The journey to establishing an IT-infrastructure within the German Biobank Alliance

Background Biobanks ensure the long-term storage and accessibility of biospecimens and corresponding data sets. Thus, they form the foundation for many research projects which may contribute to improving medical care. With the establishment of the German Biobank Node and Alliance, expertise in biobanking is bundled and strengthened. An important component within this research infrastructure is the set-up of an information technology (IT) network for allowing feasibility requests across individual biobanks. Objective We aim to describe relevant aspects that have shaped the journey to interconnect biobanks, to enhance their visibility within the research-community, to harmonize data, and to enable feasibility searches to support access to available data and biosamples. Methods To achieve this task, we resorted to a wide variety of methods: we ran a requirement analysis, decided on the mode of operation for the federated team of IT-developers and on the development approach itself, took related national and international initiatives into account, and concluded with evaluations of the developed software artefacts and the operation of the entire chain of applications. Results We drew an IT framework including all heterogeneous data aspects derived from our requirement analysis and developed a comprehensive IT infrastructure. The successful implementation benefited from a smooth interaction of a federated IT team distributed across all participating sites that was even able to manage a major technology change mid-project. Authentication and project management services from associated partners could be integrated and the graphic user interface for an intuitive search tool for biospecimens was designed iteratively. The developed code is open source to ensure sustainability and the local implementation is concluded and functioning. The evaluation of the components was positive. Conclusions The entire project had given ample opportunity for challenges, predictable and unpredictable—from the mode of operation to changing some of the initial ideas. We learned our lessons concerning personnel, budget planning and technical as well as manual monitoring as well as some requirements arising only during the process of the project. Nevertheless, we can here report a success story of a network infrastructure, highly agile and much easier in local installation than initially anticipated

Modulation of the sympathetic nervous system by renal denervation prevents reduction of aortic distensibility in atherosclerosis prone ApoE-deficient rats

Apolipoprotein E-deficient (ApoE(-/-)) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE(-/-)-rat model.Methods Normotensive, 8 weeks old ApoE−/− and Sprague–Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA).Results After 8 weeks, ApoE−/−-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE−/−-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN.Conclusion ApoE−/−-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE−/−-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels

Modulation of the sympathetic nervous system by renal denervation prevents reduction of aortic distensibility in atherosclerosis prone ApoE-deficient rats

Apolipoprotein E-deficient (ApoE(-/-)) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE(-/-)-rat model.Methods Normotensive, 8 weeks old ApoE−/− and Sprague–Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA).Results After 8 weeks, ApoE−/−-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE−/−-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN.Conclusion ApoE−/−-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE−/−-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels

Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy

ObjectivesWe investigated the myocardial localization and expression of tissue factor (TF) and alternatively spliced human tissue factor (asHTF) in patients with dilated cardiomyopathy (DCM).BackgroundTissue factor is expressed in cardiac muscle and may play a role in maintaining myocardial structure.MethodsMyocardial biopsies were obtained from patients with a normal or mildly impaired ejection fraction (EF) (≥50%) and moderate to severely reduced EF (<50%). Explanted DCM hearts were also examined. Myocardial TF expression level was assessed by real-time polymerase chain reaction, TF protein by enzyme-linked immunosorbent assay, and localization by immunohistochemistry.ResultsWe report the identification of asHTF in the human myocardium: it was located in cardiomyocytes and endothelial cells. Quantification of myocardial TF messenger ribonucleic acid in DCM revealed a decrease in the TF/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratio (1.76 × 10−1± 6.08 × 10−2for EF ≥50% [n = 19] vs. 1.06 × 10−1± 5.26 × 10−2for EF <50% [n = 27]; p < 0.001) and asHTF/GAPDH ratio (13.91 × 10−5± 11.20 × 10−5for EF ≥50% vs. 7.17 × 10−5± 3.82 × 10−5for EF <50%; p = 0.014). Tissue factor isoform expression level was also decreased in explanted DCM hearts (p < 0.01; n = 12). Total TF protein was reduced by 26% in DCM (p < 0.05). The TF/GAPDH ratio correlated positively with the EF (r = 0.504, p < 0.0001). Immunohistochemistry showed TF localized to the sarcolemma and Z-bands of the cardiomyocytes in patients with normal EF, whereas TF was found in the cardiomyocytic cytosol around the nucleus in DCM.ConclusionsTissue factor was down-regulated in the myocardium of DCM patients. The reduction in TF expression and change in localization may influence cell-to-cell contact stability and contractility, thereby contributing to cardiac dysfunction in DCM

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

SIMPLE SUMMARY: Anaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK(+) and ALK(−) ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL. ABSTRACT: In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK(+)) ALCL. Key pathogenic events in ALK-negative (ALK(−)) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK(+) and ALK(−) ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK(+) ALCL or of CD95 death-receptor signaling in ALK(−) ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity

Genomic loss of the putative tumor suppressor gene E2A in human lymphoma

The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity