RESUMEN
A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
RESUMEN
BACKGROUND: Drug-induced liver injury (DILI) is a serious concern during drug development and the treatment of human disease. The ability to accurately predict DILI risk could yield significant improvements in drug attrition rates during drug development, in drug withdrawal rates, and in treatment outcomes. In this paper, we outline our approach to predicting DILI risk using gene-expression data from Build 02 of the Connectivity Map (CMap) as part of the 2018 Critical Assessment of Massive Data Analysis CMap Drug Safety Challenge. RESULTS: First, we used seven classification algorithms independently to predict DILI based on gene-expression values for two cell lines. Similar to what other challenge participants observed, none of these algorithms predicted liver injury on a consistent basis with high accuracy. In an attempt to improve accuracy, we aggregated predictions for six of the algorithms (excluding one that had performed exceptionally poorly) using a soft-voting method. This approach also failed to generalize well to the test set. We investigated alternative approaches-including a multi-sample normalization method, dimensionality-reduction techniques, a class-weighting scheme, and expanding the number of hyperparameter combinations used as inputs to the soft-voting method. We met limited success with each of these solutions. CONCLUSIONS: We conclude that alternative methods and/or datasets will be necessary to effectively predict DILI in patients based on RNA expression levels in cell lines. REVIEWERS: This article was reviewed by Pawel P Labaj and Aleksandra Gruca (both nominated by David P Kreil).
