Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Thyroid ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308024

RESUMO

Background: Galectin-3 (LGALS3) is an important glycoprotein involved in the malignant transformation of thyrocytes acting in the extracellular matrix, cytoplasm, and nucleus where it regulates TTF-1 and TCF4 transcription factors. Within LGALS3 gene, a common single-nucleotide polymorphism (SNP) (c.191C>A, p.Pro64His; rs4644) encoding for the variant Proline to Histidine at codon 64 has been extensively studied. However, data on rs4644 in the context of thyroid cancer are lacking. Thus, the aim of the present work was to evaluate the role of the rs4644 SNP as risk factor for differentiated thyroid cancer (DTC) and to determine the effect on the transcriptome in thyrocytes. Methods: A case/control association study in 1223 controls and 1142 unrelated consecutive DTC patients was carried out to evaluate the association between rs4644-P64H and the risk of DTC. We used the nonmalignant cell line Nthy-Ori (rs4644-C/A) and the CRISPR/Cas9 technique to generate isogenic cells carrying either the rs4644-A/A or rs4644-C/C homozygosis. Then, the transcriptome of the derivative and unmodified parental cells was analyzed by RNA-seq. Genes differentially expressed were validated by quantitative reverse transcription PCR and further tested in the parental Nthy-Ori cells after LGALS3 gene silencing, to investigate whether the expression of target genes was dependent on galectin-3 levels. Results: rs4644 AA genotype was associated with a reduced risk of DTC (compared with CC, ORadj = 0.66; 95% confidence interval = 0.46-0.93; Pass = 0.02). We found that rs4644 affects galectin-3 as a transcriptional coregulator. Among 34 genes affected by rs4644, HES1, HSPA6, SPC24, and NHS were of particular interest since their expression was rs4644-dependent (CC>AA for the first and AA>CC for the others), also in 574 thyroid tissues of Genotype-Tissue Expression (GTEx) biobank. Moreover, the expression of these genes was regulated by LGALS3-silencing. Using the proximity ligation assay in Nthy-Ori cells, we found that the TTF-1 interaction was genotype dependent. Conclusions: Our data show that in thyroid, rs4644 is a trans-expression quantitative trait locus that can modify the transcriptional expression of downstream genes, through the modulation of TTF-1.

2.
Invest New Drugs ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33300108

RESUMO

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

3.
Front Genet ; 11: 975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014022

RESUMO

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test's accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual's genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker.

4.
Int J Mol Sci ; 21(14)2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659970

RESUMO

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression ("passenger genes"). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of EIF4G1 and RAN significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-ß. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.

5.
Thyroid ; 30(11): 1579-1588, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32228166

RESUMO

Background: Sporadic medullary thyroid carcinoma (sMTC) is an uncommon neoplasia arising from the calcitonin-producing parafollicular cells of the thyroid. Previous studies evaluated whether single nucleotide polymorphisms (SNPs) within RET (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. Methods: In this work, we evaluated the association of RET-SNPs c.74-126G>T (rs2565206), p.Gly691Ser (rs1799939, G>A), p.Leu769 = (rs1800861, G>T), p.Ser836 = (rs1800862, C>T), and p.Ser904 = (rs1800863, C>G) (listed in the order of their chromosomal location) with sMTC. This is one of the largest case-control association studies carried out on sMTC, including 585 sMTC cases (negative for germline mutations within RET), 1529 patients affected by sporadic nonmedullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. Results: sNMTC patients showed similar genotype and allele frequencies compared with healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769 = was less frequent (OR = 0.70 [CI 0.58-0.84], p = 1.9 × 10-4) and rare homozygotes TT showed an OR = 0.32 ([CI 0.17-0.60], p = 2.3 × 10-4). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs) was observed (p = 3.9 × 10-3). The SNPs were not associated with the expression of RET mRNA, that is, they did not exert an effect in cis as quantitative trait locus (cis-eQTL). However, a strong eQTL association was found for p.Leu769 = and the neighboring gene CSGALNACT2 (p = 9.3 × 10-50; effect-size = -0.65), whose function in cancer is unknown. Conclusions: This study shows that specific RET haplotypes, in particular haplotype 2 and the T-allele of p.Leu769 = , are associated with a reduced risk of sMTC in Italians.

6.
Int J Cancer ; 146(2): 363-372, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.


Assuntos
Neoplasias do Colo/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Adulto , Idoso , Variação Biológica da População/genética , Carcinogênese/genética , Estudos de Casos e Controles , Colo/patologia , Neoplasias do Colo/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/patologia , Reto/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Proteínas Supressoras de Tumor/genética , Adulto Jovem
7.
Occup Environ Med ; 74(6): 456-463, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28343162

RESUMO

BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of the mesothelin (MSLN) gene could affect the levels of SMRP. OBJECTIVES: To focus on SNPs located within MSLN promoter as possible critical genetic variables in determining SMRP levels. METHODS: The association between SMRP and SNPs was tested in 689 non-MPM subjects and 70 patients with MPM. Reporter plasmids carrying the four most common haplotypes were compared in a dual luciferase assay, and in silico analyses were performed to investigate the putative biological role of the SNPs. RESULTS: We found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (in strong linkage disequilibrium with rs2235504) and rs2235503 in non-MPM subjects. Inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the group with MPM showed the same trend of association. According to the in vitro luciferase study, rs3764247 itself had a functional role. In silico approaches showed that the binding sites for transcription factors such as Staf and ZNF143 could be affected by this SNP. The other SNPs were shown to interact with each other in a more complex way. CONCLUSIONS: These data support the suggestion that SMRP performance is affected by individual (ie, genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mesotelioma/diagnóstico , Mesotelioma/genética , Idoso , Alelos , Análise de Variância , Asbestos/efeitos adversos , Biomarcadores Tumorais/sangue , Feminino , Genótipo , Humanos , Itália , Luciferases , Neoplasias Pulmonares/sangue , Masculino , Mesotelioma/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
8.
Minerva Endocrinol ; 42(1): 64-76, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26112458

RESUMO

Sorafenib (Nexavar), is a multikinase inhibitor, which has demonstrated both antiproliferative and antiangiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumoral cells (c-RAF [proto-oncogene serine/threonine-protein kinase], BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3) and in tumor vessels (c-RAF, vascular endothelial growth factor receptor [VEGFR]-2, VEGFR-3, and platelet-derived growth factor receptor ß). Sorafenib was initially approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. Experimental studies have demonstrated that sorafenib has both antiproliferative and antiangiogenic properties in vitro and in vivo, against thyroid cancer cells. Furthermore, several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary, follicular and medullary aggressive thyroid cancer. The results of the different studies showed good clinical responses and stabilization of the disease and suggested that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies (such as radioiodine). Currently, USA Food and Drug Administration has approved the use of sorafenib for metastatic differentiated thyroid cancer.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Humanos , Metástase Neoplásica , Niacinamida/uso terapêutico , Sorafenibe
9.
Arch Toxicol ; 90(11): 2617-2642, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27538405

RESUMO

Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.


Assuntos
Medicina Baseada em Evidências , Neoplasias Pancreáticas/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Animais , Carcinógenos Ambientais/toxicidade , Fatores de Confusão Epidemiológicos , Dieta Saudável , Dieta Ocidental/efeitos adversos , Progressão da Doença , Suscetibilidade a Doenças , Estilo de Vida Saudável , Humanos , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/fisiopatologia , Neoplasias Induzidas por Radiação/prevenção & controle , Pâncreas/efeitos dos fármacos , Pâncreas/fisiopatologia , Pâncreas/efeitos da radiação , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/prevenção & controle , Radiação Ionizante , Fatores de Risco , Fumar/efeitos adversos
10.
Curr Drug Targets ; 17(5): 515-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25547908

RESUMO

Many studies have suggested that CXCR3, CXCR5, CXCR6 and CXCR7 chemokine receptors are determinant in type 1 diabetes (T1D), expecially in autoimmunity and ß-cell destruction. In particular circulating CXCL10 level (the ligand of CXCR3) is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Blocking the CXCL10/CXCR3 axis in newly onset of diabetes seems to be a potential strategy for the therapy of T1D. Attempts have been done in modulating or blocking CXCR5, CXCR6 and CXCR7 chemokine receptors in experimental settings of T1D. More researches are necessary to evaluate the interplay among cytokines, chemokines and the pathogenesis and therapy of T1D.


Assuntos
Quimiocina CXCL10/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Receptores CXCR/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Regulação da Expressão Gênica , Humanos , Receptores CXCR3/metabolismo , Receptores CXCR5/metabolismo , Receptores CXCR6 , Receptores de Quimiocinas/metabolismo , Receptores Virais/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Autoimmun Rev ; 14(2): 174-80, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25461470

RESUMO

Autoimmune thyroid diseases (AITD) result from a dysregulation of the immune system leading to an immune attack on the thyroid. AITD are T cell-mediated organ-specific autoimmune disorders. The prevalence of AITD is estimated to be 5%; however, the prevalence of antithyroid antibodies may be even higher. The AITD comprise two main clinical presentations: Graves' disease (GD) and Hashimoto's thyroiditis (HT), both characterized by lymphocytic infiltration of the thyroid parenchyma. The clinical hallmarks of GD and HT are thyrotoxicosis and hypothyroidism, respectively. The mechanisms that trigger the autoimmune attack to the thyroid are still under investigation. Epidemiological data suggest an interaction among genetic susceptibility and environmental triggers as the key factor leading to the breakdown of tolerance and the development of disease. Recent studies have shown the importance of cytokines and chemokines in the pathogenesis of AT and GD. In thyroid tissue, recruited T helper 1 (Th1) lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 (the prototype of the IFN-γ-inducible Th1 chemokines) secretion from the thyroid cells, therefore creating an amplification feedback loop, initiating and perpetuating the autoimmune process. Associations exist between AITD and other organ specific (polyglandular autoimmune syndromes), or systemic autoimmune disorders (Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, cryoglobulinemia, sarcoidosis, psoriatic arthritis). Moreover, several studies have shown an association of AITD and papillary thyroid cancer. These data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other autoimmune disorders.


Assuntos
Tireoidite Autoimune/imunologia , Citocinas/imunologia , Predisposição Genética para Doença , Humanos , Fatores de Risco , Neoplasias da Glândula Tireoide/imunologia
12.
World J Diabetes ; 5(5): 586-600, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25317237

RESUMO

Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.

13.
Autoimmun Rev ; 13(11): 1160-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25172242

RESUMO

To our knowledge, no study has evaluated the involvement of T helper (Th)1- and Th2-chemokines in extra-ocular muscle (EOM) myopathy in "patients with thyroid-associated ophthalmopathy" (TAO-p). We tested the effects of interferon (IFN)γ and tumor necrosis factor (TNF)α stimulation, and of increasing concentrations of peroxisome proliferator-activated receptor (PPAR)γ agonists (pioglitazone or rosiglitazone; 0.1 µM-20 µM), on Th1-chemokine [C-X-C motif ligand (CXCL)10] and Th2-chemokine [C-C motif ligand (CCL)2] secretion in primary EOM cultures from TAO-p vs. control myoblasts. Moreover, we evaluated serum CXCL10 and CCL2 in active TAO-p with prevalent EOM involvement (EOM-p) vs. those with prevalent orbital fat expansion (OF-p). Serum CXCL10 was higher in OF-p and EOM-p vs. controls, while serum CCL2 was not significantly different in controls, or in OF-p and EOM-p. We showed the expression of PPARγ in EOM cells. In primary EOM cultures from TAO-p: a) CXCL10 was undetectable in the supernatant, IFNγ dose-dependently induced it, whereas TNFα did not; b) EOM produced basally low amounts of CCL2, TNFα dose-dependently induced it, whereas IFNγ did not; c) the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion; and d) PPARγ agonists have an inhibitory role on the modulation of CXCL10, while they stimulate CCL2 secretion. EOM participates in the self-perpetuation of inflammation by releasing both Th1 (CXCL10) and Th2 (CCL2) chemokines under the influence of cytokines, in TAO. PPARγ agonist activation plays an inhibitory role on CXCL10, but stimulates the release of CCL2.


Assuntos
Quimiocina CCL2/metabolismo , Quimiocina CXCL10/metabolismo , Oftalmopatia de Graves/imunologia , Músculo Esquelético/imunologia , PPAR gama/imunologia , Humanos , Músculo Esquelético/metabolismo , Mioblastos/imunologia , Mioblastos/metabolismo
14.
Surgery ; 156(5): 1167-76, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25151558

RESUMO

BACKGROUND: We report the antineoplastic and anti-angiogenic activity of the pyrazolo[3,4-d]pyrimidine derivative CLM3 and the cyclic amide CLM94, both multiple tyrosine kinase inhibitors (TKIs), in human primary medullary thyroid cancer (P-MTC) cells, and in vitro in the medullary thyroid cancer (MTC) cell lines TT (harboring a RET C634W activating mutation) and MZ-CRC-1 (carrying the MEN2B RET mutation Met891Thr). METHODS: The antiproliferative and proapoptotic effects of CLM3 and CLM94 (1, 5, 10, 30, and 50 µmol/L) were tested in P-MTC cells obtained at operation, and in TT cells. In addition, the antiproliferative effects of CLM3 and CLM94 (0.005, 0.05, 0.5, and 5 µmol/L) were tested in TT and MZ-CRC-1 cells after 7 days of treatment to compare the results with those previously reported in the literature. RESULTS: CLM3 and CLM94 (30 or 50 µmol/L) inhibited (P < .01) the proliferation of the P-MTC cells, TT cells, and MZ-CRC-1 cells and increased the level of apoptosis in a dose-dependent manner at 10, 30, and 50 µmol/L (P < .001), while having no effect on migration or invasion. The inhibition of proliferation by CLM3 and CLM94 was similar among P-MTC cells with/without RET mutations, and similar effects were observed regarding the increased level of apoptosis. Furthermore, CLM3 and CLM94 significantly decreased vascular endothelial growth factor-A expression in TT cells. CONCLUSION: The antitumor activities of the multiple TKIs CLM3 and CLM94 were demonstrated in both primary MTC cultures as well as 2 established MTC cell lines in vitro, opening an avenue for future clinical evaluations.


Assuntos
Benzamidas/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sacarina/análogos & derivados , Neoplasias da Glândula Tireoide/tratamento farmacológico , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Carcinoma Neuroendócrino , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sacarina/farmacologia , Sacarina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
15.
Mol Cell Endocrinol ; 393(1-2): 56-64, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-24931161

RESUMO

CLM29 (a pyrazolo[3,4-d]pyrimidine, that inhibits RET, epidermal growth factor receptor, vascular endothelial growth factor receptor, and has an anti-angiogenic activity) has anti-neoplastic activity in papillary dedifferentiated thyroid cancer. Here we tested CLM29 in medullary thyroid cancer (MTC), in primary MTC cells (P-MTC) obtained at surgery, and in TT cells harboring (C634W) RET mutation. CLM29 (10, 30, 50 µM) inhibited significantly (P<0.001) the proliferation, and increased the percentage of apoptotic P-MTC, TT and human dermal microvascular endothelial cells. The inhibition of proliferation by CLM29 was similar in P-MTC cells with/without RET mutation. TT cells were injected sc in CD nu/nu mice, and tumor masses became detectable between 20 and 30 days after xenotransplantation; CLM29 (50mg/kg/die) reduced significantly tumor growth and weight, and microvessel density. The anti-tumor activity of CLM29 has been shown in MTC in vitro, and in vivo, opening the way to a future clinical evaluation.


Assuntos
Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-24953644

RESUMO

The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). Under the influence of interferon(IFN)γ, the IFNγ-induced protein 10 (IP-10/CXCL10) is secreted by thyrocytes, orbital fibroblasts and preadipocytes. In tissue, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates CXCL10 secretion reiterating the autoimmune process. The presence of elevated levels of CXCL10 in peripheral liquids is considered a marker of Th1 orientated immune response. High levels of circulating CXCL10 (sCXCL10) have been shown in patients with AT, overall with hypothyroidism. In GD and GO patients high sCXCL10 have been shown particularly in the active disease. A modulatory role of peroxisome proliferator-activated receptor (PPAR)γ or - α agonists on CXCR3 chemokines in AT, GD and GO and the immuno-modulatory effect of methimazole on CXCR3 chemokines in GD have been shown. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Terapia de Alvo Molecular/tendências , Receptores CXCR3/antagonistas & inibidores , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/imunologia , Quimiocina CXCL10/antagonistas & inibidores , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Oftalmopatia de Graves/tratamento farmacológico , Oftalmopatia de Graves/imunologia , Humanos , Patentes como Assunto , Tireoidite Autoimune/tratamento farmacológico , Tireoidite Autoimune/imunologia
17.
Expert Opin Drug Saf ; 13(6): 723-33, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24821006

RESUMO

INTRODUCTION: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI. AREAS COVERED: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated. EXPERT OPINION: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation.


Assuntos
Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Doenças da Glândula Tireoide/induzido quimicamente , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Doenças da Glândula Tireoide/fisiopatologia , Testes de Função Tireóidea/métodos , Hormônios Tireóideos/administração & dosagem
18.
Cytokine Growth Factor Rev ; 25(1): 57-65, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24529741

RESUMO

Type 1 diabetes (T1D) is due to antigen-specific assaults on the insulin producing pancreatic ß-cells by diabetogenic T-helper (Th)1 cells. (C-X-C motif) ligand (CXCL)10, an interferon-γ inducible Th1 chemokine, and its receptor, (C-X-C motif) receptor (CXCR)3, have an important role in different autoimmune diseases. High circulating CXCL10 levels were detected in new onset T1D patients, in association with a Th1 autoimmune response. Furthermore ß-cells produce CXCL10, under the influence of Th1 cytokines, that suppresses their proliferation. Viral ß-cells infections induce cytokines and CXCL10 expression, inducing insulin-producing cell failure in T1D. CXCL10/CXCR3 system plays a critical role in the autoimmune process and in ß-cells destruction in T1D. Blocking CXCL10 in new onset diabetes seems a possible approach for T1D treatment.


Assuntos
Quimiocina CXCL10/fisiologia , Diabetes Mellitus Tipo 1/etiologia , Receptores CXCR3/fisiologia , Animais , Autoanticorpos/fisiologia , Doenças Autoimunes/imunologia , Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/complicações , Hepatite C/complicações , Humanos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/fisiologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Paratuberculose/complicações
19.
BioDrugs ; 27(6): 615-28, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23818056

RESUMO

Sorafenib (Nexavar) is a multikinase inhibitor, which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumor cell [c-RAF (proto-oncogene serine/threonine-protein kinase), BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3] and in tumor vessels (c-RAF, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, and platelet-derived growth factor receptor ß). For several years, sorafenib has been approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. After previous studies showing that sorafenib was able to inhibit oncogenic RET mutants, (V600E)BRAF, and angiogenesis and growth of orthotopic anaplastic thyroid cancer xenografts in nude mice, some clinical trials demonstrated the effectiveness of sorafenib in advanced thyroid cancer. Currently, the evaluation of the clinical safety and efficacy of sorafenib for the treatment of advanced thyroid cancer is ongoing. This article reviews the anti-neoplastic effect of sorafenib in thyroid cancer. Several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary and medullary aggressive thyroid cancer. The results suggest that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies.


Assuntos
Antineoplásicos/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Carcinoma Neuroendócrino , Carcinoma Papilar , Humanos , Camundongos , Camundongos Nus , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Thyroid ; 23(11): 1461-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23721189

RESUMO

BACKGROUND: Chemokine (C-X-C motif) ligand (CXCL)9 and CXCL11 play an important role in the initial phases of autoimmune thyroiditis (AT); however, their serum levels in patients with Graves' disease (GD) have never been evaluated in relation to thyroid function and treatment. METHODS: To evaluate CXCL9 and CXCL11 serum levels in GD and to relate these parameters to the clinical phenotype, we measured CXCL9 and CXCL11 serum levels in 91 GD patients; 91 AT, 34 nontoxic multinodular goiters (MNGs), 31 toxic nodular goiters (TNGs), respectively; and 91 healthy controls (age- and sex-matched). RESULTS: Mean CXCL9 and CXCL11 levels were higher in GD in comparison with controls, euthyroid AT, MNG, or TNG (p < 0.05, ANOVA; CXCL9: 274 ± 265, 76 ± 33, 132 ± 78, 87 ± 48, and 112 ± 56 pg/mL; CXCL11: 140 ± 92, 64 ± 20, 108 ± 48, 76 ± 33, 91 ± 41 pg/mL, respectively). Hyperthyroid GD patients had significantly higher CXCL9 or CXCL11 than euthyroid or hypothyroid GD patients. GD patients with untreated hyperthyroidism had higher CXCL9 or CXCL11 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment. Comparable CXCL9 and CXCL11 levels were observed in newly diagnosed untreated hyperthyroid GD versus untreated patients with relapse of hyperthyroidism after a previous MMI course. CONCLUSIONS: Serum CXCL9 and CXCL11 levels are associated with the active phase of GD both in newly diagnosed and relapsing hyperthyroid patients. The reduction of serum CXCL9 and CXCL11 levels in treated patients with GD may be related to the immunomodulatory effects of MMI.


Assuntos
Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Doença de Graves/sangue , Doença de Graves/tratamento farmacológico , Interferon gama/metabolismo , Metimazol/uso terapêutico , Adulto , Idoso , Antitireóideos/uso terapêutico , Estudos de Casos e Controles , Quimiocina CCL2/sangue , Feminino , Bócio/sangue , Bócio/tratamento farmacológico , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fenótipo , Recidiva , Glândula Tireoide/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...