Biomedical subjects

Fuad G Gwadry

Publications and source records attributed to Fuad G Gwadry.

6 recordsLinked to original sources

PubMed2006

Implication of SSAT by gene expression and genetic variation in suicide and major depression.

CONTEXT: A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors. OBJECTIVE: To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions. DESIGN: Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation. SUBJECTS: We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin. MAIN OUTCOME MEASURES: Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. RESULTS: Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P<or=.01] in at least 2 regions). The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02). Further investigation of this variant in an independent sample of 181 male suicide completers and 80 male controls showed a higher frequency of the SSAT342C allele among suicide cases (odds ratio, 2.7; 95% confidence interval, 1.4-5.3; P = .005), suggesting that this allele may increase predisposition to suicide. CONCLUSIONS: These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.

Acetyltransferases↗

PubMed2005

Molecular characterization of suicide by microarray analysis.

Several lines of evidence support the idea that individuals who commit suicide have a certain biological predisposition, part of which is given by genes. Studies investigating genetic factors increasing suicide predisposition have been limited by current knowledge of the suicide neurobiology and have typically investigated one or a few genes at a time, whereas it is anticipated that several genes account for the total genetic variance mediating suicide. This review focuses on the advantages and the interest of using the microarray technology to investigate the neurobiology of suicide and discusses, by means of a data analysis example, the possible methodological problems and bioinformatic strategies that should be employed in order to separate the signal from the large amount of background noise, which is usually generated in such studies. Microarray expression studies and related platforms are promising tools to gain better insight into the neurobiology of suicide.

Brain↗

PubMed2003

Comparing cDNA and oligonucleotide array data: concordance of gene expression across platforms for the NCI-60 cancer cells.

Microarray gene-expression profiles are generally validated one gene at a time by real-time RT-PCR. We describe here a different approach based on simultaneous mutual validation of large numbers of genes using two different expression-profiling platforms. The result described here for the NCI-60 cancer cell lines is a consensus set of genes that give similar profiles on spotted cDNA arrays and Affymetrix oligonucleotide chips. Global concordance is parameterized by a 'correlation of correlations' coefficient.

Algorithms↗

PubMed2003

Diagnostic markers that distinguish colon and ovarian adenocarcinomas: identification by genomic, proteomic, and tissue array profiling.

Colon and ovarian cancers can be difficult to distinguish in the abdomen, and the distinction is important because it determines which drugs will be used for therapy. To identify molecular markers for that differential diagnosis, we developed a multistep protocol starting with the 60 human cancer cell lines used by the National Cancer Institute to screen for new anticancer agents. The steps included: (a) identification of candidate markers using cDNA microarrays; (b) verification of clone identities by resequencing; (c) corroboration of transcript levels using Affymetrix oligonucleotide chips; (d) quantitation of protein expression by "reverse-phase" protein microarray; and (e) prospective validation of candidate markers on clinical tumor sections in tissue microarrays. The two best candidates identified were villin for colon cancer cells and moesin for ovarian cancer cells. Because moesin stained stromal elements in both types of cancer, it would probably not have been identified as a marker if we had started with mRNA or protein profiling of bulk tumors. Villin appears at least as useful as the currently used colon cancer marker cytokeratin 20, and moesin also appears to have utility. The multistep process introduced here has the potential to produce additional markers for cancer diagnosis, prognosis, and therapy.

Adenocarcinoma↗

PubMed2002

Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: microarray analysis of dose- and time-dependent effects.

cDNA microarray technology can be used to establish associations between characteristic gene expression patterns and molecular responses to drug therapy. In this study, we used cDNA microarrays of 1694 cancer-related genes to monitor the gene expression consequences of the treatment of HCT116 colon cancer cells with the topoisomerase I inhibitor camptothecin (CPT). To obtain a more homogeneous cellular response, we synchronized the cells in S-phase using aphidicolin (APH) before CPT treatment. Brief incubation with 20 and 1000 nM CPT caused reversible and irreversible G(2) arrest, respectively, and the patterns of gene expression change (with reference to untreated controls) were strikingly different at the two concentrations. Thirty-three genes, mainly divided into three groups, showed characteristic changes in the first 20 h as a consequence of treatment. Northern blots performed for five of these genes (each under eight experimental conditions) were quite consistent with the microarray results (average correlation coefficient, 0.86). Several p53-activated stress response genes were up-regulated after treatment with 1000 nM CPT or prolonged exposure to APH, but it seemed that the up-regulation did not directly cause cell cycle arrest because the up-regulation induced by prolonged treatment with APH did not prevent cell cycle progression after removal of APH. In contrast, cell cycle-dependent up-regulation of a group of mitosis-related genes was delayed or blocked after CPT treatments. The interrupted up-regulation of this group of genes was directly associated with G(2) arrest. In addition, we observed down-regulation of gene expression in cells that were recovering from cell cycle delay. The observations reported here suggest a fundamental difference at the gene expression level between the molecular mechanism of reversible G(2) delay that follows mild DNA damage and the mechanism of permanent G(2) arrest that follows more extensive DNA damage.

Aphidicolin↗

PubMed1994

The factor structure of the Coping Strategies Questionnaire.

The Coping Strategies Questionnaire (CSQ) (Rosenstiel and Keefe 1983) is the most widely used measure of pain coping strategies. To date, with one exception (Tuttle et al. 1991), studies examining the factor structure of the CSQ have used the composite scores of its 8 a-priori theoretically derived scales rather than the 48 individual items. An examination of the match between the 8 theoretically derived scales and scales empirically extracted from an item analysis is lacking. Accordingly, the CSQ was administered to 126 chronic pain (whiplash) patients. Factor analyses of the individual items revealed an 8-factor structure to be uninterpretable. Of the 2-9-factor solutions tested, the 5-factor structure was the most interpretable: Factor 1, Distraction; Factor 2, Ignoring Pain Sensations; Factor 3, Reinterpreting Pain Sensations; Factor 4, Catastrophizing; Factor 5, Praying and Hoping. Eighteen Ph.D. or M.D. level clinicians classified items into their corresponding category with a high degree of accuracy (on average, 90.2%), attesting to the face and construct validity of the subscales. Four subscales, Catastrophizing, Reinterpreting Pain Sensations, Praying and Hoping and (to a lesser degree) Ignoring Pain Sensations, correspond with parallel subscales proposed by Rosensteil and Keefe (1983). The fifth subscale, Distraction, is comprised of items from their Diverting Attention and Increasing Activity Level subscales, suggesting that cognitive and behavioural distraction comprise 1 rather than 2 coping strategies. That CSQ items on the original Coping Self-Statements and the Increasing Pain Behaviour subscales failed to load consistently on any factor suggests that they do not reliably measure distinct coping strategies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗