Bioimage analysis of fluorescent labels is widely used in the life sciences. Recent advances in deep learning (DL) allow automating time-consuming manual image analysis processes based on annotated training data. However, manual annotation of fluorescent features with a low signal-to-noise ratio is somewhat subjective. Training DL models on subjective annotations may be instable or yield biased models. In turn, these models may be unable to reliably detect biological effects. An analysis pipeline integrating data annotation, ground truth estimation, and model training can mitigate this risk. To evaluate this integrated process, we compared different DL-based analysis approaches. With data from two model organisms (mice, zebrafish) and five laboratories, we show that ground truth estimation from multiple human annotators helps to establish objectivity in fluorescent feature annotations. Furthermore, ensembles of multiple models trained on the estimated ground truth establish reliability and validity. Our research provides guidelines for reproducible DL-based bioimage analyses.
Centrocytic lymphoma, or mantle cell lymphoma (MCL), is characterized by a chromosomal translocation t(11;14) (q13;q32) involving the bcl-1 locus on chromosome 11. Cyclin D1 is a cell-cycle regulatory protein essential for G1-S transition and has been identified as a potential transforming gene affected by the translocation. In this study, 32 cases of MCL were analysed for the bcl-1 rearrangement and cyclin D1 protein expression. In 17 cases, a rearrangement at the major translocation cluster of bcl-1 could be detected. Twenty-four cases exhibited nuclear cyclin D1 expression that was not detectable in other B-cell lymphomas (n = 40) or in normal B-cells. In nine MCL samples, cyclin D1 was expressed without a detectable bcl-1 rearrangement. The detection of a t(11;14) by means of classical cytogenetics in one of these cases, however, may suggest that this discrepancy could be due to chromosomal breakages outside the typical translocation cluster region. In two cases, a bcl-1 rearrangement was not accompanied by cyclin D1 expression. This study provides further evidence that cyclin D1 is involved in the pathogenesis of MCL and can be exploited as a diagnostic marker in the differential diagnosis of B-cell lymphomas and in the identification of MCL.
Centrocytic lymphoma, or mantle cell lymphoma (MCL), is characterized by a chromosomal translocation t(11;14) (q13;q32) involving the bcl‐1 locus on chromosome 11. Cyclin D1 is a cell‐cycle regulatory protein essential for G1–S transition and has been identified as a potential transforming gene affected by the translocation. In this study, 32 cases of MCL were analysed for the bcl‐1 rearrangement and cyclin D1 protein expression. In 17 cases, a rearrangement at the major translocation cluster of bcl‐1 could be detected. Twenty‐four cases exhibited nuclear cyclin D1 expression that was not detectable in other B‐cell lymphomas (n=40) or in normal B‐cells. In nine MCL samples, cyclin D1 was expressed without a detectable bcl‐1 rearrangement. The detection of a t(11;14) by means of classical cytogenetics in one of these cases, however, may suggest that this discrepancy could be due to chromosomal breakages outside the typical translocation cluster region. In two cases, a bcl‐1 rearrangement was not accompanied by cyclin D1 expression. This study provides further evidence that cyclin D1 is involved in the pathogenesis of MCL and can be exploited as a diagnostic marker in the differential diagnosis of B‐cell lymphomas and in the identification of MCL.
The cell cycle regulatory protein cyclin D1 is essential for G1-S phase transition in several epithelial and mesenchymal tissues but is apparently not essential in normal mature B cells. An overexpression of cyclin D1 is induced by the chromosomal translocation t(11; 14)(q13; q32), which characterizes non-Hodgkin's lymphomas (NHLs) of mantle cell type. We studied 26 cases of mantle cell lymphoma (MCL) for the expression of cyclins D1 and D3. A total of 23 lymphomas showed a nuclear staining for cyclin D1, whereas reactive B cells of residual germinal centers were constantly negative. When compared with cyclin D3, an inverse staining pattern emerged. Whereas the B cells of residual germinal centers reacted strongly positive for cyclin D3, there was low or missing expression of cyclin D3 in MCL cells. In other B-cell lymphomas (n = 55), including chronic lymphocytic leukemia, low-grade lymphomas of mucosa-associated lymphatic tissue, follicular lymphomas, and diffuse large B-cell lymphomas, no cyclin D1 expression could be detected and 89% of these cases displayed cyclin D3 positivity. Lymphoma cell lines harboring the t(11; 14) showed cyclin D1 protein but no or very low levels of cyclin D3; three other B-cell lines, a T-cell line, and peripheral blood lymphocytes strongly expressed cyclin D3 and reacted negatively for cyclin D1. We conclude that the chromosomal translocation t(11; 14) leads to an abnormal protein expression of cyclin D1 in the tumor cells of MCL and induces a consecutive downregulation of cyclin D3. In contrast to other B-NHLs, cyclin D1 and D3 expression in MCL is not related to the growth fraction.
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