Widely used as anti-cancer and immunosuppressive agents, thiopurines have narrow therapeutic indices due to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and its clinical implications remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore, and Japan, we identified 4 NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, p.Val18_Val19insGlyVal) that resulted in 74.4%–100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across three cohorts (P=0.021, 2.1×10−5, and 0.0054, respectively; meta-analysis P=4.45×10−8, allelic effect size=−11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased its cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive thiopurine active metabolites and toxicity. Taken together, our results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
Versatile devices, especially tunable ones, for terahertz imaging, sensing and high-speed communication, are in high demand. Liquid crystal based components are perfect candidates in the optical range; however, they encounter significant challenges in the terahertz band, particularly the lack of highly transparent electrodes and the drawbacks induced by a thick cell. Here, a strategy to overcome all these challenges is proposed: Few-layer porous graphene is employed as an electrode with a transmittance of more than 98%. A subwavelength metal wire grid is utilized as an integrated high-efficiency electrode and polarizer. The homogeneous alignment of a high-birefringence liquid crystal is implemented on both frail electrodes via a non-contact photo-alignment technique. A tunable terahertz waveplate is thus obtained. Its polarization evolution is directly demonstrated. Furthermore, quarter-wave plates that are electrically controllable over the entire testing range are achieved by stacking two cells. The proposed solution may pave a simple and bright road toward the development of various liquid crystal terahertz apparatuses.
Intraductal meibomian gland probing demonstrated significant efficacy in symptom relief and tear film stabilization. Probing helped release accumulated meibum and could help increase the accessibility of diseased meibomian glands to topical corticosteroids.
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