This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically ...relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene–drug associations and genotype–phenotype relationships. Curators assign levels of evidence to variant–drug associations using well‐defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high‐quality information supporting personalized medicine–implementation projects.
Clinical Pharmacology & Therapeutics (2012); 92 4, 414–417. doi:10.1038/clpt.2012.96
•UV-C/H + E juice resulted enriched in polyphenol levels and antioxidant activity.•Native flora of UV-C/H + E juice was inhibited along 24 days of storage.•The proposed treatment preserved colour, ...pH, °Brix and turbidity along storage.•UV-C/H + E juice was labeled as a drink with intense herbal taste and aroma.•A group of consumers was interested in the bitter taste of the proposed blend.
Carrot-orange juice processed by UV-C (10.6 kJ/m2) assisted with mild heat (H, 50 °C) and yerba mate addition (E) was obtained. UV-C/H + E treated juice was examined for native flora, polyphenol content (PC), total antioxidant activity (TAA), colour, turbidity, °Brix and pH along storage (4 °C). Consumer profiling studies were performed. UV-C/H + E provoked 2.6–5.7 native flora log reductions, preventing from recovery during 24 day-storage. The UV-C/H + E juice exhibited a significant increase in PC (720.2 µg/mL) and TAA (5.5 mg/mL) compared to untreated (PC = 205.0 µg/mL/TAA = 0.7 mg/mL) and single treated juices (PC = 302.1–408.0 µg/mL/TAA = 0.7–2.4 mg/mL), remaining constant throughout storage. UV-C/H + E juice exhibited scarce changes in colour. Nevertheless, increases in °Brix and turbidity were observed compared to single treatments. A cluster sensory analysis revealed that one group showed a marked interest in UVC/H + E beverages with herbal taste and strong aroma. CATA question revealed that some improvements should be introduced in order to satisfy the consumers' ideally beverage.
Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 ...(CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.
Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159
The conserved yeast E3 ubiquitin ligase Bre1 and its partner, the E2 ubiquitin-conjugating enzyme Rad6, monoubiquitinate histone H2B across gene bodies during the transcription cycle
. Although ...processive ubiquitination might-in principle-arise from Bre1 and Rad6 travelling with RNA polymerase II
, the mechanism of H2B ubiquitination across genic nucleosomes remains unclear. Here we implicate liquid-liquid phase separation
as the underlying mechanism. Biochemical reconstitution shows that Bre1 binds the scaffold protein Lge1, which possesses an intrinsically disordered region that phase-separates via multivalent interactions. The resulting condensates comprise a core of Lge1 encapsulated by an outer catalytic shell of Bre1. This layered liquid recruits Rad6 and the nucleosomal substrate, which accelerates the ubiquitination of H2B. In vivo, the condensate-forming region of Lge1 is required to ubiquitinate H2B in gene bodies beyond the +1 nucleosome. Our data suggest that layered condensates of histone-modifying enzymes generate chromatin-associated 'reaction chambers', with augmented catalytic activity along gene bodies. Equivalent processes may occur in human cells, and cause neurological disease when impaired.
5-hydroxytryptamine type 3 (5-HT
3
) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting.
CYP2D6
polymorphisms can ...influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on
CYP2D6
genotype (updates at
www.pharmgkb.org
).
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the ...cytochrome P450–2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer–reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1
Clinical Pharmacology & Therapeutics (2011) 90 4, 625–629. doi:10.1038/clpt.2011.185
Understanding the climatic drivers of present-day agricultural yields is critical for prioritizing adaptation strategies to climate change. However, unpacking the contribution of different ...environmental stressors remains elusive in large-scale observational settings in part because of the lack of an extensive long-term network of soil moisture measurements and the common seasonal concurrence of droughts and heat waves. In this study, we link state-of-the-art land surface model data and fine-scale weather information with a long panel of county-level yields for six major US crops (1981-2017) to unpack their historical and future climatic drivers. To this end, we develop a statistical approach that flexibly characterizes the distinct intra-seasonal yield sensitivities to high-frequency fluctuations of soil moisture and temperature. In contrast with previous statistical evidence, we directly elicit an important role of water stress in explaining historical yields. However, our models project the direct effect of temperature-which we interpret as heat stress-remains the primary climatic driver of future yields under climate change.
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