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Biomedical subjects

N R Farid

Publications and source records attributed to N R Farid.

At least 19 recordsLinked to original sources
PubMed2007

The C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours.

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid-specific proteins and hormones, although they possess an intact thyroid-stimulating hormone receptor-adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender-matched healthy blood donors and a series of 327 non-oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non-oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C-allele frequency when compared with all non-oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure.

Adenoma↗
PubMed2005

S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma.

Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01). These data suggest that overexpression of S100A4 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.

Carcinoma, Papillary↗
PubMed2005

Gene profiling identifies genes specific for well-differentiated epithelial thyroid tumors.

Thyroid nodules are common. It would very helpful if genetic markers that can diagnose malignancy from fine needle aspiration samples were available. Few such markers has been thus identified and none are specific. Large panels of potential markers can be screened by microarray technology. Studies done to date have concentrated on single tumor types and thus provide no help in identifying tumor subtype specific markers. To that end we have studied gene profiles of 5 types of benign and malignant thyroid nodular tissue (multinodular goiter, follicular adenoma, papillary and follicular carcinomas). We have identified 195 genes whose differential expression clustered into clinically relevant groups. Twenty-eight genes were selected for further confirmation using real time quantitative polymerase chain reaction. Despite the differences in the microarray panels used, we confirmed the differential regulation of 12 genes previously reported in thyroid cancer, although we found the expression of several genes to be regulated in other histological tumor subtypes than originally described. We found, PCSK2, TRIB1, RAP1 GA1 to be specifically overexpressed in follicular cancer and S100A4 and GK2 in papillary carcinoma. SERP1, RNASE 2 and STATA5 were suppressed in papillary thyroid cancer. We have thus identified new potential markers specific to malignant thyroid tumors. It is apparent that a range of nodular thyroid tissue using large tumor sample numbers is necessary to establish robust markers for malignancy and to categorize tumors on the basis of small tumor samples.

Adenocarcinoma, Follicular↗
PubMed2002

Soluble CD4 concentrations predict relapse of post-partum thyroiditis.

Post-partum thyroiditis (PPT) is a common autoimmune thyroid disorder which results in significant morbidity at a critical time of a woman's life. The presence of anti-thyroglobulin (anti-TG) and, more so, anti-thryroperoxidase (anti-TPO) antibodies in the first trimester of pregnancy has been reported to forecast subsequent PPT. Despite their predictive value, these tests lack in specificity. We have sought to find an alternative that is more specific and, ideally, which could be tested immediately proximate to the event. We have taken advantage of the high recurrence rate of PPT in subsequent pregnancies to perform a prospective study of serum soluble CD4 (sCD4) and CD8 (sCD8) levels in 22 pregnant women who had at least one previous episode of PPT. This group was matched with 21 pregnant women of comparable age with no evidence of thyroid disease. Both groups of women were sampled in each of the three trimesters of pregnancy, 1 month, 3 months and 6 months post-partum for sCD4, sCD8, thyroid function parameters and antibodies. Twelve of the 22 women with previous PPT had recurrent disease; they were more likely to be cigarette smokers and to have a family history of autoimmune disorders (p<0.05, for both) than those who did not. Half of these women had high anti-TG or anti-TPO each in the first trimester compared to none among those without recurrent PPT and 2/21 controls. Serum sCD8 levels showed no changes over the observation points among the two PPT patient subsets and were comparable to those of the controls. By contrast, serum sCD4 concentrations showed divergent changes in the group with recurrent PPT in the course of pregnancy and postpartum period compared to those without disease recurrence and controls: sCD4 failed to show the physiological fall in the third trimester of pregnancy [19.0+/-1.7 (+/-SD) U/ml vs 15.6+/-2.3 U/ml in controls, NS]. This trend was continued into the first month post-partum when sCD4 levels were clearly higher than in controls (22.1+/-2.6 U/ml compared to 17.9+/-1.9 U/ml in controls, p<0.001) and well before the episode of PPT. An sCD4 serum level outside the 95% reference range at 1 month post-partum (9/12 in recurrent PPT, 1/21 in controls) yields a relative risk of 6.9 (chi2=14.67, p<0.001) compared to 3.3 for first trimester thyroid antibody positivity (p=0.029). In summary, we describe a reliable test for forecasting PPT that can be obtained immediately proximate to the possible event. If our findings are verified in larger studies, the measurement of serum sCD4 concentration drawn in the first month post-partum may prove an ideal test for population screening for impending PPT.

Adult↗
PubMed2002

Does smoking increase relapse rates in Graves' disease?

We wondered whether the relapse rate of Graves' hyperthyroidism was increased amongst patients who smoked. To this end, a retrospective analysis of clinical and laboratory data of consecutive patients with Graves' disease was carried out. All patients were treated with thionamide anti-thyroid drugs (ATD) for at least one year and remission was defined as continued and biochemical euthyroidism, at least 6 months after discontinuing ATD. The study comprised 221 subjects with Graves' disease from a hospital-based population over 9 years. We took the following variables into account when assessing contribution to disease relapse: Goiter, Thyroid Associated Ophthalmopathy (TAO), and Time to euthyroidism after starting ATD and interaction between smoking and sex. Smoking had a marginally significant (p=0.081) deleterious effect on the likelihood of remission after ATD treatment for Graves' disease. The effect of smoking was, however, highly significant in males and indeed the deleterious effect on remissions may be restricted to males (odds ratio, 11.1; 95% confidence interval, 1.25 to 98.5). The presence of goiter (odds ratio, 3.8; 95% confidence interval, 2.05 to 7.1) and TAO (odds ratio, 1.8; 95% confidence interval, 0.993 to 3.18) forecasted lower chances of achieving remission. The shorter the time a patient became euthyroid after starting ATD the more likely his disease was to remit. We conclude that cigarette smoking increases the likelihood of Graves' disease recurrence in males treated with anti-thyroid drugs. Thus, smoking appears to be an important risk factor in the pathogenesis and outcome of Graves' disease patients at least in subsets of patients.

Adult↗
PubMed2001

Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: relevance of cross-population studies.

Recent studies of Graves disease (GD) employing genome scanning techniques excluded the major histocompatibility complex as a contributor to disease liability. These findings contradict earlier population association studies. Our own earlier studies have also emphasized that genetic variation in human populations may give novel clues to disease liability and manifestations. To this end, we studied HLA class II alleles in 47 Latvian GD patients and 111 matched healthy controls. As expected, we found that DRB1*03 and DQA1*0501 (OR = 3.6, P = 0.029 and OR 2.35, P = 0.0373, respectively) were associated with GD. Unforeseen, DRB1*04 was found to be significantly increased in the patients compared to controls (OR 3.267, corrected P = 0.0319). The two DRB1 alleles conferred two non-overlapping and independent susceptibilities to GD, in that only three patients were positive for both alleles, and the removal of each allele in turn resulted in only the other DRB1 allele showing significant association with the disease. There was no heterogeneity between the two patient groups (DRB1*03 positive and DRB1*04 positive) in clinical characteristics or disease manifestations. The phenotype DRB1*03 and/or DRB1*04 was found in 34/47 patients compared to 27/111 controls yielding an OR of 7.395 (P corrected = 0.000019). We examined the structural basis of DRB1 susceptibility to GD in light of this and previous studies, showing that DRB1*03, 04, and 08 were positively associated with the disease, whereas DRB1*07 was negatively associated. Differences in protein sequences were noted at residues 54, 57, 59, and 66; positions 54, 57, and 66 are on the same face of the alpha helix. The canonical arginine 54 is replaced by glutamine in DRB1*07. At position 66, asparagine in DRB1*03 and tyrosine in DRB1*04 are replaced by phenylalanine in DRB1*07. Residue 59, likely involved in pocket formation in the antigen binding groove, is modified by replacement of tyrosine in DRB1*03, 08, and 04 and by leucine in DRB1*07. The predicted differences in the shape and charges of the proximal reaches of the antigen binding groove between DRB1*07, and 03, 04, and 08, could determine whether or not a peptide from an auto-antigen would be bound or not. Genetic variation among human populations may yield important clues to specific disease liability.

Adolescent↗
PubMed2001

Thyroid carcinoma is characterized by genomic instability: evidence from p53 mutations.

p53 is a transcription factor with multifaceted regulatory functions in cell cycle progression, DNA repair, and programmed cell death. Inactivating mutations have been described in 50% of human cancers. These mutations appear to be important in tumor progression and response to chemotherapy and radiation treatment and thus clinical outcome. p53 mutations are found in 14% of malignant thyroid tumors and are more frequent in poorly differentiated and anaplastic tumors. Given that p53 is a late event in the notional multistep pathogenesis of cancer, we examined its mutation rates as a measure of genomic instability (hypermutability) of malignant thyroid tumors and also wondered whether radiation enhances that proclivity to genomic instability. To that end we have extracted all available data from the p53 mutation database (http://www.perso@curie.fr), verified, extended, where applicable, and supplemented that information from published reports. We were able to identify 100 entries. The distribution of the p53 mutational events--deletions/insertions, transitions versus transversion mutations--was similar to that of the database as a whole. The silent mutation rate of 17.8%, not different from the expected 25%, is consistent with a random occurrence of these mutations. The silent mutation rate is 120 times that expected and is 6 times that of the database. Moreover, the distribution of p53 mutations is compatible with Poisson's distribution, which taken with silent mutation rates indicates that p53 is particularly hypermutable in thyroid carcinomas. Epigenetic deamination of CpG dinucleotide at highly oncogenic DNA-contact residues is a feature of poorly differentiated tumors and thus associated with tumor progression. The rates of p53 mutations (15.4%) in radiation-related cancers were very similar to those in apparently spontaneously arising tumors, although there was a highly significant heterogeneity (P < 0.0005) in the residues mutated. None involved CpG deamination. It is apparent that thyroid cancer exhibits remarkable genomic instability evidenced by p53 hypermutability. Spontaneous epigenetic mutational events are involved in tumor progression and while radiation increases the absolute prevalence of thyroid cancer in the susceptible it does not increase the rate of p53 mutation and seemingly targets different non-DNA-contact residues than those in spontaneously arising tumors.

Codon↗
PubMed2001

Multiple endocrine neoplasia type 1Burin from Mauritius: a novel MEN1 mutation.

We describe a kindred from Mauritius with an incomplete variant of multiple endocrine neoplasia type 1 (MEN 1Burin). In this family the syndrome is related to a novel MEN 1 gene mutation (deletion of A) at nucleotide 1021 of codon 304 resulting in frame shift and downstream protein truncation at codon 320. Compared to mainstream MEN 1, MEN 1Burin is characterized by a high prevalence of prolactin-secreting pituitary adenomas, late-onset of hyperparathyroidism and rare pancreatic involvement. The family described represents the fifth in the literature with the MEN 1 Burin phenotype; 2 out of the other 4 were related to R460X, Y312X respectively and no mutation within the coding sequence of MEN 1 was found in the other 2. Thus, similar to the classic syndrome, MEN 1Burin phenotype shows poor correlation to MEN 1 genotype.

Adenoma↗
PubMed2000

Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9.

FHIT (fragile histidine triad), a candidate tumour suppressor gene, has recently been identified at chromosomal region 3p14.2, and deletions of the gene have been reported in many types of human cancer. However, the biological function of the Fhit protein has not been fully characterized yet. Using the yeast two-hybrid screen to search for proteins that interact with Fhit in vivo, we identified a protein that is specifically associated with Fhit. This association was confirmed in both immunoprecipitation and glutathione S-transferase pull-down assays. The sequence of the protein is identical with that of human ubiquitin-conjugating enzyme 9 (hUBC9). The last 21 amino acids at the C-terminus of hUBC9 appear to be unimportant for its biological activity, since an hUBC9 mutant harbouring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homologue UBC9 gene. Mutational analysis indicated that hUBC9 was associated with the C-terminal portion of Fhit. Neither a single amino acid substitution at codon 96 (His-->Asn) nor triple amino acid substitutions (His-->Asn) at a histidine triad (codons 94, 96 and 98) affected the association, whereas Fhit triphosphate (diadenosine 5',5"'-P(1),P(3)-triphosphate) hydrolase activity has been reported to be eliminated by either type of mutation, suggesting that the interaction between Fhit and hUBC9 is independent of Fhit enzymic activity. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Fhit may be involved in cell cycle control through its interaction with hUBC9.

Acid Anhydride Hydrolases↗
PubMed2000

A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect.

We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility. The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 microg/pulse, sc, every 90 min). However, GnRH triggered free alpha-subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced. This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.

Amino Acid Sequence↗
PubMed2000

The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations.

OBJECTIVES: To find whether germline and somatic gain-of-function mutations of the thyrotropin receptor (TSHR) differ in location and/or mutational mechanisms, as well as to explore the degree to which these mutations are specific to TSHR compared with pituitary glycoprotein hormone receptors. METHODS: We examined the data on the TSHR website (www.unvi-leipzeig approximately innerre/TSH) supplemented with recent literature. Comparisons were also made with gain-of-function mutations of lutropin/choriogonadotropin (LH/CGR) and follicle-stimulating hormone receptors (FSHR). RESULTS: Some mutations (at residues 183, 505, 509 and 597) are exclusively germline, whereas mutations at 630 and 633 are characteristic of somatic mutations. Several residues located mainly in a mutation cluster region (619-639) are shared by both. Germline mutations are more likely to be transitions than transversions compared with somatic mutations. The lack of mutations involving deamination of CpG dinucleotides, a common mechanism for C-->T transitions, reflects the low CG prevalence in the mutable regions of TSHR. Comparison of the mutation sites with the equivalent positions in LH/CGR showed a significant difference (P<0.0001), whereas those in the mutation cluster region comprising the sixth transmembrane helix (TM6) and the adjoining third intracellular loop were concordant (P>0.90). We suggest that there is specific clustering of mutations in the juxtacytoplasmic end of TM6 in LH/CGR, a hydrophobic patch that is tightly packed with a face on TM5 whose sequences diverge from those of TSHR. CONCLUSIONS: TSHR exhibited frequent mutations outside the mutation cluster region. A role for a mutagenic environment created by the thyroid for other TSHR-specific codons cannot be discounted, nor can genetic factors, when accounting for the variation in the prevalence of TSHR-activating mutations worldwide.

Amino Acid Sequence↗
PubMed1999

FHIT gene abnormalities in both benign and malignant thyroid tumours.

FHIT, a candidate tumour suppressor gene, has recently been identified at chromosomal region 3p14.2, and deletions of the gene have been reported in many types of human cancers. Loss of heterozygosity (LOH) at this region has also been found frequently in follicular thyroid carcinoma (FTC). To investigate the potential role of FHIT in thyroid tumorigenesis, we examined 57 thyroid tumour specimens (eight benign adenomas, 40 papillary, four follicular and five anaplastic carcinomas), and two thyroid carcinoma cell lines (NPA, SW579) for genetic alterations by using reverse transcription-polymerase chain reaction (RT-PCR), PCR product sequencing, single-strand conformation polymorphism (SSCP) and Southern blot analysis. Two cervical carcinoma cell lines (C-33A, HeLa) were included as positive controls. We detected truncated FHIT transcripts in three of eight (38%) benign adenomas, nine of 40 (23%) papillary, and two of five (40%) anaplastic carcinomas, and in three cell lines (SW579, C-33A, HeLa). Most of the truncated transcripts lacked exons 4 or 5 to 7 or 8 of the gene and were presumably non-functional as the translation start site is located in exon 5. SSCP analysis of the coding exons failed to detect any point mutations among the samples without abnormal FHIT transcripts. Southern blot analysis demonstrated either loss or reduced intensity of major Bam HI restriction fragments in the three cell lines found to have abnormal FHIT transcripts, indicating, respectively, either intragenic homozygous or heterozygous deletions of the FHIT gene. Intragenic homozygous deletions were also found in two papillary thyroid carcinoma specimens: one was missing a 13 kb Bam HI fragment which contains exon 4, the other had deletions of 15.5, 13 and 4.2 kb fragments which contain exons 2 and 9, 4, and 5, respectively. The absence of a defective FHIT gene in FTC indicates that an additional tumour suppressor gene may reside in this region and be involved in the development of FTC. Given that defective FHIT genes were found in both benign and malignant thyroid tumours, the inactivation of this putative tumour suppressor gene is likely to be an early event in the pathogenesis of some forms of thyroid neoplasms.

Acid Anhydride Hydrolases↗
PubMed1999

Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma.

Tumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre (P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor.

Adult↗
PubMed1998

Inhibitory effect of pentoxifylline on HLA-DR expression and glycosaminoglycan synthesis by retrobulbar fibroblasts.

OBJECTIVE: Glycosaminoglycan (GAG) production by retro-ocular fibroblasts (REF) is increased in patients with thyroid-associated ophthalmopathy (TAO). Various cytokines stimulate REFs to proliferate and elaborate GAG, free oxygen radicals as well as induce HLA-DR expression on these cells. Pentoxifyllin (Ptx) regulates the production of several cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and, interferon gamma (IFN-gamma). We wished in this study to determine whether Ptx modified the spontaneous and cytokine-induced GAG synthesis by REF and IFN-gamma induced HLA-DR expression. DESIGN: REF derived from extraocular muscles of healthy subjects were cultured without and with cytokines (IFN-gamma, TNF alpha and IL-1) and the effect of Ptx on the production of GAG by REF and HLA-DR expression was determined. MEASUREMENTS: Glycosaminoglycan was measured by incorporation of (3H) glycosamine into GAG. HLA-DR expression was analyzed by fluorescence activated cell sorter. RESULTS: Both spontaneous and cytokine induced GAG synthesis by REF was inhibited by Ptx (100, 500 and 1000 mg/l, respectively). IFN-gamma (50, 100 and 500 U/ml) induced a dose-dependent increase in the expression of HLA-DR molecules by REF. Ptx, which was not toxic to REF, inhibited HLA-DR expression on those cells dose-dependently. CONCLUSIONS: Our in vitro results suggest that Ptx reduces cytokine-induced GAG production and HLA-DR expression by REF. It thus has potential as a therapeutic agent which regulates the function of lymphocytes infiltrating the retro-orbital tissues, and which are instrumental in TAO.

Culture Techniques↗