RESUMO
A real-time processing system for the two-color CO2 laser interferometer on the JT-60SA has been developed for density feedback control. The system has a novel feature that can detect fringe jumps due to off-normal events, such as loss detection due to displacement of the beam axis and changes in the laser wavelengths. Because a phase change due to the JT-60SA plasma is smaller than π/2, corresponding to the line-integral electron density NL of â¼6×1019 m-2 in a short interval of 500 ns, the threshold of the fringe jump detection is decided to be π/2. Hence, off-normal events can be detected from a fringe jump, leading to the abort of the real-time feedback control. In the density feedback control of the JT-60SA plasma, the system is employed as a density monitor, with NL being successfully controlled at 16.8% ± 6.6% lower than the reference.
RESUMO
BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.
Assuntos
Adenocarcinoma , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Incidência , Antígeno Carcinoembrionário/metabolismo , Antígeno Carcinoembrionário/uso terapêutico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamento farmacológico , Junção Esofagogástrica/metabolismo , Junção Esofagogástrica/patologia , Recidiva Local de Neoplasia/patologia , Adenocarcinoma/terapia , Adenocarcinoma/tratamento farmacológicoRESUMO
BACKGROUND: The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice. METHODS: We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model. RESULTS: A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74). CONCLUSIONS: The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy.
Assuntos
Neoplasias Gástricas , Continuidade da Assistência ao Paciente , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
We have developed a denoising autoencoder based neural network (NN) method to determine a spectral line intensity with an uncertainty lower than the uncertainty determined by fitting the spectral line. The NN method processes the measured raw spectral line shape, providing a single Gaussian shape based on the training dataset, which consists of synthetically prepared Doppler shift and broadening free spectral lines in the present work. It is found that the uncertainty reduction level significantly depends on the training dataset. Limitations originating from the training dataset are also discussed.
RESUMO
Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor ß gene, ESR2, correlate with colorectal cancer survival. To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C>A) and rs3020443 (T>G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T>C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Receptor beta de Estrogênio/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Japão , Estimativa de Kaplan-Meier , Los Angeles , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Fenótipo , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores de Tempo , Resultado do TratamentoRESUMO
Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.
Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Imunomodulação/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Intervalo Livre de Doença , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/genética , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: Nuclear factor-kappaB (NF-κB) and CCL2/CCR2 chemokine axis play a central role in tumor progression such as stimulation of angiogenesis, acceleration of tumor invasion and migration, and suppression of innate immunosurveillance in the macrophage-related functions. There have been few reports regarding association of the macrophage function-related genes with the clinical outcome in gastric cancer. We hypothesized that variants in genes encoding for NF-κB and CCL2/CCR2 axis may predict prognosis in gastric cancer and tested whether the functional single-nucleotide polymorphisms (SNPs) will be associated with clinical outcome in patients with gastric cancer across two independent groups. PATIENTS AND METHODS: This study enrolled two cohorts which consisted of 160 Japanese patients and 104 US patients with locoregional gastric cancer. Genomic DNA was analyzed for association of 11 SNPs in NFKB1, RELA, CCL2, and CCR2 with clinical outcome using PCR-based direct DNA sequencing. RESULTS: The univariable analysis showed four SNPs had significant association with clinical outcome in the Japanese cohort, NFKB1 rs230510 remained significant upon multivariable analysis. The patients with the A allele of the NFKB1 rs230510 had significantly longer overall survival (OS) compared with those with the T/T genotype in both the Japanese and US cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared with the C/C genotype in the US cohort [hazard ratio (HR) 2.43; P = 0.015] but longer OS in the Japanese cohort (HR 0.58; P = 0.021), resulting in the statistically significant opposite impact on OS (P = 0.001). CONCLUSIONS: Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with the clinical outcome in patients with locoregional gastric cancer. These results also suggest that the genetic predisposition of the host may dictate the immune-related component of the tumor for progression in gastric cancer.
Assuntos
Quimiocina CCL2/genética , Macrófagos/imunologia , NF-kappa B/genética , Receptores CCR2/genética , Neoplasias Gástricas/genética , Fator de Transcrição RelA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidadeRESUMO
In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Receptor alfa de Estrogênio/genética , Polimorfismo Genético/genética , Proteínas Quinases/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Doença , Éxons/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Linfonodos/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Receptor ErbB-2/genética , Transdução de Sinais/genética , Tamoxifeno/uso terapêuticoRESUMO
Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin-fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Proteínas de Ligação a DNA/genética , Sistemas de Liberação de Medicamentos , Endonucleases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Neoplasias Retais/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-ß (platelet-derived growth factor receptor-ß; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-ß (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Pericitos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab , Camptotecina/administração & dosagem , Neoplasias Colorretais/diagnóstico , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.
Assuntos
Neoplasias do Colo/genética , Integrinas/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Feminino , Fluoruracila/uso terapêutico , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Adulto JovemRESUMO
A Rogowski probe consisting of a small multi-layer Rogowski coil, five magnetic pick-up coils, and a Langmuir probe was developed to measure the local current density and its direction. It can be moved along the major radius and can be turned around its axis. This probe was used to measure the current density profile near the last closed flux surface of Ohmic plasmas in Tokyo Spherical Tokamak-2. The current density profile was measured successfully with a signal to noise ratio of greater than 20.
RESUMO
The multi-pass Thomson scattering (TS) scheme enables obtaining many photons by accumulating multiple TS signals. The signal-to-noise ratio (SNR) depends on the accumulation number. In this study, we performed multi-pass TS measurements for ohmically heated plasmas, and the relationship between SNR and the accumulation number was investigated. As a result, improvement of SNR in this experiment indicated similar tendency to that calculated for the background noise dominant situation.
RESUMO
In multi-pass Thomson scattering (TS) scheme, a laser pulse makes multiple round trips through the plasma, and the effective laser energy is enhanced, and we can increase the signal-to-noise ratio as a result. We have developed a coaxial optical cavity in which a laser pulse is confined, and we performed TS measurements using the coaxial cavity in tokamak plasmas for the first time. In the optical cavity, the laser energy attenuation was approximately 30% in each round trip, and we achieved a photon number gain of about 3 compared with that obtained in the first round trip. In addition, the temperature measurement accuracy was improved by accumulating the first three round trip waveforms.
RESUMO
The number of CA tandem repeats (CA)n in a highly polymorphic region of EGFR (epidermal growth factor receptor) intron 1 may affect gene transcription; the potential impact of allelic variants on the efficacy of cetuximab in metastatic colorectal cancer (mCRC) patients is debated for long. This study aimed at prospectively estimating the impact of EGFR intron 1 (CA)n variants on clinical outcome in KRAS exon 2 and BRAF wild-type chemo-refractory mCRC patients, receiving cetuximab and irinotecan. Variants presentingAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico
, Camptotecina/análogos & derivados
, Neoplasias Colorretais/tratamento farmacológico
, Receptores ErbB/genética
, Íntrons
, Adulto
, Idoso
, Camptotecina/uso terapêutico
, Cetuximab
, Neoplasias Colorretais/genética
, Neoplasias Colorretais/mortalidade
, Neoplasias Colorretais/patologia
, Feminino
, Humanos
, Irinotecano
, Masculino
, Pessoa de Meia-Idade
, Metástase Neoplásica
, Polimorfismo Genético
, Estudos Prospectivos
, Proteínas Proto-Oncogênicas/genética
, Proteínas Proto-Oncogênicas B-raf/genética
, Proteínas Proto-Oncogênicas p21(ras)
, Proteínas ras/genética
RESUMO
Wnt/ß-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/ß-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/ß-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.
Assuntos
Neoplasias do Colo/genética , Recidiva Local de Neoplasia/genética , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Etnicidade/genética , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.
Assuntos
Neoplasias Colorretais/genética , Fluoruracila/efeitos adversos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Caracteres Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
The brain aromatase (oestrogen synthase) hypothesis predicts that oestrogen plays important roles in both sexual behaviours and brain sexual differentiation. To elucidate the functions of oestrogen in the brain, we generated aromatase knockout (ArKO) mice, which showed undetectable oestrogen and enhanced androgen levels in blood. These ArKO mice exhibited an enhanced appetite and disorders in sexual motivation, sexual partnership preference, sexual performance, aggressive behaviour, parental behaviour, infanticide behaviour and exploratory (anxiety) behaviour. We characterised the brain-specific promoter of the mouse aromatase gene, and identified several crucial cis-acting elements and the minimal essential promoter region for brain-specific expression. Next, we introduced a transgene of human aromatase, controlled by the minimal promoter region, into the ArKO mouse. The resulting mouse (ArKO/hArom), whose preoptic area, hypothalamus and amygdala were exposed to oestrogens only in the perinatal period, and then to enhanced androgens and no oestrogens in adulthood, showed near recovery from behavioural disorders. These results suggest that local oestrogens acting in specific brain regions are involved in the organisation of sex-specific neural networks during the perinatal period. Finally, we examined effects of oestrogens on gene expression within specific brain regions in mice during the perinatal period using DNA microarray analysis. This assay revealed both up-regulated and down-regulated brain-specific genes, including those related to neuronal function. Specifically, genes involved in energy metabolism, cell proliferation/apoptosis and secretory/transport system were altered in ArKO mice compared to wild mice. These results suggest that brain oestrogens participate in the sexual differentiation of the brain by influencing gene expression.
Assuntos
Aromatase/genética , Aromatase/metabolismo , Encéfalo/metabolismo , Estrogênios/metabolismo , Expressão Gênica , Animais , Ansiedade/fisiopatologia , Encéfalo/crescimento & desenvolvimento , Comportamento Alimentar/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Comportamento Paterno , Regiões Promotoras Genéticas , Comportamento Sexual Animal/fisiologia , Comportamento SocialRESUMO
This study was carried out to determine risk factors for delirium after major head and neck cancer surgery. The postoperative experience of 38 patients who underwent major head and neck cancer surgery and were managed in the high care unit was retrospectively examined by reviewing their medical records. Delirium was defined as confusion and abnormal behavior that interfered with postoperative recovery. Postoperative delirium occurred in 10 patients (26.3%) who all had stage IV cancer, flap reconstruction, an operative time of more than 10 h, blood transfusion of more than 4 units or infusion of more than 5000 ml, which together suggested the risk of delirium increased significantly with extensive surgery. Delirium occurred less frequently in patients with minor tranquilizer use for postoperative sleep disorder. Multivariative analyses showed an operative time of >10 h and no use of minor tranquilizer as significant factors for increasing the incidence of delirium, with odds ratios (95% confidence interval) of 11.4 (1.5-83.8) and 9.8 (1.5-66.0), respectively.
Assuntos
Delírio/etiologia , Neoplasias de Cabeça e Pescoço/cirurgia , Procedimentos Cirúrgicos Bucais/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiolíticos/administração & dosagem , Delírio/prevenção & controle , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Retalhos Cirúrgicos , Fatores de TempoRESUMO
Compounds can be screened for pharmaceutical activity either by detecting interactions with specified target molecules such as receptors or enzymes (molecular screening) or observing effects on the structure or physiological activities of cells or tissues (phenotypic screening). Screening at the molecular level has been greatly enhanced by fluorescence methods. Especially the combination of confocal detection with measurements of the amplitudes and time courses of fluorescence fluctuations have reduced sample volumes to < microliters and have increased throughputs to >100000 compounds per day. Screening at the molecular level, however, does not provide information about the effects of test compounds on cellular functions. Phenotypic screening, although much slower than molecular screening, does provide information about effects on cell or tissue structure or function and therefore can be used to eliminate at an early stage compounds that are toxic or do not produce the desired cellular response. Tissue constructs reconstituted using cells of specified types and defined extracellular matrix components provide test systems for detecting the effects of test compounds on cellular mechanical functions such as the development of contractile force and on cell and matrix structure and stiffness. For example, constructs based on vascular smooth muscle cells provide information about effects on cellular contractile force that can be used to identify agents that control blood pressure. Tissue constructs that mimic skeletal, smooth and heart muscles and connective tissues have been produced and can be used to study mechanical and structural responses to active compounds.