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.
Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of ...benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).
We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.
Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval CI, 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .).
Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut
Stable isotope analysis is a powerful tool for assessing plant carbon and water relations and their impact on biogeochemical processes at different scales. Our process-based understanding of stable ...isotope signals, as well as technological developments, has progressed significantly, opening new frontiers in ecological and interdisciplinary research. This has promoted the broad utilisation of carbon, oxygen and hydrogen isotope applications to gain insight into plant carbon and water cycling and their interaction with the atmosphere and pedosphere. Here, we highlight specific areas of recent progress and new research challenges in plant carbon and water relations, using selected examples covering scales from the leaf to the regional scale. Further, we discuss strengths and limitations of recent technological developments and approaches and highlight new opportunities arising from unprecedented temporal and spatial resolution of stable isotope measurements.
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
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature ...and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).
Permafrost soils in boreal and Arctic ecosystems store almost twice as much carbon as is currently present in the atmosphere. Permafrost thaw and the microbial decomposition of previously frozen ...organic carbon is considered one of the most likely positive climate feedbacks from terrestrial ecosystems to the atmosphere in a warmer world. The rate of carbon release from permafrost soils is highly uncertain, but it is crucial for predicting the strength and timing of this carbon-cycle feedback effect, and thus how important permafrost thaw will be for climate change this century and beyond. Sustained transfers of carbon to the atmosphere that could cause a significant positive feedback to climate change must come from old carbon, which forms the bulk of the permafrost carbon pool that accumulated over thousands of years. Here we measure net ecosystem carbon exchange and the radiocarbon age of ecosystem respiration in a tundra landscape undergoing permafrost thaw to determine the influence of old carbon loss on ecosystem carbon balance. We find that areas that thawed over the past 15 years had 40 per cent more annual losses of old carbon than minimally thawed areas, but had overall net ecosystem carbon uptake as increased plant growth offset these losses. In contrast, areas that thawed decades earlier lost even more old carbon, a 78 per cent increase over minimally thawed areas; this old carbon loss contributed to overall net ecosystem carbon release despite increased plant growth. Our data document significant losses of soil carbon with permafrost thaw that, over decadal timescales, overwhelms increased plant carbon uptake at rates that could make permafrost a large biospheric carbon source in a warmer world.
Some patients with idiopathic pulmonary fibrosis experience acute exacerbations in their respiratory status leading to substantial morbidity and mortality. Occult aspiration of gastric contents has ...been proposed as one possible mechanism leading to these acute exacerbations. We sought to determine whether pepsin, a marker of gastric aspiration, is elevated in bronchoalveolar lavage fluid obtained from patients during acute exacerbation of idiopathic pulmonary fibrosis, compared with that obtained in stable disease. Lavage samples were obtained in a case-control study of well-characterised patients. Acute exacerbation was defined using standard criteria. Levels of lavage pepsin were compared in cases and controls, and were correlated with clinical features and disease course. 24 cases with acute exacerbations and 30 stable controls were identified. There were no significant differences in baseline demographics between the two groups. Pepsin level was an indicator of acute exacerbation status (p=0.04). On average, pepsin appeared higher in patients with acute exacerbations compared with stable controls. This difference was driven by a subgroup of eight patients (33%) with pepsin levels ≥70 ng·mL(-1). Pepsin level was not an independent predictor of survival time. These results suggest occult aspiration may play a role in some cases of acute exacerbation of idiopathic pulmonary fibrosis.
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
Vascular endothelial cells (ECs) are constantly exposed to blood flow-induced shear stress. Our previous study demonstrated that disturbed flow with low and oscillatory shear stress (OSS) induces ...bone morphogenetic protein receptor (BMPR)-specific Smad1/5 activation in ECs, but the underlying mechanisms and the in vivo functional role of Smad1/5 remain unclear.
Here we elucidated the molecular mechanisms by which OSS activates EC Smad1/5 and its in vivo functional role.
Lentiviral Smad5-specific short hairpin RNA (Lenti-shSmad5) was constructed and intra-arterially injected into the lumen of stenosed abdominal aorta in bromodeoxyuridine-infused rats. Co-immunoprecipitation and in situ proximity ligation assays were performed on ECs exposed to OSS (0.5 ± 4 dynes/cm(2) ) in a parallel-plate flow chamber to investigate BMPR-integrin interactions and their regulatory role in OSS-activation of EC Smad1/5.
Intra-arterial administration of Lenti-shSmad5 inhibited bromodeoxyuridine uptake of ECs at post-stenotic sites, where disturbed flow with OSS occurs. OSS induced sustained BMPRIB-αv β3 integrin association in ECs, which was mediated by the intracytoplasmic kinase domain of BMPRII and subsequently activated the Shc/focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) cascade, leading to Smad1/5 activation. This OSS-activation of Smad1/5 induced its association with and activation of runt-related transcription factor-2 (Runx2), leading to activations of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K), a pathway critical for EC proliferation in response to OSS.
Oscillatory shear stress induces synergistic interactions between specific BMPRs and integrin to activate Smad1/5 through the Shc/FAK/ERK pathway, which leads to the activation of the Runx2/mTOR/p70S6K pathway to promote EC proliferation.
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