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PubMed2001

Catalog of 46 single-nucleotide polymorphisms (SNPs) in the microsomal glutathione S-transferase 1 (MGST1) gene.

A major goal in our laboratory is to understand the role of common genetic variations among individual patients as regards susceptibility to common diseases and differences in therapeutic efficacy and/or side effects of drugs. As an addition to the high-density SNP (single-nucleotide polymorphism) maps of 12 glutathione S-transferase and related genes reported earlier, we provide here an SNP map of the microsomal glutathione S-transferase 1 (MGST1) gene. Among 48 healthy Japanese volunteers examined. we identified a total of 46 SNPs at this locus, 36 of which had not been reported before: 4 in the promoter region, 34 in introns, 3 in the 3' untranslated region, and 5 in the 3' flanking region. No SNP was found in 5'untranslated or coding regions. The ratio of transition to transversion was approximately 1.2:1. Among the 13 insertion-deletion polymorphisms was a 2-bp deletion in the coding region of MGST1 in DNA from one of the volunteers, which resulted in a frame-shift mutation. Since the gene product encoded by this mutant allele would lack the C-terminal half including the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) domain, MGST1 activity is likely to be reduced in the carrier's cells. The SNP map presented here adds to the archive of tools for studying complex genetic diseases, population migration patterns, and a variety of pharmacogenetic possibilities.

3' Untranslated Regions↗

PubMed2005

Identification of early-responsive genes correlated to valproic acid-induced neural tube defects in mice.

BACKGROUND: Valproic acid (VPA) causes the failure of neural tube closure in newborn mice. However, the molecular mechanism of its teratogenesis is unknown. This study was conducted to investigate the genomewide effects of VPA disruption of normal neural tube development in mice. METHODS: Microarray analysis was performed on the head part of NMRI mouse embryos treated for 1 hr with VPA on gestational day (GD) 8. Subsequently, we attempted to isolate genes that changed in correlation with the teratogenic action of VPA by employing reduced teratogenic VPA analogs, valpromide (VPD) and valnoctamide (VCD), in a real-time PCR study. RESULTS: Microarray results demonstrated that during neurulation, many genes, some of whose functions are known and some unknown, were either increased or decreased after VPA injection. Some genes were affected by VPD or VCD in the same way as VPA, but others were not changed by the analogs. In this way, our system identified 11 increased and 20 decreased genes. Annotation analysis revealed that the increased genes included gadd45b, ier5, per1, phfl3, pou3f1, and sox4, and the decreased genes included ccne2, ccnl, gas5, egr2, sirt1, and zfp105. CONCLUSIONS: These findings demonstrate that expression changes in genes having roles in the cell cycle and apoptosis pathways of neural tube cells were strongly expected to relate to the teratogenic, but not antiepileptic, activity of VPA. Our approach has allowed the expansion of the catalog of molecules immediately affected by VPA in the developing neural tube.

Abnormalities, Drug-Induced↗

PubMed2001

Implications of the Human Genome Project for obstetrics and gynecology.

The initial sequencing of the human genome should be regarded as a milestone in a road that stretches years into the future; the full ramifications of the Human Genome Project are still only being theorized. Researchers will benefit from the catalog of human genes in studies of the genetics of disease susceptibility and the cell biology of gene interactions. Clinicians will increasingly offer genetic or biochemical testing to identify those at highest risk for a number of diseases. Drug discovery will eventually follow newly possible studies of gene expression and protein function. However the Human Genome Project eventually shapes medicine, it is certain that physicians, particularly obstetricians and gynecologists, will need to be well versed in the scientific and ethical issues involved, inasmuch as we will likely be at the center of the most heated debates.

Cell Communication↗

PubMed2001

Catalog of 434 single-nucleotide polymorphisms (SNPs) in genes of the alcohol dehydrogenase, glutathione S-transferase, and nicotinamide adenine dinucleotide, reduced (NADH) ubiquinone oxidoreductase families.

An approach based on development of a large archive of single-nucleotide polymorphisms (SNPs) throughout the human genome is expected to facilitate large-scale studies to identify genes associated with drug efficacy and side effects, or susceptibility to common diseases. We have already described collections of SNPs present among various genes encoding drug-metabolizing enzymes. Here we report SNPs for such enzymes at additional loci, including 8 alcohol dehydrogenases, 12 glutathione S-transferases, and 18 belonging to the NADH-ubiquinone oxidoreductase family. Among DNA samples from 48 Japanese volunteers, we identified a total of 434 SNPs at these 38 loci: 27 within coding elements, 52 in 5' flanking regions, five in 5' untranslated regions, 293 in introns, 20 in 3' untranslated regions, and 37 in 3' flanking regions. The ratio of transitions to transversions was approximately 2.1 to 1. Among the 27 coding SNPs, 13 were nonsynonymous changes that resulted in amino acid substitutions. Our collection of SNPs derived from this study should prove useful for investigations designed to detect associations between genetic variations and common diseases or responsiveness to drug therapy.

Alcohol Dehydrogenase↗

PubMed1994

Construction of a normalized cDNA library by introduction of a semi-solid mRNA-cDNA hybridization system.

We report a novel procedure to construct a normalized (equalized) cDNA library. By introduction of the highly efficient self-hybridization system between a whole mRNA population and their corresponding cDNA immobilized on latex beads, which involves relatively simple manipulations, we were able to generate an mRNA population in which the copy number of abundant species was reduced while that of rare species was enriched. In a typical experiment, after several cycles of self-hybridization on the beads, the ratio of the most to the least abundant marker mRNA species dropped by a factor of 300 (from 10,000 to 30) while the complexity and length of mRNAs in the population remained unchanged. The procedure should provide a potent tool for the expression cloning of cDNA and also facilitate the construction of whole cDNA catalogs from specific tissues (or cell types) from higher organisms.

Animals↗

PubMedDate not supplied

Tumor suppressor genes (TSG).

In the last two decades the field of tumor suppressor genes (TSG) has developed from a novel epidemiology-based concept into one of the pillars of cancer research. New TSG are being discovered and although at a painstakingly slower pace, their functions are also being unravelled. These breakthroughs have not only brought about immediate benefits to clinical medicine such as genetic predictive testing for familial cancer syndromes, but have also introduced new strategies against cancer including early intervention, prevention and promising anti-cancer drugs. Despite that, we are still far from fully understanding the functional complexity of TSG with each discovery leading to even more queries. New developments that challenge the paradigm of TSG have also surfaced warranting verification and there is still a lack of consensual criteria and systematic cataloging for TSG. With the advent of high throughput sequencing and powerful bio-informatics, it is expected that the field of TSG will be expanding at an even faster pace. This review is to give a summary of the history, new concepts and recent advancements in the field of TSG in the hope that some of these concepts and works can be evaluated, expanded or even challenged.

Cell Transformation, Neoplastic↗

PubMed2006

Variation in the human genome and the inherited basis of common disease.

The availability of a reference human genome sequence-an increasingly dense catalog-knowledge of common genetic variation, and new developments in technology present an unprecedented opportunity to systematically explore the genetic basis of complex human diseases such as cancer. An understanding of the common mutations that can cause distinct human cancers will be critical for identifying new targets for drug discovery, patient stratification for clinical trials, and analysis of drug response data to delineate classes of patients that respond to therapy. The genome structure of cancer can be investigated in several ways. Germline mutations can be investigated in large-scale, case-control, or family studies. Somatic alternations can be identified using state-of-the-art genomic technologies such as high-density oligonucleotide arrays and targeted resequencing. Combined, these approaches will lead to a better understanding of the cancer genome.

Gene Expression Profiling↗

PubMed2002

Laboratory testing in rheumatoid arthritis patients taking disease-modifying antirheumatic drugs: clinical evaluation and cost analysis.

OBJECTIVE: To develop and validate evidence-based recommendations for routine laboratory tests in patients with rheumatoid arthritis (RA) receiving traditional disease-modifying antirheumatic drugs (DMARDs), and to calculate the monitoring costs. METHODS: Outpatient charts of 362 RA patients taking DMARDs were reviewed, and all laboratory abnormalities recorded. Recommendations on monitoring DMARD therapy were derived and then tested in an independent validation cohort of 231 patients. Cost analysis was performed using a cost catalog. RESULTS: Laboratory abnormalities were seen in 10% of treatment courses; relevant abnormalities were seen only during the first 4 months of therapy. Laboratory tests should be performed in week 2 and 4, then monthly for the first 4 months of therapy, then 2 to 4 times per year. These were capable of detecting 98.3% of laboratory abnormalities in a timely manner in another RA cohort. Up to 78% of costs can be saved when the presented recommendations are compared with those of international rheumatology societies. CONCLUSION: Laboratory tests can be reduced substantially in patients receiving DMARD therapy. In consequence, costs can decrease significantly without oversight of adverse events.

Antirheumatic Agents↗

PubMed2006

Usability of BioCon2 for nucleic acid structures in database.

With the specific three-dimensional structure, DNA/RNA molecules express the specific structural and catalytic functions. The knowledge integration based on three dimensional structures can be used to explain biochemical observations, to predict biological functions and to design drugs specific to a given complex system. In the large RNAs, the helical stems close to each other with specific arrangement. The polymorphic nature of multiple stranded helical structure of nucleic acid relates a promising technique of achieving base sequence specific recognition and hence artificial gene regulation. The database cataloging the interaction motifs of nucleic acid moieties has been developed. Skew matrix, a kind of kink parameter, affords the structural description between the adjacent moieties. The program BioCon2 for estimating these skew matrix and cataloguing for multiple stranded helices has been developed. New version allows for the good properties, i.e., impregnable and flexible presentation of multiple helices. The tentative database including these parameters with the species and physical properties of the surrounding nucleic acid components and amino acids has been constructed.

Databases, Nucleic Acid↗

PubMedDate not supplied

Acupuncture in the treatment of asthma: a critical review.

BACKGROUND: Increasingly, patients are turning to treatments and drugs that are considered "alternative" or "complementary" as part of their healthcare. In response, the National Institutes of Health (NIH) established an Office of Alternative Medicine (OAM) in 1992 to facilitate identification and evaluation of alternative and complementary therapies. Acupuncture, a therapy that has been used to treat disease in China for approximately 2,500 years has attracted considerable attention. NIH in a consensus statement derived from a Fall of 1997 consensus conference to assess acupuncture has indicated that acupuncture was useful in pain control and maybe a useful adjunct treatment for the management of asthma. Further, the US Food and Drug Administration has removed acupuncture from the "experimental medical devices" category. METHODS: We have extensively searched the literature for reports addressing the use of acupuncture in asthma treatment. We sought these using the National Library of Medicine, the Office of Alternative Medicine's database as well as other databases both English language based as well as other languages that catalog literature pertaining to alternative and complementary therapies. We then reviewed these reports and weighted the validity of the conclusions reached in the reports based on assessment of study design, number of subjects studied, duration of studies, types and number of controls, and statistical analyses used. RESULTS: Data presently in the literature do not provide sufficient support for a useful role for acupuncture in asthma management. CONCLUSIONS: Further properly designed clinical studies examining the use of acupuncture in asthma are extremely important and urgently needed.

Acupuncture Therapy↗

PubMed2001

Transgenic and knockout databases: behavioral profiles of mouse mutants.

Genetically engineered strains of mice, modified by transgenesis or gene targeting ("knockouts") are being generated at an impressive rate and used, among other areas, as premiere research tools in deciphering the genetic basis of behavior. As behavioral phenotyping strategies continue to evolve, characterization of these "designer" mice will provide models to evaluate the efficacy of new pharmacological and gene therapy treatments in human hereditary diseases. Reported behavioral profiles include aberrant social, reproductive, and parental behaviors, learning and memory deficits, feeding disorders, aggression, anxiety-related behaviors, pain/analgesia, and altered responses to antidepressants, antipsychotics, ethanol, and psychostimulant drugs of abuse. The Induced Mutant Resource (IMR) at The Jackson Laboratory (TJL, Bar Harbor, ME, USA) imports, cryopreserves, develops, maintains, and distributes biomedically important stocks of transgenic and targeted mutant mice to the research community. Information on neurological/behavioral strains--including behavioral performance, husbandry requirements, strain availability, and genetic typing protocols--is provided through the IMR database (http://www.jax.org/resources/documents/imr/). A catalog of available strains is readily accessible via the JAX Mice website at http://jaxmice.jax.org/index.shtml. In addition, TJL is now host to TBASE (http://tbase.jax.org/), a comprehensive, public-domain database with primary emphasis on mouse knockouts. TBASE contains an exhaustive list of knockout-related citations and provides an extensive phenotypic characterization of numerous behavioral mutants that is extracted directly from the literature. Present efforts to merge the two resources into a novel, schematically enhanced database, provisionally named Transgenic and Targeted Mutation Database (TTMD), will be briefly discussed.

Animals↗

PubMed2001

[Introduction of ancient Bencao works stored overseas yet not included in Quanguo Zhongyi Tushu Lianhe Mulu (National Coalition Catalogue of TCM Works)].

This paper briefly introduces 14 ancient Bencao works stored overseas yet not included in Quanguo Zhongyi Tushu Lianhe Mulu, with the information, including the authors, accomplish date, number of volume, categories, quantity of drugs, characteristics of content, store sites, and the condition of returned duplicated edition in China, and etc. Among the 14 works, 2 were accomplished in the Yuan dynasty, 9 in the Ming dynasty and 3 in the Qing dynasty.

Books↗

PubMed1997

A review of the contribution of whole embryo culture to the determination of hazard and risk in teratogenicity testing.

Whole embryo culture appears to be an excellent method to screen chemicals for teratogenic hazard. Compared to in vivo testing it is cheap and rapid and does not involve experimentation on live adult animals. Also in the important area of risk estimation whole embryo culture offers distinct advantages over in vivo teratogenicity testing. Adverse embryonic outcomes (malformations or embryotoxicity) are directly related to the serum concentration of the compound being tested and can be compared to the serum concentration in the human. A similar comparison is not possible after in vivo testing because for most compounds there are major pharmacokinetic differences between humans and experimental animals. In vivo testing is also limited by the possibility that metabolites that occur in the human do not occur in the test animal. This problem can be overcome in the in vitro system by adding the metabolite directly at the desired concentration either with or without the parent compound. There is only one major disadvantage to in vitro testing and that is the limited period of embryogenesis that is undertaken in the commonly used culture system. This restricts the range of malformations that can be induced and may render the testing system unsuitable for compounds that are likely to exert their major toxicological effect late in gestation. Any evaluation of whole embryo culture for hazard and risk assessment in teratology must take into account the limited value of currently used in vivo methods. Over 2000 chemicals have been reported to be teratogenic in experimental animals exposed in vivo (Shepard, Catalog of Teratogenic Agents, 1989). In comparison only about 20 chemicals are known to cause birth defects in the human. This large number of in vivo false-positive cannot easily be distinguished from true-positives. In this respect in vivo testing is severely deficient. The embryo culture testing system would also be expected to produce many false-positives; but by comparing effective drug concentrations with human therapeutic concentrations they can be differentiated from true-positives. The most serious deficiency for an in vivo or in vitro teratogenicity testing system would be false-negatives. This has not been a problem in the validation of in vitro testing so far (except perhaps procarbazine), but difficult drugs such as thalidomide were not included. Thalidomide remains an important index chemical because it is not teratogenic in rats or mice but is teratogenic in the rabbit and human. It is likely that these species differences are due to metabolic differences between species and it is possible that if the proximate teratogen/s of thalidomide were identified they would be teratogenic in rat embryo culture. Whole embryo culture remains a very powerful technique that should continue to contribute to the determination of the safety of drugs and other chemicals during pregnancy.

Abnormalities, Drug-Induced↗

PubMed2005

International Union of Pharmacology. XLVI. G protein-coupled receptor list.

NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) and its subcommittees provide authoritative reports on the nomenclature and pharmacology of G protein-coupled receptors (GPCRs) that summarize their structure, pharmacology, and roles in physiology and pathology. These reports are published in Pharmacological Reviews (http://www.iuphar.org/nciuphar_arti.html) and through the International Union of Pharmacology (IUPHAR) Receptor Database web site (http://www.iuphar-db.org/iuphar-rd). The essentially complete sequencing of the human genome has allowed the cataloging of all of the human gene sequences potentially encoding GPCRs. The IUPHAR Receptor List (http://www.iuphar-db.org/iuphar-rd/list/index.htm) presents this catalog giving IUPHAR-approved nomenclature (where available), known ligands, and gene names for all of these potential receptors (excluding sensory receptors and pseudogenes) together with links to curated sequence, descriptive information, and additional links in the Entrez Gene database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene). This list is a major new initiative of NC-IUPHAR that, through continuing curation, defines the target of our ongoing receptor classification and invites further input from the scientific community.

Animals↗

PubMed1998

Providing patients with written medication information.

OBJECTIVE: To review the literature and provide recommendations for the development and dissemination of written medication information to patients and their care providers. DATA SOURCES: A MEDLINE search (1966-1997) of the English-language literature was performed to identify articles pertaining to the development or use of written medication information. A search of the Internet was conducted by using Yahoo as the guide and "medication information" as the search term. Additional resources were obtained through texts, bibliographies, and catalogs from medical publishers. DATA EXTRACTION: Reports documenting the creation and use of written medication information systems were reviewed, as well as studies of readability and reading skills assessment. Examples of materials available for purchase by laypeople and healthcare providers were also examined. DATA SYNTHESIS: Current statistics support the widespread availability of written medication information for patients and care providers. The goal set forth by the Food and Drug Administration of having 75% of patients receive written information by the year 2000 appears achievable. However, there are still many issues to address. Content is not standardized, and materials are frequently written at reading levels higher than that of the average patient. The development and use of resources requiring only minimal reading skills and an increase in the availability of materials written in Spanish are needed. CONCLUSIONS: Written medication information provides a useful addition to counseling by healthcare professionals. A wide variety of prepared materials is available, as well as resources for those interested in developing tools for a specific patient, population, or setting. Healthcare professionals should be aware of the limitations of some resources. Content and readability must be appropriate for the intended audience for these tools to serve a useful role in patient education.

Counseling↗

PubMed2004

Serial Analysis of Gene Expression: Applications in Malaria Parasite, Yeast, Plant, and Animal Studies.

The serial analysis of gene expression (SAGE) method is based on the isolation of unique sequence tags from individual transcripts and concatenation of tags serially into long DNA molecules. SAGE is an innovative technique that offers the potential of cataloging both the identity and relative frequencies of mRNA transcripts in a given RNA preparation. It can quantify low-abundance transcripts and reliably detect relatively small differences in transcript abundance between cell populations. SAGE data can be used to complement studies in cases where other gene expression methods may be more convenient or efficient. SAGE can be used in a wide variety of applications to identify disease-related genes, to analyze the effect of drugs on tissues, and to provide insights into the disease pathways. The most important application of SAGE is the identification of differentially expressed genes. In this review, we describe various applications of this powerful technology in malarial parasite, yeast, plant, and animal systems.

Journal Article↗

PubMedDate not supplied

A hierarchical clustering approach for large compound libraries.

A modified version of the k-means clustering algorithm was developed that is able to analyze large compound libraries. A distance threshold determined by plotting the sum of radii of leaf clusters was used as a termination criterion for the clustering process. Hierarchical trees were constructed that can be used to obtain an overview of the data distribution and inherent cluster structure. The approach is also applicable to ligand-based virtual screening with the aim to generate preferred screening collections or focused compound libraries. Retrospective analysis of two activity classes was performed: inhibitors of caspase 1 [interleukin 1 (IL1) cleaving enzyme, ICE] and glucocorticoid receptor ligands. The MDL Drug Data Report (MDDR) and Collection of Bioactive Reference Analogues (COBRA) databases served as the compound pool, for which binary trees were produced. Molecules were encoded by all Molecular Operating Environment 2D descriptors and topological pharmacophore atom types. Individual clusters were assessed for their purity and enrichment of actives belonging to the two ligand classes. Significant enrichment was observed in individual branches of the cluster tree. After clustering a combined database of MDDR, COBRA, and the SPECS catalog, it was possible to retrieve MDDR ICE inhibitors with new scaffolds using COBRA ICE inhibitors as seeds. A Java implementation of the clustering method is available via the Internet (http://www.modlab.de).

Algorithms↗

PubMed1994

Gastritis: terminology, etiology, and clinicopathological correlations: another biased view.

The histological approach to gastritis, especially the chronic forms, has undergone a series of re-evaluations by different experts over the past decade, mainly because of the recognition of individual disease patterns that have specific clinical and epidemiological implications. The most spectacular of these was the discovery of Helicobacter pylori and its common gastritis, its relation to almost all duodenal peptic ulcers and to most gastric peptic ulcers, its potential as a precursor of first multifocal atrophic gastritis and later tubule-forming gastric carcinomas, and its status as a cause of gastric mucosal lymphomas. During this same decade other classes of gastric reaction and inflammations have been recognized, including chemical injury and lymphocytic gastritis. Also in the same decade the importance of non-steroidal anti-inflammatory drugs (NSAIDs) has emerged as a cause of gastric mucosal injuries. To add emphasis to all these discoveries, biopsies are being performed on stomachs in almost epidemic numbers and each biopsy specimen has the potential of having the features of one or more of these injuries as well as injuries that have yet to be described. To cope with this rapidly expanding gastric inflammatory informational extravaganza, pathologists need some way of dealing with the various entities comfortably and some method of cataloging them in ways that are understandable both to them and to the endoscopists with whom they work. However, if emerging data about the chronic gastritides are correct, it is conceivable that the need to diagnose them, from a strictly clinical standpoint, is limited. Either we may know what is in the biopsy specimen before we see it or what we see may not be important, although it may be intellectually challenging.

Acute Disease↗