Publications (21) View all
-
Article: Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies?
[show abstract] [hide abstract]
ABSTRACT: Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.The Pharmacogenomics Journal advance online publication, 26 June 2012; doi:10.1038/tpj.2012.26.The Pharmacogenomics Journal 06/2012; · 4.54 Impact Factor -
Article: Reactive oxygen species initiate luminal but not basal cell death in cultured human mammary alveolar structures: a potential regulator of involution.
[show abstract] [hide abstract]
ABSTRACT: Post-lactational involution of the mammary gland is initiated within days of weaning. Clearing of cells occurs by apoptosis of the milk-secreting luminal cells in the alveoli and through stromal tissue remodeling to return the gland almost completely to its pre-pregnant state. The pathways that specifically target involution of the luminal cells in the alveoli but not the basal and ductal cells are poorly understood. In this study we show in cultured human mammary alveolar structures that the involution process is initiated by fresh media withdrawal, and is characterized by cellular oxidative stress, expression of activated macrophage marker CD68 and finally complete clearing of the luminal but not basal epithelial layer. This process can be simulated by ectopic addition of reactive oxygen species (ROS) in cultures without media withdrawal. Cells isolated from post-involution alveoli were enriched for the CD49f(+) mammary stem cell (MaSC) phenotype and were able to reproduce a complete alveolar structure in subcultures without any significant loss in viability. We propose that the ROS produced by accumulated milk breakdown post-weaning may be the mechanism underlying the selective involution of secretory alveolar luminal cells, and that our culture model represents an useful means to investigate this and other mechanisms further.Cell Death & Disease 01/2011; 2:e189. · 5.33 Impact Factor -
Article: International network of cancer genome projects
[show abstract] [hide abstract]
ABSTRACT: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.Nature 04/2010; 464:993-998. · 36.28 Impact Factor -
Article: Genomic databases access agreements: legal validity and possible sanctions.
[show abstract] [hide abstract]
ABSTRACT: Large-scale, public genomic databases have greatly improved the capacity of researchers to do genomic research. In order to ensure that the scientific community uses data from these public resources properly, data access agreements have been developed to complement already existing legal and ethical norms. Sanctions to address cases of data misuse constitute an essential part of this compliance framework meant to protect stakeholders in genomic research. Yet very little research and community debate has been done on this most important topic. This paper presents a review of different sanctions that could be invoked in cases of non-compliance from data users. They have been identified through comprehensive research and analysis of over 450 documents (journal articles, policy, guidelines, access policies, etc.) related to this topic. Given the considerable impact on users of even the milder sanctions considered in our paper, it is essential that stakeholders strive to achieve the highest degree of standardization and transparency when designing controlled-access agreements. It is only fair, after all, that users be able to expect that the border between acceptable and unacceptable conduct is clearly delineated and predictable in controlled-access policies. This suggests the importance for researchers to undertake additional empirical studies on the clarity and accessibility of existing database access agreements and related policies in the near future.Human Genetics 06/2011; 130(3):441-9. · 5.07 Impact Factor -
Article: International network of cancer genome projects
[show abstract] [hide abstract]
ABSTRACT: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.Nature 04/2010; 464:993-8. · 36.28 Impact Factor
