RESUMO
BACKGROUND: This study examined the relationship between rapid weight gain during infancy and/or early childhood and anthropometric measurements [body mass index (BMI), percent body fat (%BF), waist circumference (WC) and waist-to-height ratio (WHtR)] in preadolescence by sex. METHODS: Subjects were fourth-grade school children (aged 9 to 10 years) from elementary schools in Ina-town, Japan, in 2010. Measurements of height, weight, %BF and WC were conducted for each subject. We obtained data on height and weight of subjects at birth, age 1.5 years and age 3 years from the Maternal and Child Health handbook. Rapid weight gain was defined as a change in weight-for-age standard deviation score greater than 0.67 from birth to age 1.5 years (infancy) or from age 1.5 to 3 years (early childhood). RESULTS: All anthropometric variables (BMI, %BF, WC and WHtR) at age 9 to 10 years were significantly higher in the rapid weight gain during both infancy and early childhood period group than in the no rapid weight gain group, regardless of sex. When compared with the no rapid weight gain group, rapid weight gain during early childhood period had significantly higher BMI and WC in boys and BMI, %BF and WC in girls. Compared with the no rapid weight gain group, the rapid weight gain during infancy group had a significantly higher WC in boys and significantly higher BMI and WC in girls. CONCLUSION: Rapid weight gain during both infancy and early childhood was related to higher anthropometric measurements, including WHtR, among Japanese preadolescents, regardless of sex. This study suggests that rapid weight gain during infancy and early childhood may be a risk factor for general/abdominal obesity later in life.
Assuntos
Obesidade Infantil/epidemiologia , Aumento de Peso/fisiologia , Estatura , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Japão/epidemiologia , Masculino , Obesidade Infantil/prevenção & controle , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Risco , Circunferência da CinturaRESUMO
Despite improvements in surgical techniques, perioperative management, and multidisciplinary therapy, treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC) remain poor. Therefore, development of novel molecular biomarkers, which either predict patient survival or become therapeutic targets, is urgently required. In the present study, to facilitate early detection of ESCC and predict its clinical course, we investigated the relationship of the serum level of melanoma-associated antigen (MAGE)-D4 to patients' clinicopathological characteristics. Using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays, we determined the levels of MAGE-D4 mRNA and protein in cell lysates and conditioned medium of cultures, respectively, of nine ESCC cell lines. Further, we determined MAGE-D4 levels in serum samples collected from 44 patients with ESCC who underwent radical esophagectomy without neoadjuvant therapy as well as from 40 healthy volunteers. Samples of conditioned medium and cell lysates contained comparable levels of MAGE-D4 that correlated closely with the levels of MAGE-D4 mRNA. Preoperative MAGE-D4 levels in the sera of 44 patients with ESCC, which varied from 0 to 2,354 pg/mL (314 ± 505 pg/mL, mean ± standard deviation), were significantly higher compared with those of healthy volunteers. By setting the cutoff at the highest value for healthy volunteers (50 pg/mL), the MAGE-D4-positive group of patients was more likely to have shorter disease-specific and disease-free survival compared with those of the MAGE-D4-negative group, although the differences were not statistically significant. Our results indicate that the elevation of preoperative serum MAGE-D4 levels in some patients with ESCC was possibly caused by excess production of MAGE-D4 by tumor cells followed by its release into the circulation. Clinical implications of serum MAGE-D4 levels should be validated in a large population of patients with ESCC.
Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Esofágicas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago , Esofagectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.
Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Laríngeas/terapia , Laringectomia , Neoplasias Primárias Múltiplas/terapia , Neoplasias Faríngeas/terapia , Faringectomia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Carcinoma de Células Escamosas do Esôfago , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Terapia de Salvação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4â mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4â mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4â mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4â mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥65 years), lymphatic involvement, and high MAGE-D4â mRNA expression as significant prognostic factors; high MAGE-D4â mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4â mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.
Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , RNA Mensageiro/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Peritoneal lavage cytology (CY) is used in the diagnosis and staging of various cancers. The clinical significance of positive cytology results in patients with pancreatic cancer is yet to be determined. METHODS: Peritoneal washing samples were collected from consecutive patients with pancreatic cancer between July 1991 and December 2012. The correlations between cytology results, clinicopathological parameters and recurrence patterns were evaluated. The prognostic impact of CY status, regarding resectability and the effectiveness of adjuvant chemotherapy, were analysed. RESULTS: Of 523 included patients, 390 underwent resection. Patients with tumours at least 2 cm in diameter were more likely to have CY+ status than patients with tumours smaller than 2 cm (48 of 312 versus 3 of 78 respectively; P = 0·005) and there was a significant correlation between CY+ status and tumour invasion of the anterior pancreatic capsule (43 of 276 versus 8 of 113 with no invasion of the capsule; P = 0·030). Although the overall survival of patients with resected CY+ tumours was worse than that of patients with resected CY- tumours, it was significantly better than the survival of unresected patients regardless of CY status. Multivariable analysis of all patients who had pancreatectomy did not identify CY+ as an independent prognostic factor. Patients with CY+ tumours tended to develop peritoneal metastasis more often than those with CY- tumours, although not significantly so. The median survival time of 34 patients with resected CY+ tumours who received adjuvant chemotherapy was better than that of 17 patients who had surgery alone, although this was not statistically significant (15·3 versus 10·0 months; P = 0·057). CONCLUSION: CY+ status is not clinically equivalent to gross peritoneal metastasis in patients with pancreatic cancer. Curative resection is still recommended regardless of CY status.
Assuntos
Neoplasias Pancreáticas/patologia , Lavagem Peritoneal/métodos , Peritônio/patologia , Quimioterapia Adjuvante , Citodiagnóstico/métodos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Peritoneais/secundárioRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem, and identification of new tumor-related genes is an urgent task. METHODS: To detect tumor-related genes effectively, we performed double-combination array analysis, which consisted of an expression array and a single nucleotide polymorphism (SNP) array of a single surgical HCC specimen. RESULTS: Expression array analysis identified AKAP12 as one of the genes with reduced expression in HCC tissues when compared with non-cancerous adjacent hepatic tissues. In addition, AKAP12 expression levels in tumor tissues from 48 HCC samples were significantly lower (P < 0.001) than those in normal tissues, and the downregulation was significantly correlated with poor overall survival rate (P = 0.003). However, SNP array analysis revealed that locus 6q24-q25 where AKAP12 was located did not show chromosomal deletion. In contrast, hypermethylation in the AKAP12 promoter regions was observed in 41 of 48 HCC samples. We then confirmed that AKAP12 gene re-expression occurs after 5-aza-2'-deoxycytidine (5-aza-dC) treatment through direct sequence analysis of the AKAP12 promoter region in HCC cell lines. CONCLUSIONS: The current data suggest that AKAP12 is downregulated in cancer tissues through promoter hypermethylation, and may have a role as a candidate tumor suppressor gene for HCC.
Assuntos
Proteínas de Ancoragem à Quinase A/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Hepáticas/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Adulto , Idoso , Apoptose , Azacitidina/análogos & derivados , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Decitabina , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions, and about 5% of human births have a recognizable malformation. In order to find clues to the mechanisms of malformation and abortion, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53-/-) and wild-type (p53+/+) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, p53-/- mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53+/+ mice had a 20% incidence of anomalies and a 60% incidence of deaths. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent "guardian" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of cells with apoptotic DNA fragments was greatly increased in tissues of the p53+/+ fetuses but not in those of the p53-/- fetuses.
Assuntos
Apoptose , Embrião de Mamíferos/anormalidades , Proteína Supressora de Tumor p53/deficiência , Animais , Morte Fetal/veterinária , Deformidades Congênitas dos Membros , Camundongos , Camundongos Transgênicos , Defeitos do Tubo Neural , Proteína Supressora de Tumor p53/genética , Raios X/efeitos adversosRESUMO
The purpose of this study was to develop a computerized method for estimation of the location of a lung tumor in cine images on an electronic portal imaging device (EPID) without implanted markers during stereotactic body radiotherapy (SBRT). Each tumor region was segmented in the first EPID cine image, i.e., reference portal image, based on a multiple-gray level thresholding technique and a region growing technique, and then the image including the tumor region was cropped as a 'tumor template' image. The tumor location was determined as the position in which the tumor template image took the maximum cross-correlation value within each consecutive portal image, which was acquired in cine mode on the EPID in treatment. EPID images with 512 x 384 pixels (pixel size: 0.56 mm) were acquired at a sampling rate of 0.5 frame s(-1) by using energies of 4, 6 or 10 MV on linear accelerators. We applied our proposed method to EPID cine images (226 frames) of 12 clinical cases (ages: 51-83, mean: 72) with a non-small cell lung cancer. As a result, the average location error between tumor points obtained by our method and the manual method was 1.47 +/- 0.60 mm. This preliminary study suggests that our method based on the tumor template matching technique might be feasible for tracking the location of a lung tumor without implanted markers in SBRT.
Assuntos
Algoritmos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Radiocirurgia/métodos , Técnica de Subtração , Cirurgia Assistida por Computador/métodos , Ecrans Intensificadores para Raios X , Inteligência Artificial , Humanos , Reconhecimento Automatizado de Padrão/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Alteration in transforming growth factor-beta signalling pathway is one of the main causes of pancreatic cancer. The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including pancreatic cancer. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human pancreatic cancer. Thirty-two patients with pancreatic cancer were investigated in this study. We examined the methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and conducted a mutation analysis. The results were compared with clinicopathological data. Promoter hypermethylation was detected in 20 (62.5%) of 32 pancreatic cancer tissues, confirmed by sequence of bisulphite-treated DNA. Loss of heterozygosity was detected in 11 (34.3%) of 32 pancreatic cancers. In comparison with clinicopathological data, hypermethylation showed a relation with a worse prognosis (P=0.0143). Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in pancreatic cancer. Therefore, RUNX3 may be an important tumour suppressor gene related to pancreatic cancer.
Assuntos
Cromossomos Humanos Par 1 , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Inativação Gênica , Neoplasias Pancreáticas/genética , Adulto , Idoso , Metilação de DNA , Análise Mutacional de DNA , Epigênese Genética , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/metabolismo , Polimorfismo Conformacional de Fita Simples , Valor Preditivo dos Testes , Prognóstico , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Análise de Sobrevida , Fator de Crescimento Transformador beta/metabolismoRESUMO
Recently, the use of oncolytic viruses against cancer has attracted considerable attention. We studied the potential of the US3 locus-deficient herpes simplex virus (HSV), L1BR1, for oncolytic virus therapy. Its high specificity and potency indicate that L1BR1 is a promising candidate as a new oncolytic virus against pancreatic cancer. Moreover, the virus exhibited the unique characteristic of increasing apoptosis when used in combination with anticancer drugs. We assessed the feasibility of using the US3 locus-deficient HSV named L1BR1 as a new replication-competent oncolytic virus for the treatment of pancreatic cancer. The US3 locus of HSV has been shown to be a key gene in producing a multifunctional protein kinase that inhibits apoptosis induced by viral infections, chemicals and ultraviolet (UV) light. L1BR1 has been reported to be more than 10 000-fold less virulent than the parental virus in mice. In this study, we examined the tumor specificity and oncolytic effect of this attenuated replication-competent virus, L1BR1, in pancreatic cancers derived from SW1990, Capan2 and Bxpc-3cells compared with the parent virus and other well-known oncolytic herpes viruses (R3616 and hrR3). We also studied the efficacy of L1BR1 for the induction of apoptosis as an attribute of this virus in combination with the anticancer drugs 5FU and cisplatin. The combined treatment of the pancreatic cancer cells with L1BR1 and these anticancer drugs enhanced apoptosis significantly. More importantly, L1BR1 showed the lowest replication capacity in normal human hepatocytes, but the highest tumor-reducing effect in vivo among the oncolytic herpes viruses tested. In addition, L1BR1 significantly increased the induction of apoptosis of cancer cells when treated in combination with anticancer drugs although the parental virus inhibited the induction of apoptosis. These results suggest that L1BR1 is promising as a new anticancer oncolytic virus.
Assuntos
Terapia Viral Oncolítica , Neoplasias Pancreáticas/terapia , Proteínas Serina-Treonina Quinases/deficiência , Simplexvirus/patogenicidade , Cisplatino/farmacologia , Fluoruracila/farmacologia , Terapia Genética , Vetores Genéticos , Vírus Oncolíticos/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/virologia , Proteínas Serina-Treonina Quinases/genética , Simplexvirus/genética , Simplexvirus/fisiologia , Células Tumorais Cultivadas , Proteínas Virais/genéticaRESUMO
We have isolated a cDNA (cNPK1) that encodes a predicted protein kinase of 690 amino acids from suspension cultures of tobacco cells. The deduced sequence is closely related to those of the protein kinases encoded by the STE11 and BCK1 genes of Saccharomyces cerevisiae and the byr2 gene of Schizosaccharomyces pombe. STE11 and Byr2 function in the yeast mating pheromone response pathways, and BCK1 acts downstream of the yeast protein kinase C homolog encoded by the PKC1 gene, which is essential for normal growth and division of yeast cells. Overexpression in yeast cells of a truncated form of cNPK1, which encodes only the putative catalytic domain, replaced the growth control functions of BCK1 and PKC1 but not the mating pheromone response function of STE11. Thus, the catalytic domain of NPK1 specifically activates the signal transduction pathway mediated by BCK1 in yeast. In tobacco cells in suspension culture, the NPK1 gene is transcribed during logarithmic phase and early stationary phase but not during late stationary phase. In a tobacco plant, it is also transcribed in stems and roots but not in mature leaves, which rarely contain growing cells. The present results suggest that a signal transduction pathway mediated by this BCK1- and STE11-related protein kinase is also conserved in plants and that a function of NPK1 is controlled at least in part at a transcriptional level.
Assuntos
Genes de Plantas , MAP Quinase Quinase Quinases , Nicotiana/genética , Proteínas de Plantas/genética , Plantas Tóxicas , Proteínas Quinases/genética , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA/genética , Análise Mutacional de DNA , Expressão Gênica , Genes Reguladores , Dados de Sequência Molecular , Saccharomyces cerevisiae , Alinhamento de Sequência , Transdução de SinaisRESUMO
To recognize "normal" hepatic hemodynamics after live donor liver transplantation (LDLT), we analyzed Doppler parameters on recipients with a right liver graft and donors after extended left hepatectomy. Theoretically these values should be the same. From April 2000 to October 2004, 20 LDLTs were performed using a right liver graft. The 10 recipients without postoperative complications and their donors were included in this study. Portal venous velocity (PVV; cm/s), hepatic arterial peak systolic velocity (cm/s), and hepatic venous peak velocity (HVPV; cm/s) were measured during the first 2 weeks. In donors PVV and HVPV after LDLT were significantly higher after than before left hepatectomy: 19.2 +/- 4.2 vs. 31.5 +/- 13.0 cm/s (P = .013) and 23.0 +/- 7.2 vs. 41.8 +/- 10.3 cm/s respectively (P = .010). However, there were mild degrees of increased PVV and HVPV. In recipients, a markedly increased PVV (106.3 +/- 45.2 cm/s on day 1) was significantly higher than that in donors on each postoperative day. The hepatic arterial resistive index in recipients was also significantly higher than that in donors on each postoperative day, for example, 0.72 +/- 0.11 vs 0.62 +/- 0.04 on day 1 (P = .0326). In conclusion, we have shown "abnormal" hepatic hemodynamics in even those recipients without complications during the early postoperative period after LDLT.
Assuntos
Transplante de Fígado/fisiologia , Doadores Vivos , Período Pós-Operatório , Adulto , Velocidade do Fluxo Sanguíneo , Peso Corporal , Humanos , Fígado/anatomia & histologia , Fígado/diagnóstico por imagem , Circulação Hepática , Tamanho do Órgão , Sistema Porta , Ultrassonografia DopplerRESUMO
AIMS: In the current study, we investigated possible correlations of the mtDNA copy number in hepatocellular carcinoma (HCC) with the pathological findings and prognosis. METHODS: We studied 31 HCC specimens using quantitative real-time polymerase chain reaction analysis, and the correlation between the mtDNA copy number and the clinicopathologic parameters and mutations in the D-loop region of the mitochondrial genome. RESULTS: The mtDNA copy number was reduced in HCCs compared with the corresponding non-cancerous liver tissues (p=0.002), and significantly correlated with tumour size (p=0.014) and cirrhosis (p=0.048). Patients with a low mtDNA copy number tended to show shorter 5-year survival rates than patients with a high mtDNA copy number when assessed by Kaplan-Meier curves, but not a significant (overall survival rate, 63 vs 83%; p=0.19). The copy number of HCC with mtDNA D-loop mutation or deletion was lower, but not significantly so (p=0.656, p=0.590, respectively). CONCLUSIONS: Our results indicated that a reduced copy number of mtDNA is correlated with HCC and associated with malignant potential.
Assuntos
Carcinoma Hepatocelular/genética , DNA Mitocondrial/genética , DNA de Neoplasias/genética , Neoplasias Hepáticas/genética , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Progressão da Doença , Seguimentos , Dosagem de Genes , Hepatectomia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
We examined 61 lung cancer cases to determine whether alterations of p73, a novel monoallelically expressed p53-like molecule, may be involved in the pathogenesis of lung cancer. Allelic loss at the p73 locus at 1p36.33 was observed in 42% (11 of 26 informative cases), and squamous cell carcinoma tended to carry this lesion most frequently. Somatic mutations in the p73 gene itself, however, were not detected, despite our extensive search. We found interindividual difference in the allelic expression of p73 in normal lung, as well as intertissue variance, even within the same individual, but preferential loss of the expressed allele appeared to be an unlikely mechanism for p73 inactivation. This study, consequently, suggests the presence of an as yet unidentified tumor suppressor gene or genes within the subtelomeric region of 1p, warranting further studies aimed at its isolation.
Assuntos
Alelos , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Deleção de Genes , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Mutação , Proteínas Nucleares/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Proteína Tumoral p73 , Proteínas Supressoras de TumorRESUMO
Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.
Assuntos
DNA Mitocondrial/genética , Repetições de Microssatélites/genética , Neoplasias/genética , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Feminino , Mutação em Linhagem Germinativa , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Pulmonares/genética , Linfócitos/fisiologia , Masculino , Neoplasias/sangue , Polimorfismo Genético , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/genética , Análise de Sequência de DNARESUMO
Drug-eluting stents (sirolimus-eluting stent: Cypher stent) have showed a reducing the frequency of in-stent restenosis and a good safety profile. One case involving edge dissection with Cypher stent restenosis for 2 lesions was diagnosed in 2 months after the procedure. This case occurred in a hypertensive 63-year-old woman with complex coronary lesions. The coronary angiography showed uncovered proximal dissection with 90% restenosis in left anterior descending coronary artery to left main trunk and 75% restenosis in right coronary artery. We were able to perform semi-emergency off-pump coronary artery bypass (OPCAB). There is the relationship between coronary dissection and restenosis. Cypher stent delayed dissected arterial healing and promote some inflammation at the lesion. Patients implanted Cypher stent with uncovered coronary dissection need more frequent follow-up.
Assuntos
Ponte de Artéria Coronária sem Circulação Extracorpórea , Reestenose Coronária/cirurgia , Stents , Angina Instável/cirurgia , Reestenose Coronária/etiologia , Feminino , Humanos , Hipertensão/complicações , Pessoa de Meia-Idade , ReoperaçãoRESUMO
The mitotic checkpoint is thought to be essential for ensuring accurate chromosome segregation by implementing mitotic delay in response to a spindle defect. To date, however, very little data has become available on the defects of the mitotic checkpoint in human cancer cells. In the present study, impaired mitotic checkpoint was found in four (44%) of nine human lung cancer cell lines. To our knowledge, this is the first demonstration of frequent impairment of the mitotic checkpoint in this leading cause of cancer deaths. As an initial step towards elucidation of the underlying mechanism, we further undertook a search for mutations in a key component of the mitotic checkpoint, known as hsMAD2, and its immediate downstream molecule, p55CDC. No such mutations were found, however, in either 21 lung cancer cell lines or 25 primary lung cancer cases, although we could identify silent polymorphisms and the transcribed and processed hsMAD2 pseudogene that was subsequently mapped at 14q21-q23. The present observations appear to warrant further investigations, such as search for alterations in other components, to better understand the molecular pathogenesis of this fatal disease, and warn against potential misinterpretation when performing mutational analyses for other cancer types based on cDNA templates.
Assuntos
Proteínas de Ligação ao Cálcio , Proteínas de Transporte/genética , Proteínas de Ciclo Celular , Neoplasias Pulmonares/genética , Mitose/genética , Proteínas/genética , Antineoplásicos/farmacologia , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Pequenas/genética , Proteínas Cdc20 , Análise Mutacional de DNA , Citometria de Fluxo , Células HeLa , Humanos , Proteínas Mad2 , Microscopia de Fluorescência , Modelos Genéticos , Dados de Sequência Molecular , Nocodazol/farmacologia , Proteínas Repressoras , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico , Fatores de Tempo , Células Tumorais CultivadasRESUMO
We recently demonstrated the existence of specific patterns of somatic mitochondrial DNA (mtDNA) mutations in several cancers. Here we sought to identify the presence of mtDNA mutations in prostate cancer and their paired PIN lesions. The D-loop region, 16S rRNA, and the NADH subunits of complex I were sequenced to identify mtDNA mutations in 16 matched PIN lesions and primary prostate cancers. Twenty mtDNA mutations were detected in the tumor tissue of three patients. Identical mutations were also identified in the PIN lesion from one patient. This patient with multiple point mutations also harbored a high frequency of microsatellite instability (MSI-H) in nuclear mononucleotide repeat markers. Remarkably, identical mutations were also detected in all (3/3) matched urine and plasma samples obtained from these patients. Although mitochondrial mutations are less common in prostate adenocarcinoma, they occur early in cancer progression and they can be detected in bodily fluids of early stage disease patients. The identification of MtDNA mutations may complement other early detection approaches for prostate cancer.
Assuntos
DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Mutação , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/urina , RNA Ribossômico 16S/metabolismo , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/urina , Humanos , Masculino , Repetições de Microssatélites , NADH Desidrogenase/metabolismo , Mutação Puntual , Análise de Sequência de DNARESUMO
We previously reported the presence of mitotic check-point impairment in about 40% of lung cancer cell lines. To gain an insight into the molecular basis of this impairment, we examined 49 lung cancer specimens for alterations in the hMAD1 mitotic checkpoint gene and identified a somatic, non-conservative missense mutation, which substitutes alanine (GCG) for threonine (ACG) at codon 299, together with a number of amino acid substituting, single nucleotide polymorphisms. This is the first demonstration of hMAD1 mutation in any type of human cancers. The present finding marks hMAD1 as a potential target, although with low frequency, for genetic alterations in lung cancer. Thus, further studies of hMAD1 dysfunction caused by other mechanisms appear to be warranted, as well as potential involvement of other components of the mitotic checkpoint.
Assuntos
Proteínas de Transporte , Neoplasias Pulmonares/genética , Mitose/genética , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Repressoras , Sequência de Bases , Proteínas de Ciclo Celular , Primers do DNA , HumanosRESUMO
To study whether an in-vitro model for three different genotypes of human CYP2C9*3 polymorphism would be useful for predicting the in-vivo kinetics of (S)-warfarin in patients with the corresponding genotypes, the intrinsic clearance (Cl(int) or Vmax/Km) for (S)-warfarin 7-hydroxylation obtained from recombinant human CYP2C9*1 [wild-type (wt)] and CYP2C9*3 (Leu359/Leu) expressed in yeast and the mixture of equal amounts of these were compared with the in-vivo unbound oral CI (CI(po,u)) of (S)-warfarin obtained from 47 Japanese cardiac patients with the corresponding CYP2C9 genotypes. The in-vitro study revealed that the recombinant CYP2C9*1 (wt/wt), 2C9*3 (Leu359/Leu) and their mixture (Ile359/Leu) possessed a mean Km of 2.6, 10.4 and 6.6 microM and Vmax of 280, 67 and 246 pmol/min/nmol P450, respectively. Thus, the mean in-vitro Cl(int) obtained from recombinant CYP2C9*3 (Leu359/Leu) and the mixture (Ile359/Leu) of 2C9*3 and 2C9*1 were 94% and 65% lower than that obtained from CYP2C9*1 (wt/wt) (6.7 versus 38 versus 108 ml/min/micromol P450, respectively). The in-vivo study showed that the median Cl(po,u) for (S)-warfarin obtained from patients with homozygous (Leu359/Leu, n = 1) and heterozygous (Ile359/Leu, n = 4) CYP2C9*3 mutations were reduced by 90% (62 ml/min) and 66% (212 ml/min, P < 0.05) compared with that obtained from those with homozygous 2C9*1 (625 ml/min, n = 42). Consequently, there was a significant correlation (r = 0.99, P < 0.05) between the in-vitro Cl(int) for (S)-warfarin 7-hydroxylation and the in-vivo Cl(po,u) for (S)-warfarin in relation to the CYP2C9*3 polymorphism. In conclusion, the in-vitro model for human CYP2C9*3 polymorphism using recombinant cytochrome P450 proteins would serve as a useful means for predicting changes in in-vivo kinetics for (S)-warfarin and possibly other CYP2C9 substrates in relation to CYP2C9*3 polymorphism.