Notes

Bilateral paracentral severe midsection maculopathy and also severe macular neuroretinopathy right after COVID-19 vaccine.
AIMS A Delphi study to triangulate and determine the relative importance of the key qualities of trainees identified from qualitative interviews that sought to understand how consultant histopathologists determine diagnostic competences in trainees. METHODS Twelve participants were purposively chosen for the Delphi to form an expert panel of relevant stakeholders. Participants were asked to score and rank the items presented to them. RESULTS A total of 22 out of 27 of the key qualities of trainees (items) reached 'consensus in' after round 2 suggesting participants were able to agree that the majority of the items identified in the qualitative interviews were important to diagnostic competence. Five items reached 'no consensus'. Participants did not suggest any additional items. Participants particularly valued qualities of reflection and professionalism and trainees who understood the process of reaching a diagnosis and how their pathological report could impact on patient care. CONCLUSIONS This study has triangulated findings from our qualitative interviews and show that consultants value a wide variety of qualities when determining diagnostic competence in their trainees. The judgement is complex and is therefore best assessed longitudinally and on a number of cases, so consultants can look for consistency of both approach to diagnosis and of trainee behaviour. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.AIMS Histological grade is widely used to guide the management of invasive breast cancer (IBC). Yet, substantial interlaboratory and intralaboratory grading variations exist in daily pathology practice. To create awareness and to facilitate quality improvement, feedback reports, containing case-mix-adjusted laboratory-specific grades benchmarked against other laboratories, were sent to the individual laboratories by 1 March 2018. We studied the effect of these feedback reports on interlaboratory grading variation up till 1 year later. METHODS Overall, 17 102 synoptic pathology reports of IBC resection specimens from 33 laboratories, obtained between 1 March 2017 and 1 March 2019 were retrieved from the Dutch Pathology Registry (PALGA). An overall deviation score (ODS), representing the sum of deviations from the grade-specific overall proportions, was calculated to compare the absolute deviation for all grades at once. Case-mix correction was performed by two multivariable logistic regression analyses, providing laboratory-specific ORs for high-grade versus low-grade IBC. RESULTS After feedback, the overall range between laboratories decreased by 3.8%, 6.4% and 6.6% for grades I, II and III, respectively. Though the mean ODS remained similar (13.8% vs 13.7%), the maximum ODS decreased from 34.1% to 29.4%. The range of laboratory-specific ORs decreased by 21.9% for grade III versus grades I-II. CONCLUSIONS An encouraging decrease in grading variation of IBC was observed after laboratory-specific feedback. Nevertheless, the overall grading variation remains substantial. In view of the important role of grading in patient management, it is adamant that not only feedback should be provided on a regular basis but also other interventions, such as additional training, are required. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Iron regulatory protein 2 (IRP2) is a key regulator of iron homeostasis and is found to be altered in several types of human cancer. However, how IRP2 contributes to tumorigenesis remains to be elucidated. In this study, we sought to investigate the role of IRP2 in tumorigenesis and found that IRP2 promotes cell growth by repressing TAp63, a member of p53 tumor suppressor family. Specifically, we found that IRP2 overexpression decreased, whereas IRP2 deficiency increased, TAp63 expression. We also showed that the repression of TAp63 by IRP2 was independent of tumor suppressor p53. To uncover the molecular basis, we found that IRP2 stabilized TAp63 mRNA by binding to an iron response element in the 3'UTR of p63 mRNA. To determine the biological significance of this regulation, we showed that IRP2 facilitates cell proliferation at least in part via repressing TAp63 expression. Moreover, we found that IRP2 deficiency markedly alleviated cellular senescence in TAp63-deficient mouse embryo fibroblasts. Chaetocin molecular weight Together, we have uncovered a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities at least in part by repressing TAp63 expression. Implications We have revealed a novel regulation of TAp63 by IRP2 and our data suggest that IRP2 exerts its oncogenic activities at least in part by repressing TAp63 expression. Copyright ©2020, American Association for Cancer Research.In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition (EMT) and MAPK signaling. These data indicate that TERTp mutants are likely to generate distinctive tumor microenvironments and intercellular interactions. Analysis of high throughput screening tests of 546 small molecules on cell line growth indicated that TERTp mutants displayed heightened sensitivity to specific drugs, including RAS pathway inhibitors, and we found that inhibition of MEK1 and 2, key RAS/MAPK-pathway effectors, inhibited TERT mRNA expression. Consistent with an enrichment of mesenchymal states in TERTp mutants, cell lines and some patient tumors displayed low expression of the central adherens junction protein E-cadherin, and we provide evidence that its expression in these cells is regulated by MEK1/2. Several mesenchymal transcription factors displayed elevated expression in TERTp mutants including ZEB1 and 2, TWIST1 and 2 and SNAI1. Of note, the developmental transcription factor SNAI2/SLUG was conspicuously elevated in a significant majority of TERTp mutant cell lines, and knock-down experiments suggest that it promotes TERT expression. Implications Cancers harboring TERT promoter mutations are often more lethal, but the basis for this higher mortality remains unknown. Our study identifies that TERTp mutants, as a class, associate with a distinct gene and protein expression signature likely to impact their biological and clinical behavior and provide new directions for investigating treatment approaches for these cancers. Copyright ©2020, American Association for Cancer Research.
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