14 research outputs found
Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK‐8 in the pithed rat
No full textGenetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors
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No Evidence for Drug-Specific Activation of Circulating T Cells from Patients with HLA-DRB1∗07:01-Restricted Lapatinib-Induced Liver Injury
No full textIt is hypothesized that lapatinib-induced liver injury is caused by HLA-mediated antigen presentation to CD4 positive T cells. However, analysis of PBMC and cloned T-cells from patients with HLA-DRB1∗07:01-restricted lapatinib-induced liver injury revealed no evidence for drug-specific activation. T cells were exposed to lapatinib, the M11 aldehyde, and quinone imine [oxidized form of hydroquinone amine M1] metabolites. Reactivity of the quinone imine was confirmed by mass spectrometry
HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
No full textPURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs. PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients. RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively. CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment
Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma
No full textBoys of England and Edwin J. Brett, 1866-99
No full textBoys of England was a Victorian boys' periodical. It was published weekly by Edwin J. Brett from 1866 to 1899, initially from the Fleet Street offices of the Newsagents'
Publishing Company, and later from Brett's own `Boys of England Office'. It was the first periodical of its kind, and achieved a large sale amongst eager youngsters.
The purpose of this thesis is to provide a general history of BOE and Brett, neither of which has yet been attempted. More specifically, the thesis is intended to address
misconceptions regarding Brett and his work. Historians of boys' periodical literature have tended to portray Brett's papers as largely supportive of middle class hegemony. They
argue that they failed to connect with the lives of their upper working and lower middle class readers. However, this thesis contends that in actual fact BOE engaged closely with
the lives of its readership, comprised mainly of boys from the `respectable' working classes. Therefore, BOE should rightly be considered an important, indigenous component
of working class society and culture in mid to late Victorian Britain.
To provide as comprehensive an analysis as possible, the thesis is divided into three sections: `Paper and Proprietor'; `Content'; `Response'. These sections are divided into further chapters, each exploring a salient facet of BOE and Brett. Some of these engage with, and challenge, the existing historiography of boys' periodical literature. Others introduce historiographies previously remote from the study of boys' papers, widening the
remit of this relatively self-contained field. Some examine entirely unstudied, or largely understudied, subject matter.
Ultimately, this thesis is intended to make a valuable contribution not only to the historiography of boys' papers specifically, and children's literature in general, but also to the wider historiographies of Victorian social and cultural history and the Victorian working class
Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes.
No full textPURPOSE: Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. PATIENTS AND METHODS: Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. RESULTS: Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%). CONCLUSION: Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue
A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.
No full textWe present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity
New approaches to investigate drug-induced hypersensitivity
No full textThe workshop on "New Approaches to Investigate Drug-Induced Hypersensitivity" was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development. This perspective reviews the clinical and immunological bases of drug hypersensitivity and summarizes various experts' views on the different topics covered during the meeting
