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G Thomas

Publications and source records attributed to G Thomas.

At least 469 records · Page 26Linked to original sources
PubMed1993

EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts.

The genes involved in the t(12;22)(q13;q12) translocation found recurrently in malignant melanoma of soft parts have been characterized and shown to form, in four cases studied, hybrid transcripts. The deduced chimaeric protein encoded by the der(22) chromosome consists of the N-terminal domain of EWS linked to the bZIP domain of ATF-1, a transcription factor which may normally be regulated by cAMP. ATF-1 has not previously been implicated in oncogenesis. EWS was first identified as forming a hybrid transcript in Ewing's sarcoma, which links its N-terminal domain to the DNA binding domain of the FLI-1 gene. Thus the oncogenic conversion of EWS follows a common scheme of activation, exchanging its putative RNA binding domain with different DNA binding domains that appear to be tumour-specific.

Activating Transcription Factor 1↗
PubMed1993

Isolation of cosmids and fetal brain cDNAs from the proximal long arm of human chromosome 22.

The proximal portion of human chromosome 22q appears to carry genes implicated in the pathogenesis of various developmental disorders, including the cat eye syndrome (CES) and the DiGeorge syndrome (DGS). A cosmid library was prepared from a radiation hybrid selected for its content in chromosome 22 fragments. A large fraction of cosmids containing human DNA were found to derive from the juxtacentromeric region of chromosome 22, as shown by fluorescence in situ hybridization (FISH) performed using individual cosmids or cosmid pools as probes. Finer mapping was obtained for individual cosmids by hybridization to a somatic cell hybrid mapping panel which splits the long arm of the chromosome into 14 bins numbered 1 to 14 from the centromere to the telomere. Of the 10 cosmids mapped, eight belonged to group 1, the other two to group 14, in agreement with FISH data. Rare endonuclease sites and fragments conserved between species were searched in single cosmids, resulting in the selection of seven cosmid fragments which were used to screen a human fetal brain cDNA library. Three cDNAs were identified, encoded from two chromosome 22 genes which appeared to be novel, as determined from partial end sequence and comparison with the database entries. Fine localization of the 30.9 cDNA indicated that the corresponding gene was located in a segment of proximal 22q overlapping with the critical DGS region.

Animals↗
PubMed1993

Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease which predisposes to the development of schwannomas, meningiomas, ependymomas, and juvenile cataracts. The NF2 gene (NF2) has recently been isolated and maps to chromosome 22q12 between the loci D22S212 and D22S32. Deletion studies in sporadic and NF2 associated schwannomas and meningiomas, and the presence of inactivating mutations in NF2 in patients suggest that it acts as a tumor suppressor gene. A candidate meningioma gene (MEN) has also been isolated from the same interval. A new highly polymorphic (CA)n marker, D22S268, which maps very near to NF2, has allowed us to identify a kindred with three living affected individuals, where the disease is presumably caused by a large germline deletion. Fluorescence in situ hybridization and pulsed field gel electrophoresis confirm the presence of a 700kb deletion which includes the neurofilament heavy chain subunit gene locus (NEFH), D22S268, NF2 and the putative MEN gene. The absence of meningiomas in this pedigree raises doubts as to the existence of a separate MEN locus in this region. These results support the hypothesis that NF2 results from the inactivation of a tumor suppressor gene on chromosome 22q.

Cells, Cultured↗
PubMed1993

Thromboxane and prostacyclin synthesis in experimental pancreas transplantation. Changes in parenchymal and vascular prostanoids.

The principal causes of failure of a pancreas transplant are rejection and vascular thrombosis. There is an unusually high attrition rate for pancreas transplants, but study models have been difficult to develop. In a rat model that allows study of acute rejection to the exclusion of nonspecific effects of transplant surgery on the pancreas, in vitro synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2) by transplanted pancreas and the blood vessels transplanted with it was measured using an RIA for their stable hydrolysis products 6-keto-prostaglandin F1 alpha and thromboxane B2 (TXB2). TXB2 synthesis was significantly greater in allotransplanted pancreas than isotransplanted pancreas from the 5th day after transplantation. Rejection was complete in the allografted group 7-9 days after transplantation. 6-Keto-prostaglandin F1 alpha synthesis was similar in the pancreas for both allografts and isografts. Similar changes were seen in aorta, celiac artery, superior mesenteric artery, and portal vein transplanted with the pancreas. In the transplanted aorta, TXB2 was significantly greater in the allograft group from the third posttransplant day. A group of CsA-treated allografts sampled after 9 days had transplanted pancreatic parenchymal and vascular prostanoid synthesis in the isograft range. The changes in PGI2 and TXA2 synthesis that accompany cellular rejection may mediate vascular failure in rejecting pancreas transplants, and changes in PGI2 and TXA2 synthesis in blood vessels transplanted with the pancreas could promote early vascular thrombosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome 22q13.1-->q13.2.

Adenylosuccinate lyase (ADSL) is an essential enzyme involved in de novo purine biosynthesis. A deficiency in ADSL in humans has been shown to predispose to a neurodevelopmental syndrome with autistic features. Using both a somatic cell hybrid mapping panel and fluorescence in situ hybridization, we have precisely localized the human ADSL gene to chromosome 22q13.1-->q13.2.

Adenylosuccinate Lyase↗
PubMed1993

Vasodilator effects of hydroxylamine in the isolated rodent lung.

Hydroxylamine is a natural product of cellular metabolism that possesses vasodilating properties similar to those of endothelium-derived relaxing factor (EDRF). In the rodent pulmonary circulation preconstricted with the endoperoxide analog U-46619, hydroxylamine relaxed the vasculature in a concentration-dependent manner. Blockade of the hydroxylamine vasodilator response by methylene blue indicated that the mechanism of vasorelaxation is similar to that of EDRF. In this preparation, hydroxylamine is a more potent vasodilator than nitroglycerin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Alcohol-related offending in male special hospital patients.

In a sample of 61 male Special Hospital patients, 11 (18%) were identified as having alcohol-related problems prior to admission. Ten of these alcohol-abusers were interviewed to gather further information about their drinking, offending, and the relationship between the two. Alcohol abusers showed more serious criminality than non-abusers, having significantly more previous convictions and being responsible for a disproportionately high number of offences of murder and manslaughter. Alcohol-related problems appear to have developed quickly in adolescence culminating in the index offence at around 30 years of age. At this time, the mean self-reported weekly alcohol consumption was 240 units (one unit = 8.5gm alcohol). All but one man admitted to a relationship between alcohol and crime, and most showed motivation to change their future drinking behaviour.

Adult↗
PubMed1993

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Adult↗
PubMed1993

Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men.

To evaluate the effects of obesity on the hypothalamo-pituitary-testicular axis, we compared total and free (FT) testosterone (T), androstenedione, dehydroepiandrosterone and its sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide, and estradiol levels in a group of 35 obese [body mass index (BMI), > 30] men (aged 17-61 yr) to levels in a nonobese control group. We observed a highly significant negative correlation (P < 0.001) between plasma (F)T levels and BMI and a significant positive correlation (P < 0.01) between E2 levels and BMI. There were no differences between the obese and the nonobese men in levels of androstenedione, dehydroepiandrosterone sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide. Insulin levels were significantly higher in obese men and were significantly (P < 0.02) correlated with the waist hip girth ratio. To evaluate the role of the hypothalamo-pituitary complex in the decreased (F)T levels in obese men, diurnal (0800-2000 h) LH pulsatility was studied in eight obese middle-aged men and eight age-matched controls. The pulsatility of plasma cortisol levels was also studied. Whereas LH pulse frequency was similar in the obese and control subjects, mean diurnal LH levels, mean diurnal LH pulse amplitude, and the sum of all diurnal LH pulse amplitudes and secretory masses were significantly lower in the obese than in the controls. Moreover, there was a highly significant correlation between the sum of LH pulse amplitudes and plasma (F)T levels. This decrease in LH pulse amplitude is not an isolated phenomenon of hypothalamo-pituitary dysfunction in obese men, because the pulse amplitude of plasma cortisol levels was also decreased. The decreased LH pulse amplitude together with the normal respond of Leydig cells to hCG stimulation reported in the literature suggest by inference that the decreased FT levels in obese men are the consequence of a hypogonadotropism. The decreased LH pulse amplitude and the decreased amplitude of cortisol pulses, and hence probably of ACTH pulses, point toward a general alteration of hypothalamo-pituitary function in obese men.

Adolescent↗
PubMed1993

Non-responsiveness of serum gonadotropins and testosterone to pulsatile GnRH in hemochromatosis suggesting a pituitary defect.

We investigated the potential pituitary origin of gonadal insufficiency in hemochromatosis. Gonadotropin secretion was studied in seven patients with hemochromatosis and hypogonadism, before and after chronic pulsatile GnRH therapy. Pulsatile LH secretion was studied before (sampling every 10 min for 6 h) and after 15-30 days of chronic pulsatile GnRH therapy (10-12 micrograms per pulse). Prior to GnRH therapy, all the patients had low serum testosterone, FSH and LH levels. LH secretion was non-pulsatile in four patients, while a single pulse was detected in the remaining three. Chronic pulsatile GnRH administration did not increase serum testosterone levels; similarly, serum LH levels remained low: neither pulse frequency nor pulse amplitude was modified. We conclude that hypogonadism in hemochromatosis is due to pituitary lesions.

Adolescent↗
PubMed1993

Reverse transcriptase PCR amplification of EWS/FLI-1 fusion transcripts as a diagnostic test for peripheral primitive neuroectodermal tumors of childhood.

The peripheral primitive neuroectodermal tumors (pPNETs) of childhood, including Ewing's sarcoma, peripheral neuroepithelioma, and Askin's tumor, often present significant diagnostic challenges for the anatomic pathologist. One consistent feature of these tumors is the presence of the t(11;22)(q24;q12) in tumor cells, and this translocation has been useful as a marker for this group of tumors. The recent cloning of the t(11;22) breakpoint has revealed the fusion of the human FLI-1 gene on chromosome 11q24 with a gene of unknown function called EWS on 22q12, and fusion transcripts have been detected. These findings have raised the possibility of using molecular genetic analysis as a tool to diagnose pPNETs. To this end, we have tested pPNETs for the presence of EWS/FLI-1 fusion transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR) using EWS and FLI-1 specific primers. Eight (80%) of 10 pPNET cell lines were positive for amplified products using this technique. These results were confirmed by Southern analysis, which revealed rearrangements of EWS using genomic EWS probes in all eight positive cell lines. We then tested 20 primary pPNET tumors, and identified fusion transcripts by RT-PCR in 18 (90%) of these cases. Cloning and sequencing of PCR products confirmed the presence of EWS and FLI-1 sequences in these products. Furthermore, fusion transcripts were not detected by this technique in a series of non-pPNET pediatric solid tumors. Detection of EWS/FLI-1 fusion transcripts by RT-PCR therefore provides a novel adjunctive tool in the diagnosis of pPNETs.

Adolescent↗
PubMed1993

[Genetic heterogeneity of certain sporadic colorectal cancers].

Intratumoral heterogeneity provides information concerning the timing of genetic events which occur during colorectal carcinogenesis. In a series of 14 colorectal adenocarcinomas, the following genetic alterations were characterized: loss of heterozygosity on chromosomes 17 p, 1 p, 18 q, 5 q and 22 q, point mutations on TP53 and K-RAS genes, change in DNA index. Six of the 14 initial samples were investigated for putative genetic heterogeneity. In two cases, variations in genetic alterations on chromosome 17 p and gene TP53 were demonstrated. These events seem to occur at a late stage in colorectal carcinogenesis.

Adenocarcinoma↗
PubMed1993

Efficient screening of p53 mutations by denaturing gradient gel electrophoresis in colorectal tumors.

Alterations in exons 5-8 of the p53 gene have been found in the vast majority of human tumors. Although some specific codons have been revealed as preferential mutational sites in defined tumor types, mutations are generally so scattered within this region that various screening methods for their detection have been widely used. However, the capacity of these techniques to detect exhaustively all mutations has not been evaluated. In this report, conditions for analysing exons 5-8 of the p53 gene by denaturing gradient gel electrophoresis (DGGE) have been elaborated using the Melt87 and SQHTX computer programs. The procedure requires five different amplifications. The screening of 90 colorectal tumors revealed 56 amplification products demonstrating abnormal DGGE behavior. Direct sequencing of these amplification products after asymmetric polymerase chain reaction (PCR) showed, besides polymorphism, 49 somatically mutated DNA samples (54.4%) corresponding to 38 different p53 variants. Moreover, 25 additional p53 variants identified in other tumor types were also detectable with our conditions. Thus, altogether the procedure has been successfully used in the detection of 63 different p53 variants. The experimental differences in migration between the wild-type homoduplex DNA molecule and the heteroduplex(es) containing one mismatch were systematically compared with those calculated by the SQHTX program. The computer program was found to be reliably predictive. This DGGE procedure appears thus to be effective and reliable for detecting mutations in exons 5-8 of the p53 gene.

Base Sequence↗