RESUMEN
We conducted study to determine whether and how the expression of the hypoxia-inducible factor 1alpha (HIF-1alpha) gene relates to outcome in patients with epithelial ovarian cancer. A total of 66 patients with epithelial ovarian cancer, who underwent primary surgery followed by platinum-based chemotherapy, were entered into this study. We confirmed the expression of HIF-1alpha and the vascular endothelial growth factor (VEGF) by immunohistochemistry. To determine the quantity of HIF-1alpha and VEGF expression, messenger RNA of each gene was measured by real-time reverse transcription-polymerase chain reaction. The cutoff values were determined by the receiver-operating characteristic curve according to survival. The protein expressions of HIF-1alpha and VEGF were strongly observed in the cancer cells. The cutoff value of HIF-1alpha and VEGF gene expression was 6.0 and 3.0, respectively. The expression of HIF-1alpha did not relate to clinical stage, but tumor with low VEGF expression was observed more frequently in stage I patients. The response rate to chemotherapy did not differ between high and low expression of both genes. The overall survival for patients with high expression of HIF-1alpha was significantly lower, but disease-free survival did not differ between high and low expression of HIF-1alpha, whereas both overall and disease-free survival for patients with high expression of VEGF were significantly lower. Multivariate analysis revealed that FIGO stage and HIF-1alpha expression were independent prognostic factors but that VEGF was not. The present study suggested that the expression level of HIF-1alpha could be an independent prognostic factor in epithelial ovarian cancer.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Quimioterapia Adyuvante , Terapia Combinada , Intervalos de Confianza , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Ovariectomía/métodos , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Our previous findings suggested that lower cell proliferation of clear cell carcinoma (CCC) of the ovary may contribute to its resistance to chemotherapy. We conducted the present study to find the gene that regulates cell proliferation of CCC and to elucidate whether it contributes to cisplatin (CDDP) resistance. Complementary DNA microarray analysis revealed that the gene expression level of galectin-3 of CCC cell lines (KK, RMG-I, HAC-2) was over threefold higher than that of ovarian serous adenocarcinoma (SAC) cell lines (HRA, KF). S-phase fraction increased after knocking down galectin-3 using small interfering RNA in RMG-I, KK, and HAC-2 cells. The protein expression of p27 decreased after knocking down galectin-3. CDDP-induced apoptosis was increased after knocking down galectin-3, and this cytotoxic effect was canceled by roscovitine. Immunohistochemical staining showed that galectin-3 expression in tumors of 20 CCC was significantly more frequent than that of 20 SAC (70.0% vs 15.0%, P = 0.0004). The present study showed that the expression of galectin-3 in CCC might contribute to its lower cell proliferation and lead to CDDP resistance.
Asunto(s)
Adenocarcinoma de Células Claras/metabolismo , Resistencia a Antineoplásicos/genética , Galectina 3/fisiología , Neoplasias Ováricas/metabolismo , Adenocarcinoma de Células Claras/química , Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Cisplatino/uso terapéutico , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Galectina 3/análisis , Galectina 3/genética , Humanos , Inmunohistoquímica , Neoplasias Ováricas/química , Neoplasias Ováricas/tratamiento farmacológico , ARN Interferente Pequeño/farmacologíaRESUMEN
We conducted the present study to investigate whether and how chemosensitivity can be determined by means of genetic diagnosis using drug-resistance genes in patients with epithelial ovarian cancer. A total of 75 patients who had epithelial ovarian cancer with measurable lesions were entered into this study. Thirty-three patients received first-line chemotherapy, consisting of paclitaxel and carboplatin (TJ). Forty-two patients received second-line chemotherapy, 22 received EP therapy consisting of etoposide and cisplatin (CDDP), and 20 received irinotecan (CPT-11) and CDDP (CPT-11/CDDP) therapy. Tumor samples were obtained before chemotherapy. MessengerRNA expressions of the multidrug-resistance (MDR)-1 gene, MDR-associated protein-1 (MRP-1), topoisomerase (topo) I, and topo IIalpha were measured by real-time reverse transcription-polymerase chain reaction. The cutoff values of each gene were determined by the receiver operating characteristic curve. MDR-1 expression was significantly higher in patients who did not respond to TJ therapy. The expression of topo IIalpha was significantly higher in patients who did respond to EP therapy. The expression of topo I was significantly higher in patients who did respond to CPT-11/CDDP. MRP-1 expression did not differ between responders and nonresponders in all regimens. The cutoff value was 80 for MDR-1, 90 for topo IIalpha, and 200 for topo I. Next, to evaluate genetic diagnosis, 31 patients were newly added. The accuracy of this genetic diagnosis for chemosensitivity was 85.7% for TJ, 77.8% for EP, and 100.0% for CPT-11/CDDP therapy. The present study suggests that genetic diagnosis may be useful to determine chemosensitivity in patients with epithelial ovarian cancer.
Asunto(s)
Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo I/genética , Proteínas de Unión al ADN/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Adulto , Anciano , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , ADN-Topoisomerasas de Tipo I/biosíntesis , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/biosíntesis , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/metabolismo , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Células Epiteliales/patología , Femenino , Genes MDR , Humanos , Irinotecán , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/biosíntesis , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
Doxorubicin, platinum compounds, and taxanes represent the chemotherapeutic agents with the greatest activity in endometrial cancer. We conducted an optimal-dose determination of combination chemotherapy consisting of paclitaxel (TXL), doxorubicin, and carboplatin (CBDCA) (TAC) in patients with endometrial cancer. Patients with epithelial endometrial cancer requiring adjuvant therapy were enrolled between June 2003 and March 2005. No patients had received prior radiotherapy, and only two patients had previously undergone chemotherapy. Doxorubicin was infused on day 1, and TXL followed by CBDCA was administered on day 2. The starting dose was doxorubicin 35 mg/m(2), TXL 120 mg/m(2), and CBDCA area under the curve (AUC). The dose of each agent was gradually escalated. Patients were scheduled to receive at least four cycles of therapy. If patients experienced grade 4 neutropenia or neutropenic fever with grade 3 neutropenia, they were permitted to be administered granulocyte colony-stimulating factor after the second course. Twenty-seven patients were enrolled. Although four patients out of 27 experienced dose-limiting toxicities, a maximum tolerated dose was not established at the final dose level. Five patients (three for recurrent and two for advanced) had measurable lesions. There were four responders (three for partial response and one for complete response) in our series. The recommended dose of TAC therapy for endometrial cancer was doxorubicin 45 mg/m(2) for day 1, TXL 150 mg/m(2) and CBDCA AUC 5 for day 2.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Adulto , Anciano , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversosRESUMEN
Radiation-induced apoptosis is thought to underlie the toxicity of radiation to normal tissues as well as to cancer cells. We hypothesized that specific ectopic overexpression of the antiapoptotic molecule Bcl-2 in normal cells would inhibit radiation-induced apoptosis and thereby reduce radiation-induced toxicity in normal cells. To express Bcl-2 specifically in normal cells (which have wild-type (wt) p53) but not in cancer cells (which often have mutated p53), we constructed a Bcl-2 expression plasmid (PG13-Bcl-2) with a minimal promoter regulated by multiple wt p53 DNA-binding sites and found that the presence of wt p53 protein strongly upregulated Bcl-2 expression through this plasmid. Transfection of NIH 3T3 fibroblasts, which express wt p53, with PG13-Bcl-2 increased cell survival and reduced apoptosis; however, transfection of MDA-MB-231 breast cancer cells, which have mutated p53, did not affect survival and apoptosis of those cells. These results indicate that irradiation of normal cells rapidly upregulates the expression of wt p53, which binds to the p53 binding sequence of the PG13-Bcl-2 plasmid and increases the transcriptional activity of Bcl-2. Ectopic expression of Bcl-2 reduced radiation-induced apoptosis only in normal cells (not in cancer cells). Bcl-2 expression was detected in the lung from mice injected via a tail vein with LPD-PG13-Bcl-2 or LPD-CMV-Bcl-2, but did not in the lung from mice treated with DOTAP or LPD-PG13-mock. This novel approach to inhibiting radiation-induced apoptosis in normal cells may allow such cells to be protected from radiation-induced toxicity. Further preclinical in vivo studies are needed.
Asunto(s)
Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Traumatismos por Radiación/prevención & control , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/genética , Línea Celular Tumoral , Femenino , Expresión Génica , Humanos , Pulmón/química , Pulmón/citología , Pulmón/efectos de la radiación , Ratones , Ratones Endogámicos , Células 3T3 NIH , Plásmidos/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Traumatismos por Radiación/genética , Traumatismos por Radiación/metabolismo , Activación Transcripcional , Proteína p53 Supresora de Tumor/genética , Regulación hacia ArribaRESUMEN
We conducted the present study to determine the outcome of patients with early ovarian cancer who underwent three courses of adjuvant chemotherapy after complete surgical staging. One hundred consecutive patients with stage I-II epithelial ovarian cancer who had undergone complete surgical staging and received three courses of platinum-based chemotherapy were entered in this study. Twenty-one patients were low risk, defined as stage IA-B, grade 1 and histologic types except for clear cell adenocarcinoma, and remaining 79 were high risk. All patients with stage IA or IB, whatever histologic type and histopathologic grade, were alive without disease. The 5-year survival rate was 89.4% for patients with stage IC and 76.2% for those with stage II. The 5-year survival rate for low- and high-risk patients was 100% and 89.4%, respectively. The survival rate for grade 1 was significantly better than that for grade 2 or 3. Multivariate analysis revealed that histologic grade was an independent prognostic factor in stage IC-II ovarian cancer. The outcome of patients with early ovarian cancer undergoing three courses of chemotherapy after complete surgical staging was favorable even in high-risk patients.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Adenocarcinoma/patología , Adulto , Anciano , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Pronóstico , Análisis de SupervivenciaAsunto(s)
Dismenorrea/epidemiología , Adulto , Femenino , Humanos , Japón/epidemiología , Persona de Mediana Edad , Paridad , PrevalenciaRESUMEN
Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. The BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Similarities in characteristics of endometriosis at a molecular level with gynaecological tumours are also discussed. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.
Asunto(s)
Apoptosis/fisiología , Endometriosis/patología , Endometrio/citología , Proteína Ligando Fas , Femenino , Humanos , Glicoproteínas de Membrana/fisiología , Ciclo Menstrual/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Receptor fas/fisiologíaRESUMEN
To clarify whether and how PTEN and the phosphatidylinositol 3-kinase/Akt pathway relates to endometrial cancer we examined the expression of these pathway-related proteins in patients with endometrial cancer. Of 103 endometrial cancers, 37 (36%) showed negative immunohistochemical staining for PTEN. Western blotting revealed that the level of phosphorylated Akt expression in PTEN-negative cases was significantly higher compared with that in positive cases. We found a significant inverse correlation between PTEN and phosphorylated Akt. The present study indicates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial cancers. In order to investigate the relationship between PTEN expression and prognosis in endometrial cancer, 98 patients with advanced endometrial cancer were newly enrolled. The survival rate for PTEN-positive patients was significantly higher than that for PTEN-negative or -heterogeneous staining patients. Of the 98 patients, 25 underwent radiation therapy, 62 received chemotherapy after surgery, and the remaining 11 did not have any postoperative treatment. When patients underwent chemotherapy, the survival rate for PTEN-positive cases was clearly higher than that for PTEN-negative or -heterogeneous cases (62.4 vs 11.8%). Subsequent multivariate analysis revealed that PTEN staining was an independent prognostic factor for patients undergoing chemotherapy. The current study demonstrates that PTEN-positive staining is a significant prognostic indicator of favorable survival for patients with advanced endometrial cancer who undergo postoperative chemotherapy.
Asunto(s)
Neoplasias Endometriales/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Proteínas Portadoras/metabolismo , Neoplasias Endometriales/genética , Femenino , Silenciador del Gen , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Estadificación de Neoplasias , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Pronóstico , Proteínas Proto-Oncogénicas c-akt , Tasa de Supervivencia , Proteína Letal Asociada a bclRESUMEN
This multicenter collaborative study prospectively evaluated the effect of omentoplasty and omentopexy on the prevention of complications after pelvic lymphadenectomy. Sixty-four consecutive patients (42 cervical and 22 endometrial cancer) were enrolled and examined periodically for 12 months. All patients underwent simple, semiradical, or Okabayashi's radical hysterectomy and complete pelvic lymphadenectomy. The infracolic omentum was longitudinally divided in half and omentoplasty was performed so that bilateral omental flaps would reach the pelvic floor. The omental flaps were inserted into the retroperitoneal space and the edges of the flaps were sutured to the psoas muscle. The omental flap was then covered by the peritoneum. Incidence of lymphocele, lymphedema, and severe complications associated with lymphocele, such as infection or urinary stenosis, was evaluated at intervals for at least one year after surgery. Among the 64 patients, 12 patients received pelvic radiation because of occult lymph node metastasis. Planned omentoplasty was not possible in one patient because her omentum was too small; therefore, only unilateral omentopexy was performed. Asymptomatic lymphoceles only were detected by ultrasonogram in 12 patients (18.8%). Three patients (4.7%) had a symptomatic but pressure-only lymphocele. Hydronephrosis and bladder compression probably due to lymphocele were observed in one patient, respectively (3.1%), but resolved within 6 months. Lymphedema was observed in seven patients (10.9%) and persisted for more than 6 months in two patients (3.1%). We conclude that this simple technique of omentoplasty and omentopexy appeared to be effective in reducing the incidence of complications after pelvic lymphadenectomy.
Asunto(s)
Neoplasias Endometriales/cirugía , Procedimientos Quirúrgicos Ginecológicos/métodos , Escisión del Ganglio Linfático/métodos , Epiplón/cirugía , Complicaciones Posoperatorias/prevención & control , Neoplasias del Cuello Uterino/cirugía , Adulto , Anciano , Femenino , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Humanos , Histerectomía/métodos , Escisión del Ganglio Linfático/efectos adversos , Persona de Mediana Edad , Pelvis , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: To determine whether and how apoptosis through the p53-Bax pathway affects sensitivity to chemotherapy in cervical cancer. MATERIALS AND METHODS: Thirty patients with cervical squamous cell carcinoma, who had human papilloma virus (HPV) and underwent neoadjuvant chemotherapy, were entered in the present study. Tumor specimens were obtained before and after chemotherapy. HPV was detected by polymerase chain reaction. The expression of Ki-67, p53, Bax and Bcl-2 proteins was determined by immunohistochemical staining. Apoptotic cells were identified by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling method. RESULTS: Of 30 patients, 18 responded to chemotherapy and 12 did not. The apoptotic index in tumors of responders was significantly higher than in non-responders after chemotherapy. The Ki-67 labeling index (LI) in responders was significantly higher than in non-responders before chemotherapy. Patients with tumors >33% of the LI, which was determined by a receiver operating characteristic curve, had a better survival rate. The incidence of p53 protein expression did not differ between responders and non-responders. After chemotherapy, the expression of Bax protein in responders was more frequent and Bcl-2 protein expression was less frequent than in non-responders. CONCLUSIONS: Chemosensitivity in cervical cancer may be associated with apoptosis via the p53-Bax pathway.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatología , Genes p53 , Proteínas Proto-Oncogénicas/biosíntesis , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/fisiopatología , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Antígeno Ki-67/biosíntesis , Persona de Mediana Edad , Terapia Neoadyuvante , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/biosíntesis , Infecciones Tumorales por Virus/complicaciones , Neoplasias del Cuello Uterino/tratamiento farmacológico , Proteína X Asociada a bcl-2RESUMEN
OBJECTIVE: To review the literature on the role of cytokines in the pathogenesis of endometriosis and endometriosis-associated infertility. DESIGN: Pertinent studies were identified by a computer search of MEDLINE. References of selected articles were hand-searched for additional citations. RESULT(S): Recent studies suggest that the peritoneal fluid of women with endometriosis contains an increased number of activated macrophages that secrete various local products, such as growth factors and cytokines. Levels of several cytokines were reported to be elevated in the peritoneal fluid of women with endometriosis. Because the peritoneal environment may be controlled by locally regulated factors, cytokines are believed to play a role in the development and progression of endometriosis and endometriosis-associated infertility. A possible pathogenic mechanism links cytokines with endometriosis. CONCLUSION(S): Cytokines, which are produced by many cell types including endometriotic tissues, play diverse roles in the pathogenesis of endometriosis and endometriosis-associated infertility. More studies about the specific role of these cells and soluble factors are needed to improve understanding of endometriosis and to develop novel therapies.
Asunto(s)
Citocinas/fisiología , Endometriosis/fisiopatología , Líquido Ascítico/metabolismo , Endometriosis/complicaciones , Endometriosis/etiología , Femenino , Humanos , Infertilidad Femenina/etiologíaRESUMEN
We have investigated the possible roles of oncostatin M (OSM), which is a member of the interleukin-6 family of cytokines, in endometrial and endometriotic stromal cell growth. Endometrial and endometriotic stromal cells were collected from the uterus or ovarian chocolate cysts. We observed the expression of mRNA transcripts for OSM, OSM receptor subunit beta, leukaemia inhibitory factor receptor subunit (LIFR), and glycoprotein 130 in endometrial and endometriotic stromal cells. We also examined the effects of OSM (0-50 ng/ml) and LIF (0-10 ng/ml) on endometrial and endometriotic stromal cell proliferation and evaluated the effects of OSM on endometrial stromal cell differentiation. The presence of 10-50 ng/ml OSM significantly suppressed endometrial stromal cell growth in secretory phase tissue but not in proliferative phase tissue. In contrast, stromal cells in endometriotic tissues were resistant to the inhibitory effects of OSM. Addition of LIF did not influence the growth of endometrial stromal cells. We also showed that 10 ng/ml OSM stimulated markers of differentiation causing increased prolactin secretion and cyclooxygenase-2 gene expression in endometrial stromal cells from the secretory phase. These results suggest that OSM may play a pivotal role in regulating the growth and differentiation of endometrial cells. Endometriotic cells may behave differently from normal endometrial cells in terms of the inhibitory response to OSM.
Asunto(s)
Endometrio/citología , Ciclo Menstrual/fisiología , Péptidos/metabolismo , Células del Estroma/citología , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Receptor gp130 de Citocinas , Endometrio/metabolismo , Femenino , Humanos , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Oncostatina M , Péptidos/genética , Péptidos/farmacología , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores OSM-LIF , Receptores de Oncostatina M , Células del Estroma/metabolismoRESUMEN
We conducted the present study to determine the relationship between p53-dependent apoptosis and telomerase activity in ovarian cancer cells. A human ovarian adenocarcinoma cell line, SK-OV-3 that had homozygous deletion of the p53 gene was used in this study. Wild-type p53 genes were transducted to SK-OV-3 cells with a recombinant adenovirus that contained a wild-type p53 gene (AxCAp53). IC(50)to cisplatin (CDDP) was 12.9 microM for SK-OV-3 cells and 9.2 microM for p53 gene-transducted SK-OV-3 cells. The apoptotic index for cells with p53 gene transduction was significantly higher than cells without transduction. Additionally, p53 gene transduction significantly enhanced CDDP-induced apoptosis. Bax protein in SK-OV-3 cells did not differ before and after exposure to CDDP. In SK-OV-3 cells with transduction of the p53 gene, the expression of p53 and Bax proteins increased after exposure to CDDP. Expression of Bcl-xL decreased after exposure to CDDP in SK-OV-3 cells with and without transduction. The telomerase activity in SK-OV-3 cells with the p53 gene was significantly lower compared with the cells without the p53 gene. CDDP exposure did not affect telomerase activity and human telomerase reverse transcriptase (hTERT) expression in both cell lines. We suggest that the p53 gene may relate to telomerase activity, but that p53-dependent apoptosis does not affect the activity.
Asunto(s)
Adenocarcinoma/patología , Apoptosis , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Neoplasias Ováricas/patología , ARN , Telomerasa/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Proteínas de Unión al ADN , Femenino , Humanos , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/genética , Células Tumorales CultivadasRESUMEN
In the presence of severe hyperbilirubinemia in Crigler-Najjar syndrome Type II, a fetus is at risk for kernicterus. A 34-year-old woman, gravida 4, para 1, with Crigler-Najjar syndrome Type II was treated with phenobarbital administration following phototherapy during each of 2 pregnancies. Both infants were healthy and developed normally.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Síndrome de Crigler-Najjar/terapia , Fenobarbital/uso terapéutico , Fototerapia , Complicaciones del Embarazo/terapia , Adulto , Femenino , Humanos , Recién Nacido , Embarazo , Resultado del EmbarazoRESUMEN
OBJECTIVE: The purpose of this study was to assess the accuracy, informative rate, detection rate, and clinical utility of prenatal interphase fluorescence in situ hybridization (FISH) analysis of amniotic fluid samples from Japanese women. METHODS: Amniotic fluid specimens from 2,639 Japanese women were received for prenatal interphase FISH and chromosome analysis. A questionnaire was designed to evaluate FISH clinical utility by collaboration sites. RESULTS: Based on 2,319 tested samples, the accuracy (100%), informative (94%), and detection (87.6%) rates were all high. The accuracy (100%), informative (90.2%), and detection (90.0%) rates were also remarkable in third-trimester pregnancies. We perceive significant advantages from this test regarding medical management and patient satisfaction. CONCLUSIONS: This novel report shows that in Japan prenatal interphase FISH testing is highly informative and accurate, not only in second-trimester pregnancies but also in third-trimester pregnancies. This test provides advantages to both physicians and patients, provided that its capabilities and limitations are understood.
Asunto(s)
Aberraciones Cromosómicas/diagnóstico , Hibridación Fluorescente in Situ , Diagnóstico Prenatal , Adulto , Líquido Amniótico , Trastornos de los Cromosomas , Femenino , Humanos , Satisfacción del Paciente , Valor Predictivo de las Pruebas , Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Encuestas y CuestionariosRESUMEN
To evaluate whether mutations in the human multidrug resistance (MDR)-1 gene correlate with placental P-glycoprotein (PGP) expression, we sequenced the MDR-1 cDNA and measured PGP expression by Western blotting in 100 placentas obtained from Japanese women. Nine single nucleotide polymorphisms (SNPs) were observed with an allelic frequency of 0.005 to 0.420. Of these SNPs, G2677A (allelic frequency = 0.18) and G2677T (0.39) in exon 21 were associated with an amino acid conversion from Ala to Thr and to Ser, respectively. Sixty-one of 65 samples (93.8%), which had a C3435T allele, also had a mutant G2677(A,T) allele, suggesting an association between the two SNPs. Correlations of mutations with expression levels were observed; individuals having the G2677(A,T) and/or T-129C (p < 0.05) allele had less placental PGP. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based genotyping tests were developed for the detection of these SNPs. The PCR, in which genomic DNAs obtained from healthy subjects (n = 48) are used as samples, was successful. The frequency of mutations in placental cDNA was identical with that in genomic DNA. When genotype results were compared between Caucasians and Japanese, ethnic differences in the frequency of polymorphism in the MDR-1 gene were suspected. Although it remains to be determined whether these SNPs influence the pharmacokinetic and dynamic properties of clinically useful drugs that are substrates of PGP, the polymorphism of the MDR-1 gene presented here may provide useful information in in vivo study of these issues.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Genes MDR/genética , Placenta/metabolismo , Polimorfismo de Nucleótido Simple , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Alelos , Sustitución de Aminoácidos , Pueblo Asiatico/genética , Western Blotting , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Ligamiento Genético , Genotipo , Humanos , Inmunohistoquímica , Japón , Placenta/citología , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Población Blanca/genéticaRESUMEN
OBJECTIVE: To examine gene expression of hepatocyte growth factor (HGF), the receptor for HGF, c-met, and the receptor for stem cell factor (SCF), c-kit, in the human ovary and to investigate the effects of HGF and SCF on the proliferation and function of granulosa and theca cells. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Six premenopausal women. INTERVENTION(S): Follicular fluid and granulosa cells were collected during IVF cycles. Ovarian tissues were obtained from women who underwent surgery. MAIN OUTCOME MEASURE(S): Gene expression of HGF, c-met, and c-kit in the human ovary was determined. RESULT(S): Reverse-transcription polymerase chain reaction showed the presence of HGF and c-kit mRNA in the theca and stroma cells of the ovary, whereas c-met mRNA was observed in the granulosa, theca, and stroma cells. HGF increased the expression of SCF gene in granulosa cells, and SCF reciprocally increased the expression of HGF gene in theca cells. SCF stimulated the proliferation of theca cells. HGF stimulated progesterone production in granulosa cells. CONCLUSION(S): A positive feedback loop between theca cells and granulosa cells was identified that is mediated by HGF and SCF. HGF and SCF modulate the interplay between theca and granulosa cells by promoting cell proliferation and steroid hormone production.
Asunto(s)
Células de la Granulosa/fisiología , Factor de Crecimiento de Hepatocito/fisiología , Factor de Células Madre/fisiología , Células Tecales/fisiología , Adulto , Comunicación Celular/fisiología , Diferenciación Celular/fisiología , División Celular/fisiología , Estradiol , Femenino , Líquido Folicular/fisiología , Regulación de la Expresión Génica/fisiología , Células de la Granulosa/citología , Factor de Crecimiento de Hepatocito/biosíntesis , Factor de Crecimiento de Hepatocito/genética , Humanos , Modelos Lineales , Reacción en Cadena de la Polimerasa , Progesterona/biosíntesis , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/fisiología , Proteínas Proto-Oncogénicas c-met/biosíntesis , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/fisiología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Factor de Células Madre/biosíntesis , Factor de Células Madre/genética , Células Tecales/citologíaRESUMEN
The tumor suppressor PTEN acts as a lipid phosphatase, regulates the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway, and modulates cell cycle progression and cell survival. Somatic mutations of PTEN have been reported in a variety of cancers, especially in endometrial carcinoma. To clarify whether and how PTEN and the PI3K/Akt pathway relates to endometrial carcinoma, we examined the expression of those pathway-related proteins in patients with endometrial carcinoma. Of 103 endometrial carcinomas, 37 (36%) showed negative immunohistochemical staining of PTEN. Western blotting revealed that the expression of PTEN in PTEN-negative cases was significantly lower compared with that in positive cases. In contrast, phospho-Akt level in negative cases was significantly higher. We found a significant inverse correlation between PTEN and phospho-Akt (r = -0.796). The expression of phospho-Bad was greater in negative cases, suggesting that Bad might be a target for AKT: The present study demonstrates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial carcinomas.