摘要:

The recently amplified pace of development in the technologies to study both normal and aberrant cellular physiology has allowed for a transition from the traditional reductionist approaches to global interrogations of human biology. This transformation has created the anticipation that we will soon more effectively treat or contain most types of diseases through a ‘systems-based’ approach to understanding and correcting the underlying etiology of these processes. However, to accomplish these goals, we must first have a more comprehensive understanding of all the elements involved in human cellular physiology, as well as why and how they interact. With the vast number of biological components that have and are being discovered, creating methods with modern computational techniques to better organize biological elements is the next requisite step in this process.This article aims to articulate the importance of the organization of chemical elements into a periodic table had on the conversion of chemistry into a quantitative, translatable science, as well as how we can apply the lessons learned in that transition to the current transformation taking place in biology.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Inflammatory bowel disease (IBD), with its two subforms of Crohn disease and ulcerative colitis, is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition. The first risk gene underlying susceptibility to Crohn disease has been identified asCARD15(located on chromosome 16q12, encoding NOD2). Three single nucleotide polymorphisms in the leucine rich region (LRR) of this gene are strongly and independently associated with Crohn disease susceptibility and explain up to 20% of the total genetic predisposition for Crohn disease. These variants have been consistently replicated as associated with a particular sub-phenotype characterized by small bowel (ileum) involvement and early age at onset. Presently, genetic testing for theCARD15variants has only a modest relevance in clinical practice.The most attractive use of genetic testing is for the prediction of response to therapy. Most therapies only show efficacy in subgroups of patients and no clinical parameters are available to distinguish, prior to therapy, whether the patients will be responders or non-responders, or if the patients will experience adverse effects. The pharmacogenetic basis of toxicity is well known for azathioprine: several thiopurine methyltransferase (TPMT) polymorphisms that are associated with reduced activity of this thiopurine drug metabolizing enzyme result in cytotoxic and immunosuppressive adverse effects of azathioprine. Genetic screening, which has found its way into routine clinical diagnostics, allows the identification of the patients who will not tolerate a standard dose of the drug. The extensive search for genetic predictors of response to the anti-tumor necrosis factor treatment with infliximab, which results in a remission rate of 30–40%, has, however, failed to indentify a variation associated with a differential response.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

In the last few years, DNA methylation has become one of the most studied gene regulation mechanisms in carcinogenesis as a result of the cumulative evidence produced by the scientific community. Moreover, advances in the technologies that allow detection of DNA methylation in a variety of analytes have opened the possibility of developing methylation-based tests. A number of studies have provided evidence that specific methylation changes can alter the response to different therapeutic agents in cancer and, therefore, be useful biomarkers. For example, the association of the methylation status of DNA repair genes such asMGMTandMLH1illustrate the two main mechanisms of response to DNA damaging agents. Loss of methylation ofMGMT, and the subsequent increase in gene expression, leads to a reduction in response to alkylating agents as a result of enhanced repair of drug-induced DNA damage. Conversely, the increase in methylation ofMLH1and its resulting loss of expression has been consistently observed in drug-resistant tumor cells.MLH1encodes a mismatch repair enzyme activated in response to DNA damage; activation ofMLH1also induces apoptosis of tumor cells, and thus loss of its expression leads to resistance to DNA-damaging agents. Other methylation-regulated genes that could serve as biomarkers in cancer therapy include drug transporters, genes involved in microtubule formation and stability, and genes related to hormonal therapy response. These methylation markers have potential applications for disease prognosis, treatment response prediction, and the development of novel treatment strategies.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Autism is a complex neurodevelopmental disorder with a broad spectrum of symptoms and varying severity. Currently, no biological diagnosis exists. Although there has been a significant increase in autism genetics research recently, validated susceptibility genes for the most common, sporadic forms of autistic disorder, as well as familial autism, have yet to be identified. The identification of autism-susceptibility genes will not only assist in the identification and/or development of better medications that can help improve the health and neurodevelopment of children with autism, but will also allow for better perinatal diagnosis. The Autism Genome Project (AGP) is a large-scale, collaborative genetics research project initiated by the National Alliance for Autism Research and the National Institutes of Health, and is aimed at sifting through the human genome in search of autism-susceptibility genes. Phase I of the AGP will consist of genome-wide scans utilizing both SNP array and microsatellite technologies. Linkage analysis will subsequently be performed on approximately 1500 pedigrees as will downstream fine-mapping and sequencing of the critical linkage intervals. Ultimately, the vision will be to identify the exact nucleotide variants within genes which give rise to predisposition. The AGP intends to move the field of autism clinical management forward by answering questions about the causal mechanisms underlying the pathophysiology of autism. From this knowledge, therapeutic targets for drug treatments, and ultimately, a newborn screening diagnostic that would allow for early intervention, can begin to be developed.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

This is the second part of a four-part review on potential therapeutic targeting of oncogenes. The previous part introduced the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes, which we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part I included a discussion of growth factors and tyrosine kinases. This portion of the review covers intermediate signaling molecules and the various strategies used to inhibit their expression or decrease their activities.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

The continuing improvement and refinement of proteomic and bioinformatic tools has made it possible to obtain increasing amounts of structural and functional information about proteins on a global scale. The emerging field of neuroproteomics promises to provide powerful strategies for further characterizing neuronal dysfunction and cell loss associated with neurodegenerative diseases. Neuroproteomic studies have thus far revealed relatively comprehensive quantitative changes and post-translational modifications (mostly oxidative damage) of high abundance proteins, confirming deficits in energy production, protein degradation, antioxidant protein function, and cytoskeletal regulation associated with neurodegenerative diseases such as Alzheimer and Parkinson disease. The identification of changes in low-abundance proteins and characterization of their functions based on protein-protein interactions still await further development of proteomic methodologies and more dedicated application of these technologies by neuroscientists. Once accomplished, however, the resulting information will certainly provide a truly comprehensive view of neurodegeneration-associated changes in protein expression, facilitating the identification of novel biomarkers for the early detection of neurodegenerative diseases and new targets for therapeutic intervention.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveNormalization is a standard low-level preprocessing procedure in microarray data analysis to minimize the systematic technological variations and produce more reliable results. A variety of normalization approaches have been introduced and are widely applied. Normalization, however, remains controversial. The sensitivity of array results to normalization is an open question. No clear standard for comparing or judging normalization methods has yet emerged, and the effects of normalization on gene-to-gene co-expression are unclear.MethodsIn this investigation, we applied 1-, 2-, andN-quantile normalization to several publicly available microarray datasets quantified with either MAS 5.0 or dCHIP and evaluated the effect on gene-to-gene co-expression. We introduced a graphical method to explore trends in gene correlation.ResultsWe found clear differences in the distributions of gene dependencies by normalization method. Increasing the number of standardized quantiles in the normalization reduced trends in correlation by signal intensity in MAS 5.0 quantifications but not dCHIP. Increasing the number of standardized quantiles did not markedly reduce the correlation of known overlapping targets with MAS 5.0.ConclusionsNormalization plays a very important role in the estimation of inter-gene dependency. Caution should be used when making inferences concerning gene-wise dependencies with microarrays until this source of variation is better understood.

ISSN:1175-2203    

出版商:ADIS    

年代:2005

数据来源: ADIS