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G Guanti

Publications and source records attributed to G Guanti.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of prostaglandin E(2) on the proliferation, Ca(2+) mobilization and cAMP in HT-29 human colon adenocarcinoma cells.

Several lines of evidence suggest that non-steroidal antiinflammatory drugs (NSAIDs) have anticarcinogenic effects. The causal relationship linking the preventive effect of NSAIDs on colon cancer and the inhibition of prostaglandin synthesis is questioned by the contrasting results obtained by many laboratories. The experiments reported in this paper demonstrate that prostaglandin E(2) (PGE(2)) did not stimulate the proliferation in HT-29 human colon adenocarcinoma cells under several experimental conditions. Moreover, PGE(2) and 17-phenyl trinor prostaglandin E(2) (a specific agonist of EP1 receptors) did not increase intracellular Ca(2+) concentration. Finally, PGE(2) did not affect the intracellular cAMP and did not reduce the isoproterenol dependent increase in cAMP. These results indicate that in HT-29 cells: (1) proliferation is not directly sensitive to PGE(2); and (2) PGE(2) does not stimulate a signal transduction pathway leading to intracellular increase in cAMP or Ca(2+) mobilization. Therefore, other cell lines should be used to assess the direct role played by prostanoids in promoting cell proliferation in colon cancer.

Adenocarcinoma↗
PubMed2000

Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis.

So far, somatic mutations of the PTEN gene have been found in several different neoplasms but not in colorectal tumours. As exons 7 and 8 of the PTEN coding sequence contain an (A)(6)repeat and mononucleotide repeat sequences are targets for mutations in tumours with microsatellite instability (MI), we screened a panel of sporadic colorectal tumours exhibiting MI to test whether PTEN gene repeats are frequently mutated in MI(+)colorectal cancers. Of 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with consequent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D10S541, was detected in two of three informative samples. To further address the role of the PTEN gene in MI(+)colorectal cancer, in the six patients with mutated PTEN, we analysed the mononucleotide repeats of six other genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC. In two of these six patients, mutations of the TGFbRII gene only were present, indicating that PTEN may have a role in the mutator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI(+)colorectal tumours. The mutation of both PTEN alleles and evidence that the PTEN protein is expressed in normal colon suggest that loss of function of this gene could play a direct role in tumorigenesis.

Colorectal Neoplasms↗
PubMed2000

17-alpha-ethinylestradiol and norgestrel in combination induce micronucleus increases and aneuploidy in human lymphocyte and fibroblast cultures.

Oral contraceptives are highly efficient and easily administered drugs; however, it must not be forgotten that they are composed of chemical substances which can be classified as potential carcinogens. Testing of a substance for genotoxicity represents a reliable approach both to evaluate the genetic hazard and to obtain information on its possible tumorigenic (cancerogenic) properties. The present study was undertaken to evaluate through carefully planned and controlled investigations the in vitro cytogenetic effects of oral contraceptives (ethynilestradiol and norgestrel mixed in the proportion 1:5) using three different concentrations, with two different durations of treatment (48 and 72 h), on two types of human cells (lymphocytes and fibroblasts) and a series of short-term test procedures: sister chromatid exchange (SCE), micronucleus test (MN), and chromosome aberrations (CA). In addition, the FISH procedure and in vitro anaphase and metaphase preparation analyses were performed. In contrast to CA and SCE frequencies, the frequency of MN in treated blood lymphocytes showed higher values by comparison with the controls, although the difference was statistically significant only for the lowest concentration (P = 0. 016). When using pancentromeric alphoid probes, the FISH procedure gave positive signals in more than 85% of micronuclei, clearly indicating that MN may contain whole chromosomes rather than acentric fragments. Unlike the lymphocytes, the fibroblasts showed dose-dependent effects, although those treated with the highest hormone concentrations showed an increased number of highly damaged cells (cytoplasmatic vacuolization, nuclear fragmentation, etc.), a decreased number of anaphase cells, a large number of which were abnormal, and a reduction of mitotic index. In conclusion, our data confirm that hormones do not induce structural chromosome aberrations in lymphocytes and indicate that ethynilestradiol and norgestrel have an aneugenic effect on fibroblast and lymphocyte cultures; FISH analysis on micronuclei from lymphocyte cultures and anaphase preparations from fibroblast cultures support this hypothesis. Teratogenesis Carcinog. Mutagen. 20:147-159, 2000.

Aneuploidy↗
PubMed2000

Increment of sister chromatid exchange frequencies (SCE) due to epichlorohydrin (ECH) in vitro treatment in human lymphocytes.

Although several studies have examined the effects on health of exposure to epichlorohydrin (ECH) through normal industrial operations and production, there is still considerable interest in its potential harmful effects on humans. The aim of the present study was to evaluate ECH effects in vitro through controlled investigations by using sister chromatid exchange (SCE), micronucleus (MN), and chromosome aberrations (CA) as the test battery. Cultures for cytogenetic tests were set up from blood samples of four healthy non-smoking and three smoking males. The experiments were performed using four different concentrations: 10(-10) M, 10(-8) M, 10(-6) M, and 10(-4) M, of ECH in DMSO. Analysis of variance showed that concentrations of ECH had significant effects on SCE/cell frequencies in the lymphocyte cultures of all donors (F=100.25, P<0.001). We were unable to find any evidence of significant increases in CA and MN frequencies in ECH-treated lymphocyte cultures with respect to the controls.

Adult↗
PubMed2000

Hereditary colorectal cancer syndromes.

Tumors of large bowel continue to be one of the leading causes of morbidity and mortality with about 300,000 new cases and 200,000 deaths per year in Europe and USA despite recent technological advancements. In sharp contrast with these discouraging data, the basic knowledge of colorectal neoplasms has grown remarkably in the last decades especially with the genetic elucidation of the two inherited cancer-predisposition syndromes, familial polyposis (FAP) and hereditary non polyposis colorectal cancer (HNPCC). Recognition of the genetic component of CRC is growing; gene mutations responsible for cell transformation can be present as inherited germline defect or arise in somatic cells as consequence of environmental insults. The two main hereditary syndromes, FAP and HNPCC, account for about 6-10% of CRCs, remaining cases are attributed to so called sporadic cancer. Although the timescale of the appearance and risk of recurrence of the hereditary and sporadic forms are quite different, they share a common pathway: the adenoma to carcinoma sequence. In 1990 Fearon and Vogelstein proposed a multistep model for the molecular events underlying colorectal tumorigenesis. The model was based on two assumptions: the first one is that the tumors are clonal, the second assumption is that the colorectal tumorigenesis occurs as succession of a series of events that can be described as dyplasia-carcinoma sequence or adenoma-carcinoma sequence. The initial alterations which are not detectable on histologic examination, are subtle changes in the normal balance between cell growth and cell death. With progression precursors to adenoma, the foci of aberrant cripts become detectable. Few adenomas progress to carcinoma, however if the progression of these lesions remain unchecked, there is an increased risk of tumor diffusion. As the cells need time to accumulate the genetic defects including mutational activation of oncogenes and inactivation of tumor suppressor genes to undergo full malignant transformation, CRC occurs mainly in the elderly. If one of these defects are present at birth as germline mutations, fewer mutational events will be requested to reach malignant transformation and the disease will appear earlier().

Adenomatous Polyposis Coli↗
PubMed1999

Comparison of clinical and demographic features between affected pairs of Italian multiple sclerosis multiplex families; relation to tumour necrosis factor genomic polymorphisms.

We conducted a comparative analysis of clinical and demographic findings between pairs of relatives (36 sibling and 9 parent/child), concordant for Multiple Sclerosis (MS), from 40 MS Italian Multiplex families. A genetic TNF (alpha and beta) loci typing in 51 affected and 69 healthy relatives belonging to 25 of these families was also performed. The sib pairs resulted significantly concordant for age at onset (r=0.414, P<0.013), Progression Index (r=0.34, P<0.05) and sensory symptoms at onset (k=0.37), and significantly not concordant for sex (k=-0.37), whereas no concordance was found for year at onset and disease course. The only significant result in the small group of parent/child pairs was that parents developed MS at an age of 18.74 years significantly (P=0.020) greater than their children. Genomic analysis identified 13 variants of TNF-a alleles, 7 of TNF-b, 6 of TNF-d and 3 of TNF-e. No differences in the frequencies of the various TNF alleles were observed between affected and healthy relatives. The two-point lod-score analysis of the TNF locus showed not significant or negative results for the TNFalpha loci and slightly positive results (Zmax=0.4 at theta=0.2 cM) for the TNFbeta-b locus in the lowest penetrance dominant model. The Sib pair analysis, using combined TNFalpha and TNFbeta haplotypes, demonstrated a TNF allele sharing between affected sib-pairs which did not exceed the expected 50%. These results suggest that genetic factors may partially influence the disease onset and the progression rate in sibling pairs. A recall bias and/or an 'anticipation phenomenon' could explain the development of MS at an older age in parents than in their children. In this small-sized cohort of MS Italian families no significant associations were confirmed between TNF polymorphism and MS.

Adult↗
PubMed1999

Two B1 and B2 bradykinin receptor antagonists fail to inhibit the Ca2+ response elicited by bradykinin in human skin fibroblasts.

The elevation of intracellular [Ca2+] induced by bradykinin (Bk) was monitored with fura-2 fluorescence in human skin fibroblasts. Neither [des-Arg10][Leu9]kallidin nor D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE140) inhibited the Ca2+ response stimulated by Bk. Moreover, each behaved as a partial agonist causing the elevation of intracellular [Ca2+].

Adolescent↗
PubMed1999

Molecular and cytogenetic characterisation of an unusual case of partial trisomy/partial monosomy 13 mosaicism: 46,XX,r(13)(p11q14)/46,XX,der(13)t(13;13)(q10;q14).

A female infant with multiple malformations and mental retardation was noted to have a rare de novo chromosome abnormality involving mosaicism with two cell lines, one with a ring chromosome 13, and the other with partial trisomy 13 owing to a complex rearrangement. Cytogenetic examination excluded the presence of a t(13q;13q) cell line and showed a cell line with a marker chromosome containing two chromosome 13 long arms joined together after deletion of a part (q11-->q14) of one of them. In addition, the absence of a cell line with two normal chromosomes 13 or a cell line with a t(13q;13q) implies that the ring (13) and the marker (13) arose from a single event at the first cleavage division. The two cell lines were present in different proportions in both peripheral blood lymphocytes and skin fibroblasts. The results of microsatellite characterisation clearly indicate the paternal origin and the absence of recombination, supporting the postzygotic origin of both the ring and the marker chromosome.

Abnormalities, Multiple↗
PubMed1998

STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer.

A potential tumor suppressor gene, STK11 , encoding a serine threonine kinase, has recently been identified on chromosome 19p13. Germ-line mutations of this gene have been found in patients with Peutz-Jeghers syndrome (PJS). To further investigate the relevance of STK11 mutations in PJS, we analyzed its coding sequence in nine patients and identified two deletions and three missense mutations. Because intestinal carcinomas have been observed to develop in association with PJS, we analyzed tumors from 71 patients for allelic deletions (loss of heterozygosity) and STK11 gene mutations, to elucidate the etiological role of STK11 gene in sporadic colorectal cancer. Loss of heterozygosity, evaluated using the microsatellite D19S886, was observed in 10 of 52 informative cases. No somatic mutations were detected except for a missense alteration in one tumor. Our data indicate the heterogeneity of PJS and the infrequent involvement of the STK11 gene in colorectal cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

Sister chromatid exchange (SCE) and micronucleus (MN) frequencies in lymphocytes of gasoline station attendants.

Peripheral blood lymphocytes from 22 men with low average exposure (229 micrograms/m3 = 0.72 ppm) to benzene and 19 control men were investigated for Sister Chromatid Exchange (SCE) frequency. The majority of the men (21 exposed, 19 controls) were also investigated using the micronucleus assay (MN). The exposed subjects were employed at 10 different gas stations in or near the city (Bari/South Italy). SCE frequencies were significantly related with age and smoking habits, on the contrary no relation was observed between SCE and length of employment (SCE = 7.41 + 0.03.age (*) + 0.0001.length of employment (n.s.) + 0.03.cigarette consumption (*); F = 4.87; p < 0.01; (*) significant; (n.s.) non-significant). MN frequencies were significantly increased in relation with length of employment; but no relation was observed when age and smoking habits were taken into consideration (regression model: MN = 18.03 + 0.006.age (n.s.) + 0.32.length of employment (*) - 0.1.cigarette consumption (n.s.); F = 4.138; p < 0.05).

Benzene↗
PubMed1998

The familial adenomatous polyposis region exhibits many different haplotypes.

In the present study, we used five different polymorphic markers to construct the haplotype at the adenomatous polyposis coli (APC) locus in families with familial adenomatous polyposis (FAP) and in the normal Italian population. Non-ambiguous haplotypes were reconstructed from 246 normal chromosomes and 65 FAP chromosomes. In the control population, the four polymorphisms intragenic to APC gave rise to 16 haplotypes, the most common of which (II and XV) accounted for over 50% of all chromosomes. In FAP patients, 13 haplotypes were found but their distribution was not statistically different from normal subjects. Eighty complete chromosomal haplotypes (many fewer than the theoretical maximum of 208) for the five polymorphic sites assayed were observed in the control population, 35 being found in the FAP patients. We compared the distribution of these haplotypes within the two groups; no statistically significant differences between normal and FAP chromosomes were found. The elevated heterogeneity of FAP chromosomes was clearly confirmed by the observation that 19 patients who carried one or other of the two most common APC mutations (nt 3183 and nt 3927) showed 18 different haplotypes. On the basis of these results, we were not able to identify a founder FAP chromosome. Various mechanisms are presented to explain this observation.

Adenomatous Polyposis Coli↗
PubMed1998

Network analyses of Y-chromosomal types in Europe, northern Africa, and western Asia reveal specific patterns of geographic distribution.

In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinucleotide microsatellites was analyzed within three "frames" that are defined by mutations that are nonrecurrent, or nearly so. The rapid generation and extinction of new dinucleotide length variants causes the haplotypes within each lineage to diverge from one another. We constructed networks of "adjacent" haplotypes within each frame, by assuming changes of a single dinucleotide unit. Two small and six large networks were obtained, the latter including 94.9% of the sampled Y chromosomes. We show that the phenetic relationships among haplotypes, represented as a network, result largely from common descent and subsequent molecular radiation. The grouping of haplotypes of the same network thus fits an evolutionarily relevant criterion. Notably, this method allows the total diversity within a sample to be partitioned. Networks can be considered optimal markers for population studies, because reliable frequency estimates can be obtained in small samples. We present synthetic maps describing the incidence of different Y-chromosomal lineages in the extant human populations of the surveyed areas. Dinucleotide diversity also was used to infer time intervals for the coalescence of each network.

Africa, Northern↗
PubMed1996

COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation.

Congenital hepatic fibrosis (CHF) is probably the most common cause of non-icteric hepatosplenomegaly and is encountered mainly in children and young adults. We describe here two brothers from healthy, non-consanguineous parents. The patients showed early hepatosplenomegaly, portal hypertension, and no apparent kidney involvement. Clinical and laboratory findings were similar in both patients. Liver biopsies showed the presence of broad septa of fibrous tissue containing abundant bile ducts, portal tracts enlarged by fibrosis, and preserved lobular architecture. The histological findings were suggestive of CHF. Ophthalmological assessment demonstrated visual impairment with mild exotropia, nystagmus, and oculomotor apraxia. Neurological examination showed moderate mental retardation and cerebellar ataxia. Brain MRI confirmed cerebellar malformation with inferior vermis hypoplasia. This pattern of defects is consistent with COACH syndrome (Cerebellar vermis hypoplasia, Oligophrenia, congenital Ataxia, Coloboma, Hepatic fibrocirrhosis) which has previously been reported in five other cases. Our report may contribute to a better delineation of the COACH syndrome phenotype in the spectrum of oculo-encephalohepato-renal disorders.

Abnormalities, Multiple↗
PubMed1996

An unusual dicentric Y chromosome with a functional centromere with no detectable alpha-satellite.

We describe an unusual marker chromosome Y. This marker is present in 5% of the lymphocytes of a dysgenetic woman showing a mosaic karyotype 45,X/46,XY/47,XY+mar. Q-banding revealed that the marker was morphologically identical to the Y chromosome of the patient but presented the primary constriction in the heterochromatic region. C-banding confirmed that the heterochromatic region was C-positive; furthermore, it showed two spots in the euchromatic region in a position corresponding to that of the centromere in the normal Y. Fluorescence in situ hybridization with the centromere-specific probe pDP 97 and the pancentromeric alpha-satellite probe alpha 27 alpha 30 failed to detect any signal at the primary constriction site. To improve the characterization of the marker chromosome, hybridization was performed using pDP 105, a probe located on the short arm of the Y chromosome, together with chromosome-Y-specific paint-hybridizing to the single sequence spanning the Y short arm. In both cases, positive signals telomeric to the inactive centromere were observed. Possible mechanisms resulting in the formation of the marker chromosome are discussed.

Adult↗