RESUMEN
Stroke can be a cause of death, while in non-fatal cases it is a common cause of various disabilities resulting from associated brain damage. However, whether a specific periodontal pathogen is associated with increased risk of unfavorable outcome after stroke remains unknown. We examined risk factors for unfavorable outcome following stroke occurrence, including serum antibody titers to periodontal pathogens. The enrolled cohort included 534 patients who had experienced an acute stroke, who were divided into favorable (n = 337) and unfavorable (n = 197) outcome groups according to modified ranking scale (mRS) score determined at 3 months after onset (favorable = score 0 or 1; unfavorable = score 2-6). The associations of risk factors with unfavorable outcome, including serum titers of IgG antibodies to 16 periodontal pathogens, were examined. Logistic regression analysis showed that the initial National Institutes of Health stroke scale score [odds ratio (OR) = 1·24, 95% confidence interval (CI) = 1·18-1·31, P < 0·001] and C-reactive protein (OR = 1·29, 95% CI = 1·10-1·51, P = 0·002) were independently associated with unfavorable outcome after stroke. Following adjustment with those, detection of the antibody for Fusobacterium nucleatum ATCC 10953 in serum remained an independent predictor of unfavorable outcome (OR = 3·12, 95% CI = 1·55-6·29, P = 0·002). Determination of the antibody titer to F. nucleatum ATCC 10953 in serum may be useful as a predictor of unfavorable outcome after stroke.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Fusobacterium nucleatum/metabolismo , Inmunoglobulina G/sangre , Accidente Cerebrovascular/sangre , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/inmunología , Femenino , Fusobacterium nucleatum/inmunología , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Accidente Cerebrovascular/inmunologíaRESUMEN
BACKGROUND: Atrial fibrillation is common after oesophageal surgery. The aim of this study was to evaluate whether landiolol hydrochloride was effective and safe in the prevention of atrial fibrillation after oesophagectomy, and to see whether a reduction in incidence of atrial fibrillation would reduce other postoperative complications. METHODS: This single-centre study enrolled patients scheduled for transthoracic oesophagectomy in a randomized, double-blind, placebo-controlled trial between March 2013 and January 2016. Enrolled patients were randomized with a 1 : 1 parallel allocation ratio to either landiolol prophylaxis or placebo. The primary endpoint was the occurrence of atrial fibrillation after oesophagectomy. Secondary endpoints were incidence of postoperative complications, and effects on haemodynamic and inflammatory indices. RESULTS: One hundred patients were enrolled, 50 in each group. Postoperative atrial fibrillation occurred in 15 patients (30 per cent) receiving placebo versus five (10 per cent) receiving landiolol (P = 0·012). The overall incidence of postoperative complications was significantly lower in the landiolol group (P = 0·046). In the landiolol group, postoperative heart rate was suppressed effectively, but the decrease in BP was not harmful. The interleukin 6 level was significantly lower on days 3 and 5 after surgery in the landiolol group (P = 0·001 and P = 0·002 respectively). CONCLUSION: Landiolol was effective and safe in preventing atrial fibrillation after oesophagectomy. Registration number: UMIN000010648 (http://www.umin.ac.jp/ctr/).
Asunto(s)
Antiarrítmicos/uso terapéutico , Fibrilación Atrial/prevención & control , Esofagectomía/efectos adversos , Morfolinas/uso terapéutico , Urea/análogos & derivados , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/cirugía , Método Doble Ciego , Neoplasias Esofágicas/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Resultado del Tratamiento , Urea/uso terapéuticoRESUMEN
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
AIMS: Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper-phosphorylated tau protein. Recently, several other molecules, including flotillin-1, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] and cyclin-dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. METHODS: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. RESULTS: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 µm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3ß and spleen tyrosine kinase. CONCLUSIONS: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation.
Asunto(s)
Enfermedad de Alzheimer/patología , Vesículas Citoplasmáticas/ultraestructura , Ovillos Neurofibrilares/ultraestructura , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Vesículas Citoplasmáticas/patología , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/ultraestructura , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Fosforilación , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Células Piramidales/metabolismo , Células Piramidales/patología , Células Piramidales/ultraestructura , Quinasa Syk/metabolismoRESUMEN
BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms in DM1, but the cause of muscle wasting is still unknown. By contrast, many forms of muscular dystrophy are caused by abnormalities of the dystrophin-glycoprotein complex (DGC). alpha-Dystrobrevin is a key component of the DGC in striated muscle and plays important roles in maturation and signal transduction by interacting with alpha-syntrophin. The goal of this study was to investigate alternative splicing of alpha-dystrobrevin in DM1 and examine alpha-syntrophin binding of different alpha-dystrobrevin splice isoforms. METHODS: Splicing patterns of alpha-dystrobrevin in DM1 muscle were studied by reverse-transcriptase PCR. Expression of the variant splice isoform was examined by immunoblotting and immunohistochemistry. Alternatively spliced isoforms were expressed in cultured cells to investigate interaction with alpha-syntrophin. alpha-Syntrophin expression was examined by immunoblotting. RESULTS: alpha-Dystrobrevin mRNA including exons 11A and 12 was increased in both skeletal and cardiac muscle of DM1 patients. The aberrantly spliced alpha-dystrobrevin isoform was localized to the sarcolemma, and showed increased binding with alpha-syntrophin. Furthermore, levels of alpha-syntrophin associated with the DGC were increased in DM1 muscle. CONCLUSION: Alternative splicing of alpha-dystrobrevin is dysregulated in myotonic dystrophy type 1 (DM1) muscle, resulting in changes in alpha-syntrophin binding. These results raise the possibility that effects on alpha-dystrobrevin splicing may influence signaling in DM1 muscle cells.
Asunto(s)
Empalme Alternativo/genética , Proteínas Asociadas a la Distrofina/genética , Distrofia Miotónica/genética , Empalme del ARN/genética , Factores de Edad , Animales , Proteínas de Unión al Calcio/genética , Línea Celular , Exones/genética , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/patología , Proteínas Musculares/genética , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Miocardio/patología , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/patología , Polimiositis/genética , Polimiositis/patología , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcolema/patología , Especificidad de la Especie , Transcripción Genética/genética , Transfección , Repeticiones de TrinucleótidosRESUMEN
OBJECTIVE: To evaluate the FAO/WHO/UNU equations for predicting resting metabolic rate (RMR) in Vietnamese adolescents. DESIGN: A cross-sectional study involving healthy subjects was carried out at the Basic Nutrition Department, National Institute of Nutrition, Vietnam. The RMR was measured by indirect calorimetry and anthropometric indices were recorded. Equations derived by linear regression of RMR and body weight were compared to the FAO/WHO/UNU (1985) predictive equations. SUBJECTS: A total of 110 subjects who had normal body mass index (5-85 percentile) and divided into two groups by sex. RESULTS: Mean RMRs (MJ/kg/day) were 0.1146+/-0.0054 for males and 0.1062+/-0.0103 for females. Compared to the FAO/WHO/UNU equation, our findings were 7.8% and 11.7% lower in the two groups, respectively (P<0.001). CONCLUSION: Our findings suggest that the FAO/WHO/UNU equations may overestimate RMR in Vietnamese adolescents. Further studies on establishing reference of daily energy needs for Vietnamese adolescents should be carried out.
Asunto(s)
Metabolismo Basal/fisiología , Calorimetría Indirecta/métodos , Matemática , Adolescente , Antropometría , Índice de Masa Corporal , Peso Corporal/fisiología , Calorimetría Indirecta/normas , Estudios Transversales , Metabolismo Energético/fisiología , Femenino , Humanos , Modelos Lineales , Masculino , Valor Predictivo de las Pruebas , Valores de Referencia , VietnamRESUMEN
OBJECTIVE: Elderly patients often have impaired taste, nausea, anorexia and delayed healing of decubitus. In many of these patients, serum zinc levels are low and they respond to zinc supplementation. To date, no epidemics of zinc deficiency have been reported in Japan. We studied the prevalence of zinc deficiency and its causative factors in a typical local town in Japan. DESIGN: Cross-sectional study. SETTING: Nagano Prefecture (central Japan). SUBJECTS AND METHODS: Serum zinc levels were measured in 1009 habitants (18-96 years old) who participated in an annual mass health examination program of the City in 2003. Of all subjects, 86 with low serum zinc (<65 microg/dl) or high zinc (> or =90 microg/dl) levels were randomly selected, and a dietary survey using 24-h recalling methods for 2 consecutive days was performed in 2004. Among them, blood was collected in the morning from 50 subjects (26-94 years old). RESULTS: The percentage of those with low serum zinc levels (2.5th percentile of Americans) was 37.9% in the elderly (> or =60 years old). The age-adjusted prevalence of low serum zinc was 21.1% in the aged population. A positive correlation was detected between zinc intake and serum zinc levels in elderly subjects (> or =60 years old). CONCLUSIONS: The possibility of zinc deficiency in adult inhabitants in central Japan rises with age. The deficiency correlates with dietary zinc intake.
Asunto(s)
Enfermedades Carenciales/epidemiología , Dieta , Oligoelementos/sangre , Oligoelementos/deficiencia , Zinc/sangre , Zinc/deficiencia , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios Transversales , Enfermedades Carenciales/etiología , Dieta/normas , Ingestión de Energía/fisiología , Femenino , Encuestas Epidemiológicas , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Oligoelementos/administración & dosificación , Zinc/administración & dosificaciónRESUMEN
OBJECTIVE: To determine the prevalence of dental caries and the level of sugar consumption among 6-12-y-old schoolchildren in La Trinidad, Benguet, Philippines. DESIGN: A Cross-sectional study as a baseline survey for a later intervention program. A questionnaire was distributed to obtain information on dental history and total consumption of food with sugar. Caries were diagnosed based on the WHO recommendation. RESULTS: A total of 1200 schoolchildren, aged 6-12 y were included. The prevalence of dental caries in primary dentition was 71.7% and in the permanent dentition, 68.2%. The mean total decayed, extracted due to caries and filled primary teeth (DMFT) and decayed, missing and filled permanent teeth (DMFT) were 4.12 (s.d. 4.03) and 2.40 (s.d. 2.57), respectively. As age increased the mean DMFT increased. Majority (70%) had tooth brushing practices, and less than half (42.5%) had a dental visit only when necessary. Their sugar intake was twice more than the WHO recommendation with a mean daily total intake of 59 g per person. Most common sources of dietary sugar were hard candies (89%), banana cue (84.9%), camote cue (84.9%) and soft drinks (84.4%). No significant correlation was found between sugar intake and dental caries. CONCLUSION: The results indicate that dental caries is highly prevalent and increase with augmented sugar consumption. This maybe due to a widespread neglect of oral health and an increased availability of refined sugary products. Caries rates mirrored those of the developing countries with untreated lesions dominating all ages. The high level of untreated caries in all age groups is a cause for concern.
Asunto(s)
Atención Dental para Niños/estadística & datos numéricos , Caries Dental/epidemiología , Encuestas de Salud Bucal , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/efectos adversos , Niño , Estudios Transversales , Caries Dental/etiología , Femenino , Humanos , Masculino , Salud Bucal , Filipinas/epidemiología , Prevalencia , Encuestas y Cuestionarios , Cepillado DentalRESUMEN
OBJECTIVE: To evaluate the FAO/WHO/UNU equations for predicting resting metabolic rate (RMR) in Vietnamese adults. DESIGN: A cross-sectional study with healthy subjects was carried out at the Basic Nutrition Department, National Institute of Nutrition, Vietnam. RMR was measured by indirect calorimetry, and anthropometric indices were recorded. Equations derived by linear regression of RMR vs body weight were compared to the FAO/WHO/UNU 1985 predictive equations. SUBJECTS: A total of 188 subjects (98 males and 90 females) had a normal body mass index (BMI) and were divided into four groups by sex and age (male and female subjects 18-29 and 30-60 y old). RESULTS: Mean RMR (MJ/kg/day) in males was lightly significant by higher than that in female subjects in the 18-29 y old age group (0.1074+/-0.0100 vs 0.0965+/-0.0123) and the same result was seen in the 30-60 y old group (0.1018+/-0.0114 vs 0.0922+/-0.0129). However, differences were not statistically significant in the two age groups. Compared to the FAO/WHO/UNU equation, our findings were 7.4, 9.0, 11.7, and 13.5% lower in the four groups, respectively (P < 0.001). CONCLUSION: Our findings suggest that the FAO/WHO/UNU equations may overestimate RMR in Vietnamese adults. Further studies examining the relationship between body weight and RMR are needed, and establishing new predictive equations for RMR in Vietnamese should be a priority.
Asunto(s)
Metabolismo Basal/fisiología , Peso Corporal/fisiología , Adolescente , Adulto , Factores de Edad , Antropometría/métodos , Calorimetría Indirecta/métodos , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores Sexuales , VietnamRESUMEN
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
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
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
A 66-year-old man developed progressive painful dysesthesia in his hands and feet over 3 months. His vibration sense was impaired and sensory nerve action potentials of the limbs were not evoked. Biopsy of the peroneal nerve revealed sensory neuropathy. Positive anti-Hu antibody facilitated delineation of a right hilar mass and a metastatic lymph node in thoracic CT scan. He was diagnosed as small cell lung cancer associated with paraneoplastic sensory neuropathy. A complete response was achieved through chemotherapy (carboplatin and etoposide) and subsequent radiation therapy. Notably, his neurological conditions, although not changed during the hospitalization, gradually improved afterwards.
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Autoanticuerpos/sangre , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Polineuropatía Paraneoplásica/inmunología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Células Pequeñas/inmunología , Etopósido/administración & dosificación , Humanos , Neoplasias Pulmonares/inmunología , Masculino , Resultado del TratamientoRESUMEN
We report a 70-year-old woman with Isaacs' syndrome (acquired neuromyotonia) who showed a marked improvement after immunoadsorption plasmapheresis (IAP). She developed hyperhidrosis in her teens, and slowly progressive symptoms of neuromyotonia for over 50 years. An in vitro investigation of her serum with patch-clamp technique suggested the presence of antibodies against potassium channels. She was treated with IAP, which brought disappearance of her symptoms. Though the symptoms started to recur in 3 weeks, moderate improvement has been maintained by immunosuppressive drug treatment.
Asunto(s)
Síndrome de Isaacs/terapia , Plasmaféresis/métodos , Anciano , Femenino , Humanos , Técnicas de InmunoadsorciónRESUMEN
Selective gene targeting using the carcinoembryonic antigen (CEA) promoter is useful in gene therapy for gastrointestinal cancer. However, the expression of the CEA promoter is not sufficient. In this study, we tried to enhance CEA promoter activity using the Cre/loxP system. The double infection of CEA-producing cells such as MKN45 and LoVo with AxCEANCre and AxCALNLZ at a total multiplicity of infection (MOI) of 50 achieved 7-fold higher expression level of beta-galactosidase activity than single infection of those cells with AxCEALacZ at 50 MOI. On the other hand, the double infection of CEA-nonproducing cells such as MKN1 and HeLa cells showed a very low expression of beta-galactosidase activity. In the subcutaneous tumor models, the administration of AxCEANCre and AxCALNLZ into the CEA-producing tumor showed stronger expression of the LacZ gene in tumor tissue than that of AxCEALacZ. In the experiment using orthotopic models of CEA-producing gastric cancer, intraperitoneal double administration of AxCEANCre and AxCALNLZ caused evident LacZ gene expression in transplanted gastric tumors, but no LacZ gene expression in the normal stomach or liver. It was confirmed that enhanced tissue-specific gene transduction under control of CEA promoter using the Cre/loxP system was useful not only in vitro, but also in vivo, especially in orthotopic models.
Asunto(s)
Adenoviridae/genética , Antígeno Carcinoembrionario/genética , Regulación Neoplásica de la Expresión Génica , Integrasas/genética , Regiones Promotoras Genéticas/genética , Proteínas Virales , Animales , Antígeno Carcinoembrionario/biosíntesis , Femenino , Regulación Viral de la Expresión Génica , Marcación de Gen , Terapia Genética , Vectores Genéticos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/terapia , Activación Transcripcional , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIMS: One of the most important factors in the prevention of postoperative infection is the patient's own capacity to protect against infection. Neutrophils play a major role in this protection through phagocytosis and superoxide generation. Inflammatory cytokines are suitable for estimating the degree of surgical stress. The present study was designed to elucidate whether neutrophil functions are impaired in gastric cancer patients, and are related with cytokine production after surgery. METHODOLOGY: Phagocytosis and superoxide generation by neutrophils was studied in 84 patients with gastric cancer by flow cytometry. IL-6, IL-8 and tumor necrosis factor alpha were studied in 18 patients with gastric cancer by enzyme-linked immunosolubent assay. RESULTS: In gastric cancer patients phagocytosis was not impaired, whereas superoxide generation was lower than benign diseases and it was inhibited relative to the clinical stage. Moreover, superoxide generation was correlated with the nutritional parameters and was more suppressed in 7 patients who suffered from postoperative infection than in 40 patients whose postoperative course were uneventful. The fluctuation of superoxide generation correlated well with the serum cytokine levels in the postoperative course and its correlation was clarified in vitro. Nine patients with gastric cancer received intravenous hyperalimentation, and their superoxide generation was increased. CONCLUSIONS: Superoxide generation by neutrophils was suppressed in gastric cancer patients and it is suggested that nutritional support prevents postoperative infection via the augmentation of superoxide generation.
Asunto(s)
Citocinas/inmunología , Citocinas/metabolismo , Neutrófilos/fisiología , Neoplasias Gástricas/metabolismo , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Interleucina-6/inmunología , Interleucina-6/metabolismo , Interleucina-8/inmunología , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Apoyo Nutricional , Fagocitosis , Estadísticas no Paramétricas , Neoplasias Gástricas/cirugía , Superóxidos/inmunología , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
To develop a new therapy against colon cancer, we investigated two kinds of strategy using a cancer-specific approach. First, we employed the Cre/loxP regulation system to enhance the specific expression by carcinoembryonic antigen (CEA) promotor in CEA-producing tumor cells, and examined whether sufficient enhancement to transcriptional activity of CEA promotor, which maintains its specificity in vitro and in vivo, could be obtained. Next, using dendritic cells pulsed with HLA-A24 epitope peptides of CEA, we performed a Phase I study of active immunotherapy in patients with advanced colon cancer. These results suggest that the newly developed therapy for colon cancer is a promising strategy; however, minor modification may be necessary.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Colon/terapia , Células Presentadoras de Antígenos , Antígeno Carcinoembrionario/genética , Neoplasias del Colon/genética , Medicina Basada en la Evidencia , Marcación de Gen , HumanosRESUMEN
We report a patient with Gerstmann-Sträussler-Scheinker syndrome (GSS102) who developed optic atrophy. He had been complaining of slowly progressive postural unsteadiness and pain in both legs for 3 years. Visual acuity subacutely worsened in the last half year. His father and two aunts, who already died, had been diagnosed to have dementia. It is uncertain whether they had optic atrophy or not. He was alert but apathetic. Neurological examination revealed cerebellar ataxia, painful dysesthesia and loss of deep tendon reflexes in the lower limbs. Fundoscopic examination revealed bilateral optic atrophy without retinal degeneration, which has never been reported in GSS. A brain MRI showed mild atrophy of cerebellar hemispheres without signal abnormalities of optic nerves. DNA analysis of prion gene revealed point mutation at codon 102 (P102L), which was relatively common mutation in GSS. Other mutations were not found. Only two patients of Creutzfeldt-Jakob disease with optic atrophy have been reported. This case seems to be important to investigate why optic tracts are generally spared in prion disease.