Best-practice data models harmonize semantics and data structure of medical variables in clinical or epidemiological studies. While there exist several published data sets, it remains challenging to find and reuse published eligibility criteria or other data items that match specific needs of a newly planned study or registry. A novel Internet-based method for rapid comparison of published data models was implemented to enable reuse, customization, and harmonization of item catalogs for the early planning and development phase of research databases.

A thorough analysis of clonal evolution commonly requires integration of diverse sources of data (e.g., karyotyping, next-generation sequencing, and clinical information). Subsequent to actual reconstruction of clonal evolution, detailed analysis and interpretation of the results are essential. Often, however, only few tumor samples per patient are available. Thus, information on clonal development and therapy effect may be incomplete. Furthermore, analysis of biallelic events-considered of high relevance with respect to disease course-can commonly only be realized by time-consuming analysis of the raw results and even raw sequencing data.

The human heart controls blood flow, and therewith enables the adequate supply of oxygen and nutrients to the body. The correct function of the heart is coordinated by the interplay of different cardiac cell types. Thereby, one can distinguish between cells of the working myocardium, the pace-making cells in the sinoatrial node (SAN) and the conduction system cells in the AV-node, the His-bundle or the Purkinje fibres. Tissue-engineering approaches aim to generate hiPSC-derived cardiac tissues for disease modelling and therapeutic usage with a significant improvement in the differentiation quality of myocardium and pace-making cells. The differentiation of cells with cardiac conduction system properties is still challenging, and the produced cell mass and quality is poor. Here, we describe the generation of cardiac cells with properties of the cardiac conduction system, called conduction system-like cells (CSLC). As a primary approach, we introduced a CrispR-Cas9-directed knockout of the NKX2-5 gene in hiPSC. NKX2-5-deficient hiPSC showed altered connexin expression patterns characteristic for the cardiac conduction system with strong connexin 40 and connexin 43 expression and suppressed connexin 45 expression. Application of differentiation protocols for ventricular- or SAN-like cells could not reverse this connexin expression pattern, indicating a stable regulation by NKX2-5 on connexin expression. The contraction behaviour of the hiPSC-derived CSLCs was compared to hiPSC-derived ventricular- and SAN-like cells. We found that the contraction speed of CSLCs resembled the expected contraction rate of human conduction system cells. Overall contraction was reduced in differentiated cells derived from NKX2-5 knockout hiPSC. Comparative transcriptomic data suggest a specification of the cardiac subtype of CSLC that is distinctly different from ventricular or pacemaker-like cells with reduced myocardial gene expression and enhanced extracellular matrix formation for improved electrical insulation. In summary, knockout of NKX2-5 in hiPSC leads to enhanced differentiation of cells with cardiac conduction system features, including connexin expression and contraction behaviour.

The utilisation of smart devices, such as smartwatches and smartphones, in the field of movement disorders research has gained significant attention. However, the absence of a comprehensive dataset with movement data and clinical annotations, encompassing a wide range of movement disorders including Parkinson's disease (PD) and its differential diagnoses (DD), presents a significant gap. The availability of such a dataset is crucial for the development of reliable machine learning (ML) models on smart devices, enabling the detection of diseases and monitoring of treatment efficacy in a home-based setting. We conducted a three-year cross-sectional study at a large tertiary care hospital. A multi-modal smartphone app integrated electronic questionnaires and smartwatch measures during an interactive assessment designed by neurologists to provoke subtle changes in movement pathologies. We captured over 5000 clinical assessment steps from 504 participants, including PD, DD, and healthy controls (HC). After age-matching, an integrative ML approach combining classical signal processing and advanced deep learning techniques was implemented and cross-validated. The models achieved an average balanced accuracy of 91.16% in the classification PD vs. HC, while PD vs. DD scored 72.42%. The numbers suggest promising performance while distinguishing similar disorders remains challenging. The extensive annotations, including details on demographics, medical history, symptoms, and movement steps, provide a comprehensive database to ML techniques and encourage further investigations into phenotypical biomarkers related to movement disorders.

The TCF4 gene encodes for the basic helix-loop-helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development.

Information systems are a key success factor for medical research and healthcare. Currently, most of these systems apply heterogeneous and proprietary data models, which impede data exchange and integrated data analysis for scientific purposes. Due to the complexity of medical terminology, the overall number of medical data models is very high. At present, the vast majority of these models are not available to the scientific community. The objective of the Portal of Medical Data Models (MDM, https://medical-data-models.org) is to foster sharing of medical data models.

Replicative senescence hampers application of mesenchymal stromal cells (MSCs) because it limits culture expansion, impairs differentiation potential, and hinders reliable standardization of cell products. MSCs can be rejuvenated by reprogramming into induced pluripotent stem cells (iPSCs), which is associated with complete erasure of age- and senescence-associated DNA methylation (DNAm) patterns. However, this process is also associated with erasure of cell-type and tissue-specific epigenetic characteristics that are not recapitulated upon re-differentiation towards MSCs. In this study, we therefore followed the hypothesis that overexpression of pluripotency factors under culture conditions that do not allow full reprogramming might reset senescence-associated changes without entering a pluripotent state. MSCs were transfected with episomal plasmids and either successfully reprogrammed into iPSCs or cultured in different media with continuous passaging every week. Overexpression of pluripotency factors without reprogramming did neither prolong culture expansion nor ameliorate molecular and epigenetic hallmarks of senescence. Notably, transfection resulted in immortalization of one cell preparation with gain of large parts of the long arm of chromosome 1. Taken together, premature termination of reprogramming does not result in rejuvenation of MSCs and harbours the risk of transformation. This approach is therefore not suitable to rejuvenate cells for cellular therapy.

The application of next-generation sequencing in research and particularly in clinical routine requires valid variant calling results. However, evaluation of several commonly used tools has pointed out that not a single tool meets this requirement. False positive as well as false negative calls necessitate additional experiments and extensive manual work. Intelligent combination and output filtration of different tools could significantly improve the current situation.

Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options.

Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi.

Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Standardization in clinical documentation can increase efficiency and can save time and resources.

Spiral drawings on paper are used as routine measures in hospitals to assess Parkinson's Disease motor deficiencies. In the age of emerging mobile health tools and Artificial Intelligence a comprehensive digital setup enables granular biomarker analyses and improved differential diagnoses in movement disorders. This study aims to evaluate on discriminatory features among Parkison's Disease patients, healthy subjects and diverse movement disorders. Overall, 24 Parkinson's Disease patients, 27 healthy controls and 26 patients with similar differential diagnoses were assessed with a novel tablet-based system. It utilizes an integrative assessment by combining a structured symptoms questionnaire-the Parkinson's Disease Non-Motor Scale-and 2-handed spiral drawing captured on a tablet device. Three different classification tasks were evaluated: Parkinson's Disease patients versus healthy control group (Task 1), all Movement disorders versus healthy control group (Task 2) and Parkinson's Disease patients versus diverse other movement disorder patients (Task 3). To systematically study feature importances of digital biomarkers a Machine Learning classifier is cross-validated and interpreted with SHapley Additive exPlanations (SHAP) values. The number of non-motor symptoms differed significantly for Tasks 1 and 2 but not for Task 3. The proposed drawing features partially differed significantly for all three tasks. The diagnostic accuracy was on average 94.0% in Task 1, 89.4% in Task 2, and 72% in Task 3. While the accuracy in Task 3 only using the symptom questionnaire was close to the baseline, it greatly improved when including the tablet-based features from 60 to 72%. The accuracies for all three tasks were significantly improved by integrating the two modalities. These results show that tablet-based drawing features can not only be captured by consumer grade devices, but also capture specific features to Parkinson's Disease that significantly improve the diagnostic accuracy compared to the symptom questionnaire. Therefore, the proposed system provides an objective type of disease characterization of movement disorders, which could be utilized for home-based assessments as well.Clinicaltrials.gov Study-ID: NCT03638479.

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect.

Almost all medulloblastomas (MB) of the Wingless/Int-1 (WNT) type are characterized by hotspot mutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations. Additional alterations in SMARCA4 are detected in around 20% of WNT MB, but their functional role is mostly unknown. We therefore amended previously described Blbp-cre::Ctnnb1(ex3)fl/wt mice by the introduction of floxed Smarca4 alleles. Unexpectedly, mutated and thereby stabilized β-catenin on its own induced severe developmental phenotypes in male and female Blbp-cre::Ctnnb1(ex3)fl/wt mice in our hands, including a thinned cerebral cortex, hydrocephalus, missing cerebellar layering, and cell accumulations in the brain stem and cerebellum. An additional loss of SMARCA4 even resulted in prenatal death for most mice. Respective Blbp-cre::Ctnnb1(ex3)fl/wt::Smarca4fl/rec mutants (male and female) developed large proliferative lesions in the cerebellum evolving from E13.5 to E16.5. Histological and molecular analysis of these lesions by DNA methylation profiling and single-cell RNA sequencing suggested an origin in early undifferentiated SOX2-positive cerebellar progenitors. Furthermore, upregulated WNT signaling, altered actin/cytoskeleton organization, and reduced neuronal differentiation were evident in mutant cells. In vitro, cells harboring alterations in both Ctnnb1 and Smarca4 were negatively selected and did not show tumorigenic potential after transplantation in adult female recipient mice. However, in cerebellar explant cultures, mutant cells displayed significantly increased proliferation, suggesting an important role of the embryonic microenvironment in the development of lesions. Altogether, these results represent an important first step towards the unravelling of tumorigenic mechanisms induced by aberrant WNT signaling and SMARCA4 deficiency.Significance Statement Our study shows cooperative effects between activated Wingless/Int-1 (WNT) signaling induced by a stabilizing β-catenin mutation and a loss of chromatin remodeler SMARCA4 in driving the development of highly proliferative cerebellar lesions. This observation could have important implications for WNT medulloblastoma patients, who are frequently affected by both alterations with the functional role of SMARCA4 mutations in tumorigenesis not deciphered so far. Additionally, this work highlights divergence of mouse phenotypes after brain-specific activation of WNT signaling from previously published studies and proposes potential reasons for varying recombination using the brain lipid binding protein (Blbp)-cre mouse strain.

Most patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative resection relapse within months, often with liver metastases. The hepatic microenvironment determines induction and reversal of dormancy during metastasis. Both tumor growth and metastasis depend on the Tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). This study investigated the interplay of TRAIL-R2 and the hepatic microenvironment in liver metastases formation and the impact of surgical resection. Although TRAIL-R2-knockdown (PancTu-I shTR2) decreased local relapses and number of macroscopic liver metastases after primary tumor resection in an orthotopic PDAC model, the number of micrometastases was increased. Moreover, abdominal surgery induced liver inflammation involving activation of hepatic stellate cells (HSCs) into hepatic myofibroblasts (HMFs). In coculture with HSCs, proliferation of PancTu-I shTR2 cells was significantly lower compared to PancTu-I shCtrl cells, an effect still observed after switching coculture from HSC to HMF, mimicking surgery-mediated liver inflammation and enhancing cell proliferation. CXCL-8/IL-8 blockade diminished HSC-mediated growth inhibition in PancTu-I shTR2 cells, while Vascular Endothelial Growth Factor (VEGF) neutralization decreased HMF-mediated proliferation. Overall, this study points to an important role of TRAIL-R2 in PDAC cells in the interplay with the hepatic microenvironment during metastasis. Resection of primary PDAC seems to induce liver inflammation, which might contribute to outgrowth of liver metastases.

StudyPortal was implemented as the first multilingual search platform for geographic visualization of clinical trials and scientific articles. The platform queries information from ClinicalTrials.gov, PubMed, a geodatabase and geographic maps to enable geospatial study search and real-time rendering of study locations or research networks on a map. Thus, disease-specific clinical studies or whole research networks can be shown in a geographic proximity. Moreover, a semantic layer enables multilingual disease input and autosuggestion of medical terms based on the Unified Medical Language System. The portal is accessible on https://studyportal.uni-muenster.de. This paper presents details on implementation of the novel search platform, its search evaluation and future work.

Screening for eligible patients continues to pose a great challenge for many clinical trials. This has led to a rapidly growing interest in standardizing computable representations of eligibility criteria (EC) in order to develop tools that leverage data from electronic health record (EHR) systems. Although laboratory procedures (LP) represent a common entity of EC that is readily available and retrievable from EHR systems, there is a lack of interoperable data models for this entity of EC. A public, specialized data model that utilizes international, widely-adopted terminology for LP, e.g. Logical Observation Identifiers Names and Codes (LOINC®), is much needed to support automated screening tools.

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or -KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.