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BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateâ , moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.
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COVID-19 , Pulmón , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Cohortes , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , COVID-19/epidemiología , Disnea/etiología , Pueblos del Este de Asia , Japón/epidemiología , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Alta del Paciente , Estudios Prospectivos , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Sociedades Médicas , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
A 71-year-old woman was treated with osimertinib for stage IV adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Treatment led to improvements in the primary tumor, multiple lung metastases, and multiple bone metastases. However, nine months later, she presented with marked liver dysfunction and jaundice. Chest and abdominal computed tomography did not show abnormal findings in the liver parenchyma or biliary system. However, blood tests were positive for hepatitis B surface antigen and hepatitis B virus DNA, suggesting hepatitis B virus reactivation. The patient died of liver failure despite treatment with steroids and antiviral drugs.
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Bronquiolitis , Neoplasias Pulmonares , Neumonía , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neumonía/inducido químicamente , Neumonía/diagnóstico por imagen , Neumonía/tratamiento farmacológico , Bronquiolitis/inducido químicamente , Bronquiolitis/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.
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A 78-year-old woman with multiple lung nodules, epithelial growth factor receptor (EGFR) exon 20 insertion mutations, and diagnosed with advanced lung adenocarcinoma (cT4N3M1a, stage IVA), was referred to our hospital. She received immune checkpoint inhibitor (ICI) therapy. The therapy showed remarkable antitumor effects; only a single nodule remained in the right upper lobe. The nodule was diagnosed as adenocarcinoma through a biopsy. We subsequently performed right upper lobectomy for multiple primary lung cancer (MPLC). The surgical specimen contained EGFR exon 19 deletion mutations and not exon 20 insertion mutations.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/cirugía , Anciano , Receptores ErbB/genética , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , MutaciónRESUMEN
BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have recently been shown to have clinical benefits in patients with advanced non-small cell lung cancer (NSCLC). The novel tumour responses to these agents are changing the management of patients with cancer. Pseudo-progression of disease (pseudo-PD), that is, an initial flare followed by shrinkage of the tumour, has been described as a distinctive response to ICIs. However, pseudo-PD manifest initial progression and is difficult to segregate with hyper progressive disease (HPD). We, therefore, analysed a case with pseudo-PD histologically. PATIENTS AND METHODS: A 68-year-old Japanese man with stage IV non-small cell lung carcinoma (NSCLC) was treated by anti-PD-1 antibody (pembrolizumab). Four weeks later after second time treatment with pembrolizumab, the patient showed severe melena followed by Trousseau syndrome and died at day 174 after first treatment by pembrolizumab, suggesting HPD clinically. Primary lesion and metastatic lesions were analysed histologically. RESULTS: Histological analysis revealed that NSCLC cells expressed PD-L1, and CD8+ tumor-infiltrated lymphocytes (TILs) were observed. CD8+ TILs showed higher rates of PD-1 indicating that lesions were of the inflamed type and the case was pseudo-PD. Furthermore, it was found that cancer cells expressed MUC1. CONCLUSION: The clinical appearance of the case was aggressive after treatment by pembrolizumab, and the case seemed to be HPD; however, histological analysis revealed that the case was likely pseudo-PD. Therefore, careful histological evaluation is important when investigating the clinical response to an ICI and mucin expression might be a predictive marker for Trousseau syndrome.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anciano , Linfocitos T CD8-positivos/efectos de los fármacos , Progresión de la Enfermedad , Humanos , MasculinoRESUMEN
The human DNA molecule is a 2-m-long polymer collapsed into the micrometer space of the cell nucleus. This simple consideration rules out any "Maxwell demon"-like explanation of regulation in which a single regulatory molecule (e.g., a transcription factor) finds autonomously its way to the particular target gene whose expression must be repressed or enhanced. A gene-by-gene regulation is still more contrasting with the physical reality when in the presence of cell state transitions involving the contemporary expression change of thousands of genes. This state of affair asks for a statistical mechanics inspired approach where specificity arises from a selective unfolding of chromatin driving the rewiring of gene expression pattern. The arising of "expression waves" marking state transitions related to chromatin structural reorganization through self-organized critical control of whole-genome expression will be described in the present paper. We adopt as a model system the gene expression time course of a cancer cell (MCF-7) population exposed to an efficient stimulus causing a state transition in comparison with an ineffective stimulus. The obtained results will be put into the perspective of biological adaptive systems living on the edge of chaos.
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BACKGROUND: Thymic large cell neuroendocrine carcinoma (LCNEC) is extremely rare. The detailed clinical features of thymic LNCECs remain unknown. CASE PRESENTATION: A 90-year-old man with a history of diabetes mellitus, chronic renal failure, and an abdominal aortic aneurysm underwent computed tomography for follow-up, which showed an anterior mediastinal tumor, measuring 31 mm × 28 mm in diameter. Magnetic resonance imaging showed an iso-intensity mass on T1-weighted images and high intensity on T2-weighted images. 18F-Fluorodeoxyglucose-positron emission tomography showed marked uptake in the mass, which was diagnosed as invasive thymoma or thymic carcinoma. Video-assisted thoracic surgery through the left thoracic cavity was converted to median sternotomy due to severe adhesions between the left lung and the chest wall. Partial thymectomy and combined partial resection of left upper lobectomy and the first and the second costal cartilages were performed. The pathologic diagnosis was thymic LCNEC, Masaoka stage III. The patient developed pleural dissemination and left lung metastases in 5 months and died 12 months after surgery. CONCLUSIONS: Thymic LCNEC has high malignant potential. More cases need to be studied.
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BACKGROUND: A fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization. PRINCIPAL FINDINGS: Building upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change. CONCLUSION AND SIGNIFICANCE: 'Whole-genome' regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non-equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression.
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Regulación de la Expresión Génica/fisiología , Genoma Humano/fisiología , Modelos Biológicos , Células HL-60 , Humanos , Células MCF-7RESUMEN
To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx) mice against doxycycline (DOXY)-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip) 8 weeks after the operation, 30 min after apocynin (5 mg/kg) or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox) inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.
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BACKGROUND: The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue in bioscience. We addressed it in terms of phase transition by a systemic approach based on both density analysis and characteristics of temporal fluctuation for the time-course mRNA expression in differentiating MCF-7 breast cancer cells. METHODOLOGY: In a recent work, we suggested criticality as an essential aspect of dynamic control of genome-wide gene expression. Criticality was evident by a unimodal-bimodal transition through flattened unimodal expression profile. The flatness on the transition suggests the existence of a critical transition at which up- and down-regulated expression is balanced. Mean field (averaging) behavior of mRNAs based on the temporal expression changes reveals a sandpile type of transition in the flattened profile. Furthermore, around the transition, a self-similar unimodal-bimodal transition of the whole expression occurs in the density profile of an ensemble of mRNA expression. These singular and scaling behaviors identify the transition as the expression phase transition driven by self-organized criticality (SOC). PRINCIPAL FINDINGS: Emergent properties of SOC through a mean field approach are revealed: i) SOC, as a form of genomic phase transition, consolidates distinct critical states of expression, ii) Coupling of coherent stochastic oscillations between critical states on different time-scales gives rise to SOC, and iii) Specific gene clusters (barcode genes) ranging in size from kbp to Mbp reveal similar SOC to genome-wide mRNA expression and ON-OFF synchronization to critical states. This suggests that the cooperative gene regulation of topological genome sub-units is mediated by the coherent phase transitions of megadomain-scaled conformations between compact and swollen chromatin states. CONCLUSION AND SIGNIFICANCE: In summary, our study provides not only a systemic method to demonstrate SOC in whole-genome expression, but also introduces novel, physically grounded concepts for a breakthrough in the study of biological regulation.
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Genómica , Transcriptoma , Simulación por Computador , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Genoma Humano , Humanos , Células MCF-7 , Neurregulina-1/genética , Neurregulina-1/metabolismo , ARN Mensajero/metabolismoRESUMEN
Understanding the basic mechanism of the spatio-temporal self-control of genome-wide gene expression engaged with the complex epigenetic molecular assembly is one of major challenges in current biological science. In this study, the genome-wide dynamical profile of gene expression was analyzed for MCF-7 breast cancer cells induced by two distinct ErbB receptor ligands: epidermal growth factor (EGF) and heregulin (HRG), which drive cell proliferation and differentiation, respectively. We focused our attention to elucidate how global genetic responses emerge and to decipher what is an underlying principle for dynamic self-control of genome-wide gene expression. The whole mRNA expression was classified into about a hundred groups according to the root mean square fluctuation (rmsf). These expression groups showed characteristic time-dependent correlations, indicating the existence of collective behaviors on the ensemble of genes with respect to mRNA expression and also to temporal changes in expression. All-or-none responses were observed for HRG and EGF (biphasic statistics) at around 10-20 min. The emergence of time-dependent collective behaviors of expression occurred through bifurcation of a coherent expression state (CES). In the ensemble of mRNA expression, the self-organized CESs reveals distinct characteristic expression domains for biphasic statistics, which exhibits notably the presence of criticality in the expression profile as a route for genomic transition. In time-dependent changes in the expression domains, the dynamics of CES reveals that the temporal development of the characteristic domains is characterized as autonomous bistable switch, which exhibits dynamic criticality (the temporal development of criticality) in the genome-wide coherent expression dynamics. It is expected that elucidation of the biophysical origin for such critical behavior sheds light on the underlying mechanism of the control of whole genome.
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Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/metabolismo , Algoritmos , Biología Computacional , Factor de Crecimiento Epidérmico/metabolismo , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Células MCF-7 , Modelos Genéticos , Modelos Estadísticos , Neurregulina-1/metabolismo , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
AIMS: We reported that interleukin-6 (IL-6) plays a protective role in the development of cisplatin-induced acute renal failure (ARF) through upregulation of anti-oxidative stress factors. In this study, we examined the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on the development of cisplatin-induced ARF in wild-type (WT) and IL-6(-/-) mice to determine how IL-6 contributes to modulation of oxidative stress caused by cisplatin. MAIN METHODS: WT and IL-6(-/-) male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100mg/kg) or saline was given 30 min before cisplatin or saline administration. Blood and kidney samples were collected on days 1 and 3 after cisplatin administration. KEY FINDINGS: In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-α, Bax and c-fos and increased the expression levels of IL-6, Bcl-xL and Nrf2 in WT mice. Reduced reactive oxygen species (ROS) by DMTU resulted in increases of IL-6, anti-apoptosis and anti-oxidant gene expression levels. In IL-6(-/-) mice, DMTU also improved cisplatin-induced renal dysfunction and reduced expression levels of TNF-α, Bax and c-fos, but not Bcl-xL and Nrf2. Since Nrf2 induces IL-6 expression, IL-6 and Nrf2 may influence each other during anti-oxidant responses. The basal level of HO-1 in IL-6(-/-) mice was higher than that in WT mice. SIGNIFICANCE: In IL-6(-/-) mice, overproduction of ROS by cisplatin results in upregulation of HO-1 expression in order to eliminate oxidative stress. IL-6 mediates the generation and elimination of ROS during cisplatin-induced ARF.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Técnicas de Inactivación de Genes , Interleucina-6/genética , Riñón/efectos de los fármacos , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/genética , Lesión Renal Aguda/fisiopatología , Animales , Depuradores de Radicales Libres/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Tiourea/análogos & derivados , Tiourea/uso terapéuticoRESUMEN
A 75-year-old man was admitted with bloody sputum. His chest radiogram and CT revealed a fungus ball within a cavity lesion of the right upper lung field. Aspergillus fumigatus was cultured from bronchoalveolar lavage fluid. He was treated with itraconazole (ITCZ) and micafungin (MCFG), but his fungus ball increased. One year after initiating voriconazole (VRCZ) therapy. After 1 year, the fungus ball had significantly reduced, with no significant adverse events. This case suggests that administration of VRCZ can be recommended for pulmonary aspergilloma of responding poorly to other antifungal agents.
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Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Pirimidinas/uso terapéutico , Triazoles/uso terapéutico , Anciano , Humanos , Masculino , VoriconazolRESUMEN
BACKGROUND: Recent reports suggest that small airway as well as large airway involvement in asthma is important. We investigate the therapeutic effects of a meter-dose inhaler of chrolofluorocarbon-beclomethasone dipropionate (CFC-BDP) and dry-powder fluticasone (DP-FP). METHODS: Lung specimens obtained at operation due for small size lung cancer in 16 asthmatic patients and 16 controls were evaluated immunohistochemically using antibodies of EG2 (eosinophil), AA1 (mast cell), CD68 (macrophage), and CD34 (pluripotent hematopoietic stem cell). We calculated the number of each cell type in 5 fields in the inner and outer areas of large airways (luminal diameter; > or =2 mm) and small airways (<2 mm) using computer software. RESULTS: In asthmatic patients eosinophils were significantly increased in both inner and outer areas of small airways and the number of CD34+ cells was significantly elevated in inner areas as compared with controls. Although the density of eosinophils in the inner area of large airways was significantly suppressed (p < 0.02), there was no such suppression in the inner areas of small airways in asthmatic patients treated with CFC-BDP or DP-FP. CONCLUSIONS: It was speculated that inhaled CFC-BDP and DP-FP might deposit mainly in large airways and fail to fully reach small airways, consequently allowing eosinophilic inflammation to continue in small airways.
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Corticoesteroides/farmacología , Asma/tratamiento farmacológico , Bronquios/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Administración por Inhalación , Corticoesteroides/administración & dosificación , Anciano , Asma/patología , Bronquios/patología , Eosinofilia/patología , Eosinofilia/prevención & control , Eosinófilos/patología , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Submucosal hypervascularity is part of airway remodeling in patients with asthma; however, its existence in the small airways and its contribution to airflow limitation remain controversial. METHODS: We investigated bronchial wall vascularity and angiogenic cells between medium airways (inner diameter, 2 to 5 mm) and small airways (inner diameter, < 2 mm) in patients with asthma (n = 9) and COPD (n = 11), and in 8 control subjects. The lung specimens obtained during surgery were immunostained to detect CD31, CD34, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: The number of vessels in both the medium and small airways in patients with asthma was significantly (p < 0.01) increased compared to those in patients with COPD and control subjects, and the percentage of vascularity was significantly (p < 0.01) increased in the medium airways in asthma patients and in the small airways in COPD patients. Patients with moderate asthma showed a greater increase in vascularity than those with mild asthma (p < 0.01), and the number of angiogenic factor-positive cells increased in asthma patients compared with control subjects. In asthmatic subjects, inverse correlations were found between FEV(1) percentage of predicted and the number of vessels (r = -0.85; p < 0.01), or the percentage of vascularity (r = -0.72; p < 0.03) in the inner area of the medium airways, but they were not found for the small airways. In COPD patients, no correlations were demonstrated. CONCLUSIONS: The number of vessels in the medium and small airways in asthma patients shows a greater increase than those in COPD patients, and the vascular area in the small airways is increased in COPD patients but not in asthma patients. Enhanced vascularity in the inner area of the medium airways, but not in the small airways, might contribute to airflow limitation in asthma patients.
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Asma/patología , Bronquios/irrigación sanguínea , Neovascularización Patológica , Enfermedad Pulmonar Obstructiva Crónica/patología , Anciano , Antígenos CD34/análisis , Asma/metabolismo , Asma/fisiopatología , Bronquios/patología , Endotelio Vascular/química , Femenino , Factor 2 de Crecimiento de Fibroblastos/análisis , Humanos , Inmunohistoquímica , Masculino , Microcirculación/química , Microcirculación/patología , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
Hypervascularity in the bronchial wall is part of airway remodeling, but has remained an ill-defined process in asthma pathogenesis. Previous morphologic assessment has been limited to biopsy specimens, and therefore a high-magnification bronchovideoscope (side-viewing type) was developed for less invasive examination of subepithelial vessels. We evaluated vascularity in the lower trachea, using this novel scope in 12 normal control subjects, 13 patients with chronic obstructive pulmonary disease, and 24 subjects with stable asthma; 8 were steroid naive with newly diagnosed asthma (Group A) and 16 had been treated with inhaled corticosteroids for more than 5 years (Group B). The redness of bronchial mucosa in patients with asthma observed by conventional fiberoptic bronchoscopy proved to be due to a fine vascular network. Morphometric measurements of subepithelial vessels showed that both vessel area density and vessel length density were significantly (p<0.0001) increased in subjects with asthma as compared with control subjects and patients with chronic obstructive pulmonary disease. The degree of increase in vessels did not differ between Group A and Group B. The increase in subepithelial vessels of the airway is present even in newly diagnosed asthma. This novel bronchovideoscope is useful for assessment of vessel network in the surface of the airway lumen in vivo.
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Asma/fisiopatología , Bronquios/irrigación sanguínea , Broncoscopía/métodos , Neovascularización Patológica/diagnóstico , Adulto , Anciano , Asma/diagnóstico , Broncoscopios , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/fisiopatología , Grabación en VideoRESUMEN
We have found that Juzen-taiho-to has a preventive effect on endometrial carcinogenesis in mice (Carcinogenesis 22 (2001) 587). In the present study, the constituents of Juzen-taiho-to responsible for this effect were explored using a short-term experiment. Thirty female ICR mice were divided into five groups: Group 1 was given a diet containing 0.2% of Juzen-taiho-to and 5ppm estradiol-17beta (E(2)); Group 2 was given a diet containing Shimotsu-to (0.07%) and E(2) (5ppm); Group 3 received Shikunshi-to (0.08%) and E(2) (5ppm) in the diet; Group 4 was given 5ppm E(2) in the diet; and Group 5 served as a control. Exposure of Juzen-taiho-to or Shimotsu-to decreased E(2)-stimulated expression of estrogen-related gene c-fos mRNA (P<0.05), and the cytokines interleukin-1alpha mRNA and tumor necrosis factor alpha mRNA P<0.01). A similar trend was not found upon treatment with Shikunshi-to. These findings suggest that Shimotsu-to is responsible for the inhibitory effects of Juzen-taiho-to on the estrogen-related endometrial carcinogenesis in mice.
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Anticarcinógenos/farmacología , Medicamentos Herbarios Chinos/farmacología , Neoplasias Endometriales/prevención & control , Animales , Estradiol/toxicidad , Femenino , Genes fos , Genes jun , Interleucina-1/genética , Ratones , Ratones Endogámicos ICR , ARN Mensajero/análisis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.