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1.
Int J Oral Maxillofac Surg ; 52(8): 831-838, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36639343

RESUMO

Up to 30% of oral squamous cell carcinoma (OSCC) patients develop local recurrence and distant metastasis. The molecular status of histologically cancer-free tumour margins could be a critical factor in predicting tumour behaviour. The aim of this study was to detect somatic genomic imbalances in OSCC with emphasis on the surgical margins. DNA was isolated from tumour tissues, margin tissues, and blood samples (used as control) obtained from 11 OSCC patients, and genome-wide array comparative genomic hybridization was performed. Imbalances were present in both tumours and margins, although, as expected, they were more prevalent in tumours (duplications, P = 0.0002; deletions, P = 0.0001). Duplications were more frequent than deletions in both tumours and margins, but without statistical significance. Fifteen imbalances in tumour tissues were recurrent and all of them were duplications. Four of these were found both in tumours and margins and involved chromosomes 1q, 8p, Xp, Yp, and Yq. Four imbalances were recurrent in margin tissue and all of them were duplications (autosomes 8 and 17 and both sex chromosomes). Histologically 'cancer-free' margins hide genomic alterations consistent with unexplained OSCC recurrences. Establishing the molecular status of the margins could improve outcome prediction.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/cirurgia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Hibridização Genômica Comparativa , Margens de Excisão , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Genômica
2.
Transplant Proc ; 51(9): 2917-2920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711577

RESUMO

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/metabolismo , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/metabolismo , Tacrolimo/uso terapêutico , Adulto , Idoso , Monitoramento de Medicamentos , Feminino , Genótipo , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Medicina de Precisão/métodos , Estudos Retrospectivos
3.
BMC Ophthalmol ; 17(1): 107, 2017 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-28659124

RESUMO

BACKGROUND: We report the ophthalmic findings of a patient with type Ia glycogen storage disease (GSD Ia), DiGeorge syndrome (DGS), cataract and optic nerve head drusen (ONHD). CASE PRESENTATION: A 26-year-old white woman, born at term by natural delivery presented with a post-natal diagnosis of GSD Ia. Genetic testing by array-comparative genomic hybridization (CGH) for DGS was required because of her low levels of serum calcium. The patient has been followed from birth, attending the day-hospital every six months at the San Paolo Hospital, Milan, outpatient clinic for metabolic diseases and previously at another eye center. During the last day-hospital visit, a complete eye examination showed ONHD and cataract in both eyes. Next Generation Sequencing (NGS) was subsequently done to check for any association between the eye problems and metabolic aspects. CONCLUSIONS: This is the first description of ocular changes in a patient with GSD Ia and DGS. Mutations explaining GSD Ia and DGS were found but no specific causative mutation for cataract and ONHD. The metabolic etiology of her lens changes is known, whereas the pathogenesis of ONHD is not clear. Although the presence of cataract and ONHD could be a coincidence; the case reported could suggest that hypocalcemia due to DGS could be the common biochemical pathway.


Assuntos
Catarata/etiologia , Síndrome de DiGeorge/complicações , Doença de Depósito de Glicogênio/complicações , Drusas do Disco Óptico/etiologia , Campos Visuais , Adulto , Catarata/diagnóstico , Hibridização Genômica Comparativa , Síndrome de DiGeorge/diagnóstico , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Drusas do Disco Óptico/diagnóstico , Tomografia de Coerência Óptica , Acuidade Visual
5.
Endocrine ; 45(1): 148-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23636804

RESUMO

The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 µM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NIS gene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Tumor de Células de Leydig/patologia , Simportadores/genética , Neoplasias Testiculares/patologia , Ácido Valproico/farmacologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Tumor de Células de Leydig/tratamento farmacológico , Tumor de Células de Leydig/genética , Masculino , Ratos , Simportadores/fisiologia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/genética , Vorinostat
6.
Oncogene ; 33(22): 2876-87, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-23831574

RESUMO

Nucleophosmin 1 (NPM1) is a nucleolar protein involved in ribosome biogenesis, stress responses and maintaining genome stability. One-third of acute myeloid leukemias (AMLs) are associated with aberrant localization of NPM1 to the cytoplasm (NPM1c+). This mutation is critical during leukemogenesis and constitutes a good prognostic factor for chemotherapy. At present, there is no clear molecular basis for the role of NPM1 in DNA repair and the tumorigenic process. We found that the nuclear apurinic/apyrimidinic endonuclease 1 (APE1), a core enzyme in base excision DNA repair (BER) of DNA lesions, specifically interacts with NPM1 within nucleoli and the nucleoplasm. Cytoplasmic accumulation of APE1 is associated with cancers including, as we show, NPM1c+ AML. Here we show that NPM1 stimulates APE1 BER activity in cells. We provide evidence that expression of the NPM1c+ variant causes cytoplasmic accumulation of APE1 in: (i) a heterologous cell system (HeLa cells); (ii) the myeloid cell line OCI/AML3 stably expressing NPM1c+; and (iii) primary lymphoblasts of NPM1c+ AML patients. Consistent with impaired APE1 localization, OCI/AML3 cells and blasts of AML patients have impaired BER activity. Cytoplasmic APE1 in NPM1c+ myeloid cells is truncated due to proteolysis. Thus, the good prognostic response of NPM1c+ AML to chemotherapy may result from the cytoplasmic relocalization of APE1 and the consequent BER deficiency. NPM1 thus has an indirect but significant role in BER in vivo that may also be important for NPM1c+ tumorigenesis.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Dano ao DNA , Reparo do DNA , Expressão Gênica , Técnicas de Inativação de Genes , Células HeLa , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Modelos Biológicos , Mutação , Neoplasias/genética , Proteínas Nucleares/genética , Nucleofosmina , Ligação Proteica , Estabilidade Proteica , Transporte Proteico
7.
Clin. transl. oncol. (Print) ; 15(1): 65-71, ene. 2013. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-126969

RESUMO

AIM AND BACKGROUND: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many important aspects of cell biology that are related to tumorigenesis. There are opposite evidences of the role of EGFR in renal cancer and the outcome of EGFR-targeted therapies, suggesting the complexity of EGFR signaling pathways. In vitro, osteopontin (OPN) and nuclear factor kappa B (NF-κB) are thought to be involved in specific ligand-independent EGFR activation that could have a role in resistance to EGFR mAb therapy. Aim of this study was to analyze the relationship between EGFR and OPN at the protein and mRNA level, as well as their relation to NF-κB in clear cell renal cell carcinoma (CCRCC). MATERIALS AND METHODS: Expression of EGFR, OPN, and p65 NF-κB protein was analyzed using immunohistochemistry and compared mutually in 88 CCRCC samples. Expression of EGFR and OPN mRNAs was analyzed using quantitative Real-time PCR in 22 CCRCC samples and compared mutually and with NF-κB protein expression. RESULTS: Epidermal growth factor receptor mRNA level was higher in CCRCC samples in comparison with normal renal tissue (p = 0.012) and was associated with high OPN mRNA level, and with NF-κB activation (p < 0.001 and p = 0.045, respectively). Immunohistochemical staining showed the inverse association; high EGFR protein expression was related with low OPN and NF-κB protein expression (p < 0.001 and p = 0.047, respectively). CONCLUSION: Epidermal growth factor receptor gene is upregulated in CRCC and associated with OPN gene expression and NF-kB signaling. The inverse relation between OPN and EGFR at the protein level could probably reflect dynamic changes that EGFR undergoes following activation (AU)


Assuntos
Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Imuno-Histoquímica , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Osteopontina/genética , Osteopontina/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo
8.
Clin Transl Oncol ; 15(1): 65-71, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22855173

RESUMO

AIM AND BACKGROUND: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many important aspects of cell biology that are related to tumorigenesis. There are opposite evidences of the role of EGFR in renal cancer and the outcome of EGFR-targeted therapies, suggesting the complexity of EGFR signaling pathways. In vitro, osteopontin (OPN) and nuclear factor kappa B (NF-κB) are thought to be involved in specific ligand-independent EGFR activation that could have a role in resistance to EGFR mAb therapy. Aim of this study was to analyze the relationship between EGFR and OPN at the protein and mRNA level, as well as their relation to NF-κB in clear cell renal cell carcinoma (CCRCC). MATERIALS AND METHODS: Expression of EGFR, OPN, and p65 NF-κB protein was analyzed using immunohistochemistry and compared mutually in 88 CCRCC samples. Expression of EGFR and OPN mRNAs was analyzed using quantitative Real-time PCR in 22 CCRCC samples and compared mutually and with NF-κB protein expression. RESULTS: Epidermal growth factor receptor mRNA level was higher in CCRCC samples in comparison with normal renal tissue (p = 0.012) and was associated with high OPN mRNA level, and with NF-κB activation (p < 0.001 and p = 0.045, respectively). Immunohistochemical staining showed the inverse association; high EGFR protein expression was related with low OPN and NF-κB protein expression (p < 0.001 and p = 0.047, respectively). CONCLUSION: Epidermal growth factor receptor gene is upregulated in CRCC and associated with OPN gene expression and NF-kB signaling. The inverse relation between OPN and EGFR at the protein level could probably reflect dynamic changes that EGFR undergoes following activation.


Assuntos
Carcinoma de Células Renais/genética , Receptores ErbB/genética , Neoplasias Renais/genética , NF-kappa B/metabolismo , Osteopontina/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , NF-kappa B/genética , Osteopontina/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Regulação para Cima
9.
J Neuroendocrinol ; 24(6): 916-29, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22356123

RESUMO

Thyroid transcription factor 1 (TTF1), a member of the Nkx family of transcription factors required for basal forebrain morphogenesis, functions in the postnatal hypothalamus as a transcriptional regulator of genes encoding neuromodulators and hypophysiotrophic peptides. One of these peptides is gonadotrophin-releasing hormone (GnRH). In the present study, we show that Ttf1 mRNA abundance varies in a diurnal and melatonin-dependent fashion in the preoptic area of the rat, with maximal Ttf1 expression attained during the dark phase of the light/dark cycle, preceding the nocturnal peak in GnRH mRNA content. GnRH promoter activity oscillates in a circadian manner in GT1-7 cells, and this pattern is enhanced by TTF1 and blunted by small interfering RNA-mediated Ttf1 gene silencing. TTF1 transactivates GnRH transcription by binding to two sites in the GnRH promoter. Rat GnRH neurones in situ contain key proteins components of the positive (BMAL1, CLOCK) and negative (PER1) limbs of the circadian oscillator, and these proteins repress Ttf1 promoter activity in vitro. By contrast, Ttf1 transcription is activated by CRY1, a clock component required for circadian rhythmicity. In turn, TTF1 represses transcription of Rev-erbα, a heme receptor that controls circadian transcription within the positive limb of the circadian oscillator. These findings suggest that TTF1 is a component of the molecular machinery controlling circadian oscillations in GnRH gene transcription.


Assuntos
Ritmo Circadiano/genética , Regulação da Expressão Gênica/genética , Hormônio Liberador de Gonadotropina/fisiologia , Proteínas de Homeodomínio/fisiologia , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Fatores de Transcrição/fisiologia , Animais , Ritmo Circadiano/fisiologia , Hormônio Liberador de Gonadotropina/biossíntese , Hormônio Liberador de Gonadotropina/genética , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Ratos , Ratos Sprague-Dawley , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
10.
Ann Oncol ; 20(2): 265-71, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18765464

RESUMO

BACKGROUND AND AIM: Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC). METHODS: Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy. RESULTS: Overall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03). CONCLUSIONS: These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Timidina Fosforilase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/uso terapêutico , Progressão da Doença , Receptores ErbB/metabolismo , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Timidina Fosforilase/análise , Fatores de Tempo , Resultado do Tratamento , Ubiquitina-Proteína Ligases/metabolismo
11.
Ann Oncol ; 19(9): 1541-6, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18441329

RESUMO

BACKGROUND: Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen. PATIENTS AND METHODS: Patients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor. RESULTS: Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). CONCLUSIONS: This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Carcinoma Ductal/secundário , Carcinoma Lobular/secundário , Timidina Fosforilase/metabolismo , Administração Oral , Adulto , Idoso , Alopecia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Neoplasias Hepáticas/secundário , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Sensibilidade e Especificidade , Análise de Sobrevida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Timidina Fosforilase/análise , Resultado do Tratamento , Regulação para Cima
12.
J Clin Pathol ; 61(4): 494-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17938160

RESUMO

BACKGROUND: Periostin is a secreted adhesion protein, normally expressed in mesenchime-derived cells. Aberrant expression of the periostin gene in epithelial tumours seems to play a role in angiogenesis and metastases. AIMS: To investigate periostin expression in a consecutive series of breast carcinomas and correlate it with established biological and prognostic factors. METHODS: A consecutive series of 206 breast carcinomas was investigated by immunohistochemistry with a specific antiperiostin antibody. Immunohistochemical expression of oestrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A, VEGFR-1 and VEGFR-2 was analysed. Periostin expression was also investigated in MCF-7 and MDA-468 cell lines by immunohistochemistry, western blot and quantitative RT-PCR. Localisation of periostin was investigated in MCF-7 cells by the green fluorescent protein (GFP) approach. RESULTS: Periostin was highly expressed in carcinoma cells, but not in normal breast tissues. The pattern of expression was mainly cytoplasmic. However, in 12% of cases a nuclear reactivity was observed. Nuclear periostin significantly correlated with tumour size, and with expression of oestrogen receptor, progesterone receptor, VEGF-A, VEGFR-1 and VEGFR-2. A nuclear localisation of periostin was also observed in MCF-7 and MDA-468 cell lines. In MCF-7 cells the nuclear localisation of periostin was also shown by transfection of a vector expressing a GFP-periostin chimeric protein. CONCLUSIONS: Results indicate that the aberrant gene expression of periostin in breast cancer cells is associated with an abnormal nuclear localisation of the protein. The nuclear localisation of periostin in breast cancer may induce significant biological effects.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Moléculas de Adesão Celular/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Moléculas de Adesão Celular/genética , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase/métodos , Prognóstico , RNA Mensageiro/genética , RNA Neoplásico/genética , Transfecção , Células Tumorais Cultivadas
13.
Cancer Invest ; 24(6): 611-4, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16982466

RESUMO

Carriers of BRCA2 germline mutation have a significantly increased lifetime risk of breast and ovarian cancer compared to non carriers. Several other carcinomas seem to be associated with BRCA2 mutations: pancreas, prostate, larynx, gallbladder, bile duct cancer, and malignant melanoma. We described a case of a 67-year-old BRCA2 mutation carrier of Caucasian, non-Jewish, ethnic origin who successively developed 4 primary malignancies in 30 months: breast ductal carcinoma, chronic lymphatic leukemia, ovarian serous papillary carcinoma, and endocervical adenocarcinoma. This is the first case of 4 primary malignancies in a BRCA mutation carrier, also occurred in such a short observation period. Chronic lymphatic leukemia and endocervical adenocarcinoma have not been yet associated to BRCA2 germline mutation.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Ovarianas/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Cistadenocarcinoma Papilar/genética , Cistadenocarcinoma Papilar/patologia , Cistadenocarcinoma Papilar/terapia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Linhagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia
14.
Minerva Ginecol ; 58(2): 171-5, 2006 Apr.
Artigo em Italiano | MEDLINE | ID: mdl-16582871

RESUMO

Genetic investigation of BRCA1 and BRCA2 germline mutations is, nowadays, a diagnostic procedure with practical clinical applications. The role of this genes in DNA repair and stability and in cancer development is now well recognised. Most involved are breast and ovarian cancers, but, less frequently, other gynecological cancers like cervical, corpus uteri and Fallopian tubes cancers and also other non gynecological malignancies. We report the case of a 67-year-old patient with strong familiarity for breast cancer, with a BRCA2 germline mutation, who developed in 30 months 4 primary malignancies: in chronological order, breast cancer, chronic lymphatic leukemia, and synchronous ovarian and endocervical adenocarcinoma. A better knowledge of the biological and clinical behaviour of BRCA related cancers is of strategical importance in the management of patients with strong familiar neoplastic history or with genetic test positivity. An adequate counselling can help in the management of these cancers in the prevention and early diagnosis taking also into consideration the possibility of a prophylactic surgery.


Assuntos
Adenocarcinoma/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Leucemia Linfocítica Crônica de Células B/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Ovarianas/genética , Neoplasias do Colo do Útero/genética , Idoso , Feminino , Humanos , Mutação , Linhagem
15.
J Endocrinol Invest ; 28(2): 137-44, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15887859

RESUMO

Differential protein arrays between nuclear extracts of human thyroid cell lines obtained from tumors with different degree of differentiation were exploited to define molecular alterations occurring during thyroid tumor progression. Nuclear extracts from the well differentiated TPC-1 (from papillary carcinoma) and the poorly differentiated ARO (from anaplastic carcinoma) cells showed an overall similar pattern of protein expression as revealed by two-dimensional gel electrophoresis analysis. However, manganese-superoxide dismutase (Mn-SOD) was clearly identified by mass spectrometry procedures as significantly less expressed in ARO compared to TPC-1 cells. A reduced expression of Mn-SOD in the nuclear compartment was confirmed by Western blot and immunofluorescence analysis. A similar expression pattern of nuclear Mn-SOD was detected by immunohistochemistry in human thyroid tumors, with the lowest or absent detection in anaplastic carcinomas. Moreover, the levels of nuclear Mn-SOD in tumor cells were lower than in the normal thyrocytes. These data indicate that an altered nuclear expression of Mn-SOD parallels, together with changes in other elements of the antioxidant protective system, the loss of differentiation occurring during the progression of thyroid tumors.


Assuntos
Carcinoma/enzimologia , Núcleo Celular/enzimologia , Proteômica , Superóxido Dismutase/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/enzimologia , Adenocarcinoma Folicular/patologia , Western Blotting , Carcinoma/patologia , Carcinoma Papilar/enzimologia , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Distribuição Tecidual
16.
Int J Gynaecol Obstet ; 88(3): 265-70, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15733879

RESUMO

OBJECTIVE: The aim of this study was to evaluate the correlation between genetic thrombophilic mutations, uterine artery Doppler at 24 weeks of gestation and preeclampsia. METHODS: In a case control study we performed the genetic analysis for Leiden mutation of factor V gene (FV), G20210A mutation of the prothrombin gene (PT) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene in 103 women that had already attended routine ultrasonography scanner at 20 weeks at our Department. RESULTS: The frequency of heterozygous carriers of the factor V Leiden was 17.4% in the women with preeclampsia and abnormal artery Doppler compared with 3.12% in the patients with normal pregnancies. This difference was statistically significant (P<0.05). The frequency of mutation G20210A of prothrombin gene was 1.5 vs. 4.3% between women with normal pregnancies and with preeclampsia. This difference is not statistically significant. The frequency of homozygous patients for the C677T mutation of MTHFR gene among the patients with preeclampsia was 21.7% and in the control group was 10.3%, but this difference is not statistically significant. No thrombophilic gene variants were found in women with preeclampsia and normal uterine artery Doppler. CONCLUSION: We demonstrated the important association between factor V Leiden mutation, abnormal uterine Doppler at 24 weeks and preeclampsia in our population.


Assuntos
Fator V/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pré-Eclâmpsia/fisiopatologia , Protrombina/genética , Útero/irrigação sanguínea , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Fluxometria por Laser-Doppler , Mutação , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Gravidez , Ultrassonografia Pré-Natal
17.
J Mol Endocrinol ; 34(1): 199-207, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15691888

RESUMO

Tumour suppressor p53 is a transcription factor essential for DNA damage checkpoints during cellular response to stress. Mutations in the p53 gene are the most common genetic alterations found in human tumours; most pathogenetic modifications are missense mutations that abolish the p53 DNA-binding function. In the same cell type, distinct p53 missense mutations may determine different phenotypes. The PC Cl3 cell line retains several markers of thyroid differentiation in vitro. Introduction of the V143A mutant p53 allele, which abolishes the p53 DNA-binding function, leads to loss of differentiation markers as well as TSH dependency for growth. Conversely, PC Cl3 cells transfected with the S392A mutant p53 allele, presenting the mutation located outside the DNA-binding domain, show only loss of TSH dependency for growth. To identify molecular differences existing between PC Cl3 cell lines transformed by the V143A and the S392A mutant alleles, a differential proteomic approach was used. Two-dimensional gel electrophoresis analyses indicated that expression of a significant portion of protein species was modified by both p53 mutants. In fact, compared with wild-type PC Cl3 cells, modification of expression in V143A mutant cells occurred in 23.6% of the entire protein species. Conversely, modification of S392A mutant cells affected 14.0% of total proteins. Among these components, 8.3% were common to both mutants. Several of these proteins were identified by mass spectrometry procedures; some proteins, such as HSP90 and T-complex proteins, are already known to be related to p53 function.


Assuntos
Transformação Celular Neoplásica/metabolismo , Proteínas de Neoplasias/metabolismo , Glândula Tireoide/metabolismo , Calreticulina/isolamento & purificação , Eletroforese em Gel Bidimensional , Galectina 1/isolamento & purificação , Proteínas de Choque Térmico HSP90/isolamento & purificação , Humanos , Proteínas de Neoplasias/isolamento & purificação , Proteoma , Proteína Supressora de Tumor p53/metabolismo , Vimentina/isolamento & purificação
18.
Minerva Ginecol ; 56(5): 385-90, 2004 Oct.
Artigo em Italiano | MEDLINE | ID: mdl-15531855

RESUMO

AIM: Pre-eclampsia is one of the major causes of maternal and fetal morbidity and mortality. The aim of this study was to evaluate the clinical usefulness of screening of genetic thrombophilic mutations and uterine artery Doppler flow velocimetry at 24 weeks of gestation in the prediction of pre-eclampsia in low risk pregnant women. METHODS: We performed the genetic analysis for Leiden mutation of factor V gene (FV), G20210A mutation of the prothrombin gene (PT) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene in 103 women that had already attended routine ultrasonography scanner at 24 weeks at our Department. RESULTS: The frequency of heterozygous carriers of the Leiden FV was 17.4% in women with pre-eclampsia and abnormal artery Doppler flow velocimetry compared with 3.12% in patients with normal pregnancies. This difference was statistically significant (P<0.05). The frequency of mutation G20210A of PT gene was 1.5% vs 4.3% between women with normal pregnancies and with pre-eclampsia. This difference is not statistically significant. The frequency of homozygous patients for the C677T mutation of MTHFR gene among patients with pre-eclampsia was 21.7% and in the control group was 10.3%, but this difference is not statistically significant. No thrombophilic genes variants were found in women with pre-eclampsia and normal uterine artery Doppler flow velocimetry. CONCLUSION: We demonstrated the important association between FV Leiden mutation, abnormal uterine artery Doppler flow velocimetry at 24 weeks and pre-eclampsia in our low-risk population.


Assuntos
Fator V/genética , Programas de Rastreamento , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Pré-Eclâmpsia/diagnóstico por imagem , Pré-Eclâmpsia/genética , Protrombina/genética , Útero/irrigação sanguínea , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Programas de Rastreamento/métodos , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Reação em Cadeia da Polimerase , Pré-Eclâmpsia/sangue , Gravidez , Segundo Trimestre da Gravidez , Fluxo Pulsátil , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia Doppler/métodos , Útero/diagnóstico por imagem
19.
Horm Metab Res ; 35(1): 24-8, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12669267

RESUMO

Relaxin is a peptide hormone that, in humans, is encoded by two genes referred to as H1 and H2, both located into chromosome 9p24.1. We have searched for polymorphisms in the 5'-flanking sequence of these genes. Both genes possess a CT repeat followed by a GT repeat. CT and GT repeats of the H2 gene are longer than those of the H1 gene. Moreover, CT and GT repeats of the H2 gene, but not those of the H1 gene, show length polymorphism. Protein-DNA interaction experiments suggest that difference between the H1 and H2 GT repeats may have arisen because the requirements of the transcriptional regulation of the two genes are different.


Assuntos
Região 5'-Flanqueadora/genética , Repetições de Dinucleotídeos/genética , Polimorfismo Genético/genética , Relaxina/genética , Actinas/genética , Sondas de DNA , Regulação da Expressão Gênica , Humanos , Repetições de Microssatélites , Polimorfismo Conformacional de Fita Simples , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Mol Cell Endocrinol ; 194(1-2): 71-6, 2002 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-12242029

RESUMO

Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated.


Assuntos
Carbono-Oxigênio Liases/biossíntese , Nódulo da Glândula Tireoide/patologia , Transporte Ativo do Núcleo Celular , Adenoma/patologia , Idoso , Carbono-Oxigênio Liases/análise , Carbono-Oxigênio Liases/metabolismo , Núcleo Celular/enzimologia , Transformação Celular Neoplásica/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Feminino , Bócio Nodular/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Transporte Proteico , Nódulo da Glândula Tireoide/enzimologia , Regulação para Cima
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