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IntroductionPerioperative adverse events increase morbidity and mortality. The rate and severity of complications and the risk for subsequent mortality are increased after high-risk procedures and in elevated-risk patients. Over the past decades, a multitude of prognostic studies identified perioperative risk factors at the population level. However, to allow for the advancement of precision surgery strategies, improved risk prediction on the individual patient level is warranted. Comprehensive, consecutive, multisource, structured, high-quality patient-related and procedure-related data sets, together with thorough follow-up and combined with state-of-the-art machine-learning analyses, are needed to facilitate precise prediction of perioperative complications. Therefore, we designed and currently conduct the Heidelberg Perioperative Deep Data study (HeiPoDD). Here, we report the rationale and design of the HeiPoDD study.Methods and analysisHeiPoDD is a prospective, single-centre, exploratory cohort study aiming to build up a large-scale deep-data base and corresponding biomaterial collection. 1040 adult patients planned for elective high-risk, non-cardiac surgery for any indication at Heidelberg University Hospital, Germany will be included. The obtained study-specific data set includes clinical data, lab values, genome- and proteome analysis as well as plasma, serum and peripheral blood mononuclear cells (PBMC) collected before and at days 1, 3 and 7 postsurgery. Urine samples are collected before and at day 1 postsurgery. Structured follow-up for perioperative complications such as redo-surgery, length of intensive care stay or length of hospital stay is conducted at days 30, 90 and 1 year postsurgery and for disease progression and survival after 3 and 5 years postsurgery. All study data will be transferred to the HeiPoDD registry to allow merging with all available routine clinical data from the hospital information system including imaging studies as well as haemodynamic and respiratory biosignals. Biomaterials will be stored in the HeiPoDD biomaterial bank to allow further analyses.Ethics and disseminationThe trial protocol and amendments were approved by the ethics committee of the University of Heidelberg (S-758/2021). The protocol is registered with the German Clinical Trial Register (DRKS00024625). Participating patients’ data will be recorded only in pseudonymised form. After completion of the study, data collected during the study will be kept on file for up to 30 years. Biomedical samples collected during the study and entered into the biobank will be held for the same amount of time. The findings will be disseminated in peer-reviewed academic journals.

Prospective data registration is the basis of clinical oncological research. Commonly, case documentation is restricted to studies investigating a defined hypothesis. Only few institutions prospectively register all oncological patients with a reliable, sustainable and continuous follow-up infrastructure. The Department of Urology of the Heidelberg University Hospital started its prospective tumor data base in 1992. Since then, the clinical course of all oncological in-patients is continuously registered within a life-long follow-up (success rate: 93%). Associated tumor tissue is stored in the Heidelberg Biobank. In 2005, the transfer of this invaluable registry from the initial InterSystemsCache®/KRAZTUR system to a modern data warehouse was initiated. However, the transfer of existing data into a new environment proved to be technically challenging. To migrate the existing data into a modern data warehouse (DATA 5.0) while maintaining data extraction functions. Additional requirements included FHIR connectivity, big data analyses and AI applications. Together with SAP SE, DATA 5.0 was developed. Based on SAP HANA® (High Performance Analytic Appliance) it allows data registration and analysis with third party analytical tools. The project was supported by members of the SAP SE executive board and funded by the Dietmar Hopp Foundation. Data Acquisition, Translation & Analysis 5.0 (DATA 5.0), a web-based tool for data registration, preservation and analysis of treatment and follow-up data, was developed to proof-of-concept stage. DATA 5.0 was then implemented into clinical practice replacing the previous system. As of today, 15,345 oncological patients and 6.7 Mio. data points are registered. Prospective long-term data was successfully migrated into DATA 5.0, allowing data preservation, flexibility and capabilities for future data sources. DATA 5.0, together with associated tumor tissue, is a lighthouse platform for oncological research, with capability for third party analytical tools, big data analysis and AI applications including training of digital twin models.

Although digital and data-based technologies are widespread in various industries in the context of Industry 4.0, the use of smart connected devices in health care is still in its infancy. Innovative solutions for the medical environment are affected by difficult access to medical device data and high barriers to market entry because of proprietary systems. In the proof-of-concept project OP 4.1, we show the business viability of connecting and augmenting medical devices and data through software add-ons by giving companies a technical and commercial platform for the development, implementation, distribution, and billing of innovative software solutions. The creation of a central platform prototype requires the collaboration of several independent market contenders, including medical users, software developers, medical device manufacturers, and platform providers. A dedicated consortium of clinical and scientific partners as well as industry partners was set up. We demonstrate the successful development of the prototype of a user-centric, open, and extensible platform for the intelligent support of processes starting with the operating room. By connecting heterogeneous data sources and medical devices from different manufacturers and making them accessible for software developers and medical users, the cloud-based platform OP 4.1 enables the augmentation of medical devices and procedures through software-based solutions. The platform also allows for the demand-oriented billing of apps and medical devices, thus permitting software-based solutions to fast-track their economic development and become commercially successful. The technology and business platform OP 4.1 creates a multisided market for the successful development, implementation, distribution, and billing of new software solutions in the operating room and in the health care sector in general. Consequently, software-based medical innovation can be translated into clinical routine quickly, efficiently, and cost-effectively, optimizing the treatment of patients through smartly assisted procedures.

Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.

1.1 Hintergrund und ZieleDie Ausbildung von Narbengewebe nach einer Gewebeverletzung stellt einen physiologischen Heilungsprozess dar, der notwendig ist, um die Funktionalität des Gewebes wiederherzustellen. Je nach Gewebetyp und der Art der Verletzung kann der Wundheilungsprozess unterschiedlich verlaufen. Zu den pathologischen Narben zählen sowohl hypertrophe Narben als auch Keloide. Hypertrophe Narben sind erhabene Narbengebilde, welche sich auf das ursprüngliche Wundareal beschränken. Morphologisch ähnlich zeigen sich Keloide, welche jedoch die Tendenz zeigen, die ursprüngliche Begrenzung des Wundareals tumorartig zu überwuchern und invasiv gesundes Hautgewebe zu infiltrieren (Broughton et al. 2006).Der genaue Pathomechanismus der Keloidentstehung ist jedoch noch nicht vollständig geklärt. Nachgewiesen ist, dass Strukturproteine wie Fibrin, Fibronektin und Glykosaminoglykane durch extrazelluläre Matrixproteine, hauptsächlich Kollagen, ersetzt werden. Außerdem zeigt sich sowohl die Aktivität von Fibroblasten als auch von inflammatorischen Zellen im Keloidgewebe erhöht. IGF-I-Rezeptor (insulin-like growth factor-I-receptor), TGF-beta (transforming growth factor), PDGF (platelet derived growth factor), CTGF (connective tissue growth factor), PAI-I (plasminogen activator inhibitor I) und HIF-I-alpha (Hypoxia inducible factor I alpha) sind prominente Zytokine, welche eine Rolle in der Pathogenese von Keloiden zu spielen scheinen (Altmeyer 2010).Aufgrund der bis heute weiterhin begrenzten Behandlungsmöglichkeiten stellen Keloide eine gravierende Dermatose dar, die die Lebensqualität betroffener Menschen stark beeinträchtigen kann. Die Entwicklung neuer therapeutischer Optionen und die Optimierung bereits bestehender Therapieoptionen setzt jedoch ein noch tieferes Verständnis der Pathophysiologie von Keloiden voraus. Daher war es Ziel dieser Arbeit, durch mondernste Methodik, der MultiAntigen-Analyse in Verbindung mit Bildanalysesoftware, unbekannte Prozesse und Zielstrukturen im Keloid zu identifizieren, auf die spezifische Pharmazeutika abzielen könnten.1.2 MethodenUm einen tieferen Einblick in diesen inflammatorischen Prozess zu erhalten, wurde im Rahmen der Forschungsarbeit „Multi-Antigen-Analyse zeigt inflammatorische DC, ADAM17 und Neprilysin als Effektoren bei der Keloidentstehung“ das Gewebe von 8 Keloid betroffenen Patienten untersucht, welche sich einer chirurgischen Intervention in der Hautklinik des 2 Universitätsklinikums Erlangen unterzogen haben. Von jedem Patienten wurden Proben aus dem aktiven Rand des Keloids und von angrenzendem makroskopisch nicht betroffenem Gewebe gewonnen. Zusätzlich wurden 5 Hautproben von nicht Keloid erkrankten Patienten untersucht. Anschließend wurden diese Proben mittels Multi-Antigen-Analyse (MAA) in Verbindung mit einem Data Mining Ansatz analysiert. Das Set der Multi-Antigen-Analyse beinhaltet 58 Antikörper mit 45 Immunzellmarkern, 5 Strukturmarkern und 8 Markern für Metalloproteasen und deren Substrate.Die MAA ist eine neuartige Technik zur Lokalisierung und Darstellung einer Vielzahl unterschiedlicher Antigenstrukturen in einem einzigen Gewebeschnitt, indem aufeinanderfolgende Sequenzen von Immunfluoreszenzfärbungen durchgeführt werden. Ein einzelner Gewebeträger wird unter ein Fluoreszenzmikroskop gelegt, das Teil der MELC Robotertechnologie ist. Dieser automatisierte und robotergestützte Prozess umfasst die Färbung des Gewebes mit markierten Antikörpern, einen Waschprozess der ungebundenen Antikörper und die Erstellung eines Fluoreszenzbildes je nach Antikörperfärbung. Nach Inaktivierung der Antikörper mittels Bleichverfahren startet eine erneute sequenzielle Runde der Immunfluoreszenzfärbung für einen weiteren Antikörper.Die zuvor aufgenommenen Fluoreszenzbilder wurden mit der StrataQuest Analysis Software© analysiert. Propidiumjodid (PI)-Färbungen wurden zur Erkennung von Zellkernen verwendet und ein vorhergesagter Zytoplasmasaum durch einen adaptiven Algorithmus hinzugefügt. Durch Überlagerung von PI-gefärbten Gewebeschnitten mit Antikörper-gefärbten Gewebeschnitten kann sowohl die quantitative Expression eines bestimmten Antigens als auch die genaue Anzahl der Zellen, die ein bestimmtes Antigen exprimieren, dargestellt werden. Außerdem kann durch Überlagerung mehrerer Gewebeschnitte die räumliche Anordnung verschiedener Antigenexpressionsmuster und Zellpopulationen zueinander darstellt und analysiert werden. Die räumliche Verteilung der Zellsubpopulationen wurde sowohl qualitativ als auch quantitativ mit Hilfe der K-Funktion von Ripley und Besag's L Funktion charakterisiert.Im Gegensatz zu herkömmlichen Immunfluoreszenzfärbungen, bei denen in der Regel lediglich ein Antigen pro Gewebeschnitt dargestellt wird, ermöglicht dieser Ansatz die Darstellung und Analyse von bis zu 100 Antigenen auf einem einzelnen Gewebeschnitt.1.3 Ergebnisse und Beobachtungen Konkordant zur aktuellen Studienlage konnte eine deutlich gesteigerte Zellularität im Keloidgewebe im Vergleich zur gesunden Kontrollhaut festgestellt werden. Neu ist jedoch, dass dies bereits im periläsionalen, makroskopisch nicht betroffenem Gewebe nachgewiesen werden konnte. Zudem dominieren vor allem von Monozyten abgeleitete inflammatorische dendritische Zellen (CD1a+, CD11c+, CD14+) und aktivierte CD4+ T-Lymphozyten (CD45 RO+) die Immuninfiltration im Keloidgewebe und sind zudem mit den im Keloid vorhandenen Fibroblasten assoziiert. Gleichermaßen zeigte das periläsionale Gewebe ein deutliches Immuninfiltrat im Vergleich zur gesunden Kontrollhaut. Interessanterweise dominieren vor allem Immunvorläuferzellen im periläsionalen Gewebe, welche sich perivaskulär konzentrieren, was darauf hindeuten könnte, dass diese von einem im Keloid vorhandenen Immunprozess angezogen werden. Normalerweise korreliert das Auftreten solcher Zellen mit einer Immunreaktion, die durch ein Antigen ausgelöst wird. Das Auftreten oder die Entwicklung von aktivierten Gedächtniszellen (CD4+ T-Lymphozyten (CD45 RO+)) würde eine solche Annahme unterstützen. Jüngste Studien haben zwar eine Vielzahl von inflammatorischen Zellen und Faktoren identifiziert, eine detaillierte Sequenz von Ereignissen wurde jedoch bisher nicht beschrieben. Die meistverwendete Methodik der klassischen Immunfluoreszenzfärbungen mit Darstellung einzelner weniger Antigene könnte hierfür ursächlich sein.Erstmalig beschrieben ist zudem, dass in Fibroblasten und Leukozyten im Keloidgewebe hohe Konzentrationen an Metalloproteasen ADAM10/17 und Neprilysin (CD10) nachgewiesen werden konnten. Die erhöhte Expression der Metalloproteasen fiel zudem mit dem Auftreten von Notch-Rezeptoren in Fibroblasten zusammen, welche Substrate von ADAM10 sind. Dies könnte auch mit einer stattfindenden Immunaktivierung korrelieren, da Metalloproteasen durch die Spaltung diverser Vorläufermoleküle zelluläre Differenzierung und Signalgebung induzieren. Die räumliche Nähe von Leukozyten zu Fibroblasten, die nur im Keloidgewebe durch Bildanalyse bestätigt werden konnte, könnte ein potenzieller Faktor der Fibroblastenaktivierung und der damit verbundenen exzessiven Kollagensynthese sein.

Experimental and clinical studies have revealed the effectiveness of a specific nutrient synergy (SNS) mixture composed of ascorbic acid (AA), lysine, proline, arginine, epigallocatechin gallate (EGCG) and other micronutrients in targeting crucial physiological mechanisms involved in cancer progression and metastasis. HTLV-1 causes adult T-cell leukemia (ATL). The spread and metastases of ATL as well as other tumors has been associated with matrix metalloproteinases, especially the gelatinases MMP-2 and MMP-9. The objective of this study was to investigate whether SNS, AA and EGCG affects the gelatinolytic activity of MMP-2 and its transcriptional and translational levels in HTLV-1-positive and -negative malignant T-cells. The results indicated that SNS and EGCG caused a dose-dependent decline in the activity, transcription and translation of MMP-2 after treatment with SNS and EGCG, while AA was only able to inhibit the activity at maximum doses tested and to some extent, the protein expression levels of MMP-2, without affecting their transcriptional levels. The highest activity was noted in the case of SNS which is likely to be due to a synergistic effect of the different constituents in the formulation. These results point towards the potential integration of SNS in the anti-invasive treatment of ATL and related diseases.

Background Adult T-cell Leukemia (ATL) is a disease with no known cure. The disease manifests itself as an aggressive proliferation of CD4 + cells with the human T-cell Lymphotropic virus type 1 (HTLV-1). The leukemogenesis of the virus is mainly attributed to the viral oncoprotein. Tax activates the Nuclear Factor kappa B (NF-κB) which stimulates the activity and expression of the matrix metalloproteinase-9 (MMP-9). The objective of this study was to investigate the efficacy of a specific nutrient synergy (SNS) on proliferation, Tax expression, NF-κB levels as well as on MMP-9 activity and expression both at the transcriptional and translational levels in two HTLV-1 positive cell lines, HuT-102 and C91-PL at 48h and 96h of incubation. Cytotoxicity of Epigallocatechin-3-gallate (EGCG) was assayed using CytoTox 96 Non-radioactive and proliferation was measured using Cell Titer96 TM Nonradioactive Cell Proliferation kit (MTT- based assay). Enzyme linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA) were used to assess the effect of SNS on NF- κ B mobility. Zymography was used to determine the effects of SNS on the activity and secretion of MMP-9. The expression of MMP-9 was done using RT-PCR at the translational level and Immunoblotting at the transcriptional level. Results A significant inhibition of proliferation was seen in both cell lines starting at a concentration of 200μg/ml and in a dose dependent manner. SNS induced a dose dependent decrease in Tax expression, which was paralleled by a down-regulation of the nuclearization of NF-κB. This culminated in the inhibition of the activity of MMP-9 and their expression both at the transcriptional and translational levels. Conclusions The results of this study indicate that a specific nutrient synergy targeted multiple levels pertinent to the progression of ATL. Its activity was mediated through the NF- κ B pathway, and hence has the potential to be integrated in the treatment of this disease as a natural potent anticancer agent.

Adult T-cell Leukemia (ATL) is a disease with no known cure. The disease manifests itself as an aggressive proliferation of CD4+ cells with the human T-cell Lymphotropic virus type 1 (HTLV-1). The leukemogenesis of the virus is mainly attributed to the viral oncoprotein. Tax activates the Nuclear Factor kappa B (NF-κB) which stimulates the activity and expression of the matrix metalloproteinase-9 (MMP-9). The objective of this study was to investigate the efficacy of a specific nutrient synergy (SNS) on proliferation, Tax expression, NF-κB levels as well as on MMP-9 activity and expression both at the transcriptional and translational levels in two HTLV-1 positive cell lines, HuT-102 and C91-PL at 48h and 96h of incubation. Cytotoxicity of Epigallocatechin-3-gallate (EGCG) was assayed using CytoTox 96 Non-radioactive and proliferation was measured using Cell Titer96TM Nonradioactive Cell Proliferation kit (MTT- based assay). Enzyme linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA) were used to assess the effect of SNS on NF-κB mobility. Zymography was used to determine the effects of SNS on the activity and secretion of MMP-9. The expression of MMP-9 was done using RT-PCR at the translational level and Immunoblotting at the transcriptional level. A significant inhibition of proliferation was seen in both cell lines starting at a concentration of 200μg/ml and in a dose dependent manner. SNS induced a dose dependent decrease in Tax expression, which was paralleled by a down-regulation of the nuclearization of NF-κB. This culminated in the inhibition of the activity of MMP-9 and their expression both at the transcriptional and translational levels. The results of this study indicate that a specific nutrient synergy targeted multiple levels pertinent to the progression of ATL. Its activity was mediated through the NF-κB pathway, and hence has the potential to be integrated in the treatment of this disease as a natural potent anticancer agent.