Klinikum Region Hannover

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies.

In Agrarlandschaften hängt die Biodiversität in hohem Maße von den Bewirtschaftungspraktiken landwirtschaftlicher Betriebe ab. Über diese Praktiken und Managemententscheidungen hinaus spielt jedoch auch der Landschaftskontext eine wichtige Rolle für die Biodiversität auf dem Betrieb. Aufgrund ihrer Komplexität werden die Auswirkungen des Landschaftskontextes bei der Bewertung der Biodiversität landwirtschaftlicher Betriebe häufig vernachlässigt. Dieser Beitrag unterstützt dabei, Wissensdefizite zum Zusammenspiel von Managementfaktoren und umgebender Landschaft zu verringern und liefert praktikable Bewertungsansätze. Die Auswirkungen des Landschaftskontextes auf die Biodiversität von Agrarbetrieben werden indikatorenbasiert beschrieben und daraus Implikationen für Managemententscheidungen der Landwirt:innen und für politische Programme abgeleitet. Der Fokus liegt auf den Lebensraumtypen Acker, Feldrain und Hecke sowie auf den Artengruppen Gefäßpflanzen, Vögel und Tagfalter. Von insgesamt zwölf relevanten Indikatoren für den Landschaftskontext, die aus Literaturauswertungen abgeleitet wurden, konnten nach Auswertung von Felddaten fünf Indikatoren herausgestellt werden, anhand derer eine positive Wirkung auf die Biodiversität (hier verstanden als Artenvielfalt) der ausgewählten Lebensraumtypen abgeleitet werden kann. Dazu zählen die landschaftliche Heterogenität, die Bewirtschaftungsform angrenzender Felder, die Breite von Krautsäumen an Hecken und der Anteil von ähnlichen Lebensräumen bzw. Quellhabitaten sowie die Fruchtartenvielfalt in der näheren Umgebung. Die Indikatoren sind geeignet, um sie in gesamtbetriebliche Bewertungen der Biodiversität einzubeziehen, da sie leicht zu erfassen sind und so die Messbarkeit und Honorierung von Maßnahmenerfolgen ermöglichen. Sie können mit bekannten Indikatoren für die Bewertung der Lebensraumqualität auf den Betrieben (z. B. Mahdhäufigkeit, Nährstoffbilanzen, Breite von Strukturelementen) kombiniert werden, um Entscheidungen über die Gestaltung und den optimalen Standort von Biodiversitätsmaßnahmen zu unterstützen. Darüber hinaus können durch die Einbindung landschaftsbezogener Indikatoren kooperative Maßnahmen gefördert werden, die auf eine Verbesserung der Biodiversität auf der Landschaftsebene abzielen. Indem Landwirt:innen befähigt werden, die Wirkung betriebsübergreifender Maßnahmen abzuschätzen, kann auch die derzeit geringe Beteiligung an förderfähigen Gemeinschaftsmaßnahmen verbessert werden.

Introduction More than 75% of the psychiatric disorders arise before the age of 30. Adolescence and young adulthood pose numerous developmental challenges like identity development, educational and occupational concerns, gaining autonomy and boundary-setting skills. The adolescent crises, which can involve a broad spectrum of psychiatric symptoms, demands a multidisciplinary approach to diagnosis and treatment. Objectives Our goal is to present a best practice example of an interdisciplinary day clinic through two case presentations, aiming improving innovative strategies for assessment/treatment of psychiatric disorders in young adulthood. Methods Via two comprehensive case presentations, we will introduce a psychotherapeutic day-clinic concept from a psychiatric training hospital in Germany. Results The day clinic’s interdisciplinary team uses therapeutic approaches like dynamic, cognitive-behavioral, and systemic therapy to understand young adults beyond just their symptoms. Milieu-therapeutic methods, family constellations, socio-therapeutic approaches and non-verbal therapies are incorporated into our concept. Case 1: A 20-year-old male patient, previously diagnosed with schizophrenia, was referred due to symptoms of living in an unreal world with perceived magical abilities and family conflicts. In the evaluation the features of high-functioning autism spectrum disorder (ASD) were more prominent than the psychotic symptoms. Developmental history and diagnostic tools yielded the diagnosis of ASD. Magical abilities in an unreal world appears to align more closely with repetitive/restrictive patterns of behavior, hereby we excluded in the follow-up the diagnosis of schizophrenia. Psychoeducation, social-skills-training and family interventions helped him to comprehend his strengths and discover a clearer direction in his life. Case 2: Another 20-year-old male patient was referred with depressive symptoms, a sense of emptiness and self-mutilation. Following routine evaluation, we employed systemic methods (genogram constellations) to gain deeper insight into the patient’s psychopathology. His mother’s migration history from Thailand, coupled with unfulfilled aspirations, echoed in his recurring thought: “Where are my roots?” During follow-up, we recognized his passive stance toward therapeutic change, addressed through a systemic intervention known as ‘taking the side of non-change.’ This shifted his position from resistance to openness. Non-verbal approaches, family interventions, and corrective in-vivo experiences significantly contributed to his stabilization. Conclusions Specialized psychiatric centers tailored to the unique needs of young adults play a critical role in evaluating, diagnosing, and treating psychiatric crises during this developmental stage. Achieving this requires the implementation of interdisciplinary holistic therapeutic approaches. Disclosure of Interest None Declared

Introduction Many individuals who suffer from one or multiple substance use disorders often also struggle with another co-morbid psychiatric condition, primarily anxiety disorders. As substance dependency develops, the loss of self-control becomes a pivotal issue, leading to challenges in self-esteem and self-respect. These challenges subsequently give rise to problems in interpersonal communication and close relationships. In addition to the biological model of substance use problems and highly manualized approaches, it is crucial to have a systemic understanding of the patient’s situation and appropriate treatment settings. This understanding allows for the proper consideration of individual differences and requirements, ultimately enabling better treatment and prevention strategies. Objectives Our aim is to present a comprehensive case that shows various facets of addiction and introduce a systemic therapy concept of an integrative/systemic day clinic from Germany. Methods Through a detailed case presentation, we will introduce a systemic-psychotherapeutic day-clinic concept from a psychiatric training hospital in Wunstorf, Germany. Results Case: In the case of a 48-year-old female patient initially diagnosed with recurrent depressive disorder, it was later revealed that she also deals with alcohol addiction and its interconnectedness with sex addiction. Shame and a lack of self-esteem in relationships played a central role in her journey. She does not perceive herself to be loved but to be harmed, which led to many violent sexual acts that increased her feelings of shame. Systemic therapeutic approaches like family constellations were applied, helping her to experience her child-ego states. This profound insight propelled her willingness to change. She began prioritizing self-care, learning to like, accept, and eventually love herself. Aromatherapy aided in calming and maintaining focus. The patient learned to redefine her emotions, aligning them with reality, thereby enabling the adaptive fulfillment of her needs. Conclusions Our interdisciplinary team at the day clinic employs therapeutic approaches like dynamic, cognitive-behavioral, and systemic therapy to thoroughly understand the patients and their conditions. This case underscores the significance of an individually tailored treatment drawing from diverse therapeutic concepts, especially in patients with addiction. The combination of different therapeutic approaches facilitates a profound engagement with the patient, potentially resulting in more intensive therapeutic work and a higher rate of success which should be evaluated in future studies. Disclosure of Interest None Declared

Middle-income economies must prioritise human capital development to ensure long-term sustainable growth and economic upgrading. While foreign direct investment (FDI) is believed to aid this endeavour, its impact on technical vocational education and training (TVET) remains understudied. This research explores the influence of FDI by multinational enterprises (MNEs) at various stages of global value chains (GVCs) on TVET graduate numbers in Vietnam and Indonesia from 2006 to 2016. Our findings reveal that greenfield FDI plays a role in shaping TVET supply, with heterogeneous effects across different GVC segments and subnational regions. Specifically, FDI in logistics, sales and marketing, and support and servicing are associated with an increase in the supply of TVET graduates in the region, whereas FDI in headquarters and production may lead to a decline in technical skills. To address these dynamics, public policies should prioritise flexible education systems capable of adapting to MNEs’ evolving skill demands. By doing so, these economies can elevate local human capital levels and avoid the stagnation often associated with middle-income traps. This research underscores the importance of aligning policy with the needs of a rapidly changing global economy to foster sustainable development.

Orbital and periocular metastatic tumors used to be considered very rare; however, with the constant updating of drugs and detection methods for cancer treatment, new chemotherapies and radiation treatments are being used. The life expectancy of cancer patients has become longer and periocular metastases are becoming easier to detect. Our knowledge of this rare disease of metastases also needs to be updated. This article reviews the incidence, symptomatic presentation, clinical features, diagnostic approaches and current treatment of metastatic tumors of the orbit and ocular adnexa in these patients.

Intraocular metastases arising from solid tumors are found in approximately 2% of patients with metastatic tumor diseases and are therefore more frequent than originally assumed. They often affect the uvea and are associated with a poor prognosis. Due to the difficult diagnosis and an inconsistent treatment regimen, ophthalmologists have a special responsibility here. This article gives a summary of the various types of intraocular metastases with respect to clinical features, diagnostics, treatment and prognosis as well as recommendations for follow-up care. A selective literature search was carried out on the topic of intraocular metastases using PubMed and Google Scholar. Intraocular metastases most frequently affect the uvea, specifically the choroid. In most cases the underlying disease is breast or lung cancer, but other rarer primary tumors have also been reported in the literature. Metastatic lesions can show very different morphological manifestations but can be distinguished based on the corresponding structure of manifestation in the eye and with the aid of targeted staging, thus providing valid information on the type of primary tumor. The treatment is partly experimental and usually depends on the primary tumor and leading symptoms of the patient. A differentiation between a curative or palliative treatment situation must always be made. Intraocular metastases are the most frequent intraocular tumor and are usually associated with a poor prognosis. Accurate diagnostics for finding the treatment as well as interdisciplinary collaboration and the presentation of the patient on the tumor board are essential.

Aims Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF‐R1), sTNF‐R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. Methods We conducted a case control study to assess serum levels of sTNF‐R1, sTNF‐R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow‐up (ROADMAP‐OFU) studies were used. Results Endostatin and sTNF‐R1 but not sTNF‐R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log 2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001–1011). sTNF‐R1 and sTNF‐R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928–1.774) and 0.874 (0.711–1.074). Conclusions sTNF‐R1 and sTNF‐R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited.

Background Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. Methods Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80–20 splitting of the data set and 10-fold cross validation. To assess performance, R², RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. Results For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R² = 0.12, RMSE = 25.40, sexual function: R² = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. Conclusion The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells), controlling lymphocyte development and activity. The role of NFAT signaling is well defined in T cells, the cytotoxic lymphocytes of the adaptive immunity. However, surprisingly little is known regarding the relevance of this transcription factor family in NK cells as effector cells of the innate immunity. Available data indicate that NFAT activity is dispensable for development of NK cells, whereas effects of the immunosuppressive drugs cyclosporin A and tacrolimus, that inhibit calcineurin and consecutively NFAT, implicate an involvement of the NFAT family in NK cell function. We here employed different genetic mouse models and functional analyses to unravel the role of NFAT1 (NFATc2) and NFAT2 (NFATc1) in NK cell reactivity. In vitro knockout (KO) of NFAT1 (NFATc2) or NFAT2 (NFATc1) enhanced NK cell degranulation and resulted in increased production of granzyme B and perforin upon stimulation of activating receptors like NK1.1 or Nkp46 or upon co-culture with different leukemia and solid tumor cells. In line, cytotoxicity assays revealed increased lysis of YAC-1 and B16F10 tumor cells by both NFAT1- and NFAT2-deficient NK cells as compared to wildtype (WT) controls. The inhibitory effect of NFAT transcription factors on NK cell effector function could also be confirmed in vivo by employing WT and NFAT KO animals in syngeneic B16F10 melanoma, RMA-S lymphoma and LL/2-luc lung carcinoma models, which revealed a significantly reduced tumor burden in NFAT1 and NFAT2 KO mice. Furthermore, we detected higher numbers of tumor infiltrating NK cells in NFAT KO mice, which suggested improved NK cell migration and homing to the tumor side. Comparative analyses with single NFAT as well as NFAT1+NFAT2 double KO and WT animals further confirmed the inhibitory effect of NFAT1 and NFAT2 and pointed to additive effects of NFAT1 and NFAT2 in NK cell tumor immunosurveillance. Proteomics analysis of NK cells from the different NFAT KO strains revealed altered expression of molecules which are regulating chemokine receptor expression as well as a decreased expression of NFκB inhibitory molecules, like NFKBIB (NFKB inhibitor beta) Commd6 (COMM domain containing 6). NFκB signaling was shown to regulate granzyme B and perforin synthesis and expression. Thus, we suggest that NFAT1 and NFAT2 inhibit NFκB signaling in NK cells, and NFAT1 and NFAT2 KO reinforce NFκB induced granzyme B and perforin expression and thereby increase NK cell cytotoxicity. Taken together, our results identify NFAT as a negative regulator of NK cell function. In addition, we provide the first evidence for a direct functional involvement of NFAT1 and NFAT2 in NK cell antitumor reactivity by regulation tumor infiltration and cytotoxicity of NK cell.

In addition to erectile dysfunction, urinary incontinence is the most common functional limitation after radical prostatectomy (RPE) for prostate cancer (PCa). The German S3 guideline recommends informing patients about possible effects of the therapy options, including incontinence. However, only little data on continence from routine care in German-speaking countries after RPE are currently available, which makes it difficult to inform patients. The aim of this work is to present data on the frequency and severity of urinary incontinence after RPE from routine care. Information from the PCO (Prostate Cancer Outcomes) study is used, which was collected between 2016 and 2022 in 125 German Cancer Society (DKG)-certified prostate cancer centers in 17,149 patients using the Expanded Prostate Cancer Index Composite Short Form (EPIC-26). Changes in the “incontinence” score before (T0) and 12 months after RPE (T1) and the proportion of patients who used pads, stratified by age and risk group, are reported. The average score for urinary incontinence (value range: 0—worst possible to 100—best possible) was 93 points at T0 and 73 points 12 months later. At T0, 97% of the patients did not use a pad, compared to 56% at T1. 43% of the patients who did not use a pad before surgery used at least one pad a day 12 months later, while 13% use two or more. The proportion of patients using pads differs by age and risk classification. The results provide a comprehensive insight into functional outcome 12 months after RPE and can be taken into account when informing patients.

Introduction We aimed to identify B-cell-mediated immunomechanisms in inclusion body myositis (IBM) and polymyositis (PM) as part of the complex pathophysiology. Materials and methods Human primary myotube cultures were derived from orthopedic surgery. Diagnostic biopsy specimens from patients with IBM (n=9) and PM (n=9) were analyzed for markers of B cell activation (BAFF and APRIL) and for chemokines that control the recruitment of B cells (CXCL-12 and CXCL-13). Results were compared to biopsy specimens without myopathic changes (n=9) and hereditary muscular dystrophy (n=9). Results The mRNA expression of BAFF, APRIL, and CXCL-13 was significantly higher in IBM and PM compared to controls. Patients with IBM displayed the highest number of double positive muscle fibers for BAFF and CXCL-12 (48%) compared to PM (25%), muscular dystrophy (3%), and non-myopathic controls (0%). In vitro, exposure of human myotubes to pro-inflammatory cytokines led to a significant upregulation of BAFF and CXCL-12, but APRIL and CXCL-13 remained unchanged. Conclusion The results substantiate the hypothesis of an involvement of B cell-associated mechanisms in the pathophysiology of IBM and PM. Muscle fibers themselves seem to contribute to the recruitment of B cells and sustain inflammation.

(1) Background: Patients with sepsis following surgical intervention may exhibit fundamental distinctions from those experiencing sepsis without prior surgery. Despite the potential clinical importance of distinguishing these two sepsis subpopulations, dissimilarities, particularly in outcome, between surgical and non-surgical patients have been subject to limited scientific investigations in the existing literature. This study aimed to investigate the differences in mortality and sepsis-associated organ dysfunction between these two groups. (2) Methods: A retrospective analysis was conducted using data from a large cohort of prospectively enrolled patients with sepsis (n = 737) admitted to three intensive care units at University Medical Center Goettingen; patients were categorized into surgical (n = 582) and non-surgical sepsis groups (n = 155). The primary outcomes assessed were 28- and 90-day mortality rates, and secondary endpoints were multiple clinical parameters and measures of sepsis-associated organ dysfunction. (3) Results: Non-surgical patients presented a significantly higher 90-day mortality (37%) compared to surgical sepsis patients (30%, p = 0.0457). Moreover, the non-surgical sepsis group exhibited increased sepsis-associated organ dysfunction, as evidenced by higher average SOFA scores (p < 0.001), elevated levels of serum Procalcitonin (p = 0.0102), and a higher utilization of organ replacement therapies such as ventilation (p < 0.001), vasopressor treatment (p < 0.001), and renal replacement therapy (p = 0.0364). Additionally, non-surgical sepsis patients had higher organ-specific SOFA respiratory (p < 0.001), cardiovascular (p < 0.001), renal (p < 0.001), coagulation (0.0335), and central nervous system (p = 0.0206) subscores. (4) Conclusions: These results suggested that patients with non-surgical sepsis may face distinct challenges and a higher risk of adverse outcomes compared to patients with sepsis following surgical intervention. These findings have important implications for clinical decision-making, patient management, and resource allocation in sepsis care.

Since about a year there has been an influx of refugees from Ukraine due to the current war situation. Data on the mental health condition of Ukrainian refugees will be reviewed and compared to the mental health conditions to refugees from other parts of the world in Germany. Moreover, the psychosocial and socioeconomic situation of refugees from Ukraine will be reflected on the background of the situation of refugees from other countries. Conclusions from the recent experiences for the mental health care system will be drawn and discussed with the aufience in a European perspective. Special highlight will be given to pilot best practice modells for mental health care of Ukrainian refugees within the German mental health care system. Disclosure of Interest None Declared