Pharmacogenomics in the clinic Relling, Mary V; Evans, William E
Nature (London),
10/2015, Letnik:
526, Številka:
7573
Journal Article
Recenzirano
Odprti dostop
After decades of discovery, inherited variations have been identified in approximately 20 genes that affect about 80 medications and are actionable in the clinic. And some somatically acquired ...genetic variants direct the choice of 'targeted' anticancer drugs for individual patients. Current efforts that focus on the processes required to appropriately act on pharmacogenomic variability in the clinic are moving away from discovery and towards implementation of an evidenced-based strategy for improving the use of medications, thereby providing a cornerstone for precision medicine.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced ...pharmacologic effects of thiopurines. Loss‐of‐function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).
The 50th anniversary of Seminars in Hematology coincides with the 50th anniversary of St. Jude Children's Research Hospital, and both milestones are inexorably linked to studies contributing to the ...cure of childhood acute lymphoblastic leukemia (ALL). We thought it fitting, therefore, to mark these events by traveling back in time to point out some of the achievements, institutions, study groups, and individuals that have made cure of childhood ALL a reality. In many instances, progress was driven by new ideas, while in others it was driven by new experimental tools that allowed more precise assessment of the biology of leukemic blasts and their utility in selecting therapy. We also discuss a number of contemporary advances that point the way to exciting future directions. Whatever pathways are taken, a clear challenge will be to use emerging genome-based or immunologic-based treatment options in ways that will enhance, rather than duplicate or compromise, recent gains in outcome with classic cytotoxic chemotherapy. The theme of this journey serves as a reminder of the chief ingredient of any research directed to a catastrophic disease such as ALL. It is the audacity of a small group of investigators who confronted a childhood cancer with the goal of cure, not palliation, as their mindset.
Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to ...clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.
Retrieving high-content gene-expression information while retaining three-dimensional (3D) positional anatomy at cellular resolution has been difficult, limiting integrative understanding of ...structure and function in complex biological tissues. We developed and applied a technology for 3D intact-tissue RNA sequencing, termed STARmap (spatially-resolved transcript amplicon readout mapping), which integrates hydrogel-tissue chemistry, targeted signal amplification, and in situ sequencing. The capabilities of STARmap were tested by mapping 160 to 1020 genes simultaneously in sections of mouse brain at single-cell resolution with high efficiency, accuracy, and reproducibility. Moving to thick tissue blocks, we observed a molecularly defined gradient distribution of excitatory-neuron subtypes across cubic millimeter-scale volumes (>30,000 cells) and a short-range 3D self-clustering in many inhibitory-neuron subtypes that could be identified and described with 3D STARmap.
Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of ...triple intrathecal therapy would improve systemic and CNS control.
Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m
versus the conventional 2,500 U/m
. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.
The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6;
= . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% 95% CI, 0.4% to 3.3%
5.7% 95% CI, 2.8% to 8.6%;
= .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.
Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
Despite their highly anisotropic complex-oxidic nature, certain delafossite compounds (e.g., PdCoO
, PtCoO
) are the most conductive oxides known, for reasons that remain poorly understood. Their ...room-temperature conductivity can exceed that of Au, while their low-temperature electronic mean-free-paths reach an astonishing 20 μm. It is widely accepted that these materials must be ultrapure to achieve this, although the methods for their growth (which produce only small crystals) are not typically capable of such. Here, we report a different approach to PdCoO
crystal growth, using chemical vapor transport methods to achieve order-of-magnitude gains in size, the highest structural qualities yet reported, and record residual resistivity ratios ( > 440). Nevertheless, detailed mass spectrometry measurements on these materials reveal that they are not ultrapure in a general sense, typically harboring 100s-of-parts-per-million impurity levels. Through quantitative crystal-chemical analyses, we resolve this apparent dichotomy, showing that the vast majority of impurities are forced to reside in the Co-O octahedral layers, leaving the conductive Pd sheets highly pure (∼1 ppm impurity concentrations). These purities are shown to be in quantitative agreement with measured residual resistivities. We thus conclude that a sublattice purification mechanism is essential to the ultrahigh low-temperature conductivity and mean-free-path of metallic delafossites.
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