RESUMEN
Several studies suggest a strong genetic component of attention-deficit/hyperactivity disorder (ADHD), a complex neurodevelopmental disorder characterized by inappropriate levels of hyperactivity, impulsivity and inattention. Determining specific genetic risk variants for each symptom dimension of ADHD may aid in the identification of the biological risk factors of the disorder. In this study, we explored the potential genetic underpinnings of the hyperactive phenotype of ADHD. To this end, we examined differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of SHR/NCrl, an animal model of ADHD, compared with its genetic control, the Wistar Kyoto (WKY/NCrl) rat and the Wistar rat, strain used to represent the 'normal' heterogeneous population. Relative to WKY/NCrl and Wistar controls, SHR/NCrl showed hyperactivity in the open-field test. Treatment with the ADHD drug, amphetamine (AMPH) reduced hyperactivity in SHR/NCrl. Meanwhile, AMPH increased locomotor activity in WKY/NCrl and Wistar rats. Gene expression analysis found 21 common upregulated and 36 downregulated genes in the PFC of drug-naive SHR/NCrl when compared with WKY/NCrl and Wistar rats. Of these DEGs, expression levels of two genes, Atxn7 and Per2, which are involved in transcription and circadian rhythm, respectively, were downregulated following AMPH treatment in SHR/NCrl. Quantitative real-time-polymerase chain reaction analyses verified expression patterns of these genes in the PFC of drug-naïve and AMPH-treated SHR/NCrl. The present findings indicate genetic risk variants that may be associated with the hyperactive phenotype in ADHD. Further studies are warranted to establish the roles of Atxn7 and Per2 in mediating hyperactivity.
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Anfetamina/farmacología , Trastorno por Déficit de Atención con Hiperactividad/genética , Estimulantes del Sistema Nervioso Central/farmacología , Corteza Prefrontal/metabolismo , Transcriptoma , Anfetamina/uso terapéutico , Animales , Ataxina-7/genética , Ataxina-7/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Estimulantes del Sistema Nervioso Central/uso terapéutico , Regulación hacia Abajo , Locomoción , Masculino , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas WistarRESUMEN
Osteopenia and osteoporosis were independent predictive factors for higher atlantoaxial subluxation occurrence in patients with lower body mass index. Our findings suggest that patients with rheumatoid arthritis with osteopenia or osteoporosis, particularly those with lower body mass index (BMI), should be screened regularly to determine the status of their cervical spines. INTRODUCTION: Cervical spine involvement in rheumatoid arthritis (RA) patients may cause serious adverse effects on quality of life and overall health. This study aimed to evaluate the association between atlantodental interval (ADI), atlantoaxial subluxation (AAS), and systemic bone mineral density (BMD) based on BMI variations among established patients with RA. METHODS: The ADI was transformed to the natural log scale to normalize distributions for all analyses. Multivariable linear regression analyses were used to identify independent predictive factors for ADI based on each BMD classification. Multivariate Cox regression analyses were also performed to identify independent predictive factors for the risk of AAS, which were classified by tertile groups of BMI. RESULTS: A total of 1220 patients with RA who had undergone at least one or more cervical radiography and BMD assessments were identified and enrolled. We found that the association between BMD and ADI (ß, -0.029; 95% CI, -0.059 to 0.002; p = 0.070) fell short of achieving statistical significance. However, the ADI showed a 3.6% decrease per 1 BMI increase in the osteoporosis group (ß, -0.036; 95% CI, -0.061 to -0.011; p = 0.004). The osteopenia and osteoporosis groups showed about a 1.5-fold and a 1.8-fold increased risk of AAS occurrence among the first tertile of the BMI group. CONCLUSIONS: Our study showed a possible association between lower BMD and AAS occurrence in patients with RA with lower BMI. Further studies are needed to confirm our findings.
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Artritis Reumatoide/complicaciones , Articulación Atlantoaxoidea , Densidad Ósea/fisiología , Enfermedades Óseas Metabólicas/complicaciones , Luxaciones Articulares/etiología , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Índice de Masa Corporal , Enfermedades Óseas Metabólicas/fisiopatología , Vértebras Cervicales , Femenino , Humanos , Luxaciones Articulares/fisiopatología , Luxaciones Articulares/prevención & control , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/fisiopatología , Inestabilidad de la Articulación/prevención & control , Masculino , Persona de Mediana Edad , Osteoporosis/complicaciones , Osteoporosis/fisiopatología , Estudios Retrospectivos , Factor Reumatoide/sangreRESUMEN
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes. Furthermore, this molecular knowledge helps to identify new actionable targets and develop novel therapeutic strategies. To advance the concept of precision patient care in the clinic, patient-derived xenograft (PDX) models have recently been developed. PDX models not only represent histology and genomic features, but also predict responsiveness to investigational drugs in patient tumors. Molecularly curated PDX cohorts will be instrumental in hypothesis generation, biomarker discovery, and drug screening and testing in proof-of-concept preclinical trials for precision therapy. In the era of precision medicine, molecularly tailored therapeutic strategies should be individualized for cancer patients. To improve the overall clinical outcome, a multimodal approach is indispensable for advanced cancer patients. Careful, oncological principle-based surgery, combined with a molecularly guided multidisciplinary approach, will open new horizons in surgical oncology.
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Medicina de Precisión , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Animales , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Humanos , Terapia Molecular Dirigida , Modelación Específica para el Paciente , Pronóstico , Neoplasias Gástricas/patologíaRESUMEN
Theories of reward learning in neuroscience have focused on two families of algorithms thought to capture deliberative versus habitual choice. 'Model-based' algorithms compute the value of candidate actions from scratch, whereas 'model-free' algorithms make choice more efficient but less flexible by storing pre-computed action values. We examine an intermediate algorithmic family, the successor representation, which balances flexibility and efficiency by storing partially computed action values: predictions about future events. These pre-computation strategies differ in how they update their choices following changes in a task. The successor representation's reliance on stored predictions about future states predicts a unique signature of insensitivity to changes in the task's sequence of events, but flexible adjustment following changes to rewards. We provide evidence for such differential sensitivity in two behavioural studies with humans. These results suggest that the successor representation is a computational substrate for semi-flexible choice in humans, introducing a subtler, more cognitive notion of habit.
RESUMEN
Reciprocal interactions between cancer cells and the tumor microenvironment drive multiple clinically significant behaviors including dormancy, invasion, and metastasis as well as therapy resistance. These microenvironment-dependent phenotypes share typical characteristics with cancer stem cells (CSC). However, it is poorly understood how metabolic stress in the confined tumor microenvironment contributes to the emergence and maintenance of CSC-like phenotypes. Here, we demonstrate that chronic metabolic stress (CMS) in a long-term nutrient deprivation induces a Wnt-dependent phenoconversion of non-stem cancer cells toward stem-like state and this is reflected in the transcriptome analysis. Addition of Wnt3a as well as transfection of dominant-negative Tcf4 establishes an obligatory role for the Wnt pathway in the acquisition of CSC-like characteristics in response to metabolic stress. Furthermore, systematic characterization for multiple single cell-derived clones and negative enrichment of CD44+/ESA+ stem-like cancer cells, all of which recapitulate stem-like cancer characteristics, suggest stochastic adaptation rather than selection of pre-existing subclones. Finally, CMS in the tumor microenvironment can drive a CSC-like phenoconversion of non-stem cancer cells through stochastic state transition dependent on the Wnt pathway. These findings contribute to an understanding of the metabolic stress-driven dynamic transition of non-stem cancer cells to a stem-like state in the tumor metabolic microenvironment.
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Neoplasias de la Mama/patología , Células Madre Neoplásicas/citología , Estrés Fisiológico/fisiología , Vía de Señalización Wnt/fisiología , Proteína Wnt3A/metabolismo , Animales , Proliferación Celular , Supervivencia Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/patología , Esferoides Celulares/patología , Transcripción Genética/genética , Activación Transcripcional/genética , Células Tumorales Cultivadas , Microambiente Tumoral/fisiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Although leptin appears to be an important local and systemic factor influencing cartilage homeostasis, the role of leptin in chondrocyte death is largely unknown. Tumor necrosis factor α (TNF-α) is a pro-inflammatory cytokine that plays a central role in the pathogenesis of articular diseases. This study examines whether leptin modulates TNF-α-induced articular chondrocyte death. METHODS: Primary rat articular chondrocytes were isolated from knee joint cartilage slices. To induce cell death, the chondrocytes were treated with TNF-α. To examine whether leptin modulates the extent of TNF-α-mediated chondrocyte death, the cells were pretreated with leptin for 3 h before TNF-α treatment followed by viability analysis. To examine the mechanism by which leptin modulates the extent of TNF-α-mediated chondrocyte death, we utilized mitochondrial membrane potential (MMP) measurements, flow cytometry, nuclear morphology observation, co-immunoprecipitation, western blot analysis and confocal microscopy. RESULTS: We demonstrated that leptin suppresses TNF-α induced chondrocyte death. We further found that apoptosis partially contributes to TNF-α induced chondrocyte death while necroptosis primarily contributes to TNF-α induced chondrocyte death. In addition, we observed that leptin exerts anti-TNF-α toxicity via c-jun N-terminal kinase (JNK) in rat articular chondrocytes. CONCLUSION: Based on our findings, we suggest that the leptin present in the articular joint fluid protects articular chondrocytes against cumulative mechanical load and detrimental stresses throughout a lifetime, delaying the onset of degenerative changes in chondrocytes. We can further hypothesize that leptin protects articular chondrocytes against destructive stimuli even in the joints of osteoarthritis (OA) patients.
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Apoptosis/efectos de los fármacos , Condrocitos/efectos de los fármacos , Cicloheximida/farmacología , Leptina/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Animales , Western Blotting , Cartílago Articular/citología , Condrocitos/metabolismo , Condrocitos/patología , Citometría de Flujo , Inmunoprecipitación , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Articulación de la Rodilla , Microscopía Confocal , RatasRESUMEN
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Additionally, environmental factors such as perinatal stress and early adversities contribute to the occurrence and severity of ADHD. Recently, DNA methylation has emerged as a mechanism that potentially mediates gene-environmental interaction effects in the aetiology and phenomenology of psychiatric disorders. Here, we investigated whether serotonin transporter gene (SLC6A4) methylation patterns were associated with clinical characteristics and regional cortical thickness in children with ADHD. METHOD: In 102 children with ADHD (age 6-15 years), the methylation status of the SLC6A4 promoter was measured. Brain magnetic resonance imaging was obtained and ADHD symptoms were evaluated. RESULTS: A higher methylation status of the SLC6A4 promoter was significantly associated with worse clinical presentations (more hyperactive-impulsive symptoms and more commission errors). Additionally, a negative correlation was observed between SLC6A4 methylation levels and cortical thickness values in the right occipito-temporal regions. CONCLUSIONS: Our results suggest that the SLC6A4 methylation status may be associated with certain symptoms of ADHD, such as behavioural disinhibition, and related brain changes. Future studies that use a larger sample size and a control group are required to corroborate these results.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo/patología , Metilación de ADN , Hipercinesia/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Niño , Femenino , Interacción Gen-Ambiente , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Regiones Promotoras Genéticas , Escalas de Valoración Psiquiátrica , República de CoreaRESUMEN
BACKGROUND: Previous studies have implicated the relationship between environmental phthalate exposure and attention deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children. METHOD: A cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated. RESULTS: Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri. CONCLUSIONS: The results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/orina , Corteza Cerebral/patología , Ácidos Ftálicos/orina , Adolescente , Análisis de Varianza , Niño , Estudios Transversales , Exposición a Riesgos Ambientales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , República de Corea , Índice de Severidad de la EnfermedadRESUMEN
Based on the work of both Eysenck and Nideffer, we hypothesized that higher ranking players (HRP) would have lower competitive anxiety and more flexible attention-shifting, compared to lower ranking players (LRP). In addition, different patterns of attention (low anxiety and flexible attention) would be represented by a different pattern of brain activity within the temporal lobe and dorsolateral prefrontal cortex. In accordance with the rookie draft ranking, the players were classified into 2 groups: HRP (top 30% of those selected in the draft) vs. LRP (bottom 30% of those selected in the draft). For assessment of executive function, a computerized version of the Wisconsin Card-sorting Test (WCST) was used. Brain activity was assessed using 1.5-Tesla functional magnetic resonance imaging. In response to scenes depicting baseball errors, HRP showed increased activation in the left cingulate cortex and decreased activation in right middle temporal gyrus, compared to LRP. In response to the simplified WCST in the scanner, HRP showed increased activation in left superior frontal cortex (DLPFC), compared to LRP. The present results suggest that HRP may demonstrate elevated cingulate activation and lower temporal cortex activation in response to scenes depicting baseball errors.
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Ansiedad , Atención/fisiología , Béisbol/psicología , Conducta Competitiva/fisiología , Corteza Prefrontal/fisiología , Lóbulo Temporal/fisiología , Adulto , Béisbol/fisiología , Función Ejecutiva/fisiología , Humanos , Imagen por Resonancia Magnética , Adulto JovenRESUMEN
AIMS: We carried out a large scale study to identify the risk factors for double primary malignancy (DPM) development in gastric cancer patients and to evaluate the clinical implications for these patients. METHODS: A total of 2593 patients who underwent gastrectomy for primary gastric cancer from January 2005 to November 2010 were reviewed with regard to DPM. We compared the clinicopathological characteristics, risk factors for developing DPM, and prognosis between the DPM+ group and the DPM- group. RESULTS: Of the 2593 patients, 152 (5.9%) were diagnosed with DPM. The most common accompanying malignancies were colorectal, lung and thyroid. Multivariate analysis indicated that age (p = 0.016) and MSI status (p = 0.002) were associated with a higher frequency of DPM. 30.3% of patients were diagnosed with DPM within 1 year around perioperative period and 53.3% of patients had DPM detected during 5 years of post-operative follow up periods. Although there was no significant difference in overall survival between the DPM+ and DPM- group, DPM+ patients had a worse prognosis than DPM- patients in stage I gastric cancer. CONCLUSIONS: Gastric cancer patients over the age of 60 or with a MSI-high status had an increased risk for developing DPM. Further, in stage I gastric cancer, the presence of DPM was associated with a worse prognosis. Therefore, careful pre- and postoperative surveillance is especially important in these patients.
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Neoplasias Colorrectales/patología , Neoplasias Pulmonares/patología , Neoplasias Primarias Múltiples/patología , Neoplasias Gástricas/patología , Neoplasias de la Tiroides/patología , Adulto , Factores de Edad , Anciano , Biopsia con Aguja , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/mortalidad , Neoplasias Primarias Múltiples/cirugía , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores Sexuales , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Análisis de Supervivencia , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/cirugía , Resultado del TratamientoRESUMEN
The aim of the present study was to evaluate the anxiolytic effects of the ethanol extract of Cirsium japonicum (CJ) in mice. The extract was orally administered at dosages of 50, 100, 200, or 400 mg/kg of body weight. The CJ-induced behavioral changes were assessed using the open-field and elevated-plus maze test. The ethanol extract of CJ did not affect overall locomotor activity of mice in the open-field test, however, it showed increase exploration in the unprotected center zone, which is thought to reflect anxiolyticlike effects. Furthermore, the CJ extract (100 and 200 mg/kg) significantly increased the percentage of time spent in the open arms of the elevated plus-maze, indicating the anxiolytic effects of the substance. This anxiolytic effects of the extract were comparable to that of the benzodiazepine, diazepam. To further characterize the anxiolytic activities of CJ, its action on human neuroblastoma cells were assessed. The CJ extract dose-dependently increased chloride ion (Cl(â)) influx, which was blocked by coadministration of the GABA(A) receptor competitive antagonist, bicuculline, suggesting a GABA(A) receptor - Cl(â)) channel mechanism of action. Taken altogether, the present study demonstrates that the ethanol extract of CJ has anxiolytic effects, probably mediated through GABAergic neurotransmission.
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Ansiolíticos/farmacología , Cloruros/metabolismo , Cirsium/química , Extractos Vegetales/farmacología , Receptores de GABA-A/metabolismo , Animales , Ansiolíticos/aislamiento & purificación , Ansiolíticos/uso terapéutico , Línea Celular Tumoral , Canales de Cloruro/metabolismo , Relación Dosis-Respuesta a Droga , Etanol/química , Humanos , Transporte Iónico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Componentes Aéreos de las Plantas , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéuticoRESUMEN
BACKGROUND: Laparoscopic and robotic gastrectomy have been adopted rapidly despite lack of evidence concerning technical safety and controversy regarding additional benefits. This study aimed to compare clinically relevant complications after open, laparoscopic and robotic gastrectomy. METHODS: This was a retrospective analysis of prospectively collected data on surgical complications in patients undergoing gastrectomy with curative intent for histologically proven adenocarcinoma between 2005 and 2010 at the Department of Surgery, Yonsei University College of Medicine in Seoul, Korea. Complications were categorized into wound infection, bleeding, anastomotic leak, obstruction, fluid collection and other. RESULTS: In a total of 5839 patients (4542 open, 861 laparoscopic and 436 robotic gastrectomies), overall complication, reoperation and mortality rates were 10·5, 1·0 and 0·4 per cent respectively. There were no significant differences between the three groups. Ileus (P = 0·001) and intra-abdominal fluid collections (P = 0·013) were commoner after conventional open surgery. However, tumour stage was higher and more complex resections were performed in the open group. Anastomotic leak, the leading cause of death, occurred more often after a minimally invasive approach (P = 0·017). CONCLUSION: Laparoscopic and robotic gastrectomy had overall complication and mortality rates similar to those of open surgery, but anastomotic leaks were more common with the minimally invasive techniques.
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Adenocarcinoma/cirugía , Gastrectomía/efectos adversos , Laparoscopía/efectos adversos , Robótica , Neoplasias Gástricas/cirugía , Absceso Abdominal/etiología , Análisis de Varianza , Fuga Anastomótica/etiología , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Femenino , Humanos , Ileus/etiología , Tiempo de Internación , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Estudios Prospectivos , Reoperación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Thrombocytosis has been associated with malignancies and poor prognostic implications in cancer patients. In the present study the prognostic significance of pretreatment platelet (PLT) level was assessed with regard to recurrence and survival in patients with primary gastric adenocarcinoma. METHODS: The authors reviewed the prospective data of 1593 gastric cancer patients who received curative gastrectomy with extended lymphadenectomy. The correlations of PLT level with recurrence and overall survival were evaluated by both univariate and multivariate analyses. RESULTS: Thrombocytosis (≥ 40 × 10(4)/ µL), present in 6.4% of the patients prior to curative surgery, was more frequently associated with advanced T and N classification, larger tumor size, anemia, and leukocytosis (p < 0.05). In patients with pretreatment thrombocytosis compared to those without it, five-year survival rate was worse (56.9% vs. 65.5%; p = 0.043), and recurrence rate was higher mainly due to the frequent hematogenous spread (51.0% vs. 34.5%; p < 0.001). Furthermore, risk of blood-borne metastasis was almost three-fold higher in patients with pretreatment thrombocytosis (Odds ratio 2.83 [95% CI 1.67-4.77], p < 0.001). CONCLUSIONS: Pretreatment thrombocytosis correlated significantly with poor prognosis and can be used as an independent predictor of recurrence by blood-borne metastasis in gastric cancer.
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Adenocarcinoma/secundario , Gastrectomía , Células Neoplásicas Circulantes , Neoplasias Gástricas/patología , Trombocitosis/complicaciones , Adenocarcinoma/complicaciones , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Activación Plaquetaria , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Análisis de SupervivenciaRESUMEN
BACKGROUND AND PURPOSE: Functional roles of the N-terminal region of rhodopsin-like GPCR family remain unclear. Using dopamine D(2) and D(3) receptors as a model system, we probed the roles of the N-terminal region in the signalling, intracellular trafficking of receptor proteins, and explored the critical factors that determine the functionality of the N-terminal region. EXPERIMENTAL APPROACH: The N-terminal region of the D(2) receptor was gradually shortened or switched with that of the D(3) receptor or a non-specific sequence (FLAG), or potential N-terminal glycosylation sites were mutated. Effects of these manipulations on surface expression, internalization, post-endocytic behaviours and signalling were determined. KEY RESULTS: Shortening the N-terminal region of the D(2) receptor enhanced receptor internalization and impaired surface expression and signalling; ligand binding, desensitization and down-regulation were not affected but their association with a particular microdomain, caveolae, was disrupted. Replacement of critical residues within the N-terminal region with the FLAG epitope failed to restore surface expression but partially restored the altered internalization and signalling. When the N-terminal regions were switched between D(2) and D(3) receptors, cell surface expression pattern of each receptor was switched. Mutations of potential N-terminal glycosylation sites inhibited surface expression but enhanced internalization of D(2) receptors. CONCLUSIONS AND IMPLICATIONS: Shortening of N-terminus or mutation of glycosylation sites located within the N-terminus enhanced receptor internalization but impaired the surface expression of D(2) receptors. The N-terminal region of the D(2) receptor, in a sequence-specific manner, controls the receptor's conformation and integration into the plasma membrane, which determine its subcellular localization, intracellular trafficking and signalling properties.
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Membrana Celular/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Secuencia de Aminoácidos , Arrestinas/metabolismo , AMP Cíclico/metabolismo , Endocitosis/fisiología , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Glicosilación , Células HEK293 , Humanos , Datos de Secuencia Molecular , Conformación Proteica , Transporte de Proteínas/fisiología , Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo , beta-ArrestinasRESUMEN
BACKGROUND: The purpose of this study was to evaluate the prognostic value of lymph node metastasis along the superior mesenteric vein (station 14v) to determine the need for 14v dissection in gastric cancer surgery. METHODS: A total of 1104 patients with gastric cancer who underwent gastrectomy including 14v dissection were enrolled. Patients were categorized into two groups: those with and those without 14v lymph node involvement by metastasis. RESULTS: Of the total study population, 73 patients (6·6 per cent) had 14v-positive gastric cancer. These patients were more likely to have advanced tumour (T), node (N) and distant metastatic (M) status, and histologically undifferentiated gastric cancers. The 3- and 5-year survival rates of patients with 14v-positive disease were 24 and 9 per cent respectively. Survival in this group was similar to that of patients who had gastric cancer with distant metastasis (M1). Multivariable analysis demonstrated that 14v status was a significant prognostic factor for gastric cancer (hazard ratio 2·13; P < 0·001). After histologically complete (R0) resection, the overall survival of 14v-positive patients with any stage of cancer was significantly worse than that for 14v-negative patients with stage IV cancer (P = 0·006). CONCLUSION: 14v status is an independent prognostic factor for gastric cancer, with 14v-positive gastric cancer having a poor prognosis, similar to that of M1 disease. The exclusion of 14v in regional lymph node dissection should be considered.
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Gastrectomía/mortalidad , Escisión del Ganglio Linfático/mortalidad , Venas Mesentéricas , Neoplasias Gástricas/cirugía , Adulto , Anciano , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
AIMS: There is little information on patient selection criteria for laparoscopy-assisted distal gastrectomy (LADG) that would facilitate a successful initial experience for a surgeon new to the procedure. This study aimed to establish patient selection criteria that will allow increased proficiency and shorter operation times for the LADG procedure. METHOD: One hundred LADG with lymphadenectomy and no other combined procedures were consecutively performed by one surgeon. These 100 consecutive LADG procedures were analyzed retrospectively from a prospectively designed computer database. Uni- and multivariate analyses were performed to identify factors influencing operation time. RESULTS: According to univariate analysis, operation time was influenced by sex, BMI, surgical experience, and tumor location, whereas multivariate analysis indicated that operation time was significantly influenced only by BMI and surgical experience. The same analyses of only the first 50 cases showed that sex, BMI, surgical experience, and tumor location were independently associated with operation time. As BMI increased, so did operation time, whereas operation time decreased with increasing surgical experience. CONCLUSION: This study suggests that surgeons who have limited experience with this advanced procedure may shorten operation time by considering patient and tumor characteristics in their early attempts at LADG. With a shortened operation time, surgeon with limited experience may become proficient to LADG rapidly.
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Gastrectomía/métodos , Laparoscopía , Neoplasias Gástricas/cirugía , Adulto , Anciano , Femenino , Humanos , Tiempo de Internación , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Selección de Paciente , Análisis de Regresión , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: During laparoscopic-assisted gastrectomy, it is impossible to identify early gastric cancer (EGC) lesions; therefore, a precise localization technique is needed. In this study, we used laparoscopic ultrasonography (LUS) after endoscopic clipping as a method of localizing EGC and evaluated the effectiveness of this method. METHODS: A prospective study of 17 patients who had undergone laparoscopic-assisted gastrectomy was performed. Three endoscopic clips were applied just proximal to the tumor during the preoperative endoscopy. The applied clips were detected from the serosal side of the stomach using LUS. The serosal surface of the lesion was marked with dye. RESULTS: In all patients, endoscopic clips were applied proximal to the lesion without complications, and the applied clips were confirmed by plain abdominal radiography. The clips were successfully detected by LUS in all patients. In the resected specimen, the serosal surface, marked with dye, was always just above the clips in the anterior wall or on the anterior wall opposite the clips applied in the posterior wall. The mean detection time was 4.7 min (range, 2-8). With this procedure, two patients underwent total gastrectomy and 15 patients underwent distal subtotal gastrectomy with gastroduodenostomy or gastrojejunostomy. Histological examination confirmed that the resection margins were tumor free in all patients. There was no operative morbidity related to the LUS procedure. CONCLUSIONS: Using LUS to detect endoscopic clips is an easy, safe, and accurate method to localize EGC lesions in laparoscopic-assisted gastrectomy.
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Gastrectomía/métodos , Cuidados Intraoperatorios , Laparoscopía , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/cirugía , Ultrasonografía Intervencional , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
PC10, a monoclonal antibody (mAb) to proliferating cell nuclear antigen (PCNA) is known to show immunoreactivity in paraffin-embedded specimens. The authors present the relation between PCNA expression and clinicopathological features in 38 intracranial meningiomas. PCNA scores were obtained by immunohistochemical staining of the paraffin-embedded sections using a streptavidin-biotin immunoperoxidase method with PC10 mAb. Univariate analysis showed that high PC10 scores were associated with old age (> or = 50 years old), male, recurrent tumours, and meningothelial type. However, these high scores did not reach a statistical significance (P> 0.05). PC10 scores of the basal meningioma tended to be higher than that of the hemispheric meningioma (P< 0.05). The staining intensity of PCNA was also markedly increased in basal meningiomas. It is suggested that the proliferative potential is higher in basal meningiomas than in hemispheric meningiomas. Moreover, these results could reflect high recurrence and difficulty in management of the skull base meningiomas.
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Biomarcadores de Tumor/análisis , Neoplasias Meníngeas/química , Meningioma/química , Proteínas de Neoplasias/análisis , Antígeno Nuclear de Célula en Proliferación/análisis , Adulto , Anciano , Edema Encefálico/etiología , Calcinosis/patología , División Celular , Femenino , Humanos , Técnicas para Inmunoenzimas , Antígeno Ki-67/análisis , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/patología , Meningioma/complicaciones , Meningioma/patología , Persona de Mediana Edad , Recurrencia Local de NeoplasiaRESUMEN
Branchio-oto-dysplasia is characterized by abnormalities of embryonic branchial arch system and deafness inherited as autosomal dominant with variable gene expression. We present a rare case of multiple intracranial aneurysms associated with branchio-oto-dysplasia. A 40-yr-old man with severe headache presented as spontaneous subarachnoid hemorrhage on brain computed tomographic scan. The patient also manifested clinical features of branchio-oto-dysplasia and right hemifacial hypoplasia. Carotid angiogram confirmed an aneurysm in the anterior communicating artery. Intraoperative findings demonstrated multiple aneurysms in the anterior communicating artery and in the left posterior communicating artery, which were clipped successfully. Postoperative course was uneventful. This condition has not been reported previously. We also reviewed literatures to discuss whether the intracranial aneurysm was as a coincidental finding or a part of this malformation.