPC is morphologically demonstrated as ductular reaction (DR). The similarity between DR and ductal plate (DP) of embryonic liver implies that LPC/DR differentiation towards hepatocytes might exploit similar mechanisms stem cells adopted in embryonic development. Tripartite motif protein (TRIM) 33 is a crucial transcription factor for differentiation of embryonic stem cells through the formation of transcription factor complexes with phosphorylated Smad2 and Smad3, the downstream substrates of activated TGF-β signaling. This transcription factor complex replaces heterochromatin protein 1, a main inhibitor of master regulators of cell differentiation, and thus opens binding sites at promoters for the additional transcription factor complexes, such as Smad4-pSmad2/3-FoxH1. The binding of the latter complexes leads to expression of master regulators of differentiation, e.g. goosecoid (GSC). The current study investigated the role of TRIM33 in LPC differentiation towards hepatocytes in ACLF.

Organoide (Patient Derived Organoids, PDOs) können mit hoher Effizienz aus gastrointestinalen Tumoren gewonnen werden und zeigen hohe Übereinstimmung mit dem Ursprungsgewebe. Daher können sie mittels ex vivo Wirkstofftests zur Etablierung neuer Therapiestrategien nützlich sein.

Fatigue und Depressionen beeinträchtigen die Lebensqualität von Patienten mit Chronisch-entzündlichen Darmerkrankungen (CED) deutlich und kommen besonders bei aktiver Erkrankung häufig vor. Die Ursachen sind weitgehend ungeklärt, eine Rolle der intestinalen Mikrobiota und -abhängiger Metabolite wird diskutiert.

Cancer cells use glutamine to meet the increased metabolic requirements imposed by rapid proliferation. The molecular role of glutamine to liver cancer is still largely unknown. Here we report that a subset of hepatocellular carcinoma (HCC) cell lines use extracellular glutamine to suppress signal transduction activities. Glutamine deprivation triggers phosphorylation of kinases, notably extracellular signal-regulated kinases (ERK), causing resistance to the anti-proliferative effects of kinase inhibitors (e.g. Sorafenib, Erlotinib, LY294002 and U0126). Genomics and metabolomics profiling showed that upon glutamine withdrawal, metabolism is severely impaired, with a significant accumulation of intracellular serine. Mechanistically, serine overload suppresses cell proliferation and contributes to ERK pathway activation and kinase inhibitor resistance. We found that in the impaired metabolic state, treatment with inhibitors of ERK pathway induced cell proliferation and pro-cancer metabolic reprogramming, including aerobic glycolysis, suppressed glucose contribution to intracellular serine, and a redirection of 13C-glucose-derived carbon towards the production of glutamine, glutamate, malate and aspartate. In conclusion, we show for the first time that HCC cell lines depend on glutamine to inhibit signaling networks, in part by preventing intracellular serine accumulation, and that inhibiting kinases in an impaired metabolic state induces tumourigenic phenotypes. These data offer novel insights for overcoming drug resistance in liver cancer.

Reactive oxygen species (ROS) initiate several liver diseases through DNA hydroxylation, lipid peroxidation, and protein adduct formation. In addition, ROS interacts with signaling pathways such as NOTCH1 and NRF2, which may have an impact on liver regeneration. In the current study, we report that the Notch ligand Jagged-1 (JAG1) is induced by ROS in hepatocytes and functionally investigate its role in liver repair processes.