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  • Identification of stable housekeeping genes for induced pluripotent stem cells and -derived endothelial cells for drug testing. Scientific reports Ong, S. L., Baelde, H. J., van IJzendoorn, D. G., BovĂ©e, J. V., Szuhai, K. 2022; 12 (1): 16160

    Abstract

    There are no validated housekeeping genes in induced pluripotent stem cells (iPSC) and derived endothelial iPSC (iPSC-EC). Thus a comparison of gene expression levels is less reliable, especially during drug treatments. Here, we utilized transcriptome sequencing data of iPSC and iPSC-EC with or without CRISPR-Cas9 induced translocation to identify a panel of 15 candidate housekeeping genes. For comparison, five commonly used housekeeping genes (B2M, GAPDH, GUSB, HMBS, and HPRT1) were included in the study. The panel of 20 candidate genes were investigated for their stability as reference genes. This panel was analyzed and ranked based on stability using five algorithms, delta-Ct, bestkeeper, geNorm, Normfinder, and Reffinder. Based on the comprehensive ranking of Reffinder, the stability of the top two genes-RPL36AL and TMBIM6, and the bottom two genes-UBA1 and B2M, were further studied in iPSC-EC with and without genetic manipulation, and after treatment with telatinib. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), it was shown that gene expression of the top two housekeeping genes, RPL36AL and TMBIM6, remained stable during drug treatment. We identified a panel of housekeeping genes that could be utilized in various conditions using iPSC and iPSC-derived endothelial cells as well as genetically modified iPSC for drug treatment.

    View details for DOI 10.1038/s41598-022-20435-w

    View details for PubMedID 36171445

    View details for PubMedCentralID PMC9519970

  • Interactions in CSF1-driven Tenosynovial Giant Cell Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research van IJzendoorn, D. G., Matusiak, M., Charville, G. W., Spierenburg, G., Varma, S., Colburg, D. R., van de Sande, M. A., van Langevelde, K., Mohler, D. G., Ganjoo, K. N., Bui, N. Q., Avedian, R. S., Bovee, J. V., Steffner, R., West, R. B., van de Rijn, M. 2022

    Abstract

    A major component of cells in Tenosynovial Giant Cell Tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here we use single cell RNA sequencing to investigate cellular interactions in TGCT.A total of 18,788 single cells from three TGCT and two Giant Cell Tumor of Bone (GCTB) samples underwent singe cell RNAseq. The three TGCTs were additionally analyzed using long read RNA sequencing. Immunofluorescence and immunohistochemistry for a range of markers was used to validate and extend the scRNAseq findings.Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to non-neoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping features between the giant cells in TGCT and GCTB.The neoplastic cells in TGCT are highly similar non-neoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the PDGF receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

    View details for DOI 10.1158/1078-0432.CCR-22-1898

    View details for PubMedID 36007098

  • Juvenile Psammomatoid Ossifying Fibroma is Defined by SATB2 Rearrangement Cleven, A., Szuhai, K., van IJzendoorn, D., Groen, E., Baelde, H., Schreuder, P., Briaire-de Bruijn, I., Genders, S., Kleijwegt, M., Kroon, H., Suurmeijer, A., Savci-Heijink, D., Baumhoer, D., Bovee, J. SPRINGERNATURE. 2022: 866
  • Juvenile Psammomatoid Ossifying Fibroma is Defined by SATB2 Rearrangement Cleven, A., Szuhai, K., van IJzendoorn, D., Groen, E., Baelde, H., Schreuder, P., Bruijn, I., Genders, S., Kleijwegt, M., Kroon, H., Suurmeijer, A., Savci-Heijink, D., Baumhoer, D., Bovee, J. SPRINGERNATURE. 2022: 866
  • Analysis of 567,758 randomized controlled trials published over 30 years reveals trends in phrases used to discuss results that do not reach statistical significance. PLoS biology Otte, W. M., Vinkers, C. H., Habets, P. C., van IJzendoorn, D. G., Tijdink, J. K. 2022; 20 (2): e3001562

    Abstract

    The power of language to modify the reader's perception of interpreting biomedical results cannot be underestimated. Misreporting and misinterpretation are pressing problems in randomized controlled trials (RCT) output. This may be partially related to the statistical significance paradigm used in clinical trials centered around a P value below 0.05 cutoff. Strict use of this P value may lead to strategies of clinical researchers to describe their clinical results with P values approaching but not reaching the threshold to be "almost significant." The question is how phrases expressing nonsignificant results have been reported in RCTs over the past 30 years. To this end, we conducted a quantitative analysis of English full texts containing 567,758 RCTs recorded in PubMed between 1990 and 2020 (81.5% of all published RCTs in PubMed). We determined the exact presence of 505 predefined phrases denoting results that approach but do not cross the line of formal statistical significance (P < 0.05). We modeled temporal trends in phrase data with Bayesian linear regression. Evidence for temporal change was obtained through Bayes factor (BF) analysis. In a randomly sampled subset, the associated P values were manually extracted. We identified 61,741 phrases in 49,134 RCTs indicating almost significant results (8.65%; 95% confidence interval (CI): 8.58% to 8.73%). The overall prevalence of these phrases remained stable over time, with the most prevalent phrases being "marginally significant" (in 7,735 RCTs), "all but significant" (7,015), "a nonsignificant trend" (3,442), "failed to reach statistical significance" (2,578), and "a strong trend" (1,700). The strongest evidence for an increased temporal prevalence was found for "a numerical trend," "a positive trend," "an increasing trend," and "nominally significant." In contrast, the phrases "all but significant," "approaches statistical significance," "did not quite reach statistical significance," "difference was apparent," "failed to reach statistical significance," and "not quite significant" decreased over time. In a random sampled subset of 29,000 phrases, the manually identified and corresponding 11,926 P values, 68,1% ranged between 0.05 and 0.15 (CI: 67. to 69.0; median 0.06). Our results show that RCT reports regularly contain specific phrases describing marginally nonsignificant results to report P values close to but above the dominant 0.05 cutoff. The fact that the prevalence of the phrases remained stable over time indicates that this practice of broadly interpreting P values close to a predefined threshold remains prevalent. To enhance responsible and transparent interpretation of RCT results, researchers, clinicians, reviewers, and editors may reduce the focus on formal statistical significance thresholds and stimulate reporting of P values with corresponding effect sizes and CIs and focus on the clinical relevance of the statistical difference found in RCTs.

    View details for DOI 10.1371/journal.pbio.3001562

    View details for PubMedID 35180228