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At least 1,045 records · Page 58Linked to original sources
PubMed2003

New tools for functional mammalian cancer genetics.

Knowledge of the function of individual genes that encode components of cell-signalling pathways is crucial to our understanding of normal growth control and its deregulation in cancer, but we have functional information for only 15% of human genes at present. Several new technologies have recently become available to identify gene function in mammalian cells using high-throughput genetic screens. These new tools will make it possible to identify new and innovative classes of anticancer drugs, including those that show synthetic lethal interactions with cancer-specific mutations.

Animals↗
PubMed1996

Molecular genetics as a diagnostic tool in farm animals.

In this review, the importance of molecular genetics for diagnostic applications in animal production and breeding is underlined. Recently, several new techniques and methods based on gene technology have been developed, such as the polymerase chain reaction, fluorescence in situ hybridization, and the use of microsatellite polymorphism. The examples include detection of favourable alleles of genes coding for milk proteins, recognition of negative recessive alleles in hereditary syndromes, the use of microsatellite variants for breeding purposes and parentage control, and application of specific DNA-probes for identification of Y-chromosome-bearing spermatozoa and the sex of embryos. It is to be understood that this list is not complete and more applications will undoubtedly show up in the future. For this review, the authors have mainly selected areas where they themselves or their co-workers have gained experience.

Amino Acid Sequence↗
PubMed1995

Genetic suppressor elements: new tools for molecular oncology--thirteenth Cornelius P. Rhoads Memorial Award Lecture.

Genetic suppressor elements (GSEs) are short biologically active gene fragments that encode dominantly acting peptides or inhibitory antisense RNAs. GSEs can be isolated from a single gene or from a multigene complex by constructing a library of short random fragments of the target gene(s) in an expression vector, followed by expression selection for the desired phenotype in a suitable cellular system. GSE selection from a single gene allows one to develop efficient and specific inhibitors of the gene function and to identify functional protein domains. GSE selection from a multigene complex, such as a normalized (uniform abundance) cDNA population from mammalian cells, makes it possible to identify genes that are involved in selectable cellular phenotypes. The potential of GSE selection for uncovering novel gene functions was first demonstrated using bacteriophage lambda as a model system. GSE selection in retroviral expression vectors has been applied in mammalian cells to identify genes responsible for sensitivity to etoposide and other chemotherapeutic drugs. GSE selection is also useful for cloning and analysis of tumor suppressor genes and can be applied to identifying tumor-specific targets for future anticancer drugs. Investigators should find this experimental strategy applicable to many different areas of medical and biological research.

Animals↗
PubMed1999

Molecular genetic analysis as a tool for evaluating stereotactic biopsies of glioma specimens.

Over the last years, distinct genetic lesions have been associated with individual tumor entities. Stereotactic biopsy has become an essential diagnostic tool in surgical neuro-oncology. In order to evaluate the potential of molecular analyses in stereotactic biopsies, we examined a series of 156 human brain tumors from patients undergoing stereotactic biopsy for molecular alterations typically seen in astrocytic gliomas and compared those results with a control group of 268 astrocytic tumors obtained at open surgery. Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades II and III showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade II from open surgery (p = 0.011). Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades III and IV showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade III from open surgery (p = 0.013). This indicates that stereotactic biopsies with features intermediate between grades are likely to correspond to the higher malignancy grade. Our data demonstrate that molecular genetic approaches can be successfully applied to stereotactic glioma biopsies. The difference in the distribution of malignancy associated genetic alterations between a stereotactic and openly resected group of gliomas indicates that histopathology may underestimate the malignant potential in some stereotactic specimens. We propose to further evaluate the molecular analysis of stereotactic glioma biopsies as a useful adjunct to standard histopathological procedures.

Biopsy↗
PubMed2000

Gene therapy for peripheral arterial disease.

Our understanding of the molecular biology of vascular disease is rapidly expanding, and this scientific growth has brought with it new opportunities for therapeutic intervention at the molecular and genetic levels. Although our tools for genetic manipulation in vivo and our knowledge of potential molecular targets are still crude and incomplete, the early application of these concepts to clinical problems is already underway, both in the pre-clinical and clinical arenas. The treatment of peripheral vascular disease, although greatly improved over recent decades by surgical and minimally-invasive techniques, remains limited by vascular proliferative lesions and by our inability to modulate the progression of native disease. This review explores some of the evolving concepts of therapeutic gene manipulation and their initial application in the peripheral circulation.

Angioplasty↗
PubMed1997

Streptococcal competence for genetic transformation: regulation by peptide pheromones.

Although the capacity for genetic transformation is perhaps the most famous attribute of pneumococcus, use of this genetic phenomenon as a tool for study of the biology of the organism and of its pathogenicity has been largely restricted to a few favored unencapsulated strains, both by the delicacy of the conditions required for development of competence, and by experience that encapsulated strains transformed poorly. We discuss here the recent discovery of a small stable inexpensive peptide pheromone that acts as a quorum-sensing signal and that induces competence under a wide variety of conditions and in encapsulated strains. Its use circumvents some if not all limitations to the expression of transformability in pneumococcus and therefore expands opportunities for application of tools molecular genetics to many strains of pneumococcus without prior genetic manipulation.

Peptides↗
PubMed2002

Microarrays and genetic epidemiology: a multipurpose tool for a multifaceted field.

The advent of molecular technologies that allow the collection and analysis of large amounts of genetic data is rapidly transforming the field of genetic epidemiology. Whether monitoring infectious outbreaks or identifying genotypic variations that underlie disease susceptibility, genetic epidemiology relies heavily on the analysis of multiple, independently derived results. By allowing the simultaneous monitoring of thousands of genetic or expression data points, microarrays are emerging as particularly powerful tools. Several recent reviews have described array manufacturing and the types of scientific questions that can exploit this technology, but few have addressed how the intended use of an array can dictate its design. This review will focus on this latter issue, with particular emphasis on the genetic epidemiology of infectious disease. The design of arrays for genotyping, expression profiling, and fingerprinting are presented, and examples of recent epidemiological studies are used to illustrate the applications' strong points and limitations. In addition to discussing arrays' ability to provide global views of gene identity or function, the review will describe design options for creating arrays that detect multiple genetic variations. It will also examine the reliability of array-generated fingerprints, assay accessibility, and possibilities for sharing and comparing data across studies. Although many challenges lie ahead, microarrays' multiple abilities appear uniquely poised to accelerate the advance of genetic epidemiology's multiple fronts.

Base Sequence↗
PubMed1991

Genetic factors in neurotoxicology and neuropharmacology: a critical evaluation of the use of genetics as a research tool.

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.

Animals↗
PubMed2004

Genetic, genomic, and bioinformatic tools for studying breast cancer progression.

Cancer susceptibility is a complex interaction of an individual's genetic composition and environmental exposures. Huge strides have been made in understanding cancer over the past 100 years, from the recognition of cancer as a genetic disease, to the identification of specific carcinogens, isolation of oncogenes and the recognition of tumor suppressors. Analysis of high-risk familial cancers has led to the discovery of new tumor suppressor genes and important cancer pathways. These families however represent only a small fraction of cancer in the general population. Most cancer instead probably results of an intricate interaction of polymorphic susceptibility genes with the sea of environmental exposures that humans experience. Although the central cadre of cancer genes is known, little is understood about the peripheral genes that likely comprise the polymorphic susceptibility loci. The challenge for cancer genetics is therefore to move forward from the Mendelian genetics of the rare familial cancer syndromes into the field of quantitative trait loci, susceptibility factors, and modifier genes. By identifying the genes that modulate an individual's susceptibility to cancer after an environmental exposure, researchers will be able to gain important insights into human biology, cancer prevention and treatment. The most efficient strategies to identify and characterize modifier loci will likely be those that are transdisciplinary, encompassing a variety of different "-omic" technologies. The application of a "trans-omic" techniques in our laboratory to the study of breast cancer dissemination is presented here as an illustration of the strategy.

Journal Article↗
PubMed1997

Genetics as a diagnostic tool in sarcomatoid renal-cell cancer.

Renal-cell cancer comprises a heterogeneous group of tumors, which currently can be sub-divided into morphologically distinct entities, each characterized by a specific combination of genetic changes. Sarcomatoid transformation might occur in any of the sub-types, resulting in tumors consisting of both carcinomatous and sarcomatous components. The specific diagnosis of these neoplasms, as to tumor sub-type, is usually made on the histologic properties of the carcinomatous tissue present. However, this might not reflect the true nature of the sarcomatous component. Since the genetic changes associated with the development of the different sub-types of renal-cell cancer are well established, this knowledge might serve as a tool in diagnosing sarcomatoid tumors. Assessing the genetic constitution of the latter may lead to correct diagnosis. It may also provide valuable information about the genetic changes associated with sarcomatoid transformation. Hence we performed a genetic characterization of a case of sarcomatoid renal-cell cancer, histologically diagnosed as being of the chromophilic type. The observed genetic changes included loss of 3p, 6q, 8p, 9, 13, 14 and 17p, and gain of 5, 12 and 20, as well as a mutation in the coding region of the p53 gene. This combination of genetic changes points to clear-cell rather than chromophilic origin of the sarcomatoid tumor investigated, indicating that the genetic constitution of sarcomatoid tumors may be a more reliable indicator of tumor sub-type than histologic appearance.

Biomarkers, Tumor↗
PubMed2006

Partial trisomy 1p due to paternal t(1;9) translocation in a family with recurrent miscarriages.

OBJECTIVE: To report a new case with partial trisomy 1p due to paternal t(1;9) translocation in a family with recurrent miscarriages. DESIGN: Case report. SETTING: Faculty of Medicine, Cukurova University. PATIENT(S): A couple with recurrent miscarriages, an abnormal fetus, a newborn infant, paternal grandfather and grandmother. INTERVENTION(S): Chorionic villi sampling (CVS), amniocentesis, lymphocytic karyotype, and genetic counseling. MAIN OUTCOME MEASURE(S): Chromosomal analysis of CVS, amniotic cells, and peripheral blood lymphocytes were performed according to standard cytogenetic methods using G-banding technique. RESULT(S): We determined the reproductive risk in a couple who carried a balance and an unbalanced rearrangement of chromosomes 1 and 9 in two generations of a normal father with derivative 9 karyotype. The prenatal and postnatal karyotypes of the newborn infant were the same as the father [46,XY,der(9)t(1:9)(p34.2;q34.3)]. He was also phenotypically normal. The abnormal fetus that was miscarried also had a derivative 9 [46,XY,der(9)t(1:9)(p34.2;q34.3)fat]. The der(9) contained the partial short arm of chromosome 1. Both chromosome 1 showed normal. Trisomy 1p in the fetus was the result of familial derivative 9. CONCLUSION(S): Partial trisomy is associated with fetal wastage, and may play a role in the etiology of the other miscarriages in certain families. The apparent lack of increased reproductive failure may result from the selective disadvantage of aneusomic gamets at fertilization or very early spontaneous abortions of unbalanced conceptuses. The detection of couples with chromosomal anomalies can undoubtedly help prevent the births of malformed infants. These findings would be used widely in clinical genetics and as an effective tool for genetic counseling and reproductive guidance.

Abortion, Habitual↗
PubMed2002

[Molecular cytogenetic detection of minute chromosomal structural abnormality on the chromosomal terminal regions].

In order to identify those easily overlooked minute chromosomal structural abnormality on the chromosomal regions, and to provide a valuable guidance for pregnancy, fluorescence in situ hybridization (FISH) technique by whole chromosome 7 painting probe, Xq probe and subterminal probe of 7q36-->qter was performed to analyze two cases. Case 1 had a history of recurrence spontaneous abotion and with an uncertain minute translocation on the chromosomal terminal regions. Case 2 was a premature ovarian failure patient with a balanced translocation between chromosome X and chromosome 7 by G banding. The results showed that case 1 was a cryptic minute translocation on the chromosomal terminal regions, and the breakpoint of case 2 was accurately determined, that is, the breakpoint was not on 7q36 but on 7qter. Therefore FISH technique with whole chromosome painting probe and subterminal probe could be used to diagnose the minute chromosomal structural abnormality on the chromosomal regions. It could be used widely in the clinical genetics and was an effective tool for genetic counseling and reproductive guidance.

Abortion, Habitual↗
PubMed2000

SMART: a web-based tool for the study of genetically mobile domains.

SMART (a Simple Modular Architecture Research Tool) allows the identification and annotation of genetically mobile domains and the analysis of domain architectures (http://SMART.embl-heidelberg.de ). More than 400 domain families found in signalling, extra-cellular and chromatin-associated proteins are detectable. These domains are extensively annotated with respect to phyletic distributions, functional class, tertiary structures and functionally important residues. Each domain found in a non-redundant protein database as well as search parameters and taxonomic information are stored in a relational database system. User interfaces to this database allow searches for proteins containing specific combinations of domains in defined taxa.

Database Management Systems↗
PubMed2006

Mouse models as a tool to unravel the genetic basis for human otitis media.

The pathogenesis of otitis media (OM) is multifactorial and includes infection, anatomical factors, immunologic status, genetic predisposition, and environmental factors. OM remains the most common cause of hearing impairment in childhood. Genetic predisposition is increasingly recognized as an important factor. The completion of the mouse genome sequence has offered a powerful basket of tools for investigating gene function and can expect to generate a rich resource of mouse mutants for the elucidation of genetic factors underlying OM. We review the literature and discuss recent progresses in developing mouse models and using mouse models to uncover the genetic basis for human OM.

Animals↗
PubMed2002

Future of genetics of mood disorders research.

This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

Genetic Linkage↗