Clinical Utility of Copy Number Abnormality Analysis in the Evaluation of Melanocytic Lesions for Diagnosis and Prognosis: An Evidence-Based Review from the Cancer Genomics Consortium Working Group for Melanocytic Lesions
Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Abstract Hypoxia‐induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF‐κB pathway through the NF‐κB transcription‐activating group P65 by phosphorylation and nuclear translocation. NF‐κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia‐induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF‐κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF‐1α/HE4/NF‐κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia‐induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.
Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation
Key Points We conducted the first exome-wide association study between germ line variant genotype and survival outcomes after unrelated-donor BMT. A number of novel genes were found to significantly affect survival outcomes.