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G Dominguez

Publications and source records attributed to G Dominguez.

At least 19 recordsLinked to original sources
PubMed2006

Adolescents carrying a missense mutation in the CART gene exhibit increased anxiety and depression.

A Leu34Phe mutation in the cocaine- and amphetamine-regulated transcript (CART) gene has been associated with severe early-onset obesity in an affected family. It has been shown that, in a cell culture system, the mutation resulted in altered CART peptide levels, and animal studies suggest that CART is involved in anxiety as well. The availability of the affected family allowed for testing of anxiety and other traits in humans carrying a mutation in CART gene. This study shows that a small group of adolescents with the mutation exhibit higher anxiety and depression scores than control subjects.

Adolescent↗
PubMed2004

Cocaine- and amphetamine-regulated transcript peptide levels in blood exhibit a diurnal rhythm: regulation by glucocorticoids.

Cocaine- and amphetamine-regulated transcript (CART) peptides are novel neurotransmitters that are implicated in several physiological functions such as control of feeding behavior, drug reward, sensory processing, stress, and development. Although a majority of studies have examined the role of CART in the brain, less is known about its function in the periphery. Therefore, the goals of this study were to examine the levels and species of CART peptides in blood, to determine whether they undergo diurnal rhythms, and to elucidate their sources and regulatory factors. RIA showed that CART peptides are present in the blood of rats and monkeys and that they exhibit a diurnal variation. Western blotting confirmed the pattern of diurnal variation in rats and, additionally, showed that CART immunoreactivity was due to a single predominant fragment with an apparent molecular weight in the range of the active CART 55-102 peptide. Adrenalectomy caused a 70% reduction in CART peptide levels in rat blood, and this was reversed by corticosterone replacement. CART levels paralleled glucocorticoid levels in rat and monkey blood. Control of CART levels by corticosterone suggests the possibility that CART peptides in blood may be influenced by hypothalamic-pituitary-adrenal interactions and that they may play a role in glucocorticoid-related processes such as stress.

Adrenalectomy↗
PubMed2003

Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer.

BACKGROUND: Survival at the intermediate stage of colorectal cancer (CRC) is less predictable than in the early and advanced stages. Several genetic markers possibly involved in growth and progression of CRC can be used for prognosis. AIMS: This study investigated the proportion of allelic loss (loss of heterozygosity (LOH)) at the BRCA1 locus in sporadic CRC and its value in patient prognosis. PATIENTS AND METHODS: A total of 314 patients were investigated for LOH at the BRCA1 locus using polymerase chain reaction by means of three intragenic polymorphic microsatellite markers. Allelic losses were compared with clinicopathological characteristics of patients, recurrence rate, disease free survival (DFS), and overall survival. RESULTS: Twenty six patients were excluded because of microsatellite instability. Of the remaining 288 cases, 244 (84.7%) were informative, with 97 (39.8%) patients bearing BRCA1 LOH. Recurrence rate was higher in patients with LOH (p=0.0003), and DFS was 73.3% (SEM 5.7) at five years in patients without LOH, and 49.2% (7.1) in cases with positive allelic loss (p=0.0004). Retention of alleles at the BRCA1 locus was associated with a favourable DFS in stages I and II (p<0.05). The presence of LOH was also significantly associated with short overall survival (p=0.02). Multivariate analysis in the complete series showed that stage (p=0.006) and lymph node metastases (> or =4 nodes, p=0.0001; 1-3 nodes, p=0.038) were independent prognostic factors. However, multivariate study by stages revealed that BRCA1 LOH was an independent prognostic factor in stages I and II (p=0.001). CONCLUSIONS: BRCA1 LOH is a molecular alteration present in CRC, with unfavourable repercussions for overall survival, that could be considered as an outstanding independent prognostic factor in stages I and II.

Aged↗
PubMed2002

CART promoter CRE site binds phosphorylated CREB.

It has been shown previously that: CART (cocaine- and amphetamine-regulated transcript) mRNA is tightly regulated in brain; protein kinase A (PKA) is involved in CART expression in GH3 cells; and a cyclic AMP-responsive element (CRE) site is present in the proximal promoter region of the CART gene. Thus, the goal of this study was to test if CRE binding protein (CREB) can bind to the consensus CRE site and if phosphorylation of CREB occurs in GH3 cells under conditions of enhanced CART gene expression. Electromobility shift assays showed that a 27-bp oligonucleotide containing the CART CRE site was indeed bound by nuclear factors. Western blotting showed that incubation of GH3 cells with forskolin, which enhances CART mRNA expression, caused an increase in phosphorylated CREB (P-CREB) levels. Supershift analyses indicated that the CART CRE oligo/protein complex interacted with a P-CREB antibody. Taken together, these data indicate that P-CREB is a likely regulator of CART expression in GH3 cells.

Animals↗
PubMed2002

CART peptides.

Explore the source record for details and available documents.

Amino Acid Sequence↗
PubMed2002

Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells.

BACKGROUND: Although circulating tumour DNA has been detected in patients with different types of cancer, little is known of free RNA in cancer patients. AIMS: We investigated the presence of RNA from epithelial tumours in plasma from patients with colorectal carcinomas, and its correlation with tumour characteristics and circulating tumour cells. METHODS: beta-actin mRNA was analysed to assess the viability of plasma RNA in samples from 53 patients with colonic cancer and 25 controls. Subsequently, nested primers were used to detect the presence of cytokeratin 19 (CK19) and carcinoembryonic antigen (CEA) RNA in the same samples. Nine clinicopathological parameters were studied to correlate the molecular and clinical parameters. Additionally, we investigated for micrometastases in blood in 18 of these patients and in 10 of the controls samples. RESULTS: All samples had detectable quantities of beta-actin RNA. In the controls, one case (4%) was positive for CEA and five (20%) for CK19 RNA; of the 53 patients, 17 cases (32%) were positive for CEA and 39 (73.6%) for CK19 RNA. This was statistically significant (p=0.000001). Advanced stages (p=0.03) and soluble CEA status (p=0.03) were associated with the presence of CEA, CK19, or both RNAs in plasma. Lymph node metastases (p=0.06) and vascular invasion (p=0.07) were almost significant. On the basis of these results, we examined the possible presence of micrometastases in blood in several of these patients. The presence of plasma tumour RNA was found to be associated with circulating tumour cells in blood (p=0.04). CONCLUSIONS: Epithelial tumour RNA is detectable in plasma from colon cancer patients. This molecular event is associated with advanced stages and circulating tumour cells. Our results could offer new approaches in the diagnosis and monitoring of colon cancer.

Actins↗
PubMed2001

Genes in drug abuse.

Because of the genome projects it will be possible to identify the changes in gene expression that are associated with drug abuse. The ultimate goal will be to determine the role and significance of the gene products. To date about 100 genes have been found with altered expression after administration of drugs. The development of new technologies such as microarrays will greatly facilitate finding such changes in expression. The rate at which levels of some gene products change is compatible with the time course of development of dependence in animals, but we must be able to establish a cause-effect relationship between genes and drug abuse, which this will be difficult. The product of the novel cocaine and amphetamine regulated transcript (CART) gene is a useful example where a gene product has been associated with drug abuse. CART was identified as an mRNA that changed in response to psychostimulant drug administration and injection of CART peptides into the ventral tegmental area produces psychostimulant-like effects. Definitive evidence, if obtainable, that specific genes are responsible for vulnerability to drug abuse could have dramatic effects on public health policy.

Animals↗
PubMed2001

Wild type p73 overexpression and high-grade malignancy in breast cancer.

The overexpression of wild type p73 is the most frequent alteration of p73 in malignancies. We investigated, in 70 breast carcinomas, p73 mRNA expression and its relationship to p53 mutations, determined by an immunohistochemical method, and loss heterozygosity (LOH) status of the 1p36 region, together with its possible implication in the pathogenesis of breast carcinomas. LOH, amplifying DNA by PCR using 5 markers, of 1p36 region (one intragenic to p73 gene) was found in 17% of cases but no significant correlation was observed with p73 overexpression. p53 positive immunostaining was present in 33% of breast carcinomas, and these exhibited a statistically significant relation with p73 overexpressed tumors. Overexpression of p73 mRNA was observed in 19 tumors (27%). The analysis of cases with p73 overexpression and cases with normal mRNA expression, in terms of age and pathologic characteristics of the tumors showed a significant association of p73 overexpression and tumors with lymph node metastases, vascular invasion and higher pathologic stage. These results suggest that p73 overexpression is a molecular alteration that could be implicated in the tumorigenesis of breast carcinomas and, eventually, in a poor clinical behavior.

Adult↗
PubMed2001

Detection of epithelial messenger RNA in the plasma of breast cancer patients is associated with poor prognosis tumor characteristics.

PURPOSE: Free plasma RNA has been scarcely studied in patients with cancer. Here we examine the presence of RNA from epithelial tumors in plasma from a series of breast cancer patients and its correlation with tumor characteristics and circulating tumor cells. EXPERIMENTAL DESIGN: beta-actin mRNA was analyzed to check the viability of plasma RNA in samples from 45 patients with breast cancer and 25 controls. Nested primers were used to detect the presence of cytokeratin 19 (CK19) and Mammaglobin in the same samples. Eleven clinicopathological parameters were studied and correlated with molecular parameters. Additionally, we looked for circulating tumor cells in 16 of these patients and in 10 of the controls. RESULTS: All samples showed detectable quantities of beta-actin RNA. In controls, 3 cases (12%) were positive for Mammaglobin, and 5 (20%) were positive for CK19 RNA; of the 45 patients, 27 cases (60%) were positive for Mammaglobin, and 22 (49%) were positive for CK19. These differences were statistically significant (P = 0.001). Tumor size (P = 0.01) and proliferative index (P = 0.02) were associated with the presence of Mammaglobin, CK19, or both RNAs in plasma. Pathological stage (P = 0.06) was close to significance. Although a statistical relationship was not demonstrated, 9 of the 10 patients with circulating tumor cells showed epithelial mRNAs in plasma. CONCLUSIONS: We conclude that epithelial tumor RNA is detectable in plasma from breast cancer patients and that this finding is associated with a probable poor prognosis and circulating tumor cells.

Actins↗
PubMed2000

Spur cell anaemia and acute haemolysis in patients with hyperreactive malarious splenomegaly. Experience in an isolated Yanomamo population of Venezuela.

A prospective study, aimed to investigate the aetiology of an unusual clustering of cases of severe acute haemolytic anaemia affecting a high percentage of the adult population, was carried out in two isolated Yanomamo communities of the Upper Orinoco basin in Venezuela. Twenty-six patients with active or recent episodes of severe haemolysis were evaluated. All of them exhibited massive liver and spleen enlargement and fulfilled the diagnostic criteria of the hyperreactive malarious splenomegaly (HMS) syndrome. In four cases with advanced non-alcohol-related chronic liver disease, hypersplenism, severe haemolytic anaemia and acanthocytosis, the characteristic clinical and laboratory findings of spur cell anaemia were documented. Chronic infection by the HBV and HCV was present in three of them. However, in most of the 22 additional HMS cases, the acute haemolytic condition appeared associated with the occurrence of a cold agglutinin-mediated autoimmune response. The clustering of a significant number of cases of severe acute haemolysis in HMS patients from this small isolated aboriginal community is most unusual, and represents a serious complicating factor for a population already beleaguered by a high prevalence of malaria due to multiresistant strains of Plasmodium falciparum. Moreover, the coexistence of HMS and severe chronic HBV or HCV infection may further aggravate the course of the haemolytic disorder, because of the occurrence of spur cell anaemia.

Acute Disease↗
PubMed2000

DNA damage after chemotherapy correlates with tumor response and survival in small cell lung cancer patients.

To explore the induction of chemotherapy (CT) DNA damage and its correlation with tumor response and patient survival, we undertook the present study in 20 small cell lung cancer (SCLC) patients. All patients underwent the same treatment based on CT courses of carboplatin and etoposide. Blood samples were taken before and immediately after CT and every 12 weeks during follow-up. Nuclear DNA damage was determined through the variations in three mitochondrial pseudogene mutations in DNA of peripheral blood mononuclear cells. They were detected by mutation-specific PCR and assessed by a semiquantitative method. The relative level of mutation rose after chemotherapy in all cases. Among the 11 patients (55%) with higher relative levels of mutations, 9 (82%) of them achieved a complete response. In contrast, of the 9 patients (45%) with lower relative levels of mutations, only 2 (18%) achieved a complete response, displaying a statistically significant difference (P=0.02). The overall survival for patients with marked genomic damage was 18 months (range 10-24), and for patients with low degree of DNA damage, it was 12 months (range 5-15) (P=0.002). Genomic damage detected after chemotherapy treatment correlates positively with tumor response and patient survival.

Adult↗
PubMed2000

Synthesis of tricyclic aromatic compounds by the intramolecular pauson-khand reaction promoted by molecular sieves(,)(1)

Pauson-Khand reactions are carried out with different substituted aromatic enynes, yielding tricyclic cyclopentenones related to natural products such as chromenes. Enynes are easily obtained in a two-step approximation from the corresponding salicylaldehydes. The reaction is promoted by dissolved TMANO (trimethylamine N-oxide) and/or 4 A molecular sieves. This new way of induction for the Pauson-Khand reaction increases yields remarkably, allowing the reaction of some substituted alkenes which fail to react in the absence of the zeolite. Isomerization of the double bond of the cyclopentenone ring is observed except when nonterminal triple bonds are used. For trisubstituted alkenes, an interrupted Pauson-Khand process is observed with moderate yields.

Journal Article↗
PubMed2000

Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors.

BACKGROUND: Inherited mutations in the BRCA1 gene may be responsible for almost half of inherited breast carcinomas. However, somatic (acquired) mutations in BRCA1 have not been reported, despite frequent loss of heterozygosity (LOH or loss of one copy of the gene) at the BRCA1 locus and loss of BRCA1 protein in tumors. To address whether BRCA1 may be inactivated by pathways other than mutations in sporadic tumors, we analyzed the role of hypermethylation of the gene's promoter region. METHODS: Methylation patterns in the BRCA1 promoter were assessed in breast cancer cell lines, xenografts, and 215 primary breast and ovarian carcinomas by methylation-specific polymerase chain reaction (PCR). BRCA1 RNA expression was determined in cell lines and seven xenografts by reverse transcription-PCR. P values are two-sided. RESULTS: The BRCA1 promoter was found to be unmethylated in all normal tissues and cancer cell lines tested. However, BRCA1 promoter hypermethylation was present in two breast cancer xenografts, both of which had loss of the BRCA1 transcript. BRCA1 promoter hypermethylation was present in 11 (13%) of 84 unselected primary breast carcinomas. BRCA1 methylation was strikingly associated with the medullary (67% methylated; P =.0002 versus ductal) and mucinous (55% methylated; P =.0033 versus ductal) subtypes, which are overrepresented in BRCA1 families. In a second series of 66 ductal breast tumors informative for LOH, nine (20%) of 45 tumors with LOH had BRCA1 hypermethylation, while one (5%) of 21 without LOH was methylated (P =.15). In ovarian neoplasms, BRCA1 methylation was found only in tumors with LOH, four (31%) of 13 versus none of 18 without LOH (P =.02). The BRCA1 promoter was unmethylated in other tumor types. CONCLUSION: Silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific histopathologic subgroups. These findings support a role for this tumor suppressor gene in sporadic breast and ovarian tumorigenesis.

Breast Neoplasms↗
PubMed2000

Absence of point mutations at codon 17 of the mdm2 gene (serine 17) in human primary tumors.

Mdm2 is a phosphoprotein that interacts with protein p53, inhibiting its activity. A serine located in position 17 of Mdm2, has been implicated in its phosphorylation process. We hypothesize that point mutations at serine 17 could block its phosphorylation and thereby increase the p53-Mdm2 interaction. This mechanism could increase the p53 degradation and cause a loss of the protective effect of p53 against tumorigenesis. This hypothesis was based on recent studies in vitro, demonstrating that when serine 17 is mutated, the DNA-dependent protein kinase, activated by genomic damage, is unable to phosphorylate it. Thus, we investigated whether structural point mutations at exon 3 of the Mdm2 gene, affecting codon 17, were present in 162 human primary tumors, 70 breast carcinomas, 14 bladder tumors, 18 colon adenocarcinomas and 60 testicular tumors. Direct sequencing of a fragment (204 bp) of exon 3 of the Mdm2 gene that contains the codon 17 showed no mutations at this position, independently of the presence or absence of p53 gene mutations in the same tumors. These results do not support the hypothesis that mutations in the Mdm2 gene at this level are involved in the tumorigenic process of human cancers.

Codon↗
PubMed2000

Clinicopathological characteristics of breast carcinomas with allelic loss in the p73 region.

p73, a new member of the p53 family, has been mapped to chromosome 1p 36, a region where loss of heterozygosity (LOH) is frequently observed in primary human tumors. Allelic loss studies involving the 1p arm in breast carcinomas offer rates ranging from 13% to 75%, depending on the genetic interval being studied. We investigated LOH in an intragenic microsatellite marker, and those centromerically flanking the p73 gene, at 1p 36, and their correlations with patient age and 10 pathologic parameters in a series of 193 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using the five markers of the 1p 36 region (p73P1, D1S2694, D1S214, D1S2666 and D1S450). LOH was found in at least one of these markers in 27% of tumors. When we established the comparison between tumors with and without LOH and the distribution of the 10 pathologic parameters considered, we observed statistically significant differences in association with higher histologic grade (p = 0.02), more advanced pathological stage (p = 0.02), peritumoral vessel involvement (p = 0.04) and poorly differentiated carcinomas (p = 0.01), as well as in tumors that concomitantly exhibited lymph node metastases, peritumoral vessel involvement and absence of steroid receptors (p = 0.02). These data suggest that LOH in the p73 region could be pathogenically related to breast cancer and possibly to a poor tumor prognosis.

Adult↗
PubMed2000

Microsatellite alterations and TP53 mutations in plasma DNA of small-cell lung cancer patients: follow-up study and prognostic significance.

BACKGROUND: Small-cell lung cancer (SCLC), one of the major types of lung cancer, is associated with many different somatic molecular genetic changes. These alterations, observed in tumor DNA, have also been identified in the plasma DNA of patients. We undertook the present study to make a prospective investigation into the correlation between abnormal plasma DNA and patient survival. PATIENTS AND METHODS: Thirty-five patients with SCLC were selected after histological diagnosis. Polymorphic markers (ACTBP2, UT762 and AR) were chosen for their reported high rate of alterations in SCLC and analyzed in tumor tissue, normal blood cells and plasma DNA. Furthermore, we looked for mutations of the TP53 gene in tumor and plasma DNA. RESULTS: In 25 patients (71%) at least one molecular change precisely matching that of the primary tumor was detected in the plasma DNA. No difference in survival was observed between patients with aberrant plasma DNA and patients without plasma DNA alterations. However, patients with microsatellite modifications and TP53 mutations concomitantly, showed a significant difference (P = 0.02) in survival compared with patients bearing only one of these molecular changes. In 15 cases it was possible to find a correlation either between tumor response and disappearance of abnormal plasma DNA, or tumor progression and persistence of plasma DNA alterations. CONCLUSIONS: Free plasma DNA with molecular alterations is present to a high degree in plasma DNA of SCLC patients and may have a role as a prognostic factor.

Adult↗