Current Pharmacogenomics and Personalized Medicine - Volume 10, Issue 2, 2012

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Blended herbal medicines are used in China (traditional Chinese medicine, TCM), Japan (Kampo medicine) and many other countries around the world. Here, we critically examine the metabolomics studies to develop a systematic understanding of Kampo medicines based on multivariate analyses in the context of an integrated platform, combining current and traditional knowledge of blended herbal medicines with data-intensive -omics approaches. First, we examine - omics analyses of herbs used in Kampo medicine. Second, we focus on defining the connections underlying metabolites in blended herbal medicines with their physiological activities in humans. Third, we develop informatics methods to systematize the globalization of blended herbal medicines. Finally, we propose that systems biology approaches applied to an integrated platform of blended herbal medicine and -omics datasets allow for the systematization of current and traditional knowledge of herbal medicines such as Kampo, and importantly, for the application of this emerging body of knowledge to the development of new personalized drugs for complex human diseases, including those which are currently untreatable. To be sure, the current convergence of genomics and –omics approaches with traditional medicine in Asia-Pacific, whether in Japan or elsewhere in the region, is here to stay with us in the coming decade. We further underscore that this body of knowledge has significance not only in the Asia-Pacific but also in global public health as traditional Asian medicine is increasingly being used in tandem with western medicine throughout the world including in developed countries. If we are to truly reap the benefits of personalized medicine in an interconnected and global science, such broadening of the focus beyond small molecule drugs and from “lab to global society” is fundamentally significant.

Doping with testosterone is conventionally detected by urinary assay of the testosterone/epitestosterone (T/E) glucuronide ratio. This ratio is strongly associated with a deletion polymorphism in the UDP-glucuronosyltransferase (UGT) 2B17 gene. The metabolism of certain UGT specific drugs has been shown to be different in men and women. The objective of this study was to evaluate the impact of gender as well as human genetic variation on testosterone metabolism and the T/E ratio. We also carried out legal and policy analysis of the extant regulatory documents with a view to assess their preparedness for the introduction of genetic testing to the field of doping, and interpretation of doping related tests in the future. Testosterone glucuronidation rate was measured in female and male liver microsomes and analyzed with HPLC. UGT2B15 mRNA was measured in human liver samples using real-time PCR. Elite athletes participating in different endurance sports were genotyped for the UGT2B17 deletion polymorphism and compared with their urinary T/E ratio. The testosterone glucuronidation rate was 1.7 times higher in male than in female liver microsomes (p <0.05). Male del/del livers had significantly higher expression of UGT2B15 compared to female del/del livers (p <0.05). Men, but not women, seem to compensate for their lack of UGT2B17 activity with increased UGT2B15 expression. The T/E ratios in males, but not in females, are strongly associated with the UGT2B17 ins/ins and ins/del genotype (p <0.05).The results presented herein directly inform the ways in which doping tests may have to be designed and interpreted in the future so as to take into account host (athletes’) individual characteristics and gene-by-gender interactions. Additionally we suggest that the current legal and policy frameworks are in need of substantive amendment if the field of doping testing is to benefit from advances in genomics technologies and personalized medicine.

Identifying novel molecular drug targets continues to be of prime interest in addressing the public health burden of breast cancer in both developed and developing countries alike. In this context, proteomics/pharmacoproteomics approaches offer a new dimension for personalized medicine. We have previously identified differentially expressed proteins with antigenic activity between SKBR3 (ER-, high HER2 expression) and MCF7 (ER+, low HER2 expression) breast cancer cell lines. The aims of the present study were (1) to develop an initial proteome based roadmap of differentially expressed proteins between the two cell lines using two-dimensional electrophoresis (2-DE), and (2) to compare them to those identified by other techniques. SKBR3 and MCF7 cell lysates were subjected to 2-DE and spots of interest were identified by MALDI-TOF/TOF MS. Upregulated proteins (≥2 fold and p<0.05) in MCF7 cells were cellular retinoic acid binding-protein-2, Hsp27, nucleophosmin, electron transfer flavoprotein-α, and profilin-2. In SKBR3 cells, upregulated proteins were RhoGDP dissociation inhibitor-α (RhoGDI-α), voltage-dependent anion channel-2, aldehyde dehydrogeanase-2 (ALDH2), LDH-A, LDH-B, pyrophosphates-1, GAPDH, cathepsin-D preprotein, F–actin capping protein β-subunit, and apolipoprotein A-I binding protein. Differential expression of RhoGDI-α, a molecule with a versatile range of biological activities in different types of breast cancer, was validated using western blotting. In conclusion, these observations using proteomics strategies serve to characterize SKBR3 and MCF7 breast cancer cell lines and offer new insights for personalized medicine on differential expression of putative drug targets between these cancer models. Further studies are warranted to examine the usefulness of SKBR3 cell line as an appropriate model for studying RhoGDI-α activities in HER2+ ER- breast cancer. Finally, we underscore that the findings presented herein also attest to an emerging strand of collaborative proteomics/OMICS studies in developing countries and resource-limited settings towards global personalized medicine, an area of postgenomics data-intensive health research that is in need of greater attention in biomedical literature.

Stakeholders’ views are invaluable in the process of garnering the resources and infrastructure necessary for public health genomics research and introducing efficient communication mechanisms and appropriate ethical frameworks. This research is crucial as pharmacogenomics applications are advancing towards public health. In order to learn about the perceptions stakeholders have towards the relevance of genomics for public health research and the related issues, we conducted qualitative social science research and interviews with genomics researchers, epidemiologists and virologists, ethics and law specialists, and decision makers. A thematic data analysis was undertaken to extract their views. Stakeholders acknowledged that genomics holds substantial potential to drive forward scientific advances. There was however no consensus on the types of interventions needed to integrate genetic information into public health research strategies. Despite their positive expectations, the respondents asserted that the integration of these two fields have to be in the public’s best interest. In particular, the importance of scientific evidence on genomic determinants of health was emphasized. Proof of transparency and accountability also needed to be taken into account. These elements were deemed to be crucial to counter the potential rejection of research at the confluence of genomics and public health, to protect individuals and engage scientists in “sound science”. Even though collective values have been an integral part of public health genomics, this new field of inquiry warrants further exploration about how, and to what ends interdisciplinary research should be carried out, the importance of efficient communication mechanisms for knowledge translation and a widening of the scope of research ethics in the near future. To the best of our knowledge, this is the first research study empirically describing public health genomics stakeholders’ views on the integration of genomics into public health research and related ethical issues.

While the personalized medicine literature has hitherto focused on diseases in developed countries, little discussion has materialized on ways in which genomics can importantly remedy highly prevalent diseases in developing countries. This paper aims to address this important lacuna in the biomedical literature—what we refer to herein as “developing world genomics” that needs recognition as an emerging subspecialty of global personalized medicine. We direct our attention on neglected tropical diseases (NTDs), a group of high prevalence chronic parasitic and related infections that affect the world's poorest people. Lymphatic filariasis (LF) is a mosquito-borne NTD caused by thread like lymphatic-dwelling nematode and causes significant disability as well as loss of productivity in developing nations. The sustainability of the ongoing efforts for vector control and chemotherapy are uncertain and new drugs are required in the absence of an adulticidal drug while some mainstay drugs are threatened with drug resistance. In this paper, we share and synthesize research findings focussed on Wolbachia, the endosymbiont bacteria of filarial parasites, which itself is a promising target for the development of personalized drugs or customized vaccines as it contributes to the normal functioning of the parasites. We analyze the recent advances in parasite and Wolbachial genomics to highlight potential applications of genomic technologies for targeted drug discovery and personalized therapeutics for this NTD with a vast burden on the global public health. Comparative genomic approaches should also be valuable for exploring genetic changes involved in resistance to antifilarial drugs and understanding the potential mechanisms of drug resistance in human parasites.

Despite the great advances made in the diagnosis and management of hepatocellular carcinoma (HCC), HCC still remains as the third leading cause of cancer-related mortality, with approximately 695,000 deaths per year. Seventy-eight percent of new cases are found in Asia, especially China, Taiwan and Hong Kong, while HCC incidence has been increasing in the United States and Europe over the past decade. Although curative therapies are available for early stage HCC, however, due to late diagnosis and the presence of underlying cirrhosis, most patients present medically with intermediate or advanced HCC, for whom curative therapies become less feasible. Potential new biomarkers have been uncovered that may allow for the early detection of HCC and provide accurate diagnosis to ensure the appropriate treatment is used. Additionally much work has been done in translating research into therapies and allowing for more personalized management of HCC. Because the majority of HCC cases are found in Asia-Pacific, this review is focused on the current management of HCC, diagnostic, treatment and theragnostic tools stemming from the Asia-Pacific region. Finally, we conclude with a discussion on the recent fusion of therapeutics and diagnostics medicine in the form of theragnostics, the need for companion diagnostic and treatment development for HCC, as well as the lessons learned in the Asia-Pacific region.

A decade after Francis Collins, then Director of the Human Genome Project, stated that: “Genetic prediction of individual risks of disease and responsiveness to drugs will reach the medical mainstream in the next decade or so” the uptake of therapeutic strategies informed by pharmacogenomic tests, often termed personalised medicine, has been limited. Several recent developments have been suggested as potential accelerating factors for the introduction of personalised medicine including the advent of commercially oriented pharmacogenomic testing and direct to consumer genetic testing. The advent of such testing has led to pharmacogenomic information becoming a commodity rather than simply medical information. Given this increasingly complex environment, the interpretation of pharmacogenomic testing has considerable implications for both health professionals and consumers. This paper asserts that both ‘push’ and ‘pull’ factors play a role for bringing pharmacogenomics tests to the clinic and public health practice. While scientists tended to concentrate on the ‘push’ factors, there has been relatively little discussion on the ‘pull’ factors such as consumer and enduser perspectives, let alone in developing countries and the Asia-Pacific region. This paper focuses on studies of consumer views concerning pharmacogenomics and discusses the implications of these views for health professionals including recent lessons learned in Australia and globally. Our review reflects a relative paucity of studies, a need for more widespread public consultation and education. It also highlights the need for a focus on educational strategies, possibly involving an increased role of pharmacists given their drug focus.