以创新精神落实科学发展观

微山县地处2省8市县结合部,南北狭长150多公里,1760平方公里的辖区面积中,湖区面积占1260平方公里,湖区、矿区、边区集于一身,一次全面检查需3～4个月的时间,行程2万多公里,地理环境和人地关系较其他市县有着非常突出的特殊性.     

Clearing the standards landscape: the semantics of terminology and their impact on toxicogenomics.

The emergence of the microarray data standards, especially the Minimum Information About a Microarray Experiment (MIAME), has spurred several organizations to develop their own standards for a myriad of technologies, including proteomics and metabolomics. These efforts have facilitated the creation of several large-scale gene expression repositories, including the toxicology-focused Chemical Effects in Biological Systems Knowledgebase at the National Institute of Environmental Health Sciences. Recently, efforts have been moved toward developing toxicogenomic data standards (e.g., MIAME-Tox), and the U.S. Food and Drug Administration and the U.S. Environmental Protection Agency either have developed or are developing regulatory guidance with respect to pharmaco- and toxicogenomics. However, for the toxicology community to be engaged in the process of standards development and approval, there needs to be a more thorough understanding of the terms associated with electronic data sharing and communication, especially with respect to defining the terms "standard," "controlled vocabulary," "object model," "markup language," and "ontology." This review will discuss these terms, especially as they pertain to toxicogenomics, how they relate to one-another, and what current efforts exist that may impact toxicology.     

Putting the diet back into diet-induced obesity: diet-induced hypothalamic gene expression

A wealth of detailed mechanistic information relating to obesity and body weight regulation has emerged from study of single gene mutation models, and continues to be generated by engineered rodent models targeting specific genes. However, as an early step in translational research, many researchers are turning to models of diet-induced obesity. Interpretation of data generated from such models is not aided by the variety of diets and rodent strains employed in these studies and a strong case could be made for rationalisation. Differences in experimental protocol, which may deploy a single obligatory solid diet, a choice of solid diets, or liquid/solid combinations, and which may or may not allow a preferred macronutrient composition to be selected, mean that different models of diet-induced obesity achieve that obesity by different routes. The priority should be to mimic the palatability- and choice-driven over-consumption that probably underlies the majority of human obesity. Some of the hypothalamic energy balance genes apparently 'recognise' developing diet-induced obesity as indicated by counter-regulatory changes in expression levels. However, substantial changes in gene expression on long-term exposure to obesogenic diets are not able to prevent weight gain. Forebrain reward systems are widely assumed to be overriding hypothalamic homeostatic energy balance systems under these circumstances. More mechanism-based research at the homeostatic/reward/diet interface may enable diets to be manipulated with therapeutic benefit, or define the contribution of these interactions to susceptibility to diet-induced obesity.     

Integrating toxicogenomics into human health risk assessment: Lessons learned from the benzo[a]pyrene case study

Abstract

The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper (Moffat et al. 2014 Moffat ID, Chepelev NL, Labib S, Bourdon-Lacombe J, Kuo B, Buick JK. et al. (2014). Comparison of toxicogenomics and traditional approaches in quantitative risk assessment of benzo(a)pyrene for drinking water. Crit Rev Toxicol 45, 1–43. [Google Scholar]), we present a case study evaluating the utility of toxicogenomics in the RA of benzo[a]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well-established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that toxicogenomics provided rich mechanistic data applicable to hazard identification, dose–response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of toxicogenomics in RA.     

The comparative toxicogenomics database: a cross-species resource for building chemical-gene interaction networks.

Chemicals in the environment play a critical role in the etiology of many human diseases. Despite their prevalence, the molecular mechanisms of action and the effects of chemicals on susceptibility to disease are not well understood. To promote understanding of these mechanisms, the Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org/) presents scientifically reviewed and curated information on chemicals, relevant genes and proteins, and their interactions in vertebrates and invertebrates. CTD integrates sequence, reference, species, microarray, and general toxicology information to provide a unique centralized resource for toxicogenomic research. The database also provides visualization capabilities that enable cross-species comparisons of gene and protein sequences. These comparisons will facilitate understanding of structure-function correlations and the genetic basis of susceptibility. Manual curation and integration of cross-species chemical-gene and chemical-protein interactions from the literature are now underway. These data will provide information for building complex interaction networks. New CTD features include (1) cross-species gene, rather than sequence, query and visualization capabilities; (2) integrated cross-links to microarray data from chemicals, genes, and sequences in CTD; (3) a reference set related to chemical-gene and protein interactions identified by an information retrieval system; and (4) a "Chemicals in the News" initiative that provides links from CTD chemicals to environmental health articles from the popular press. Here we describe these new features and our novel cross-species curation of chemical-gene and chemical-protein interactions.     

Putting evidence-based medicine into clinical practice: comparing anti-resorptive agents for the treatment of osteoporosis

OBJECTIVE: To compare the effectiveness of antiresorptive agents in reducing the risk of vertebral and non-vertebral fractures using data from published meta-analyses and the technique of adjusted indirect comparisons. RESEARCH DESIGN AND METHODS: Pairs of agents were compared by adjusted indirect comparison of 0.56 [0.40, 0.78], respectively) in reducing the their effects relative to a common comparator (placebo) using meta-analyses published by The Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. RESULTS: Adjusted indirect comparisons identified only one pair of agents that had significantly different effects on vertebral fracture incidence: alendronate was 34% more effective than calcitonin (Relative Risk: 0.66, 95% Confidence Interval: 0.48-0.90). Alendronate was significantly more effective than risedronate, calcitonin, estrogen, etidronate, and raloxifene (Relative Risks: 0.70 [0.49, 0.99], 0.64 [0.42, 0.98], 0.59 [0.41, 0.84], 0.52 [0.32, 0.82], and incidence of non-vertebral fractures. No other significant pairwise differences were observed. CONCLUSIONS: The results suggest that there are differences in anti-fracture efficacy among antiresorptive agents, particularly for non-vertebral fractures. Direct head-to-head comparisons would be needed to confirm these findings but are unlikely to be conducted.     

Incorporation of the pi subunit into functional gamma-aminobutyric Acid(A) receptors.

mRNA encoding the recently cloned gamma-aminobuytyric acid(A) receptor (GABAR) pi subunit is expressed in the hippocampus and in several non-neuronal tissues including the uterus and ovaries. Whereas native GABARs are pentamers composed primarily of alphabetagamma, alphabetadelta, or alphabetaepsilon subunits, it has not been demonstrated clearly that the pi subunit incorporates into functional GABARs to form alphabetapi receptors and, if so, with what properties. We provide electrophysiological evidence that the pi subunit can coassemble with either alpha5beta3 or alpha5beta3gamma3 subunits to produce recombinant GABARs with distinct pharmacological and biophysical properties. Compared with alpha5beta3 receptors, GABARs produced by coexpression of alpha5beta3pi subunits had a lower GABA EC(50) value, were enhanced to a lesser extent by loreclezole, had different IC(50) values for pregnenolone sulfate and lanthanum, and were insensitive to benzodiazepines. Incorporation of both pi and gamma3 subunits into an alpha5beta3gamma3pi isoform was suggested by reduced enhancement by diazepam and a high zinc IC(50) value. Current-voltage relations for the alpha5beta3pi subunit combination outwardly rectified more than currents from alpha5beta3gamma3 but less than alpha5beta3 combination GABARs. Single-channel alpha5beta3 GABAR currents had a main conductance state of 15.2 picoSeimens (pS). Coexpression of the pi subunit with alpha5beta3 subtypes increased the conductance level to 23.8 pS, similar to the conductance level of alpha5beta3gamma3 GABARs (26.9 pS). We conclude that the pi subunit coassembles with alpha, beta, and gamma subunits to form functional alphabetapi or alphabetagammapi GABARs and, thus, could have a significant impact on the function of native GABARs expressed in the brain or non-neuronal tissue.     

Putting the eco in ecotoxicology

Testing of pesticides and often other persistent chemicals increasingly involves aquatic mesocosms. Since our intention is to protect natural systems, predictions of their response based on surrogate systems are desirable. Toxicity tests at a variety of levels of biological organization are now available, ranging from single-species laboratory tests to those carried out in field enclosures of portions of natural systems. Validation is essential to determine accuracy of the predictions that will almost certainly not be identical for the wide variety of testing systems now available. Some important scientific considerations in the development of protocols are discussed.