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Effect of rubbing application on the skin permeation of a hydrophilic drug caffeine (CAF) and lipophilic drug rhododendrol (RD) from lotion and cream were investigated. Skin permeation of CAF was markedly increased by rubbing action independent of the formulation type. In addition, the skin penetration-enhancement effect was affected by the rubbing direction: rubbing application against the direction of hair growth showed the highest permeation compared with rubbing applications along the direction of hair growth and in a circular pattern on the skin. On the other hand, no enhancement effect was observed by the rubbing actions on the skin permeation of RD, regardless of formulation type. Change in the infundibula orifice size of hair follicles by the rubbing and following skin stretching may be related to the higher skin permeation for CAF. In contrast, high RD distribution into the stratum corneum may be a reason why no enhancement effect was observed by the rubbing action. These results can be helpful to predict safety and effectiveness of topically applied formulations.
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Butanoles/farmacología , Cafeína/farmacología , Pomadas/farmacología , Crema para la Piel/farmacología , Piel/efectos de los fármacos , Animales , Butanoles/química , Cafeína/química , Interacciones Hidrofóbicas e Hidrofílicas , Pomadas/química , Permeabilidad/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Crema para la Piel/química , PorcinosRESUMEN
Objective: This study aimed to clarify the assertiveness of psychiatric day care users with schizophrenia. Patients and Methods: We examined 1,179 psychiatric day care center users and 916 psychiatric hospital outpatients with schizophrenia between September 2008 and February 2009 using a questionnaire survey based on the Japanese version of the Rathus Assertiveness Schedule and the Functioning Scale. The questionnaires were distributed and collected by post by the director of each participating facility. Results: Of the 1,179 users (Users) and 916 outpatients (Patients) targeted, 366 (31.0%) and 78 (8.5%) were enrolled in this study. The mean assertiveness score of Users (-7.1 ± 20.2) was significantly higher than that of Patients (-17.3 ± 20.9; P<0.01). Assertiveness scores were higher in Users who performed housework compared with those who did not. High functioning was a background factor that improved assertiveness scores in Users. Additionally, Users could maintain a suitable assertiveness score with support from a psychiatric day care center. Conclusion: This study revealed that Users had a greater ability to self-assert than Patients; this was largely the result of being able to live in society.
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Rubbing actions are often conducted to apply topical formulations onto the skin. Although rubbing was found to increase the skin permeation of drugs, few reports have revealed whether rubbing enhanced either drug permeation through the stratum corneum (SC) or hair follicles (HFs) pathways, or through both. In the present study, we investigated the effects of rubbing on caffeine (CAF) distribution in the SC and HFs. The effect of rubbing direction on the skin penetration of CAF was also investigated. The skin concentration of CAF and its cumulative permeation amount were increased clearly by rubbing. More than six times higher CAF concentrations in the viable epidermis and dermis were observed 5 min after rubbing application compared with no rubbing. On the other hand, slightly increased CAF concentrations were observed in the SC, suggesting that CAF was delivered through the HF pathway by rubbing. Rubbing against the natural hair direction provided the highest skin permeation as well as skin concentrations. Changes in the morphology of the HF opening area might be related to the enhancement effect. These results may provide useful information to understand the effect of rubbing on the skin permeation of applied drugs.
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Cafeína/química , Folículo Piloso/química , Piel/química , Administración Cutánea , Animales , Permeabilidad , Absorción Cutánea , PorcinosRESUMEN
OBJECTIVES: To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3+ T cells in 15 fresh samples of cervical cancer. METHODS: In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3+ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry. RESULTS: Infiltration with CD8+ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3+, CD4+, CD8+, CD206+, and FOXP3+ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3+ TILs, non-Tregs (Fr-III) were found in all samples tested for this. CONCLUSIONS: The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.
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Carcinoma de Células Escamosas/terapia , Quimioradioterapia/métodos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias del Cuello Uterino/terapia , Adulto , Linfocitos T CD8-positivos , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Microambiente Tumoral , Neoplasias del Cuello Uterino/patologíaRESUMEN
Objective: This study aimed to investigate the validity and reliability of the Japanese version of the Rathus assertiveness schedule (J-RAS) in psychiatric day care users with schizophrenia. Subjects and Methods: We examined 715 psychiatric day care users with schizophrenia by conducting the test twice between September 2007 and February 2008 using a questionnaire-based survey. We examined construct validity and used the internal reliability test, split-half method, and test-retest method to examine reliability. The questionnaires were distributed and collected by post via the director of each facility. Results: Of the 1272 psychiatric day care users, 715 users (56.2%) were enrolled in the study. Seven factors were extracted for construct validity. The cumulative contribution rate of these factors was 49.4% and the internal consistency of 30 items of the J-RAS was α = 0.72. The split-half method revealed a significant correlation between the total scores of the odd- and even-numbered items (r = 0.64, p < 0.01). The test-retest method revealed a significant difference between the total scores of the first and second tests of the 30 items of the J-RAS (r = 0.73, P < 0.01). Conclusion: We confirmed the validity and reliability of the J-RAS in psychiatric day care users with schizophrenia and demonstrated its efficacy in evaluating psychiatric day care users.
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Development of an appropriate method to evaluate drug disposition or targeting ability in hair follicles (HFs) is urgently needed in order to develop useful pharmaceutical products with pharmacological effects in HFs. In the present study, a cyanoacrylate biopsy (CB) method was used to measure drug disposition in HFs using a model hydrophilic drug, caffeine (CAF), and a lipophilic drug, 4-butylresorcinol (BR), in excised porcine skin. As a result, the height of HF replicas and the recovery ratio decreased with an increase in the application times of the CB method. HF replicas with a length of approximately 175⯵m were obtained using a single application of the CB method. Drug distribution in the HF was detected even 5â¯min after topical application regardless of the lipophilicity of the drugs, although no drug disposition was observed in the deeper layers of the stratum corneum at the same time (5â¯min). Furthermore, significantly higher amounts of BR were observed in the stratum corneum and HF, compared with those of CAF. These results suggested that the CB method could be useful to evaluate the safety and efficacy as well as the disposition of topically applied chemicals, especially for HF-targeting drugs.
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Cafeína/farmacocinética , Folículo Piloso/metabolismo , Resorcinoles/farmacocinética , Animales , Biopsia , Cianoacrilatos , Absorción Cutánea , PorcinosRESUMEN
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8+ T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8+ T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8+ T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8+ T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8+ T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8+ FOXP3+ T cells and immunodysfunctional CD8+ GATA3+ T cells were increased in adenocarcinoma of non-smokers. CD4+ FOXP3+ regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163+ M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.
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Adenocarcinoma/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Escape del Tumor , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Supervivencia sin Enfermedad , Femenino , Factores de Transcripción Forkhead/análisis , Factor de Transcripción GATA3/análisis , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Factores de TiempoRESUMEN
Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.
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Cuello del Útero/patología , Cuello del Útero/virología , Genotipo , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Adulto , Estudios Transversales , ADN Viral , Femenino , Técnicas de Genotipaje , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Adulto Joven , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/etiología , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: Immune responses in the uterine cervix are considered to play an important role in persistent human papillomavirus (HPV) infection and carcinogenesis, but many aspects of the mechanism are still unclear. The goal of this study was to measure cytokines to analyze immune responses in patients with cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: The levels of 17 cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, INF-γ, MCP-1, MIP-1ß, and TNFα) in cervical mucus were simultaneously measured using a multiplex immunoassay in 52 high-grade squamous intraepithelial lesion (HSIL) cases and overproduction of IL-1ß, IL-8, and MIP-1ß was identified. The levels of these 3 cytokines were measured in 130 patients with or without CIN lesions using enzyme-linked immunosorbent assay. The associations of the cytokine levels with the cytology, infecting HPV type, and status of cigarette smoking were investigated. RESULTS: IL-1ß and IL-8 levels were associated with the cytology, and these levels were higher in HSIL cases than in NILM (negative for intraepithelial lesion and malignancy) and LSIL (low-grade squamous intraepithelial lesion) cases (P = 0.005, P = 0.001, respectively). The MIP-1ß level was significantly lower in smokers (P = 0.018) and high-risk (HR)-HPV-infected patients (P = 0.021). CONCLUSIONS: Enhanced expression of IL-1ß and IL-8 indicates that Th2 inflammatory responses become stronger in the local uterine cervical region with the progression of CIN lesions, and a decrease in the MIP-1ß level may be advantageous for immunoescape of HPV. Cigarette smoking may further facilitate persistent HPV infection.
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Membrana Mucosa/inmunología , Displasia del Cuello del Útero/inmunología , Neoplasias del Cuello Uterino/inmunología , Adulto , Pueblo Asiatico , Quimiocina CCL4/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-1beta/inmunología , Interleucina-8/inmunología , Membrana Mucosa/patología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/patología , Fumar/inmunología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/inmunología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: p16(INK4a) immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16(INK4a) immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16(INK4a) and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16(INK4a)/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. METHODS: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16(INK4a)/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. RESULTS: p16(INK4a)/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16(INK4a)/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0-93.8 %) and 76.4 % (71.6-80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6-54.0 %) and 96.4 % (93.4-98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16(INK4a)/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test CONCLUSIONS: Compared with high-risk HPV genotyping, p16(INK4a)/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/inmunología , Antígeno Ki-67/inmunología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/diagnóstico , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Pueblo Asiatico , Células Escamosas Atípicas del Cuello del Útero , Femenino , Genotipo , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Sensibilidad y Especificidad , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Neoplasias del Cuello Uterino/patología , Adulto Joven , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: Previous studies of human papillomavirus (HPV)16/18 genome methylation have concluded that methylation status of the L1 gene might act as a biomarker for cervical intraepithelial neoplasia (CIN). OBJECTIVES: We investigated the correlation between methylation status in the L1 gene and the long control region (LCR) of HPV52/58 and CIN. STUDY DESIGN: Exfoliated cervical cells were taken from 54 HPV52-positive and 41 HPV58-positive women. The HPV genome was examined using bisulfite modification, polymerase chain reaction amplification, and sequencing. RESULTS: The CpGs were unmethylated or hypomethylated in the HPV52/58 LCR. In contrast, the methylation status of the HPV52 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 15%, 34%, and 52% for cervicitis/CIN1, CIN2, and CIN3, respectively (P<0.05). Methylation status of the HPV52 L1 gene was also correlated with the prognosis of CIN1/2, with median percentages of 15% and 35% for regression and persistence/progression, respectively (P<0.05). The methylation status of the HPV58 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 12%, 38%, and 61% for cervicitis/CIN1, CIN2, and CIN3, respectively (P<0.05). CONCLUSIONS: The increased methylation at the CpG sites in the HPV52/58 L1 gene was correlated with the severity of cervical neoplasia, similar to HPV16/18 in previous studies. These data suggest that HPV methylation status of the L1 gene is a candidate biomarker of CIN for detecting CIN2 and CIN3.
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Biomarcadores/análisis , Proteínas de la Cápside/genética , ADN Viral/química , Técnicas de Diagnóstico Molecular/métodos , Proteínas Oncogénicas Virales/genética , Neoplasias del Cuello Uterino/diagnóstico , Metilación de ADN , ADN Viral/aislamiento & purificación , Femenino , Humanos , Índice de Severidad de la Enfermedad , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virologíaRESUMEN
OBJECTIVE: In cervical intraepithelial neoplasia (CIN), p16(INK4a) immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16(INK4a) immunohistochemistry and the outcomes of CIN. Here, we report p16(INK4a) immunohistochemistry as an effective biomarker to predict the outcomes of CIN. METHODS: p16(INK4a) immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16(INK4a) expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes. RESULTS: A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16(INK4a) overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16(INK4a) overexpression than for those not showing p16(INK4a) overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16(INK4a) overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively). CONCLUSION: p16(INK4a) overexpression was correlated with the outcome of CIN 1-2, and p16(INK4a) is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.
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Fcγ receptor IIa (FcγRIIa) plays an important role in antibody-dependent cellular cytotoxicity and inflammation. Changes in FcγRIIa expression levels or activity caused by genetic polymorphisms in FCGR2A, the gene encoding FcγRIIa, may lead to differences in disease progression as well as efficacy of antibody therapeutics between individuals. In this study, we sequenced the 5'-flanking region along with all exons and their flanking regions of FCGR2A from 111 Japanese subjects. Forty-eight genetic variations were found including 12 novel ones. Beside the well-known functional 497A > G (H166R) polymorphism, we detected 818T > C (L273P) at 0.005 frequency. Since the functional significance of this polymorphism has not been revealed, we next assessed the functions of the L273P substitution by expressing wild-type and the variant proteins in human Jurkat cells. The L273P variant protein showed similar cell surface expression and IgG-binding properties as the wild-type, but it exhibited a stronger signal transduction activity based on the approximately 2-fold enhancement of tyrosine phosphorylation of FcγRIIa itself. The current results suggest that L273P could have functional significance in the antibody-dependent clinical responses through FcγRIIa.
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Pueblo Asiatico/genética , Polimorfismo Genético , Receptores de IgG/genética , Línea Celular , Exones , Humanos , Células Jurkat , Leucina/genética , Fosforilación , Prolina/genética , Transducción de Señal/genética , Tirosina/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to investigate the risk and recurrence of early invasive adenocarcinoma of the cervix, and to determine whether non-radical methods of management could be performed. METHODS: The medical and histopathological records of 50 patients with early invasive adenocarcinoma of the cervix treated at Keio University Hospital between 1993 and 2005 were reviewed, and compared with the literature. RESULTS: The median follow-up period was 64.3 months. The depth of stromal invasion was ≤3 mm in 33 cases and >3 mm, but ≤5 mm in 17 cases. The horizontal spread was ≤7 mm in 25 cases and >7 mm in 25 cases. One of the 33 cases that had tumor volumes of ≤500 mm(3), and three of the 17 cases with tumor volumes of >500 mm(3) were positive for lymph node metastasis. When our data were combined with previously reported results, statistically significant differences were observed between the tumor volume and the frequency of pelvic lymph node metastasis/the rate of recurrence (p<0.0001). The frequency of pelvic lymph node metastases was significantly higher in the lymphovascular space invasion (LVSI)-positive group than in the LVSI-negative group (p=0.02). No adnexal metastasis or parametrial involvement was noted. CONCLUSION: Assessment of the depth of stromal invasion, tumor volume, and LVSI is critical for selecting an appropriate therapeutic modality. Non-radical methods of management are considered suitable for patients with LVSI-negative adenocarcinoma of the cervix exhibiting a stromal invasion depth of ≤5 mm and a tumor volume of ≤500 mm(3).
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OLE1 encodes an oleosin isoprotein, a major membrane protein of the lipid-reserve organelle in seeds known as the oil body. Transgenic Arabidopsis were generated to contain an artificial chimeric transgene composed of OLE1 and green fluorescent protein (GFP). Overexpression of the fusion protein allowed visualization of the oil body size and structure in living cells using fluorescence microscopy. Two mutants, xrn4-8(OleG) and xrn4-9(OleG), accumulating enlarged oil bodies with reduced GFP fluorescence were isolated from the mutagenized progeny of a transgenic plant. Both mutants contained a defect in EXORIBONUCLEASE4 (XRN4), a gene known to encode a ribonuclease that specifically degrades uncapped mRNAs. Transgene expression was silenced in these mutants, as demonstrated by the reduced levels of the transgene mRNA and its product, OLE1-GFP. XRN4 loss of function also triggered cosuppression, i.e. simultaneous reduction in expression of the transgene and an endogenous OLE1 gene that shared a region of identical sequence. The enlarged oil bodies exhibiting reduced GFP fluorescence were formed in the xrn4-8(OleG) and xrn4-9(OleG) mutants due to the reduction of the endogenous OLE1 and the transgene product, OLE1-GFP, respectively. Cosuppression triggered by the xrn4 mutation also occurs for other genes such as PYK10, which encodes an endoplasmic reticulum (ER) body-resident ß-glucosidase. The overall results indicate that a loss of XRN4 function can potentially trigger the cosuppression in a sequence-dependent manner.
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Proteínas de Arabidopsis/biosíntesis , Arabidopsis/genética , Exorribonucleasas/metabolismo , Proteínas de Plantas/metabolismo , Interferencia de ARN , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Secuencia de Bases , Mapeo Cromosómico , Cromosomas de las Plantas/genética , Cromosomas de las Plantas/metabolismo , Clonación Molecular , Exorribonucleasas/genética , Fluorescencia , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Mutación , Fenotipo , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Plásmidos/genética , Plásmidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Almacenamiento de Semillas/genética , Proteínas de Almacenamiento de Semillas/metabolismo , Semillas/metabolismo , Transformación Genética , Transgenes , beta-Glucosidasa/genética , beta-Glucosidasa/metabolismoRESUMEN
Glutathione S-transferases (GSTs) play a vital role in the phase II biotransformation of many chemicals, including anticancer drugs. In this study, to elucidate the haplotype structures of the two closely related alpha-class genes GSTA1 and GSTA2, we screened for genetic variation in 214 Japanese colorectal cancer patients who received oxaliplatin-based chemotherapy. By direct resequencing of the 5'-flanking region, all the exons, and their flanking introns for 107 patients, 29 and 27 variants were identified in GSTA1 and GSTA2, respectively. The known functional single nucleotide polymorphisms (SNPs) -567T>G, -69C>T, and -52G>A in GSTA1*B were found at allele frequencies of 0.140. Of the four major GSTA2 allelic variants reported previously (GSTA2*A, *B, *C, and *E), only GSTA2*B (frequency = 0.154), *C (0.706), and *E (0.140) were detected. Following linkage disequilibrium analysis, haplotypes of both genes were separately estimated. Then, rapid genotyping methods for 7 and 6 SNPs tagging common haplotypes of GSTA1 and GSTA2, respectively, were developed using the single-base extension assay, and an additional 107 patients were genotyped. Finally, haplotype combinations of both genes were classified into 3 major types: GSTA1*A-GSTA2*C, GSTA1*A-GSTA2*B, and GSTA1*B-GSTA2*E. These findings will be useful in pharmacogenomic studies on xenobiotics including anticancer drugs.
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Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Glutatión Transferasa/genética , Isoenzimas/genética , Pueblo Asiatico , Exones , Frecuencia de los Genes , Técnicas de Genotipaje/métodos , Haplotipos , Humanos , Intrones , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Xenobióticos/farmacologíaRESUMEN
Neonatal Fc receptor (FcRn) plays an important role in regulating IgG homeostasis in the body. Changes in FcRn expression levels or activity caused by genetic polymorphisms of FCGRT, which encodes FcRn, may lead to interindividual differences in pharmacokinetics of therapeutic antibodies. In this study, we sequenced the 5'-flanking region, all exons and their flanking regions of FCGRT from 126 Japanese subjects. Thirty-three genetic variations, including 17 novel ones, were found. Of these, two novel non-synonymous variations, 629G>A (R210Q) and 889T>A (S297T), were found as heterozygous variations. We next assessed the functional significance of the two novel non-synonymous variations by expressing wild-type and variant proteins in HeLa cells. Both variant proteins showed similar intracellular localization as well as antibody recycling efficiencies. These results suggested that at least no common functional polymorphic site with amino acid change was present in the FCGRT of our Japanese population.
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Pueblo Asiatico/genética , Antígenos de Histocompatibilidad Clase I/genética , Receptores Fc/genética , Variación Genética , Células HeLa , Humanos , Inmunoglobulina G/inmunología , Japón , Polimorfismo GenéticoRESUMEN
INTRODUCTION: Although the colposcopic features of cervical glandular disease and cervical adenocarcinoma are not widely well known, unique microvascular patterns are reportedly useful for identifying such diseases. The narrow band imaging (NBI) system used in endoscopy can be used to obtain high-contrast vascular images. Therefore, we examined the utility of NBI colposcopy and compared the results with those of conventional colposcopy. METHODS: Twenty-one patients with adenocarcinoma in situ or early invasive adenocarcinomas were examined using digital NBI colposcopy, and the photo records were compared with those of conventional colposcopy. The histological examination and immunohistochemistry with anti-CD31 antibody confirmed the microvascular pattern. RESULTS: Digital NBI colposcopy depicted the fine vascular texture on the surface of the cervix more clearly than conventional colposcopy. The vascular pattern was depicted in 86% (18/21) of glandular disease cases. The characteristic fine vascular patterns were critical for identifying cervical glandular diseases. CONCLUSIONS: Digital NBI colposcopy was useful for identifying early cervical adenocarcinoma as well as adenocarcinoma in situ. This system yields cervical glandular disease-related colposcopic findings that may be useful for both clinical and educational purposes.
Asunto(s)
Adenocarcinoma/diagnóstico , Carcinoma Adenoescamoso/diagnóstico , Colposcopía , Diagnóstico por Imagen , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , PronósticoRESUMEN
AIM: We aimed to clarify the relationship between assertiveness and burnout among nurse managers at university hospitals. METHODS: The directors at three university hospitals agreed to cooperate with our study. During a one-month period from May to June 2007, a self-administered questionnaire was distributed to 203 nurse managers (head and sub-head nurses). The Japanese version of the Rathus Assertiveness Schedule (J-RAS) and the Japanese version of the Maslach Burnout Inventory (MBI) were used as scales. Burnout was operationally defined as a total MBI score in the highest tertile. RESULTS: Valid responses were obtained from 172 nurse managers. The mean J-RAS score of the burnout group (-14.3) was significantly lower than that of the non-burnout group (-3.3). Responses about work experience and age showed no significant group difference. Total MBI score was inversely correlated with J-RAS score (R = -0.30, P < 0.01). Multiple logistic regression analyses indicated a decrease in the risk of burnout by 26% (0.74 times) for every 10 point increase in the J-RAS score, and by 60% (0.40 times) for greater satisfaction with own care provision. CONCLUSIONS: The results suggest that increasing assertiveness and satisfaction with own care provision contributes to preventing burnout among Japanese nurse managers.