RESUMEN
Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.
Asunto(s)
Enfermedades Cardiovasculares , Neoplasias , Accidente Cerebrovascular , Humanos , Adulto , Animales , Leche , Estudios Prospectivos , Factores de Riesgo , Enfermedades Cardiovasculares/complicaciones , Accidente Cerebrovascular/etiología , Neoplasias/complicaciones , Pueblo EuropeoAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained. Dormant lung cancer cells were found to be resistant to EGFR tyrosine kinase inhibitor (TKI) treatment. In terms of mechanism, we found that a negative regulator of ERBB signaling, MIG6/ERRFI1/RALT/Gene33, was induced by hypoxia both in vitro and in vivo. MIG6 expression prevented heterodimer formation of ERBB family RTKs, and suppressed their downstream signaling. Knockdown of MIG6 enhanced tumor cell growth under hypoxic conditions, and promoted the phosphorylation of ERK and AKT via increased EGFR-HER3 binding. Critically, sensitivity to an EGFR-TKI, as well as to irradiation under hypoxic conditions, was increased in MIG6 knockdown cells. The expression of MIG6 was partly correlated with a pS6 negative zone in patient tumors. Analyses of tumor sections from 68 patients with activating EGFR mutations showed that patients with high MIG6 expression showed significantly shorter survival after EGFR-TKI treatment than other groups. Collectively, our data suggest that dormant cancer cells with a high MIG6 expression level might be one of the causes of EGFR-TKI resistance in EGFR mutant lung cancer cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptores ErbB/genética , Hipoxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/química , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/genética , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ratones , Fosforilación , Pronóstico , Unión Proteica , Multimerización de Proteína , Transducción de Señal , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Gefitinib treatment results in considerably better progression-free survival compared with that of platinum doublets in the first line treatment of nonsmall-cell lung cancer (NSCLC) carrying an activating epidermal growth factor receptor (EGFR) mutation. Some patients who respond to gefitinib have an overall survival (OS) of more than 5 years, whereas other initial responders do less well. Although there has been considerable effort made to elucidate the mechanisms of acquired resistance, there have only been a few studies that addressed the effect of clinical backgrounds and treatment histories on the survival of the patients who had responded to an EGFR-tyrosine kinase inhibitor (TKI). In this study, we especially focused on the clinical benefit of EGFR-TKI administration after progression. PATIENTS AND METHODS: We retrospectively analyzed consecutive patients with advanced NSCLC who were diagnosed before October 2010, treated with gefitinib after July 2002, and responded to it. The primary objective of this study was to evaluate how clinical backgrounds and treatment histories influence survival of the patients who respond to gefitinib. The secondary objectives were to evaluate the safety of long-term gefitinib use and to establish the optimal treatment sequence using a dynamic treatment regimen analysis (DTRA). RESULTS: A total of 335 patients were recruited. Twenty-eight (8.4%) patients survived more than 5 years. Sixty-five and 93 patients received gefitinib as rechallenge and beyond progressive disease (BPD), respectively. A statistically significant difference in OS was observed between the patients who underwent gefitinib rechallenge and those who did not rechallenge (median: 1272 days vs. 774 days; p < 0.001), a result supported by a DTRA. Patients treated with gefitinib BPD also showed a tendency of longer survival. CONCLUSIONS: Gefitinib rechallenge and BPD played a central role in long term survival of the patients who initially responded to gefitinib.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Gefitinib , Humanos , Japón , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: This is a randomized, double-blind, dose-ranging study in patients receiving highly emetogenic chemotherapy (HEC) to evaluate the safety, efficacy, and pharmacokinetics of palonosetron, in combination with dexamethasone. MATERIALS AND METHODS: We randomized 233 patients to receive palonosetron as a single i.v. bolus dose of 0.075, 0.25, or 0.75 mg before administration of HEC. Dexamethasone (12-16 mg i.v. on day 1, 8 mg i.v. on day 2, and 4-8 mg i.v. on day 3) was administered for prophylactic antiemesis. Pharmacokinetics of palonosetron was analyzed in 24 patients. RESULTS: In this study, all patients were given > or =50 mg/m(2) cisplatin, which was considered to be HEC. No significant differences in complete response (CR: no emesis and no rescue medication) rates were found in the first 24 h between the 0.075-, 0.25-, and 0.75-mg groups (77.6%, 81.8%, and 79.5%, respectively). In the 120-h period of overall observation, CR rates increased in a dose-dependent manner. In the 0.75-mg group, we observed a significantly longer time to treatment failure than in the 0.075-mg group (median time >120 versus 82.0 h, P = 0.038). Palonosetron was tolerated well and did not show any dose-related increase in adverse effects. CONCLUSIONS: Palonosetron at doses of 0.25 and 0.75 mg was shown to be effective in preventing chemotherapy-induced nausea and vomiting with high CR rates of patients treated with HEC in Japan. All tested doses of palonosetron were tolerated well.
Asunto(s)
Antieméticos/administración & dosificación , Dexametasona/administración & dosificación , Isoquinolinas/administración & dosificación , Náusea/prevención & control , Quinuclidinas/administración & dosificación , Vómitos/prevención & control , Adulto , Anciano , Antieméticos/efectos adversos , Antieméticos/farmacocinética , Antineoplásicos/efectos adversos , Área Bajo la Curva , Cisplatino/efectos adversos , Dexametasona/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Palonosetrón , Quinuclidinas/efectos adversos , Quinuclidinas/farmacocinética , Vómitos/inducido químicamente , Adulto JovenRESUMEN
BACKGROUND: This report describes quality of life (QoL) findings of a randomized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer. PATIENTS AND METHODS: This open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m(2)/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline. RESULTS: Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55-6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13-6.49, P < 0.001], although differences did not meet the clinically relevant six-point change. There were no significant differences between treatments in LCS improvement rates (23% versus 20%, P = 0.562) or mean change from baseline score (0.63 points, 95% CI -0.07 to 1.34, P = 0.077). CONCLUSIONS: Gefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Calidad de Vida , Quinazolinas/uso terapéutico , Taxoides/uso terapéutico , Pueblo Asiatico , Docetaxel , Gefitinib , Humanos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
We report a case with surgery for the 2nd primary double lung cancers-adenocarcinoma and squamous cell carcinoma which developed in the right upper lobe after 5 years successful control by chemotherapy for small cell lung cancer in the left upper lobe. Long term survivors with small cell lung cancer have recently increased as a result of progress of chemotherapy. Therefore, 2nd primary lung cancer is not rare after the treatment for the initial small cell lung cancer. Although several causes have been proposed on the development of 2nd primary lung cancer after small cell lung cancer treatment, smoking history was strongly suggested as a cause in this case. Careful follow-up especially focusing on 2nd primary lung cancer development is necessary for patients after successful treatment for small cell lung cancer.
Asunto(s)
Adenocarcinoma/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Neoplasias Primarias Secundarias , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Anciano , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Masculino , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/patología , Resultado del TratamientoRESUMEN
Serum fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor and important for the regulation of inorganic phosphate (Pi) homeostasis. In this study, we examined an acute effect of oral Pi loading on serum FGF23 levels to clarify the role in rapid adjustment of serum Pi level. We performed a randomized, double-blind, crossover study in eight healthy male volunteers. The subjects were alternately served one of three test meals containing different Pi amounts (400 mg (P400), 800 mg (P800), and 1200 mg (P1200)) as lunch at noon. The postprandial changes in serum levels of Pi, Ca, 1,25-dihydroxyvitamin D, intact-parathyroid hormone (iPTH), intact-FGF23 (iFGF23), and urinary excretion of Pi and Ca until 8 h after Pi loading were estimated. Serum Pi levels and urinary Pi excretion significantly increased within 1 h after P400 and P800 intake. Serum iPTH levels at 1-2 and 4-6 h after P1200 intake was significantly higher than those of P400 intake. Serum iFGF23 levels slightly decreased up to 8 h after P400 intake and up to 6 h after P800 intake, but not changed in P1200 intake. Significant increase of iFGF23 was observed at 8 h after P1200 intake compared with both P400 and P800 intake. Additionally, negative association was detected between iFGF23 and serum Pi, whereas positive association was observed between iPTH and serum Pi during the short period. We conclude that oral Pi loading cannot rapidly increase serum FGF23 level. FGF23 may be not associated with rapid adaptation of Pi homeostasis.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Fosfatos/administración & dosificación , Fosfatos/sangre , Administración Oral , Adulto , Calcio/sangre , Estudios Cruzados , Factor-23 de Crecimiento de Fibroblastos , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Masculino , Hormona Paratiroidea/sangre , Fosfatos/farmacocinética , Fosfatos/orina , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
We report herein a case of incarcerated paraesophageal hernia associated with perforation of the fundus of the stomach. A 71-year-old woman was transferred to our hospital after a diagnosis of gastrointestinal tract perforation had been made at a local hospital. Her history included an esophageal hiatal hernia. A laparotomy was performed which revealed that the antrum of stomach and the duodenal bulb had prolapsed into the esophageal hiatus and become incarcerated. This prolapse had caused stenosis in the corpus of the stomach, resulting in distension of the oral side of the stomach and thinning of the wall. A perforation, 15 mm long, was recognized in the major curvature of the fundus. The patient suffered respiratory failure postoperatively, necessitating respiratory support for 1 week. She was discharged on postoperative day 40. This case report serves to demonstrate that because of the very serious complications that may result from an untreated paraesophageal hernia, elective repair should be performed wherever possible even in asymptomatic patients.
Asunto(s)
Esófago/patología , Hernia Hiatal/complicaciones , Perforación Intestinal/etiología , Gastropatías/patología , Anciano , Procedimientos Quirúrgicos Electivos , Esófago/cirugía , Femenino , Fundus Gástrico/patología , Hernia Hiatal/patología , Hernia Hiatal/cirugía , Humanos , Perforación Intestinal/patología , Prolapso , Gastropatías/cirugíaRESUMEN
The usefulness of the in vitro chemosensitivity test, the collagen gel droplet embedded culture drug- sensitivity test (CD-DST, Int J Oncol 11: 449, 1997), in cisplatin-based combined chemotherapy for postoperative recurrent tumors in non-small cell lung cancer (NSCLC) patients was retrospectively analyzed. CD-DST data for cisplatin (or carboplatin), etoposide, 5-fluorouracil, mitomycin C, and vindesine were obtained in 311 surgically resected primary lesions. Of them, 25 patients were practically treated with first-line cisplatin- or carboplatin-based chemotherapy for postoperative initial recurrence. Nine (36%) of them responded to the combined chemotherapy for recurrent lesions, including one with complete remission, whereas 16 did not, with no change in 5 and progression in 11. Seven (70%) of 10 patients receiving combined chemotherapy using two or three in vitro sensitive chemoagents showed good responses, whereas there was no responder among the patients receiving chemotherapy including no in vitro sensitive chemoagents. In particular, of 11 patients showing good sensitivity to cisplatin or carboplatin on CD-DST, 8 (73%) responded to chemotherapy, whereas only one (7%) of 14 patients showing cisplatin- or carboplatin-resistance on CD-DST was a responder. Thus, CD-DST results for the chemoagents, especially cisplatin or carboplatin, correlated with chemotherapeutic response, indicating that the CD-DST analysis of surgically resected primary NSCLC tumors is a practically useful indicator of the clinical effect of first-line cisplatin-based combined chemotherapy for postoperative recurrence.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Carboplatino/administración & dosificación , Carboplatino/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Cisplatino/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/administración & dosificación , Etopósido/toxicidad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/toxicidad , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mitomicina/toxicidad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Vindesina/administración & dosificación , Vindesina/toxicidadRESUMEN
STUDY OBJECTIVES: We performed a clinical trial of laser-induced fluorescence endoscopy (LIFE) for detection of precancerous lesions and cancer including carcinoma in situ (CIS), which are difficult to detect by white-light bronchoscopy. DESIGN: Results with LIFE were compared with the criterion standard, white-light bronchoscopy. The evaluation of these endoscopic results spectrofluorometrically was examined, and pixels of LIFE images composed of digital signals for the intensities of red and green were analyzed. SETTING: Tertiary-level hospital treating referrals and subjects with suspicious results in mass screening. PATIENTS: We examined 65 subjects with suspected lung cancer by both methods, and performed biopsy on 216 lesions. RESULTS: The accuracy of diagnosis by white-light bronchoscopy, with histopathologic results as the standard, was 48.6%. The accuracy by LIFE was 72.7%. The sensitivity of conventional bronchoscopy for detection of severe dysplasia (21 biopsy specimens) or cancer (28 biopsy specimens) was 61.2% and specificity was 85.0%. With results by LIFE added, these values were 89.8% and 78.4%, respectively. Of nine patients with CIS, only LIFE showed one lesion, and only LIFE showed the extent of seven of the lesions. The autofluorescence of eight lesions was measured spectrofluorometrically; normal bronchial tissue, severe dysplasia, and cancerous tissue had spectral differences. The red/green intensity of cancers on histograms of LIFE images generally was greater than the ratios for metaplasia or normal bronchial wall. CONCLUSIONS: Use of both methods should facilitate early detection. Evaluation by spectrofluorometry and analysis of digital signal intensity of results by LIFE make results more objective.
Asunto(s)
Endoscopía , Fluorescencia , Rayos Láser , Neoplasias Pulmonares/diagnóstico , Espectrometría de Fluorescencia , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Broncoscopía , Carcinoma in Situ/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/diagnóstico , Sensibilidad y EspecificidadRESUMEN
1-Oleoyl lysophosphatidic acid (LPA) induces transmonolayer migration (in vitro invasion) of rat ascites hepatoma MM1 cells and their morphological changes leading to the migration. We have previously shown that an LPA analog, palmitoyl cyclic phosphatidic acid (Pal-cPA), suppresses transmonolayer migration of MM1 cells by rapidly increasing the intracellular cyclic AMP (cAMP) concentration. We report here that various cAMP-elevating agents, including dibutyryl cAMP, forskolin, cholera toxin and 3-isobutyl-1-methylxanthine, consistently inhibited LPA-induced transmonolayer migration of MM1 cells. Moreover, pull-down assays for GTP-bound, active RhoA demonstrated that the blockage by cAMP-elevating agents of morphological changes leading to the migration was probably mediated through inhibiting RhoA activation.
Asunto(s)
Carcinoma Hepatocelular/patología , AMP Cíclico/metabolismo , Neoplasias Hepáticas/patología , Lisofosfolípidos/farmacología , Proteínas de Unión al GTP rho/metabolismo , Animales , Bucladesina/farmacología , Movimiento Celular/efectos de los fármacos , Interacciones Farmacológicas , Epitelio/patología , Neoplasias Mesoteliales/patología , Ratas , Células Tumorales Cultivadas , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
In this study, cost accounting was made for a surgical case of gastrectomy according to critical path (path) and the economic contribution of the path was determined. In addition, changes in the cost percentage with changes in number of hospital days were simulated. Basically, cost accounting was done by means of cost accounting by departments, which meets the concept of direct cost accounting of administered accounts. Personnel expenses were calculated by means of both direct and indirect calculations. In the direct method, the total hours personnel participated were recorded for calculation. In the indirect method, personnel expenses were calculated from the ratio of the income of the surgical department to that of other departments. Purchase prices for all materials and drugs used were recorded to check buying costs. According to the direct calculating method, the personnel expenses came to approximately 300,000 yen, total cost was approximately 700,000 yen, and the cost percentage was 59%. According to the indirect method, the personnel expenses were approximately 540,000 yen and the total cost was approximately 940,000 yen, the cost percentage being 80%. A simulation study of changes in the cost with changes in hospital days revealed that the cost percentages were assessed to be approximately 53% in 19 hospital days and approximately 45% in 12 hospital days.
Asunto(s)
Vías Clínicas/economía , Financiación Personal/economía , Gastrectomía/economía , Tiempo de Internación , Costos y Análisis de Costo , Costos de la Atención en Salud , Humanos , Matemática , Neoplasias Gástricas/economía , Neoplasias Gástricas/cirugíaRESUMEN
Migration of rat ascites hepatoma (MM1) cells, invasion and phagokinetic movement were induced by the combination of lysophosphatidic acid (LPA) and fibronectin (FN). Induction of migratory activity was tightly correlated with morphological change of MM1 cells from spherical or polygonal-shaped cells to fusiform-shaped ones with pseudopodia. MM1 cells were mobile in a fusiform shape, whereas those of a spherical or polygonal shape were not. A small GTPase Rho and one of its downstream effectors ROCK (Rho-associated coiled-coil forming protein kinase), play essential roles in these processes, as evidenced by suppression of migration and morphological change of MM1 cells by Clostridium botulinum C3 exoenzyme, an inhibitor of Rho, or by Y-27632, an inhibitor of ROCK. Y-27632 also suppressed the formation of fusiform-shaped pseudopodia-carrying MM1 cells that was induced by stimulation with the combination of LPA and FN. LPA and FN also evoked the formation of focal adhesions and actin bundles, and tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. The inhibitory effect of Y-27632 on LPA-induced migration and morphological change of MM1 cells was considered to be mediated, at least in part, by impaired formation of focal adhesions and actin bundles. Y-27632 suppressed LPA-induced tyrosine phosphorylation of FAK and paxillin, suggesting that ROCK regulates these molecules and Y-27632 inhibits cellular migration and morphological change, at least in part, through this regulation.
Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Piridinas/farmacología , Actinas/metabolismo , Amidas/uso terapéutico , Animales , Carcinoma Hepatocelular , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteínas del Citoesqueleto/metabolismo , Interacciones Farmacológicas , Inhibidores Enzimáticos/uso terapéutico , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Hepáticas , Lisofosfolípidos/farmacología , Invasividad Neoplásica/prevención & control , Paxillin , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/uso terapéutico , Ratas , Células Tumorales Cultivadas , Tirosina/metabolismo , Quinasas Asociadas a rhoRESUMEN
Small cell lung cancer (SCLC) frequently metastasizes to bone and bone marrow. Skeletal scintigraphy and bone marrow cytology or biopsy, are incorporated into the staging procedures to examine these organs. However, skeletal scintigraphy is not highly specific to metastases, and only one or two bone marrow sites can be examined by cytology or biopsy. We have already reported that magnetic resonance imaging (MRI) could improve the sensitivity in detecting bone marrow metastases. The result of the bone marrow MRI was an independent prognostic factor of SCLC patients [9]. In the present study, we analyzed the results of skeletal scintigraphy and bone marrow aspiration with special reference to the results of MRI examination. We also analyzed the relationship between bone marrow lesions and bone lesions. For this purpose, we visualized bone marrow metastases with MRI and determined their anatomical locations and sizes. Approximately half of bone marrow lesions stayed in bone marrow during follow-up period ranging from 57 to 154 days, whereas about half of them were accompanied by hot spots in follow-up skeletal scintigraphy, which indicates the destruction of osseous structure. Additionally, 87.5% of osteolytic changes that newly appeared in skeletal scintigraphy were preceded by adjacent bone marrow lesions. All new lesions that appeared in follow-up skeletal scintigraphy within 3 months after the initial presentation had the preceding bone marrow lesions. These results mean that almost all lesions in skeletal scintigraphy derived from bone marrow metastases. Furthermore, appreciable volume of cancer cells is present in bone marrow before osteolytic changes appear in skeletal scintigraphy.
Asunto(s)
Neoplasias de la Médula Ósea/patología , Carcinoma de Células Pequeñas/patología , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Neoplasias de la Médula Ósea/diagnóstico por imagen , Neoplasias de la Médula Ósea/secundario , Carcinoma de Células Pequeñas/diagnóstico por imagen , Carcinoma de Células Pequeñas/secundario , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , CintigrafíaRESUMEN
Two cases of primitive neuroectodermal tumor of the lung are reported. The first case is a 41-year-old man with a tumor in the left upper lung, and the second case is a 30-year-old woman with a tumor in the right lower lung. In both cases, the tumors originated in the lung but not in the chest wall. No distant metastasis was detected. In case 1, transcutaneous fine-needle biopsy (TCNB) revealed small round cell proliferation, although bronchoscopic examination showed no abnormal findings. Both the expression of Mic2 protein and t(11;22)(q24;q12) translocation were proved in the tumor cells. The tumor cells were positive for periodic acid-Schiff (PAS), neuron-specific enolase (NSE), and vimentin, but negative for Leu7, chromogranin A, and pro-gastrin-releasing peptide (ProGRP). In case 2, bronchoscopic examination showed only compressive change in right lower lobe bronchi. TCNB revealed small round tumor cells expressing Mic2 protein. The tumor cells were negative for leukocyte common antigen, S100 protein, pankeratin, chromogranin A, and desmin, but weakly positive for NSE and moderately positive for Ki-67 (MIB1). Both patients were successfully treated by the combination of surgical resection and chemotherapy, and are alive with no sign of recurrence for approximately 22 months in case 1 and 16 months in case 2.
Asunto(s)
Neoplasias Pulmonares/patología , Tumores Neuroectodérmicos Periféricos Primitivos/patología , Antígeno 12E7 , Adulto , Antígenos CD/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Moléculas de Adhesión Celular/análisis , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Masculino , Tumores Neuroectodérmicos Periféricos Primitivos/genética , Tumores Neuroectodérmicos Periféricos Primitivos/inmunología , Fosfopiruvato Hidratasa/análisis , Translocación GenéticaRESUMEN
The mutation of W276 to cysteine within the human endothelin receptor subtype B (ET(B)R) is associated with Hirschsprung's disease, a congenital intestinal disease. The sequence surrounding W276 is highly conserved between the endothelin receptor subtypes A and B. We have introduced sets of mutations into W275 and W276 of the ET(B)R gene, and the corresponding W257 and W258 of the ET(A)R gene, and studied their coupling properties with G(i), G(o), and G(q) in reconstituted phospholipid vesicles. The prepared mutants all showed a similar affinity for endothelin-1. The W276C/ET(B)R and W276A/ET(B)R mutants had reduced activities in G(q) coupling but not in G(i)/G(o) coupling, while the W275A/ET(B)R displayed reduced activities in G(i)/G(q) coupling, with normal G(o) coupling. On the other hand, W257A/ET(A)R and W258A/ET(A)R exhibited wild-type activities in all examined G protein couplings. These results suggest that the defects in the G(q) signaling pathway by the ET(B)R are connected with Hirschsprung's disease and that the two conserved tryptophans play distinct roles in signal transduction by the two receptor subtypes. In addition, W275 and W276, which are thought to be located near the extracellular side of the transmembrane helix 5, play important roles in forming the active structure of ET(B)R.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Triptófano/genética , Secuencia de Aminoácidos , Animales , Bovinos , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Humanos , Membrana Dobles de Lípidos/metabolismo , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Fosfolípidos/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/aislamiento & purificación , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Triptófano/metabolismoRESUMEN
We have previously shown that the transcellular migration of rat ascites hepatoma (AH130-MM1) cells through a cultured mesothelial cell monolayer (MCL) is triggered with lysophosphatidic acid (LPA) that stimulates actin polymerization and myosin light chain phosphorylation through the activation of Rho-ROCK (Rho-kinase) cascade. When, however, the motility of MM1 cells on a glass surface was tested by phagokinetic track motility assay, LPA failed to induce the motility. Nevertheless, when the glass had been coated with fibronectin (FN), LPA could induce phagokinetic motility which was accompanied by transformation of MM1 cells to fusiform-shape and assembly of focal adhesion. beta1 integrin, the counter receptor of FN, was expressed on MM1 cells. Anti-FN antibody, anti-beta1 integrin antibody and cyclo-GRGDSPA remarkably suppressed LPA-induced phagokinetic motility. These antibodies suppressed LPA-induced transcellular migration through MCL, as well. These results indicate that actin polymerization and phosphorylation of myosin light chain through Rho activation are insufficient for inducing motility but the cooperative FN/beta1 integrin-mediated adhesion is necessary for both the phagokinetic motility and transcellular migration of MM1 cells.
Asunto(s)
Movimiento Celular , Fibronectinas/farmacología , Lisofosfolípidos/farmacología , Animales , Anticuerpos/farmacología , Carcinoma Hepatocelular , Movimiento Celular/inmunología , Fibronectinas/inmunología , Integrina beta1/inmunología , Neoplasias Hepáticas , Lisofosfolípidos/inmunología , Ratas , Células Tumorales CultivadasRESUMEN
Misexpression of the dorsal mesodermal patterning factor goosecoid on the ventral side of amphibian embryos results in inhibition of blood formation in early embryogenesis. To investigate the mechanism of this inhibition, we ectopically expressed goosecoid in erythroleukemia cells. While erythroid differentiation of these cells can be induced by activin, goosecoid expressing cells were unresponsive to activin. We demonstrate an in vitro interaction between the oncogene PU.1, an ets family transcription factor thought to play a role in erythropoiesis, and the goosecoid protein (GSC). Interaction with PU.1 was specific as GSC did not bind to the ets family members, Fli-1 or Ets-2. The ability of goosecoid expressing erythroleukemia cells to differentiate in response to activin was rescued by coexpression of the GSC-binding N-terminal portion of PU.1. The N-terminal portion of PU.1 was co-immunoprecipitated with anti-GSC antibodies as well. The N-terminal domain of PU.1 is the region recognized by the retinoblastoma protein (Rb), a tumor suppressor gene presumably involved in erythroid differentiation. We show that GSC competitively inhibits binding of Rb to PU.1. Our data suggest that the suppression of blood formation by GSC could, at least in part, be mediated by binding to PU.1.