RESUMEN
Squamous cell carcinoma of the esophagus (SCCE) has a poor prognosis compared with other gastrointestinal cancers. Many patients present with locoregional unresectable or metastatic disease at the time of diagnosis. For these patients with metastatic esophageal cancer, chemotherapy is generally indicated. The aim of this phase I/II study was to evaluate the efficacy and safety of the combined use of docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU)(DCF) in patients with recurrent/metastatic SCCE. This study adopted divided doses of docetaxel and CDDP in order to reduce the toxicities of the treatment. The dose of docetaxel was escalated using the following protocol in the phase I stage: level 1, 30 mg/m2; level 2, 35 mg/m2 and level 3, 40 mg/m2, which was intravenously infused for 2 hours on days 1 and 8. CDDP was administered at a dose of 12 mg/m2 infused for 4 hours on days 1-5. The 5-FU was administered at a dose of 600 mg/m2 continuously infused from day 1 to 5. This regimen was repeated every 4 weeks. The study subjects were nine patients (phase I) and 48 patients (phase II). The recommended dose was determined as level 3 in phase I. In the phase II stage, the overall response rate was 62.5%, with a complete response rate of 12.5%. The median progression-free survival was 6 months, and the median overall survival was 13 months. Grade 3/4 toxicities of leukopenia, neutropenia and febrile neutropenia occurred in 64.6%, 68.8% and 14.6% of the patients, while grade 3/4 non-hematological toxicities were relatively rare. No treatment-related death was recorded. This modified DCF regimen with divided doses can be a tolerable and useful regimen of definitive chemotherapy for unresectable SCCE because of its high efficacy, although adequate care for severe neutropenia must be administered.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Taxoides/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/patología , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Esquema de Medicación , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Esófago/patología , Fluorouracilo/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neutropenia/inducido químicamente , Proyectos de Investigación , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Patients' quality of life (QoL) deteriorates remarkably after gastrectomy. Billroth I reconstruction following distal gastrectomy has the physiological advantage of allowing food to pass through the duodenum. It was hypothesized that Billroth I reconstruction would be superior to Roux-en-Y reconstruction in terms of long-term QoL after distal gastrectomy. This study compared two reconstructions in a multicentre prospective randomized clinical trial to identify the optimal reconstruction procedure. METHODS: Between January 2009 and September 2010, patients who underwent gastrectomy for gastric cancer were randomized during surgery to Billroth I or Roux-en-Y reconstruction. The primary endpoint was assessment of QoL using the Functional Assessment of Cancer Therapy - Gastric (FACT-Ga) questionnaire 36 months after surgery. RESULTS: A total of 122 patients were enrolled in the study, 60 to Billroth I and 62 to Roux-en-Y reconstruction. There were no differences between the two groups in terms of postoperative complications or mortality, and no significant differences in FACT-Ga total score (P = 0·496). Symptom scales such as epigastric fullness (heaviness), diarrhoea and fatigue were significantly better in the Billroth I group at 36 months after gastrectomy (heaviness, P = 0·040; diarrhoea, P = 0·046; fatigue, P = 0·029). The rate of weight loss in the third year was lower for patients in the Billroth I group (P = 0·046). CONCLUSION: The choice of anastomotic reconstruction after distal gastrectomy resulted in no difference in long-term QoL in patients with gastric cancer. REGISTRATION NUMBER: NCT01065688 (http://www.clinicaltrials.gov).
Asunto(s)
Anastomosis en-Y de Roux/métodos , Gastrectomía/métodos , Gastroenterostomía/métodos , Calidad de Vida , Neoplasias Gástricas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Anastomosis en-Y de Roux/psicología , Femenino , Estudios de Seguimiento , Gastrectomía/psicología , Gastroenterostomía/psicología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Procedimientos de Cirugía Plástica/métodos , Neoplasias Gástricas/psicología , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Peripheral stimulation is known to influence the state of cortical excitability. The purpose of this study is to investigate whether peripheral magnetic stimulation has similar effects on cortical excitability to transcranial magnetic stimulation (TMS). A magnetic stimulator with a flat figure-of-eight coil was used for both TMS, and peripheral magnetic stimulation applied to the bilateral forearms. TMS was performed on the left primary motor cortex to evaluate influence of the peripheral magnetic stimulation, and motor evoked potential (MEP) was measured from the right first dorsal interosseous. Peripheral magnetic stimulation was performed at a stimulus frequency of 1 Hz or 10 Hz, to the stimulus sites on the right and left supination of the forearm. The effects of peripheral magnetic stimulation were evaluated by comparing the mean MEP amplitude elicited by TMS before and after peripheral magnetic stimulation. We found that cortical excitability varied according to the stimulation site and frequency of the peripheral magnetic stimulation. The inhibition of cortical excitability was observed following 1 Hz peripheral magnetic stimulation over the right forearm (p<;0.001). In contrast, increased cortical excitability was observed using 1 Hz peripheral magnetic stimulation over the left forearm and 10 Hz stimulation over either the right or left forearms. We suggest that peripheral magnetic stimulation has a similar effect to TMS, and can induce both facilitation and inhibition of cortical excitability.
Asunto(s)
Corteza Motora/fisiología , Estimulación Magnética Transcraneal/métodos , Adulto , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Antebrazo/fisiología , Humanos , MasculinoRESUMEN
The purpose of the present study was to use event-related potentials (ERP) to clarify the effect of magnetic stimulation on cognitive processing. A figure eight-shaped flat repetitive transcranial magnetic stimulation (rTMS) coil was used to stimulate either the region over the left or the right dorsolateral prefrontal cortex, which is considered to be the origin of the P300 component. Stimulus frequencies were 1.00, 0.75 and 0.50 Hz rTMS. The strength of the magnetic stimulation was set at 80% of the motor threshold for each participant. The auditory oddball task was used to elicit P300s before and shortly after rTMS, and comprised a sequence of sounds containing standard (1 kHz pure tone, 80% of trials) and deviant (2 kHz pure tone, 20% of trials) stimuli. We found that a 1.00 Hz rTMS pulse train over the left dorsolateral prefrontal cortex increased P300 latencies by 8.50 ms at Fz, 12.85 ms at Cz, and 11.25 ms at Pz. In contrast, neither 0.75 and 0.50 Hz rTMS pulse trains over the left dorsolateral prefrontal cortex nor 1.00, 0.75 and 0.50 Hz rTMS pulse trains over the right dorsolateral prefrontal cortex altered P300 latencies. These results indicate that rTMS frequency affects cognitive processing. Thus, we suggest that the effects of rTMS vary according to the activity of excitatory and inhibitory neurons in the cerebral cortex.
Asunto(s)
Cognición/fisiología , Corteza Prefrontal/fisiología , Estimulación Magnética Transcraneal/métodos , Adulto , Electrodos , Potenciales Relacionados con Evento P300/fisiología , Femenino , Humanos , Magnetismo , Masculino , Adulto JovenRESUMEN
In this paper, we report our studies of the effects of stimulating the bilateral supramarginal gyrus (SMG) with low-frequency transcranial magnetic stimulation (rTMS) or short-term rTMS on brain excitability in humans. We analyzed the effects of various durations of stimulation on P300 latencies of the event-related potential (ERP). Magnetic pulses were delivered using a figure-eight flat coil. The intensity of rTMS was set to 80 % of the subject's motor threshold. In each round of rTMS, 100 magnetic pulses were applied over the scalp at frequencies of 1.00, 0.75, and 0.50 Hz. ERPs were measured prior to magnetic stimulation as a control. The effects of magnetic stimulation were then determined by measuring its effects on P300 latencies elicited by an odd-ball task. These latencies were measured before and 0, 5, 10, and 15 min after the magnetic stimulation. 1.00 Hz low-frequency rTMS of the left SMG decreased P300 latencies for approximately 10 min. In contrast, 0.50 Hz rTMS of the left SMG resulted in delayed P300 latencies for approximately 15 min. We furthermore found that 0.75 Hz rTMS of the left SMG and 1.00, 0.75 and 0.5 Hz rTMS of the right SMG did not affect P300 latencies. These results suggest that the duration of the effects of rTMS depend on the frequency of stimulation.
Asunto(s)
Encéfalo/fisiología , Estimulación Magnética Transcraneal , Electroencefalografía , Potenciales Evocados , HumanosRESUMEN
When the odd stimulation is presented, the positive component of electroencephalograph is induced at around 300 ms after the odd stimulation. This positive component is called P300. Many studies suggest that P300 may result from the summation of activity from multiple generators located in widespread cortical and subcortical areas. However, there is still no conclusive indication of the sources of P300. In this paper, we focus on the left supramaginal gyrus as one of the sources of P300. We investigated the temporal aspect of this area using TMS (transcranial magnetic stimulation). We investigated the relationship between the latency of the P300 and an effect of TMS when the left supramarginal gyrus was stimulated by TMS. In our previous study, we reported a method of removing stimulus artifact during TMS with Sample-and-Hold circuit and electroencephalogram (EEG) activity evoked by TMS could be measured successfully. In addition to this method, independent component analysis (ICA) was also applied to recorded EEG data in order to remove the stimulus artifact by off-line analysis. By using these methods, short latency (< 15 ms) EEG responses to TMS could be obtained. We stimulated the left supramarginal gyrus using a figure-eight coil during auditory oddball task. The TMS at 150 ms and 200 ms after the oddball sounds were presented. When the TMS was applied at 200 ms after the oddball stimulation, the peak response of P300 was delayed around 50 ms. Difference of the peak latency between the control measurement and the case of TMS applying at 150 ms was not significant. However, the differences of the peak latency of the control measurement and the peak latency of the measurement in the cases of TMS applying at 200 ms and 250 ms was significant (p<0.05). We considered that this delay was due to inhibiting to recognize the target stimulation.
Asunto(s)
Potenciales Relacionados con Evento P300/fisiología , Estimulación Magnética Transcraneal , Estimulación Acústica , Ingeniería Biomédica , Corteza Cerebral/fisiología , Electroencefalografía , HumanosRESUMEN
The combination of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG) is an effective tool for investigating the cortical reactivity and the functional connectivity in the brain. In our previous study, we reported a method of removing stimulus artifact during TMS with Sample-and-Hold circuit and EEG activity evoked by TMS could be measured successfully. In addition to this method, independent component analysis (ICA) was also applied to recorded EEG data in order to remove the stimulus artifact from for off-line analysis. By using these methods, short latency ( 15 ms) EEG responses to TMS could be obtained. In this paper, we focused on the propagation of EEG activity elicited by TMS. We observed both the EEG topography and the distribution of the current density over the whole head by changing the stimulus site. When motor cortex was stimulated, the propagation of EEG activity to contralateral hemisphere could be clearly observed. However, when posterior parietal cortex was stimulated, no or less propagation of EEG responses could be recognized. These results suggest that the responses evoked by TMS over motor cortex propagate to contralateral hemisphere along the axon through the corpus callosum.
Asunto(s)
Corteza Cerebral/fisiología , Electroencefalografía/métodos , Potenciales Evocados/fisiología , Estimulación Magnética Transcraneal/métodos , Algoritmos , Artefactos , Axones/patología , Encéfalo/patología , Cuerpo Calloso/patología , Cabeza/patología , Humanos , Modelos Teóricos , Corteza Motora/patologíaRESUMEN
We experienced 2 infants in whom octreotide acetate was effective on intractable chylothorax after surgery for congenital heart diseases. They were 8- and 5-month-old. They were diagnosed as having corrected transposition of the great arteries (TGA) and tetralogy of Fallot respectively, and underwent bidirectional Glenn anastomosis and right modified Blalock Taussig shunt. Chylothorax was revealed on the 11th and the 1st postoperative day, and was not improved by any conventional therapy in either case. Then octreotide acetate was infused continuously with 0.1-0.6 micorg/kg/hour for 24 and 7 days. Chylothorax disappeared completely without any complications such as disturbance of blood sugar level or growth retardation. Octreotide acetate was effective and safe even in infants in intractable chylothorax after surgery for congenital heart diseases, as long as used for short period.
Asunto(s)
Quilotórax/tratamiento farmacológico , Cardiopatías Congénitas/cirugía , Octreótido/uso terapéutico , Complicaciones Posoperatorias , Procedimientos Quirúrgicos Cardíacos/métodos , Humanos , Lactante , Masculino , Tetralogía de Fallot/cirugía , Transposición de los Grandes Vasos/cirugíaRESUMEN
Thirteen cases of functional single ventricle who had undergone bidirectional Glenn procedure were divided into 2 groups according to presence (5) or absence (8) of additional pulmonary blood flow. Additional flow was preserved in cases with relatively small pulmonary artery index (PA index), and their sources were antegrade pulmonary blood flow (2), and Blalock-Taussig (BT) shunt (3). In the control group, PA index was reduced to about 70% of the preoperative value, while in the additional group, pulmonary artery growth was recognized without significant elevation of mean pulmonary artery pressure. However, atrioventricular valve regurgitation progressed and systemic ventricular volume did not decrease after Glenn in the additional group. Therefore special consideration for the timing of Fontan procedure is mandatory.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/métodos , Cardiopatías Congénitas/cirugía , Ventrículos Cardíacos/anomalías , Arteria Pulmonar/cirugía , Circulación Pulmonar , Vena Cava Superior/cirugía , Anastomosis Quirúrgica , Procedimiento de Fontan , Cardiopatías Congénitas/fisiopatología , Ventrículos Cardíacos/cirugía , HumanosRESUMEN
We performed aortic valve replacement in 24 patients aged over 70 with small calcified valves. The surgical management of such patients remains controversial as the extensive calcification compromises implantation. Hence, we used an ultrasonic debridement instrument to remove calcium and selected a small prosthesis with the largest possible orifice without enlargement of the aortic annulus. Echocardiography showed significant reductions in left ventricular mass index compared with preoperative values. Early and mid-term prognosis has been relatively good.
Asunto(s)
Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Calcinosis/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/fisiopatología , Superficie Corporal , Desbridamiento/métodos , Femenino , Prótesis Valvulares Cardíacas , Humanos , Litotricia/métodos , Masculino , Pronóstico , Ajuste de Prótesis , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Terapia por Ultrasonido , Función Ventricular IzquierdaRESUMEN
Mutations of codon 12 in the Ki-ras gene are frequently found in pancreatic and colorectal cancers. It has been demonstrated that human T-cells have the potential to recognise tumours expressing mutated ras-derived peptides. However, it remains unclear whether T-cells from a given individual can recognise the mutant peptides, which are expressed in that individual's tumour tissues. Mutations of the Ki-ras oncogene were analysed by the mutant-allele-specific amplification (MASA) method in pancreatic and colorectal tumour tissues, and T-cell responses against mutated Ki-ras-derived peptides were measured by [(3)H]thymidine incorporation and IFN-gamma production assays. Specific T-cell responses against Ki-ras-products were found in cancer patients, whereas no immune response was observed in normal individuals (P<0.01). Six of the eight pancreatic cancer patients (75%) and nine of 26 colorectal cancer patients (35%) had T-cell responses to mutated Ki-ras-derived-peptides. T-cell response in a given individual cannot recognise the same mutated ras peptide, which is expressed in that individual's tumour tissues. However, pancreatic and colorectal cancer patients have T-cell immunity against Ki-ras-peptides, and this provides potential target for cancer immunotherapy.
Asunto(s)
Neoplasias Colorrectales/inmunología , Neoplasias Pancreáticas/inmunología , Proteínas Proto-Oncogénicas/inmunología , Linfocitos T/inmunología , División Celular , Neoplasias Colorrectales/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos , Mutación , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas rasRESUMEN
5-Fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR), a prodrug of 5-FU, are representative of the chemotherapeutic agents for colorectal adenocarcinomas. Pyrimidine nucleoside phosphorylase (PyNPase) catalyses the conversion of 5'-DFUR to 5-FU, the activated form. Murine adenocarcinoma CT26 cells were transfected with human PyNPase cDNA. The engineered transfectants producing PyNPase augmented the response to 5'-DFUR in vitro and in vivo. Animals were administered by means of intraperitoneal (i.p.) injection, and not orally, in order to obtain a better efficiency of absorption. The tumours of the transfected cells nearly all disappeared, even following treatment with quite a small amount of the anticancer agent. The animals injected with the tranfected cells were protected against subsequent challenge with the parental tumour cell line. These findings demonstrate that PyNPase gene transfection increases the sensitivity to 5'-DFUR, and thereby decreases the toxicity of the agent.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Floxuridina/uso terapéutico , Terapia Genética/métodos , Pentosiltransferasa/biosíntesis , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Animales , Antimetabolitos Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Terapia Combinada , ADN Complementario/genética , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Floxuridina/farmacología , Fluorouracilo/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Pentosiltransferasa/genética , Profármacos/farmacología , Profármacos/uso terapéutico , Pirimidina Fosforilasas , Transfección , Células Tumorales CultivadasRESUMEN
NADPH oxidase activity, in addition to NADH oxidase activity, has been shown to be present in the respiratory chain of Corynebacterium glutamicum. In this study, we tried to purify NADPH oxidase and NADH dehydrogenase activities from the membranes of C. glutamicum. Both the enzyme activities were simultaneously purified in the same fraction, and the purified enzyme was shown to be a single polypeptide of 55 kDa. The N-terminal sequence of the enzyme was consistent with the sequence deduced from the NADH dehydrogenase gene of C. glutamicum, which has been sequenced and shown to be a homolog of NADH dehydrogenase II. In addition to high NADH-ubiquinone-1 oxidoreductase activity at neutral pH, the purified enzyme showed relatively high NADPH oxidase and NADPH-ubiquinone-1 oxidoreductase activities at acidic pH. Thus, NADH dehydrogenase of C. glutamicum was shown to be rather unique in having a relatively high reactivity toward NADPH.
Asunto(s)
Corynebacterium/enzimología , NADH Deshidrogenasa/metabolismo , NADPH Oxidasas/aislamiento & purificación , NADPH Oxidasas/metabolismo , NADP/metabolismo , Secuencia de Aminoácidos , Membrana Celular/enzimología , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , NAD/metabolismo , NADH Deshidrogenasa/genética , NADH Deshidrogenasa/aislamiento & purificación , NADPH Oxidasas/genética , Oxidación-Reducción , Análisis de Secuencia de ADNRESUMEN
The Stemona alkaloid stenine (1), isolated from Stemona tuberosa of physiologically active stemonaceous plants, possesses the structurally novel and unique azepinoindole skeleton (B,C,D-ring system). We have achieved the asymmetric total synthesis of (-)-stenine (1), starting from 1,5-pentanediol (10). The key features are an intramolecular diastereoselective Diels-Alder reaction of the (E,E,E) triene 6, prepared in a convergent fashion from three components--dienyl chloride 7, dithiane 8, and chiral phosphonate 9--and efficient construction of the tricyclic A,B,D-ring system 29 through thermodynamically controlled regioselective enolization of the bicyclic ketone 25. In this article, we describe in detail the highly stereocontrolled total synthesis of (-)-stenine (1). These results should be useful for the asymmetric total synthesis of another, more complex. molecule: tuberostemonine (2), the synthesis of which has never been reported.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/química , Plantas/química , Estereoisomerismo , TermodinámicaRESUMEN
Leukotriene B4 (LTB4) is a potent mediator of inflammation that recruits granulocytes to the site of injury during the inflammatory response. The biological activity of LTB4 is terminated by its metabolism into inactive metabolites. Recent studies have suggested that LTB4 may have additional activity as an endogenous ligand for the transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha). Based on the data presented, a model was proposed in which LTB4 acts in a negative feedback manner by inducing the transcription of genes involved its own metabolism. In the present study the effect of PPARalpha activation on LTB4 metabolism was directly investigated. Primary cultures of rat hepatocytes were treated with LTB4 or the PPARalpha agonist WY-14,643, and LTB4 metabolism was assessed by measuring levels of LTB4 and the formation of LTB4 metabolites. In addition, the effect of PPARalpha activation on levels of acyl-CoA oxidase mRNA and expression of CYP4F proteins, which are specific omega-hydroxylases for LTB4, was determined. Treatment of hepatocytes with WY-14,643, but not LTB4, was found to increase acyl-CoA oxidase mRNA and enhance expression of rat hepatic CYP4F proteins and CYP4A1. Neither WY-14,643 nor LTB4 caused an increase of the basal levels of LTB4 metabolism, and no novel metabolites were observed. These results do not support the hypothesis that a pathway of negative feedback regulation of LTB4 metabolism involving PPARalpha exists in hepatocytes, because activation of PPARalpha by LTB4 or other PPARalpha agonists did not correlate with an increase in LTB4 metabolism.
Asunto(s)
Hepatocitos/metabolismo , Leucotrieno B4/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , Animales , Biotransformación , Northern Blotting , Cromatografía Líquida de Alta Presión , Hepatocitos/efectos de los fármacos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/agonistas , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Factores de Transcripción/agonistasRESUMEN
Tumor-specific gene delivery is crucial to achieving successful effects in suicide gene therapy. Carcinoembryonic antigen (CEA) promoter has been widely used for this purpose, but the expression level of tumor-specific promoters such as CEA promoter is generally low. In the previous study, we used the Cre/loxP system and showed that LacZ expression by the CEA promoter was remarkably enhanced and maintained its specificity using the Cre/loxP regulation system. In this study, the Cre/loxP system was first applied to augmentation of selective expression of the cytosine deaminase (CD) gene as a suicide gene therapy in CEA-producing cells. The double infection with AxCEANCre expressing Cre recombinase under the control of the CEA promoter and AxCALNLCD expressing the CD gene under the control of the CAG promoter by the Cre switching system rendered CEA-producing tumor cells 13-fold more sensitive to 5-fluorocytosine (5-FC) compared with the single infection with AxCEACD expressing CD gene driven by the CEA promoter. The therapeutic efficacy of the enhanced CD/5-FC suicide gene therapy was evaluated in orthotopic implantation models of human gastric carcinoma. Adenovirus vectors (1 x 10(9) plaque-forming units) were administered i.p. into mice three times, and then 5-FC was administered i.p. for the next 10 days. Tumor volume and weight in mice treated with AxCEANCre and AxCALNLCD/5-FC were significantly reduced as compared with those in mice treated not only with Mock (AxCALacZ) but also with AxCEACD/5-FC (P < 0.0001). This beneficial effect on tumor burden was also reflected in the overall survival. The survival periods of the mice treated with AxCEANCre and AxCALNLCD/5-FC were longer than those of mice treated with Mock or AxCEACD/5-FC (P < 0.01). These results suggested that application of the Cre/loxP system could provide a new approach for enhanced selective suicide gene therapy of CD/5-FC for the treatment of advanced gastric carcinoma.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antígeno Carcinoembrionario/genética , Flucitosina/farmacología , Terapia Genética/métodos , Nucleósido Desaminasas/genética , Neoplasias Gástricas/terapia , Adenoviridae/genética , Animales , Antimetabolitos Antineoplásicos/farmacocinética , Antígeno Carcinoembrionario/biosíntesis , Citosina Desaminasa , Femenino , Flucitosina/farmacocinética , Expresión Génica , Vectores Genéticos/genética , Células HeLa , Humanos , Integrasas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nucleósido Desaminasas/metabolismo , Regiones Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Células Tumorales Cultivadas , Proteínas Virales/genéticaRESUMEN
Clinically, we have observed that a large proportion of patients presenting with low back pain as the chief complaint are smokers. It was therefore postulated that smoking might affect the intervertebral disc. We investigated the histological and functional effects of nicotine on intervertebral discs in rabbits. Rabbits were implanted subcutaneously with minipumps for the delivery of 200 microg/ml nicotine for 4 or 8 weeks. The selected dose produced blood nicotine levels equivalent to those found in heavy smokers (30 cigarettes/day). Nicotine injection caused necrosis and fibrous tissue and vitreous formation in the nucleus pulposus of the intervertebral disc, as well as hypertrophy of the fibrous ring, with partial cracks and detachment. Measurement of collagen and proteoglycan production in intervertebral discs showed reduced synthesis of these proteins in nicotine-treated rabbits compared with the control findings. Our results indicated that the harmful effects of nicotine on the integrity of the intervertebral disc might be mediated by the direct effect of nicotine, or indirectly, by causing vasoconstriction of the vascular network surrounding the intervertebral discs.
Asunto(s)
Estimulantes Ganglionares/farmacología , Disco Intervertebral/efectos de los fármacos , Nicotina/farmacología , Animales , Femenino , Hipertrofia , Disco Intervertebral/patología , Masculino , Necrosis , ConejosRESUMEN
TS-1(S-1) has been developed as a new oral anticancer drug based on the biological modulation of 5-fluorouracil. We treated a patient with highly advanced gastric carcinoma with a new combination chemotherapy of S-1 and low-dose cisplatin. Remarkable tumor reduction was observed after two cycles of this therapy in the primary tumor and metastatic lymph nodes, and the ascites disappeared. This was concluded to be a partial response. The only adverse effect was skin pigmentation of the fingers (grade 1), leading to early timing of operation after chemotherapy. The gastric tumor showed evident invasion to the serosa. Lymph nodes around the stomach were swollen. Peritoneal dissemination was also recognized in the omentum and mesocolon. Total gastrectomy with regional lymph node dissection was performed. Disseminated tumors were all resected. Histological examination showed that no tumor cells were detected in the gastric primary lesion, metastatic lymph nodes or disseminated peritoneal tumors, suggesting pathological complete remission. It was suggested that this regimen could be a potent combined therapy for the treatment of patients with highly advanced gastric carcinoma, and it could be useful as neoadjuvant chemotherapy. Further studies are necessary to evaluate the efficacy of this therapy.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gastrectomía , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Combinación de Medicamentos , Gastroscopía , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Ácido Oxónico/administración & dosificación , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Piridinas/administración & dosificación , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tegafur/administración & dosificación , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
To investigate the characteristic structure of hydatidiform mole, various types of collagen expression were determined in human villous tissues obtained from normal pregnancies (n = 17) and complete hydatidiform moles (n = 10). Indirect immunofluorescent staining was performed to detect type I, III, and VI collagen with specific monoclonal antibodies. Collagens were also extracted from the villous tissues obtained from normal pregnancy and hydatidiform mole by the salt precipitation method. Immunohistochemical staining for type I, III, and VI collagen revealed weak staining of the villous stroma in hydatidiform mole compared with that in normal pregnancy. Both the ratios of type III to type I collagen and the ratios of type V to type I collagen in the villous tissues were significantly decreased (P < 0.05) in molar pregnancy compared with those in normal pregnancy. These results suggest that alterations in the distribution and composition of collagen might play an important role in determining the pathophysiology and structure of hydatidiform mole.
Asunto(s)
Vellosidades Coriónicas/química , Colágeno/análisis , Mola Hidatiforme/química , Neoplasias Uterinas/química , Adulto , Anticuerpos Monoclonales , Electroforesis en Gel de Poliacrilamida , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Pepsina A/metabolismo , EmbarazoRESUMEN
To investigate the characteristic structure of hydatidiform mole, type IV collagen expression was determined in human villous tissues obtained from normal pregnancies (n = 17) and complete hydatidiform moles (n = 10). Indirect immunofluorescent staining was performed to detect type IV collagen with specific monoclonal antibody, and Northern blot analysis was performed to assess expression of messenger ribonucleic acid for the alpha1(IV) chain. In addition, serum levels of type I, III, and IV collagen were measured by RIA. Immunohistochemical staining for type IV collagen revealed stronger staining of the trophoblastic basement membrane in hydatidiform mole than in normal pregnancy. Northern blot analysis revealed that the villous expression of messenger ribonucleic acid for the alpha1(IV) chain was significantly increased in hydatidiform moles compared with normal pregnancy (P < 0.01). Although there were no differences in the serum type I and III collagen levels between hydatidiform mole and normal pregnancy, the type IV collagen level was significantly higher in patients with hydatidiform mole than in normal pregnancy (P < 0.05). These results suggest that type IV collagen might play an important role in determining the pathophysiology and structure of hydatidiform mole.