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1.
Br J Cancer ; 117(3): 340-346, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28641307

RESUMO

BACKGROUND: The expression of human equilibrative nucleoside transporter 1 (hENT1), the major gemcitabine transporter into cells, has been thoroughly investigated as a predictive marker of response to gemcitabine in pancreatic cancer and biliary tract cancers. Since gemcitabine is widely used in the treatment of leiomyosarcoma and angiosarcoma, we investigated the correlation between hENT1 expression and gemcitabine efficacy in these sarcoma subtypes. METHODS: We retrospectively identified 71 patients affected by advanced angiosarcoma (26) or leiomyosarcoma (45) treated within five Italian referral centres for sarcoma; among them, 49 patients (15 angiosarcoma, 34 leiomyosarcoma) were treated with gemcitabine. All tumour samples were analysed for hENT1 expression by real-time PCR. Median 2-ΔCt value was used as the cutoff to dichotomise patients into 'high' expression and 'low' expression groups. Kaplan-Meier analysis was performed to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P=0.004; OS: 14.9 vs 8.5 months, P=0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P=0.02) and OS (20.6 vs 10.8 months; P=0.001) in angiosarcoma patients treated with gemcitabine. CONCLUSIONS: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Hemangiossarcoma/genética , Leiomiossarcoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Expressão Gênica , Hemangiossarcoma/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
3.
Pancreas ; 45(5): 748-54, 2016 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26495787

RESUMO

OBJECTIVES: R1 resection rate after pancreaticoduodenectomy (PD) for cancer is highly variable. The aim of this study was to verify if a standardized histopathological work-up of the specimen affects the rate of R1 resection after PD for cancer. METHODS: Two groups of specimens were managed with (standardized method [SM] group) or without (non-standardized method [NSM] group) a SM of histopathological work-up. Each group included 50 cases of PD for periampullary cancer. Differences in terms of R1 resection rate between the 2 groups were evaluated. Correlation between R1 status and local recurrence was also evaluated. RESULTS: The cohort of 100 patients consisted of 66 pancreatic ductal adenocarcinoma, 15 cholangiocarcinoma, and 19 ampullary cancer. The R1 resection rate resulted statistically higher in the SM group (66% vs 10%). Local recurrence was more frequently related to R1 resection in the SM group (34.3% of cases) than in NSM group (20% of cases). CONCLUSIONS: The use of the SM of pathological evaluation of the specimen after PD for cancer determines a significant increase of R1 resection. This remarkable difference seems to be due to the different definition of minimum clearance. The SM seems to better discriminate patients in terms of risk of local recurrence.


Assuntos
Ampola Hepatopancreática/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Colangiocarcinoma/cirurgia , Neoplasia Residual/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Idoso , Ampola Hepatopancreática/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Patologia Clínica/métodos , Análise de Sobrevida , Fatores de Tempo
4.
J Cell Mol Med ; 17(11): 1415-21, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24283947

RESUMO

Tumour-associated Macrophages (TAM) present two different polarizations: classical (M1) characterized by immunostimulation activity and tumour suppression; alternative (M2) characterized by tumour promotion and immune suppression. In this retrospective study, we evaluated the correlation between the two forms of TAM with survival time in radically resected gastric cancer patients. A total of 52 chemo- and radio-naive patients were included. Two slides were prepared for each patient and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five representative high-power fields per slide were evaluated for TAM count. The median value of the two macrophage populations density and the median value of M1/M2 ratio were used as cut-off. Twenty-seven patients with M1 density above-the-median had a significantly higher survival compared to those below the median. Twenty-six patients with M1/M2 ratio above the median showed median OS of 27.2 months compared to 15.5 months of the patients below the median. No association between M2 macrophage density and patient's outcome was found. In multivariate analysis, M1/M2 was a positive independent predictor of survival. The M1 macrophage density and M1/M2 ratio, as confirmed in multivariate analysis, are factors that can help in predicting patients survival time after radical surgery for gastric cancer.


Assuntos
Macrófagos/fisiologia , Neoplasias Gástricas/mortalidade , Polaridade Celular , Feminino , Gastrectomia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
5.
Nat Med ; 19(10): 1288-96, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24056770

RESUMO

In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.


Assuntos
Falência Renal Crônica/metabolismo , Podócitos/citologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Progressão da Doença , Humanos , Falência Renal Crônica/patologia , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos/fisiologia , Néfrons/metabolismo , Néfrons/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/fisiologia
6.
Clin J Am Soc Nephrol ; 8(5): 749-55, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23371956

RESUMO

BACKGROUND AND OBJECTIVES: X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy. RESULTS: GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution. CONCLUSIONS: These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.


Assuntos
Autoantígenos/análise , Colágeno Tipo IV/análise , Imunofluorescência , Membrana Basal Glomerular/química , Nefrite Hereditária/metabolismo , Adolescente , Adulto , Fatores Etários , Biomarcadores/análise , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/fisiopatologia , Taxa de Filtração Glomerular , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Microscopia de Fluorescência , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Nefrite Hereditária/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Proteinúria/genética , Proteinúria/metabolismo , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
7.
Cell Transplant ; 22(3): 493-503, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22776240

RESUMO

Electrostimulation represents a well-known trophic factor for different tissues. In vitro electrostimulation of non-stem and stem cells induces myogenic predifferentiation and may be a powerful tool to generate cells with the capacity to respond to local areas of injury. We evaluated the effects of in vivo electrostimulation on infarcted myocardium using a miniaturized multiparameter implantable stimulator in rats. Parameters of electrostimulation were organized to avoid a direct driving or pacing of native heart rhythm. Electrical stimuli were delivered for 14 days across the scar site. In situ electrostimulation used as a cell-free, cytokine-free stimulation system, improved myocardial function, and increased angiogenesis through endothelial progenitor cell migration and production of vascular endothelial growth factor (VEGF). In situ electrostimulation represents a novel means to stimulate repair of the heart and other organs, as well as to precondition tissues for treatment with cell-based therapies.


Assuntos
Estimulação Elétrica , Infarto do Miocárdio/fisiopatologia , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Movimento Celular , Terapia Baseada em Transplante de Células e Tecidos , Eletrodos Implantados , Endotélio Vascular/citologia , Feminino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Neovascularização Fisiológica , Ratos , Ratos Wistar , Regeneração , Células-Tronco/citologia , Células-Tronco/metabolismo , Tomografia Computadorizada por Raios X , Fator A de Crescimento do Endotélio Vascular/metabolismo , Função Ventricular Esquerda/fisiologia
8.
Eur J Cancer ; 49(6): 1501-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23266047

RESUMO

PURPOSE: The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients. METHODS: Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n=116 and n=50, respectively) and from patients with diverticulosis as control group (n=20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome. RESULTS: The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P<.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P<.0001) and overall survival (OS) (P=.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P=.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P=.011), lower organs involvement (RR 0.79; P=.034) and low Dicer expression (RR 0.71; P=.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome. CONCLUSION: These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Bevacizumab , Neoplasias Colorretais/patologia , RNA Helicases DEAD-box/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease III/metabolismo , Resultado do Tratamento , Adulto Jovem
9.
PLoS One ; 7(9): e43110, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028444

RESUMO

Breast cancer cells with the CD44+/CD24- phenotype have been reported to be tumourigenic due to their enhanced capacity for cancer development and their self-renewal potential. The identification of human tumourigenic breast cancer cells in surgical samples has recently received increased attention due to the implications for prognosis and treatment, although limitations exist in the interpretation of these studies. To better identify the CD44+/CD24- cells in routine surgical specimens, 56 primary breast carcinoma cases were analysed by immunofluorescence and confocal microscopy, and the results were compared using flow cytometry analysis to correlate the amount and distribution of the CD44+/CD24- population with clinicopathological features. Using these methods, we showed that the breast carcinoma cells displayed four distinct sub-populations based on the expression pattern of CD44 and CD24. The CD44+/CD24- cells were found in 91% of breast tumours and constituted an average of 6.12% (range, 0.11%-21.23%) of the tumour. A strong correlation was found between the percentage of CD44+/CD24- cells in primary tumours and distant metastasis development (p = 0.0001); in addition, there was an inverse significant association with ER and PGR status (p = 0.002 and p = 0.001, respectively). No relationship was evident with tumour size (T) and regional lymph node (N) status, differentiation grade, proliferative index or HER2 status. In a multivariate analysis, the percentage of CD44+/CD24- cancer cells was an independent factor related to metastasis development (p = 0.004). Our results indicate that confocal analysis of fluorescence-labelled breast cancer samples obtained at surgery is a reliable method to identify the CD44+/CD24- tumourigenic cell population, allowing for the stratification of breast cancer patients into two groups with substantially different relapse rates on the basis of CD44+/CD24- cell percentage.


Assuntos
Neoplasias da Mama/metabolismo , Antígeno CD24/metabolismo , Carcinoma/metabolismo , Receptores de Hialuronatos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma/mortalidade , Carcinoma/patologia , Feminino , Humanos , Imunofenotipagem , Glândulas Mamárias Humanas/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias
10.
Genes Chromosomes Cancer ; 51(12): 1133-43, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22927297

RESUMO

Epigenetic alterations, such as CpG islands methylation and histone modifications, are recognized key characteristics of cancer. Glycogenes are a group of genes which epigenetic status was found to be changed in several tumors. In this study, we determined promoter methylation status of the glycogene beta-1,4-galactosyltransferase 1 (B4GALT1) in colorectal cancer patients. Methylation status of B4GALT1 was assessed in 130 colorectal adenocarcinomas, 13 adenomas, and in paired normal tissue using quantitative methylation specific PCR (QMSP). B4GALT1 mRNA expression was evaluated in methylated/unmethylated tumor and normal specimens. We also investigated microsatellite stability and microsatellite instability status and KRAS/BRAF mutations. Discriminatory power of QMSP was assessed by receiving operating curve (ROC) analysis on a training set of 24 colorectal cancers and paired mucosa. The area under the ROC curve (AUC) was 0.737 (95% confidence interval [CI]:0.591-0.881, P = 0.005) with an optimal cutoff value of 2.07 yielding a 54% sensitivity (95% CI: 35.1%-72.1%) and a specificity of 91.7% (95% CI: 74.1%-97.7%). These results were confirmed in an independent validation set where B4GALT1 methylation was detected in 52/106 patients. An inverse correlation was observed between methylation and B4GALT1 mRNA expression levels (r = -0.482, P = 0.037). Significant differences in methylation levels and frequencies was demonstrated in invasive lesions as compared with normal mucosa (P = 0.0001) and in carcinoma samples as compared with adenoma (P = 0.009). B4GALT1 methylation is a frequent and specific event in colorectal cancer and correlates with downregulation of mRNA expression. These results suggest that the glycogene B4GALT1 represent a valuable candidate biomarker of invasive phenotype of colorectal cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Galactosiltransferases/genética , Regiões Promotoras Genéticas , Idoso , Metilação de DNA , Feminino , Galactosiltransferases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , RNA Mensageiro/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
11.
Hepatology ; 56(6): 2180-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22753133

RESUMO

UNLABELLED: Evidence suggests an association between low serum 25-hydroxy-vitamin D(3) [25(OH)D(3) ] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated. We evaluated the hepatic expression of VDR along with that of vitamin D 25-hydroxylases in patients with nonalcoholic steatohepatitis (NASH) or chronic hepatitis C (CHC) and its relationship with hepatic histological features and serum 25(OH)D(3) levels. We evaluated 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy for clinical purposes and 20 subjects without liver disease. Serum 25(OH)D(3) was measured via colorimetric assay. Expression of VDR, CYP2R1, and CYP27A1 was evaluated via immunohistochemistry in hepatocytes, cholangiocytes, and liver inflammatory cells. Parenchymal and inflammatory cells from liver biopsies of patients with NASH and CHC expressed VDR, CYP2R1, and CYP27A1. In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (P < 0.02), lobular inflammation (P < 0.01), and nonalcoholic fatty liver disease score (P < 0.03). Moreover, expression of CYP2R1 in hepatocytes correlated strongly with VDR positivity on liver inflammatory cells. In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas portal inflammation was significantly higher in patients with VDR-negative inflammatory cells (P < 0.009) and low VDR expression in hepatocytes (P < 0.03). CONCLUSION: VDR is widely expressed in the liver and inflammatory cells of chronic liver disease patients and its expression is negatively associated with the severity of liver histology in both NASH and CHC patients. These data suggest that vitamin D/VDR system may play a role in the progression of metabolic and viral chronic liver damage. (HEPATOLOGY 2012;56:2180-2187).


Assuntos
Colestanotriol 26-Mono-Oxigenase/metabolismo , Fígado Gorduroso/metabolismo , Hepatite C Crônica/metabolismo , Receptores de Calcitriol/metabolismo , Adiponectina/sangue , Adulto , Idoso , Glicemia/metabolismo , Calcifediol/sangue , Estudos Transversais , Família 2 do Citocromo P450 , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Hepatócitos/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Índice de Gravidade de Doença , Estatísticas não Paramétricas
12.
J Cell Physiol ; 227(3): 927-33, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21503888

RESUMO

PML regulates a wide range of pathways involved in tumorigenesis, such as apoptosis, which is also one of the main mechanisms through which oxaliplatin and fluoropyrimidine exert their antineoplastic activity. The present study aims to investigate PML expression as a predictive factor of oxaliplatin/fluoropyrimidine therapy efficacy. Seventy-four metastatic colorectal cancer patients who received oxaliplatin/floropyrimidine-based first line therapy have been included in this retrospective study. PML expression was assessed by immunohistochemistry. PML down-regulation was detected in 39 (52.7%) patients (14 complete and 25 partial PML loss). RR was significantly lower (25.6%) in patients with PML down-regulation than in patients with preserved PML expression (60%) (P = 0.006). Median TTP was 5.5 months when PML was down-regulated versus 11.9 months in case of preserved PML expression (P < 0.0001). A statistical significant difference was also detected in OS (15.6 and 24.5 months, respectively, P = 0.003). The impact of PML down-regulation on TTP and OS was statistically significant also in a multivariate model. This study represents the first evidence of a possible correlation between PML protein expression and outcome of metastatic colorectal cancer patients treated with oxaliplatin/fluoropyrimidine-based first line therapy.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Fluoruracila/uso terapêutico , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/secundário , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Fluoruracila/análogos & derivados , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Valor Preditivo dos Testes , Proteína da Leucemia Promielocítica , Estudos Retrospectivos , Taxa de Sobrevida
13.
PLoS One ; 6(4): e19234, 2011 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-21559440

RESUMO

BACKGROUND: Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG. MATERIALS AND METHODS: We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival. RESULTS: Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that "RANK-negative" and "RANK-positive" patients had a SDFS of 105.7 months (95% CI: 73.9-124.4) and 58.9 months (95% CI: 34.7-68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029). CONCLUSIONS: This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptor Ativador de Fator Nuclear kappa-B/biossíntese , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Ligantes , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , RNA Mensageiro/metabolismo
15.
Int J Cancer ; 129(3): 536-45, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21064098

RESUMO

Mutations in DNA double-strand breaks (DSB) repair genes are involved in the pathogenesis of hereditary mammary tumors, it is, however, still unclear whether defects in this pathway may play a role in sporadic breast cancer. In this study, we initially determined mRNA expression of 15 DSB related genes by reverse transcription quantitative polymerase chain reaction in paired normal tissue and cancer specimen from 20 breast cancer cases to classify them into homogeneous clusters. G22P1/ku70, ATR and RAD51 genes were differentially expressed in the three branches recognized by clustering analysis. In particular, a breast cancer subgroup characterized by high RAD51 mRNA levels and estrogen receptor (ER)-positive/progesteron receptor (PR)-negative phenotype was identified. This result was confirmed by the analysis of G22P1/ku70, ATR and RAD51 mRNA levels on paired normal and tumor specimens from an extended breast cancer cohort (n = 75). RAD51 mRNA levels were inversely associated with PR status (p = 0.02) and the highest levels were, indeed, detected in ER-positive/PR-negative tumors (p = 0.03). RAD51 immunostaining of a tissue microarray confirmed the inverse relationship between high RAD51 expression and negative PR status (p = 0.002), as well as, the association with ER-positive/PR-negative phenotype (p = 0.003). Interestingly, the analysis of microarray expression data from 295 breast cancers indicate that RAD51 increased mRNA expression is associated with higher risk of tumor relapse, distant metastases and worst overall survival (p = 0.015, p = 0.009 and p = 0.013 respectively). Our results suggest that RAD51 expression determination could contribute to a better molecular classification of mammary tumors and may represent a novel tool for evaluating postoperative adjuvant therapy for breast cancer patients.


Assuntos
Rad51 Recombinase/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Quebras de DNA de Cadeia Dupla , Progressão da Doença , Receptor alfa de Estrogênio , Feminino , Humanos , Neoplasias Hormônio-Dependentes , Prognóstico , RNA Mensageiro/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento
16.
J Cell Physiol ; 224(3): 644-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20578240

RESUMO

To date, little is known concerning the promyelocytic leukemia gene (PML) status in tumors of different origin, and its expression has never been evaluated in soft tissue sarcoma. The aim of the present study is focused on the identification of differences in terms of PML protein expression between different types of soft tissue sarcoma and the corresponding normal surrounding tissue. PML protein expression has been assessed by immunohistochemistry in six different histologic types of soft tissue sarcoma (synovial sarcoma, myofibroblastic sarcoma, angiosarcoma, liposarcoma, pleomorphic sarcoma, and leiomyosarcoma) and in the corresponding normal surrounding tissue. PML resulted significantly down-regulated in synovial sarcoma and in myofibroblastic sarcoma specimens. Also in angiosarcoma samples a significative difference in PML expression in comparison with normal specimens has been detected. Interestingly PML protein detection showed a different pattern of expression in the three liposarcoma histology types compared with corresponding nontumoral tissues. In particular PML protein resulted significantly down-regulated in myxoid liposarcoma and in dedifferentiated liposarcoma. On the contrary no statistically significant difference was observed in pleomorphic liposarcoma compared to normal tissue specimens. Further investigations are needed to confirm these data and to assess the possible value of PML expression as a prognostic factor in these extremely aggressive diseases.


Assuntos
Regulação para Baixo , Proteínas Nucleares/metabolismo , Sarcoma/metabolismo , Sarcoma/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Humanos , Imuno-Histoquímica , Proteína da Leucemia Promielocítica , Sarcoma/terapia
17.
Pediatr Nephrol ; 25(7): 1269-75, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20238228

RESUMO

Limited and discordant data are available on cyclosporine A (CsA) treatment for proteinuria in Alport syndrome (AS). To address this lack of consistent data, we have studied 15 AS patients (14 males; mean age 15.3 +/- 6.0 years) treated with CsA. Patient selection criteria included a urinary protein/creatinine ratio > or =1 mg/mg and a creatinine clearance >40 ml/min/1.73 m(2). CsA treatment was started at an initial dose of 5 mg/kg/day and subsequently adjusted to reach target C2 levels of 500 ng/ml. Renal function, proteinuria, and blood pressure were monitored. Blood pressure was treated to avoid the administration of angiotensin converting enzyme or angiotensin receptor blockers for the first 2 years of therapy. The average follow-up was 3.5 years. Five patients had chronic renal failure at the beginning of treatment, of whom three and one reached end-stage renal failure within 1 and 3 years, respectively. In the remaining 11 patients, the glomerular filtration rate declined by 11 +/- 6% within 6 months, but remained stable thereafter. Proteinuria decreased by 63 +/- 21% from baseline, but returned nearly to baseline after 2.5 years of follow-up. Based on these results, we suggest that CsA is effective in reducing proteinuria in patients with Alport syndrome but that this effect is temporary. Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure.


Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Hereditária/tratamento farmacológico , Proteinúria/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Humanos , Falência Renal Crônica/etiologia , Masculino , Nefrite Hereditária/complicações , Nefrite Hereditária/diagnóstico , Proteinúria/etiologia , Proteinúria/patologia , Resultado do Tratamento , Adulto Jovem
19.
J Cell Physiol ; 223(2): 384-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20082300

RESUMO

Nucleoside transporter proteins are specialized proteins that mediate the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a member of these proteins and mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. We investigated the immunohistochemical expression of hENT in tumor samples from 111 patients with resected gastric adenocarcinoma, correlating these data with clinical parameters and disease outcomes. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant or neoadjuvant program. On univariate survival analysis, the hENT1 expression was associated with overall survival (OS) and disease free survival (DFS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.021) and a shorter DFS (P = 0.033). Considering only the node positive patients, higher hENT levels were associated with significantly shorter median DFS (21.7 months; 95% CI 11.1-32.4) compared with patients with low expression of hENT1. The hENT1 expression was defined, in the lymph-node positive patients, as an independent prognostic factor (P = 0.019). Furthermore, considering only patients with diffuse or mixed tumors and lymph-node positive, the expression of hENT1 was strongly related with DFS and OS. Immunohistochemistry for the hENT1 protein carries prognostic information in patients with resected gastric cancer and holds promise as a predictive factor in chemotherapy decisions.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Mucosa Gástrica/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/análise , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transportador Equilibrativo 1 de Nucleosídeo/análise , Feminino , Mucosa Gástrica/patologia , Mucosa Gástrica/fisiopatologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/fisiopatologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/prevenção & controle , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida
20.
Am J Hum Genet ; 85(5): 706-10, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19853239

RESUMO

Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Cálcio/metabolismo , Mutação , Nucleotidases/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Arginina/metabolismo , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Células Cultivadas , Pré-Escolar , Condrócitos/metabolismo , Cromossomos Humanos Par 17 , Códon sem Sentido , Consanguinidade , Retículo Endoplasmático Rugoso/ultraestrutura , Éxons , Evolução Fatal , Feminino , Fibroblastos/ultraestrutura , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Núcleo Familiar , RNA Mensageiro/metabolismo , Radiografia
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