As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
Growth retardation is a significant adverse effect of imatinib in children with CML. The failure to gain appropriate height was most discernible when imatinib was initiated in the prepubertal period. Etiology and remedial measures need to be investigated.
The predicted spontaneous remission rate with chronic ITP was 30% and 44% at 5 and 10 years, respectively. Platelet count at diagnosis and the treatment administered did not influence remission outcomes. Age <8 years and female gender were predictors of a favorable outcome.
A child's appropriate development stems in large part from proper nutrition. Malnutrition is an adverse prognostic factor in children with cancer, and its prevalence is highly variable. Currently, there is no standardized definition and assessment method of nutritional status in pediatric oncology. A complete nutritional assessment includes anthropometry, biochemical, clinical, and dietary assessments. In this article, we explore these methods and suggest practical approaches for pediatric cancer units depending on the levels of care that these can provide. We also advise on the monitoring and follow‐up of children with cancer during and after treatment, and discuss potential areas for future research.
Families spend up to seven times their monthly income over a period of 1 month on an unforeseen illness. Despite financial aid from various sources, nonmedical costs amount to nearly 2.5 times the average per capita income. Universal health insurance is the need of the hour.
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