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M Santoro

Publications and source records attributed to M Santoro.

At least 73 records · Page 4Linked to original sources
PubMed2000

Mesiodistal crown dimensions and tooth size discrepancy of the permanent dentition of Dominican Americans.

The purpose of the study was to establish normative data on the mesiodistal crown dimensions of Americans of Dominican background. The Bolton tooth size analysis was performed on a sample of 54 Dominican Americans. The mean, range and standard deviation were calculated for the size of the teeth, and a coefficient of variation was obtained for the tooth size ratio. A 2-sample t-test was used to test for the statistical difference between means. In general, the values obtained for the Dominican American sample closely resembled previous data available for the African American population. The tooth size ratios obtained were compared to the Bolton ratios. The overall ratio was found to be 91.3, equivalent to the Bolton overall ratio, whereas the anterior ratio was 78.1, larger than the 77.1 Bolton ratio. The frequency of tooth size discrepancy outside 2 standard deviations from the Bolton mean was also calculated. An overall tooth size discrepancy was found in 11% of our sample, and 28% of the sample presented an anterior tooth size discrepancy.

Adult↗
PubMed2000

Warthin-like tumour of the thyroid gland: RET/PTC expression indicates it is a variant of papillary carcinoma.

AIMS: Three cases with features of so-called 'Warthin-like tumour' of the thyroid (WaLTT) are described, in order to evaluate its relationship with papillary carcinoma (PC). METHODS AND RESULTS: We performed an histological and immunohistochemical study with emphasis on RET/PTC expression. The most striking features are represented by marked lymphocytic infiltration in the stalks of papillae and by oxyphilic metaplasia of epithelium, resembling Warthin tumour of the salivary gland. In all cases, we found nuclear features reminiscent of PC. The neoplastic cells were strongly positive for Leu M1 and epithelial membrane antigen (EMA), less for thyroglobulin and negative for calcitonin. The lymphocytic infiltrate was composed of a mixed population of B and T-cells with sparse S100-positive Langerhans cells. An interesting finding was the strong positivity with the antibody against RET/PTC. CONCLUSION: All clinicopathological data along with the presence of the extensive lymphocytic infiltrate could imply a more favourable prognosis. The expression of RET/PTC fusion gene adds support to the hypothesis that this tumour is a variant of PC, probably related to the oncocytic variant of PC.

Adenolymphoma↗
PubMed2000

Gene rearrangement and Chernobyl related thyroid cancers.

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.

Adolescent↗
PubMed2000

Nickel-titanium alloys: stress-related temperature transitional range.

The inducement of mechanical stress within nickel-titanium wires can influence the transitional temperature range of the alloy and therefore the expression of the superelastic properties. An analogous variation of the transitional temperature range may be expected during orthodontic therapy, when the archwires are engaged into the brackets. To investigate this possibility, samples of currently used orthodontic nickel-titanium wires (Sentalloy, GAC; Copper Ni-Ti superelastic at 27 degrees C, 35 degrees C, 40 degrees C, Ormco; Nitinol Heat-Activated, 3M-Unitek) were subjected to temperature cycles ranging between 4 degrees C and 60 degrees C. The wires were mounted in a plexiglass loading device designed to simulate clinical situations of minimum and severe dental crowding. Electrical resistivity was used to monitor the phase transformations. The data were analyzed with paired t tests. The results confirmed the presence of displacements of the transitional temperature ranges toward higher temperatures when stress was induced. Because nickel-titanium wires are most commonly used during the aligning stage in cases of severe dental crowding, particular attention was given to the performance of the orthodontic wires under maximum loading. An alloy with a stress-related transitional temperature range corresponding to the fluctuations of the oral temperature should express superelastic properties more consistently than others. According to our results, Copper Ni-Ti 27 degrees C and Nitinol Heat-Activated wires may be considered suitable alloys for the alignment stage.

Alloys↗
PubMed2000

RET/PTC activation in hyalinizing trabecular tumors of the thyroid.

Hyalinizing trabecular tumor (HTT) of the thyroid is a neoplasm of follicular derivation with a histogenesis that is still the subject of debate. Morphologic affinities between HTT and papillary carcinoma, including nuclear pseudoinclusions and grooves, suggest that these tumors may be of similar origin. The authors investigated the relationship between these two types of tumors by assessing HTT for the presence of rearrangements of the proto-oncogene rearranged during transfection (RET) that, in thyroid tumors, are specific for papillary carcinoma. A series of 14 HTTs, including two cases associated with classic papillary carcinoma, was studied by means of immunohistochemistry and reverse transcription-polymerase chain reaction. Seven follicular adenomas with focal hyalinized trabecular areas served as control cases. Three of the 14 HTT cases under consideration displayed rearrangements of RET generating the RET/papillary thyroid carcinoma type 1 (PTC1) oncogene. In another case, RET expression was detected focally by immunohistochemistry alone. Finally, in one mixed HTT-papillary carcinoma sample, RET/PTC1 expression was detected, but only in the papillary component. None of the control follicular adenomas contained rearrangements of RET/PTC. These findings demonstrate that a comparable percentage (28.6%) of HTTs and papillary carcinomas exhibit the same RET proto-oncogene alterations. Thus, HTT may represent the "hyalinizing trabecular" variant of papillary carcinoma rather than a separate entity.

Adenoma↗
PubMed2000

Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1).

The r-PTPeta gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPeta (the human homolog of r-PTPeta) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPeta gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Ki oncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPeta caused G(1) growth arrest and increased the cyclin-dependent kinase inhibitor p27(Kip1) protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPeta tumor suppressor activity is mediated by p27(Kip1) protein stabilization, because suppression of p27(Kip1) protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPeta. Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed thyroid cells, the p27(Kip1) protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPeta regulated p27(Kip1) stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.

Animals↗
PubMed2000

Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins.

Point mutations of the RET receptor tyrosine kinase are responsible for the inheritance of multiple endocrine neoplasia (MEN) type 2 syndromes and are also present in a fraction of sporadic medullary thyroid carcinomas. Somatic rearrangements of the RET gene generating the chimeric RET/papillary thyroid carcinoma (PTC) oncogenes are the predominant molecular lesions associated with papillary carcinoma, the most frequent thyroid malignancy in humans. Oncogenic mutations cause constitutive activation of the kinase function of RET, which, in turn, results in the autophosphorylation of RET tyrosine residues critical for signaling. In vitro kinase assays previously revealed six putative RET autophosphorylation sites. The aim of the present study was to assess the phosphorylation of two such residues, tyrosines 1015 and 1062 (Y1015 and Y1062), in the in vivo signaling of RET and RET-derived oncogenes. Using phosphorylated RET-specific antibodies, we demonstrate that both Y1015 and Y1062 are rapidly phosphorylated upon ligand triggering of RET. Moreover, regardless of the nature of the underlying activating mutation, the concomitant phosphorylation of Y1015 and Y1062 is a common feature of the various oncogenic RET products (MEN2A, MEN2B, and PTC). This study shows that Ab-pY1062 is a useful tool with which to detect activated RET in human tumor cells and surgical samples. Finally, the microinjection of Ab-pY1062 antibodies into living cells demonstrates that Ret/PTC1 signaling is required to maintain the mitogenesis of a human carcinoma cell line expressing the Ret/PTC1 oncoprotein.

Amino Acid Sequence↗
PubMed2000

Oncogenes and thyroid cancer.

Human thyroid tumors can be derived either from epithelial follicular cells or from parafollicular C-cells. Follicular cell-derived tumors represent a wide spectrum of lesions, ranging from benign adenomas through differentiated (follicular and papillary) and undifferentiated (anaplastic) carcinomas, thus providing a good model for finding a correlation between specific genetic lesions and histologic phenotype. Follicular adenomas and carcinomas show frequently the presence of mutations in one of the three ras genes. Papillary carcinomas show frequently a specific gene rearrangement which gives rise to the formation of several types of so-called RET/PTC chimeric genes. This lesions occur in almost 50% of papillary cancers and consist in the juxtaposition of the 3' or tyrosine kinase domain of the RET gene (which codes for a receptor protein not normally expressed in follicular thyroid cells) with the 5' domain of ubiquitously expressed genes, which provide the promoter and dimerization functions, necessary for the constitutive activation of RET/PTC proteins. Anaplastic carcinomas are frequently associated with mutations of the p53 tumor suppressor. Finally, point mutations of the RET gene are found in familial endocrine syndromes (FMTC; MEN2A and MEN2B), a common feature of which is the medullary thyroid carcinoma, a malignant tumor derived from parafollicular C-cells.

Animals↗
PubMed2000

Association between the expression of E1A oncogene and increased sensitivity to growth inhibition induced by sustained levels of cAMP in rat thyroid cells.

OBJECTIVE: The aim of this study was to investigate: (i) whether a persistent increase of cAMP interferes with the proliferation of transformed thyroid cells, and (ii) whether the degree of malignancy is correlated with the sensitivity to a transient and/or sustained increase in intracellular cAMP levels. DESIGN AND METHODS: To address these questions we used thyroid cell lines transformed with E1A oncogene from adenoviruses 5 (PC E1A cell line) or 2 (PC HE4 cell line), or infected with the polyoma murine leukemia virus (PC PyMLV cell line) carrying the middle T gene of the polyoma virus, or, finally, expressing both E1A and PyMLV. These cell lines present various degrees of malignancy: PC EIA and PC HE4 cells are not tumorigenic; PC PyMLV cells induce non-invasive tumors after a long latency period; and PC EIA+PyMLV cells are highly tumorigenic. RESULTS AND CONCLUSIONS: Thyroid cell proliferation required the transient increase of intracellular cAMP levels, while persistent elevation of cAMP blocked the proliferation of normal thyroid PC Cl 3 cells and of PC Cl 3 cells transformed by a variety of different oncogenes. In addition, sustained levels of cAMP induced apoptosis in cells carrying the adenovirus EIA oncogene, but not in cells transformed with other oncogenes or in the wild-type PC Cl 3 cells. Furthermore, middle T gene of the polyoma virus seemed to afford protection only from apoptosis induced by cAMP when middle T is present in thyroid cells along with the E1A gene.

Adenovirus E1A Proteins↗
PubMed2000

The highly malignant phenotype of anaplastic thyroid carcinoma cell lines is recessive.

OBJECTIVE: The aim of our studies was to determine whether the phenotype of the anaplastic thyroid carcinomas is dominant or recessive. In fact, it is hypothesized, on the basis of epidemiological and pathological data, that undifferentiated thyroid carcinomas are derived from differentiated tumours through a mechanism of tumour progression. DESIGN: Cell hybrids have been generated by cell fusion of anaplastic thyroid carcinoma cell lines, which show a highly malignant phenotype, to cell lines deriving from differentiated thyroid carcinoma, which show a non-tumorigenic or a poorly tumorigenic phenotype. All of the parental cell lines showed impaired p53 gene function. RESULTS: The cell hybrids contained alleles from the parental cell lines. All of the cell hybrids showed a lower growth rate compared with the parental undifferentiated carcinoma cell lines and were unable to grow in soft agar and to induce tumours after injection into athymic mice. CONCLUSION: Taken together, these findings suggest that the highly malignant phenotype of the anaplastic thyroid carcinoma is achieved by the impairment of gene functions that negatively regulate cell growth, rather than by the activation of dominant oncogenes.

Animals↗
PubMed2000

Identification of a novel subtype of H4-RET rearrangement in a thyroid papillary carcinoma and lymph node metastasis.

RET/PTC chimeric oncogenes are generated by the fusion of heterologous genes to the RET tyrosine kinase encoding domain. These rearrangements are typical of papillary thyroid carcinomas. RET/PTC1 is one of the most frequently found RET/PTC version and, in all the cases so far reported, it is invariably generated by the fusion of the first encoding exon of the H4 gene to the RET kinase encoding domain. This results in the generation of an oncogenic protein containing the first 101 residues of the H4 protein at the N-terminus. We report the isolation of a novel subtype of H4-RET fusion, designated RET/PTC1L, from a human papillary carcinoma of the thyroid and lymph node metastasis. At variance with the classic one, this novel rearrangement generates a protein containing the N-terminal 150 residues of H4. RET/PTC1L is able to transform NIH 3T3 cells; its transforming ability, however, is 5-fold lower than that of the classic RET/PTC1 isoform. We propose that RET/PTC1L is a novel chimeric oncogene involved in thyroid tumorigenesis; its low transforming ability may be one of the reasons explaining the low frequency by which it is found in human thyroid carcinomas.

Carcinoma, Papillary↗
PubMed2000

Glial cell line-derived neutrotrophic factor and neurturin can act as paracrine growth factors stimulating DNA synthesis of Ret-expressing spermatogonia.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are related growth factors which exert trophic effects on several neuronal populations and developing kidney. GDNF-family ligands interact with membrane receptors designated GFRalphas which, in turn, mediate stimulation of the Ret receptor tyrosine kinase. Here we show that Ret, GFRalpha-1 (the GDNF receptor), and GFRalpha-2 (the NTN receptor) are expressed by testicular germ cells, while GDNF and NTN are expressed by Sertoli cells. Both GDNF and NTN stimulate DNA synthesis in spermatogonia. Furthermore, Ret, ligands and co-receptors are expressed in germ cell tumors. Thus, GDNF-family ligands may act as paracrine factors in spermatogenesis and this circuit may be active in germ cell tumors.

Animals↗
PubMed2000

FRA-1 expression in hyperplastic and neoplastic thyroid diseases.

fra-1 gene overexpression has been shown to represent a general event in thyroid cell transformation in vitro and in vivo. Moreover, inhibition of FRA-1 protein synthesis by stable transfection with a fra-1 antisense construct significantly reduces the malignant phenotype of the transformed thyroid cells, indicating a pivotal role of the fra-1 gene product in the process of cellular transformation. In the attempt to define the potential use of FRA-1 protein detection in the diagnosis of thyroid diseases, we analyzed Fra-1 expression by a combination of immunohistochemistry and reverse transcription-PCR (RT-PCR) assay in 174 samples of thyroid nodules (22 nodular hyperplasias, 102 follicular adenomas, 34 papillary carcinomas, 12 follicular carcinomas, and 4 anaplastic carcinomas) representative of the spectrum of thyroid tumor pathology. FRA-1 protein was abundant in all of the carcinoma samples (50/50, 100%), with an intense staining in the nucleus and the cytoplasm. Positive staining was also found in most of the adenomas (90 of 102; 88%), but in this case, the staining was restricted to the nucleus. Similar results were obtained from the analysis of thyroid goiters; however, the number of positive cases is lower than adenomas (8 of 22; 36%); moreover, the staining was not observed in all of the cells. Conversely, no FRA-1 protein was detectable in 12 normal thyroid tissue samples used as controls. RT-PCR analysis confirmed a higher fra-1 expression in papillary and follicular carcinomas compared with goiters and adenomas. fra-1 expression was also analyzed on 10 fine needle aspiration biopsy (FNAB) samples by RT-PCR. fra-1-specific mRNA was detected in seven of the eight FNABs corresponding to thyroid nodules that were eventually diagnosed as adenomas (three of four) and carcinomas (four of four) after surgery. Conversely, no fra-1 gene expression was observed in two FNABs derived from normal thyroid. Further studies are required before suggesting FRA-1 protein detection as a useful tool for the diagnosis of hyperplastic and neoplastic disorders of the thyroid gland.

Biopsy, Needle↗
PubMed1999

The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis.

Rearrangements of the HMGI-C gene have frequently been detected in human benign tumors of mesenchymal origin, including lipomas. The HMGI-C protein has three AT-hook domains and an acidic COOH-terminal tail. The HMGI-C modifications consist in the loss of the C-tail and the fusion with ectopic sequences. Recent results show that the loss of the COOH-terminal region, rather than the acquisition of new sequences, is sufficient to confer to HMGI-C the ability to transform NIH3T3 cells. Therefore, transgenic mice carrying a HMGI-C construct (HMGI-C/T), containing only the three AT-hook domains, were generated. The HMGI-C/T mice showed a giant phenotype, together with a predominantly abdominal/pelvic lipomatosis, suggesting a pivotal role of the HMGI-C truncation in the generation of human lipomas.

3T3 Cells↗
PubMed1999

Medullary thyroid carcinomas in transgenic mice expressing a Polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens.

Medullary thyroid carcinoma (MTC) is a rare human tumor affecting the calcitonin-secreting c-cells of the thyroid. Here we report that two independent strains of transgenic mice expressing a Polyomavirus (Py) truncated middle-T antigen (deltaMT), consisting of the amino-terminal 304 amino acids, and the full length Py small-T antigen, developed multifocal bilateral MTCs with 100% penetrance. Occasionally one strain also developed mammary and bone tumors. Furthermore, offspring from both transgenic lines displayed pronounced waviness of the whiskers and fur, previously associated with defective epidermal growth factor receptor signaling. Transgene transcription, driven by the homologous early promoter/enhancer, and the corresponding translation products were detected in tumors and in many other organs which did not develop pathologies. The subcellular distribution of deltaMT and its interactions with the adapter proteins of the SHC family have also been analysed. Our study describes a novel murine model of MTC and provides evidence that the N-terminal 304 amino acid fragment of Py middle-T antigen, possibly in co-operation with small-T antigen, acts as a potent oncogene in c-cells of the thyroid.

Animals↗
PubMed1999

Ret-mediated mitogenesis requires Src kinase activity.

The proto-oncogene RET encodes a transmembrane growth neurotrophic receptor with tyrosine kinase (TK) activity. RET mutations are associated with several human neoplastic and nonneoplastic diseases, including thyroid papillary carcinoma, multiple endocrine neoplasia type 2 syndromes, and Hirschsprung's disease. Activation of receptor TKs results in the binding and activation of downstream signaling proteins, among which are nonreceptor TKs of the Src family. To test the involvement of c-Src in Ret-mediated signaling, we measured the levels of c-Src activity in NIH3T3 cells coexpressing Ret and the accessory GFR alpha-1 receptor or an epidermal growth factor receptor/Ret chimeric receptor when the cells were stimulated by glial cell line-derived neurotrophic factor or epidermal growth factor, respectively. Ret stimulation resulted in the activation of c-Src. We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations. These cells showed higher Src kinase activity than the normal counterpart. Furthermore, we show that Ret is able to associate with the SH2 domain of Src in a phosphotyrosine-dependent fashion. Microinjection of a kinase inactive mutant of c-Src blocked Ret-mediated mitogenic effect. These experiments demonstrate that activated Ret is able to bind and stimulate c-Src kinase and that Src activation is essential for the mitogenic activity of Ret.

3T3 Cells↗
PubMed1999

Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?

Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are two dominantly inherited neurocristopathies ascribed to mutations in the RET gene [Chakravarti, 1996; Pasini et al., 1996; Eng and Mulligan, 1997]. MEN2 is a cancer syndrome comprising three related clinical subtypes: (1) MEN type 2A (MEN2A; MIM# 171400) characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and hyperparathyroidism; (2) MEN type 2B (MEN2B; MIM# 162300), which includes MTC, Pheo, mucosal neuromas, ganglioneuromatosis of the digestive tract, and skeletal abnormalities; and (3) familial MTC (FMTC; MIM# 155240), defined by the sole occurrence of MTC. HSCR (MIM# 142623) is a congenital malformation caused by the absence of enteric plexuses in the hindgut, leading to bowel obstruction in neonates. The RET gene (MIM# 164761) codes for a transmembrane tyrosine kinase, a component of a multimeric complex that also comprises one of four members of a novel family of glycosylphosphatidylinositol (GPI)-anchored receptor, GFRalpha((1-4) (e.g., GFRA1, MIM# 601496; references are detailed in Baloh et al. [1998]. Four structurally related soluble factors-glial cell line-derived neurotrophic factor (GDNF), neurturin, persephin, and artemin-are the ligands of these multimolecular receptors in which the nature of the GFRalpha determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFRalpha-1/GDNF delivers a signal critical for the survival of the early neural crest-derived precursors that colonize the intestine below the rostral foregut and give rise to the enteric nervous plexuses [Gershon, 1997; Cacalano et al., 1998; Enomoto et al., 1998].

Drosophila Proteins↗