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G Thomas

Publications and source records attributed to G Thomas.

At least 379 records · Page 21Linked to original sources
PubMed1995

Cloning of a balanced translocation breakpoint in the DiGeorge syndrome critical region and isolation of a novel potential adhesion receptor gene in its vicinity.

Deletions of the 22q11.2 have been associated with a wide range of developmental defects (notably DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome and isolated conotruncal cardiac defects) classified under the acronym CATCH 22. A DiGeorge syndrome patient bearing a balanced translocation whose breakpoint maps within the critical region has been previously described. We report the construction of a cosmid contig spanning the translocation breakpoint and the isolation of a gene mapping 10 kb telomeric to the breakpoint. This gene encodes a novel putative adhesion receptor protein, which could play a role in neural crest cells migration, a process which has been proposed to be altered in DiGeorge syndrome.

Amino Acid Sequence↗
PubMed1995

Engineered serine protease inhibitor prevents furin-catalyzed activation of the fusion glycoprotein and production of infectious measles virus.

We have identified the major cellular endoprotease that activates the fusion (F) glycoprotein of measles virus (MV) and have engineered a serine protease inhibitor (serpin) to target the endoprotease and inhibit the production of infectious MV. The F-protein precursor of MV was not cleaved efficiently into the mature F protein in human colon carcinoma cells lacking functional furin, indicating that furin is the major enzyme responsible for activation of the MV F protein. A human serpin alpha 1-antitrypsin variant was engineered to specifically inhibit furin. When expressed from a recombinant vaccinia virus in primate cells infected by MV, the engineered serpin (alpha 1-PDX) specifically inhibited furin-catalyzed cleavage of the F-protein precursor without affecting synthesis of other MV proteins. We generated human glioma cells stably expressing alpha 1-PDX. MV infection in these cells did not result in syncytia. The infected cells produced all the MV proteins, but the F-protein precursor remained largely uncleaved. This did not prevent virus assembly. However, the released virions contained inactive F-protein precursor rather than mature F protein, and infectious-virus titers were reduced by 3 to 4 orders of magnitude. These results show that a mature F protein is not required for the assembly of MV but is crucial for virus infectivity. The engineered serpin may offer a novel molecular antiviral approach against MV.

Animals↗
PubMed1995

DNA-based presymptomatic diagnosis for the von Hippel-Lindau disease by linkage analysis.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited condition characterized by a predisposition to the development of haemangioblastoma, renal cell carcinoma and phaeochromocytoma. The gene which, when altered, causes the disease was cloned in 1993, and maps within a series of known polymorphic loci in the 3p25-p26 region. To optimize a DNA-based presymptomatic diagnosis, we have selected six highly informative microsatellite loci, closely linked to the VHL gene. Genotyping using a multiplex-PCR approach was performed in 26 affected families including 99 asymptomatic relatives born from an affected parent. Ninety-six subjects were informative with one or more markers, 76 being informative with markers on both sides of the gene. Combination of age-related and DNA-based risk information improved the accuracy of risk assessment for 90 at-risk patients (91%) and allowed attribution of risk with a confidence limit higher than 0.98 in 79 cases (88%).

Adolescent↗
PubMed1995

Patterns of drug use among white institutionalized delinquents in Georgia: evidence from a latent class analysis.

Previous research by Kandel [1] and others indicates that adolescent drug use follows a progression from legal drugs, through marijuana, to hard drugs. In this study of drug use patterns, institutionalized delinquents were found to follow a similar progression of drug use. Unlike previous studies which used "rule of thumb" methods of model assessment, this study uses probabilistic assessment of the models. Importantly, the present study supports a modified gate-way sequence, where cocaine use appears as an intermediate step between marijuana use and use of other hard drugs. It is suggested that widespread availability of cocaine in the late 1980's may have resulted in a new "step" in the drug use sequence.

Adolescent↗
PubMed1995

[Identification of oncogenes and anti-oncogenes].

In spite of early observations indicating an association of cancer with genomic alterations, the precise knowledge of the causal mutations was only initiated since the last 20 years when the techniques of molecular genetics were applied to observations obtained by investigators working in the field of retrovirology, cell biology, cytogenetics and human genetics. A large number of genes which are recurrently altered in defined tumor types has been identified. Schematically it is possible to distinguish dominant mutations which lead to the oncogenic conversion of proto-oncogenes and recessive mutations of antioncogenes which require for phenotypic expression the inactivation of the second allele. Activation of protooncogenes and inactivation of antioncogenes cooperate within the same cells to the determination of the tumor phenotype. Inherited alterations causing major predisposition to tumor development involve most frequently antioncogenes. Most proto-oncogenes and major tumor susceptibility genes are now known. However, we have a poor understanding of the pathologic mechanism triggered by their mutations.

Chromosome Deletion↗
PubMed1995

Genetic predispositions to colorectal cancer.

Genetic predispositions to colorectal cancer can schematically be divided in two categories depending on the presence or absence of a diffuse polyposis i.e.: a large number of adenomatous polyps in the colon and rectum of affected patients. These syndromes are referred as familial adenomatous polyposis coli and hereditary non polyposis colon cancer (HNPCC) respectively. The gene which when altered causes familial adenomatous polyposis coli is called APC and has been identified in 1991 but the function of its product remained elusive. Recent experimental data indicate that the APC protein can interact with catenins and tubulins, two groups of proteins known to be components of adherens junctions and cytoskeleton. Thus the APC protein may play a role in cell adhesion and in transduction of signal regulating the cell cycle. Of more immediate clinical interest is the observation that specific APC mutations appear to participate in the severity of the disease and determine the development of hypertrophy of the retinal pigment epithelium, a diagnostically important manifestation of the APC disease found in 70% of the patients. HNPCC syndromes have been recognized as being frequently associated with a defect in the DNA mismatch repair pathway. Furthermore, human genes, demonstrating homology with the bacterial DNA repair genes MutS and MutL, have been identified and shown to be altered in several HNPCC families. There are now indications that genotyping of tumor DNA at particular loci, termed microsatellite, may contribute in the identification of patients genetically predisposed to tumor development.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenomatous Polyposis Coli↗
PubMed1995

Specific inhibition of the contraction of the rat aorta by estradiol 17 beta.

Short-term exposure to estradiol 17 beta is known to inhibit the contraction of vascular smooth muscle preparations that is thought to be mediated by a [Ca++]-dependent mechanism. The purpose of this investigation was to examine the effect of prolonged exposure of vascular preparations to estradiol 17 beta to provide significant time for protein synthesis. We find that treatment of rat aortic rings with estradiol 17 beta (0.37-37 microM) for 15 to 180 min and subsequent removal of the estrogen by washing, attenuated the vasoconstrictor responses to phenylephrine and potassium chloride in a time-dependent manner. The maximum inhibitory effect took 120 min to develop. The inhibitory effect was endothelium independent and not blocked by the cyclooxygenase inhibitor, indomethacin, or by the endothelium derived relaxing factor inhibitor, Nw-nitro-L-arginine methyl ester. This effect was highly stereo-specific in that the 17 alpha isomer was significantly less potent than the 17 beta isomer of estradiol. Further, compared to other steroids, estradiol 17 beta was the most potent. The inhibitory effect of estradiol was blocked completely by pretreatment with the protein synthesis inhibitors, cycloheximide and puromycin, but not by actinomycin D. Electron microscopy showed an increase in ribosomal expression at the rough endoplasmic reticulum after incubation of the rat aorta with estradiol for 120 min. This indicates increased protein synthesis after exposure to estradiol 17 beta. We speculate that the time dependent inhibitory effect of estradiol 17 beta on vascular smooth muscle is related to protein synthesis at the translational level.

Animals↗
PubMed1995

Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome.

Rett syndrome (RS), a progressive encephalopathy with onset in infancy, has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in female MZ twins. The underlying mechanisms proposed are an X-linked dominant mutation with male lethality, uniparental disomy of the X chromosome, and/or some disturbance in the process of X inactivation leading to unequal distributions of cells expressing maternal or paternal alleles (referred to as a "nonrandom" or "skewed" pattern of X inactivation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins, two concordant for RS and one uniquely discordant for RS. Analysis of X-inactivation patterns confirms the frequent nonrandom X inactivation previously observed in MZ twins but indicates that this is independent of RS. Analysis of 29 RS females reveals not one instance of uniparental X disomy, extending the observations previously reported. Therefore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most MZ female twins with RS, which has not been observed in female twins with known X-linked mutations, argues against an X mutation.

Child↗
PubMed1995

[Clinical comparison of the calculus inhibiting effect of three commercially available toothpastes].

A twelve-week independent and double-blind clinical study was conducted on a sample of 143 calculus forming adult male and female subjects--with the average age of 39.11 years--to compare directly the anticalculus efficacy of three commercially-available dentifrices, as compared to a placebo dentifrice. The three commercially-available dentifrices were: Colgate Total toothpaste, Colgate Tartar Control toothpaste and Pepsodent Ultra toothpaste. All these three dentifrices provided statistically significant reductions in supragingival calculus formation, as compared to a placebo dentifrice. There was no statistically significant difference among the three commercially-available dentifrices with regard to anticalculus efficacy.

Adolescent↗
PubMed1995

[Towards an allotype of second generation colon cancer].

A subset of genetic alterations distinguishes two groups of colon cancers. In the first group instability of microsatellite loci due to a defective DNA mismatch repair system is observed. The second group is characterized by recurrent losses of chromosome regions, frequently associated with hyperploidization. We have developed a technique which enables a fine description of allelic losses in this second group of tumours. The typing of 278 loci in 47 hyperploid colon cancers has provided information for an average of 160 loci per tumour. The high frequency of allelic losses on chromosomes 17, 18 and 5 was confirmed thus validating our methodological approach. Several additional chromosome segments were observed lost in over 40% of the cases, suggesting that tumour suppressor genes may map within these regions. Further technical development should contribute to the identification of these genes.

Alleles↗
PubMed1994

Prejunctional actions of N-ethyl-maleimide and phenoxybenzamine in rat vas deferens.

In studies of electrically evoked isometric contractions of rat vas deferens, N-ethyl-maleimide (30 microM) pretreatment significantly reduced the prejunctional inhibitory potencies of xylazine and 5-hydroxytryptamine but failed to affect the potency of the alpha 1-adrenoceptor agonist amidephrine. Phenoxybenzamine (1 microM) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (10 microM) produced significant shifts in the potency of xylazine and significantly reduced the maximum inhibition, but the combination of phenoxybenzamine or EEDQ and N-ethyl-maleimide (30 microM) produced no further alteration in the effects of xylazine. In displacement studies, N-ethyl-maleimide displaced the binding of [3H]MK 912 ((2S,12bS)1',3'-dimethylspiro- (1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinazoline)- 2,4'- pyrimidin-2'one) to rat renal cortex membranes with a Ki of 466 +/- 133 microM (n = 5), and so does not bind to alpha 2-adrenoceptors in the concentration range in which it affects prejunctional receptor mediated responses. This may suggest that N-ethyl-maleimide has actions other than inactivation of G-proteins or that the irreversible alpha 2-adrenoceptor antagonists phenoxybenzamine and EEDQ inactivate G-proteins sensitive to N-ethyl-maleimide in concentrations at which they bind to alpha 2-adrenoceptors.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1994

Activation of p70/p85 S6 kinase by a pathway independent of p21ras.

The enzymes p70s6k and p85s6k are two isoforms of the same kinase and are important in mitogenesis. Both isoforms are activated by a complex phosphorylation event and lie on a common signalling pathway, distinct from that of the p42mapk/p44mapk kinases. Activation of p42mapk/p44mapk is triggered by sequential activation of the GDP-GTP exchange factor Sos, the GTP-binding protein p21ras, and protein kinases p74raf and p47mek (refs 7-10). As p21ras transformed cells have increased S6 phosphorylation, we tested whether the p70s6k/p85s6k signalling pathway bifurcates between p21ras and p42mapk/p44mapk. We found that mutants of p74raf and p21ras blocked activation of epitope-tagged p44mapk but not epitope-tagged p70s6k. Moreover, in cells expressing human platelet-derived growth factor receptors lacking the kinase-insert domain, the growth factor activates p21ras but not p70s6k/p85s6k. The critical autophosphorylation site for p70s6k/p85s6k activation within this domain is a tyrosine at residue 751. Our results show that the p70s6k/p85s6k signalling pathway is independent of p21ras, that it bifurcates from the p21ras pathway at the receptor, and that it is initiated by autophosphorylation at a specific site.

3T3 Cells↗
PubMed1994

Cloning and chromosome localization of the mouse Ews gene.

The human EWS gene encodes a putative RNA binding protein. As a result of acquired chromosome rearrangement, the N-terminal portion of the EWS protein is fused to the DNA binding domain of either FLI-1 or ERG in the Ewing family of tumors and to the DNA binding domain of ATF1 in malignant melanoma of soft parts. We have determined the cDNA sequence of the mouse Ews gene. Its nucleotide sequence and its translation product demonstrate 93 and 98% homology with the human EWS cDNA and protein, respectively. The murine Ews locus lies within a conserved synteny segment between human chromosome 22q12 and mouse chromosome 11A1-A3.

Amino Acid Sequence↗