To cite this article: Hong S-W, Kim M-R, Lee E-Y, Kim JH, Kim Y-S, Jeon SG, Yang J-M, Lee B-J, Pyun B-Y, Gho YS, Kim Y-K. Extracellular vesicles derived from Staphylococcus aureus induce atopic ...dermatitis-like skin inflammation. Allergy 2011; 66: 351-359. ABSTRACT: Background: Recently, we found that Staphylococcus aureus produces extracellular vesicles (EV) that contain pathogenic proteins. Although S. aureus infection has been linked with atopic dermatitis (AD), the identities of the causative agents from S. aureus are controversial. We evaluated whether S. aureus-derived EV are causally related to the pathogenesis of AD. Methods: Extracellular vesicles were isolated by the ultracentrifugation of S. aureus culture media. The EV were applied three times per week to tape-stripped mouse skin. Inflammation and immune dysfunction were evaluated 48 h after the final application in hairless mice. Extracellular vesicles-specific IgE levels were measured by ELISA in AD patients and healthy subjects. Results: The in vitro application of S. aureus EV increased the production of pro-inflammatory mediators (IL-6, thymic stromal lymphopoietin, macrophage inflammatory protein-1α, and eotaxin) by dermal fibroblasts. The in vivo application of S. aureus EV after tape stripping caused epidermal thickening with infiltration of the dermis by mast cells and eosinophils in mice. These changes were associated with the enhanced cutaneous production of IL-4, IL-5, IFN-γ, and IL-17. Interestingly, the serum levels of S. aureus EV-specific IgE were significantly increased in AD patients relative to healthy subjects. Conclusion: These results indicate that S. aureus EV induce AD-like inflammation in the skin and that S. aureus-derived EV are a novel diagnostic and therapeutic target for the control of AD.
The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Subgingival microorganisms are potentially associated with periodontal diseases. However, changes in the subgingival microbiota during the progress of periodontal diseases are poorly understood. In ...this study, we analyzed bacterial communities in the subgingival paper point samples from 32 Korean individuals with no sign of disease, gingivitis, or periodontitis using 454 FLX Titanium pyrosequencing. A total of 256,113 reads representing 26 phyla, 433 genera, and 1,016 species were detected. Bacteroidetes, Fusobacteria, Synergistetes, and Spirochaetes were the abundant phyla in periodontitis subjects, whereas Firmicutes and Proteobacteria were identified as the dominant phyla in the gingivitis and healthy subjects, respectively. Although high levels of Porphyromonas, Fusobacterium, Fretibacterium, Rothia, Filifactor, and Treponema genera were observed in the periodontitis subjects, Streptococcus, Capnocytophaga, Leptotrichia, and Haemophilus genera were found at high frequency in the gingivitis subjects. Species including Porphyromonas gingivalis, Fusobacterium nucleatum, and Fretibacterium fastidiosum were significantly increased in periodontitis subjects. On the other hand, Streptococcus pseudopneumoniae, Haemophilus parainfluenzae, and Leptotrichia hongkongensis were preferentially observed in the gingivitis subjects. Intriguingly, the halophile Halomonas hamiltonii was revealed as a predominant species in the healthy subjects. Based on Fast UniFrac analysis, distinctive bacterial clusters were classified for the healthy, gingivitis, and periodontitis state. The current findings might be useful for understanding the pathogenesis, diagnosis, and treatment of periodontal diseases.
Aim
To investigate the effects of LY2405319, an analogue of fibroblast growth factor 21 (FGF21), on glucose homeostasis in streptozotocin (STZ)‐induced insulin‐deficient mice (STZ mice).
Methods
...Nine‐week‐old male C57BL/6J mice were administered a single intraperitoneal injection of STZ (150 mg/kg). One week later, after confirmation of hyperglycaemia, saline or LY2405319 (5 mg/kg) was injected subcutaneously daily for 4 weeks. Changes in glucose homeostasis, energy metabolism and brown adipose tissue (BAT) function were assessed.
Results
The STZ mice had elevated blood glucose and reduced plasma FGF21 levels, impaired glucose uptake in the BAT, and BAT mitochondria with absent or swollen cristae and fewer lipid vacuoles. LY2405319 significantly reduced blood glucose levels and this was associated with increased BAT glucose uptake and changes in gene expression and morphology, indicating improved mitochondrial lipid metabolism in the BAT. Importantly, the ability of LY2405319 to lower blood glucose in STZ mice was compromised after removing interscapular BAT.
Conclusions
Our results show that LY2405319 reduces blood glucose levels in insulin‐deficient diabetes by improving BAT metabolism. Additional studies investigating the therapeutic potential of FGF21 for the treatment of type 1 diabetes are warranted.
Background
Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.
Objective
To evaluate whether inhalation ...of S. aureus‐derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.
Methods
Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).
Results
Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF‐α) and interleukin 6 (IL‐6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL‐6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll‐like receptor 2 (TLR2)‐dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN‐γ) or IL‐17.
Conclusion
Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2‐dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.
Background
Chronic rhinosinusitis (CRS) is an inflammatory process in the nasal cavity and paranasal sinuses, and bacteria have been considered to be a cause. Indeed, recent evidence indicates that ...bacteria‐derived extracellular vesicles (EV) appear to be an important causative agent of inflammatory diseases. Here, we aimed to evaluate the diversity of nasal microbiota and their secreted EV in patients with CRS.
Methods
Nasal lavage (NAL) fluid samples were obtained from five patients with CRS with polyposis, three patients with CRS without polyposis, and three non‐CRS controls. After preparation of bacteria and EV from samples using differential centrifugation, genomic DNA was extracted and 16S‐rDNA amplicons were subjected to high‐throughput pyrosequencing on a Roche 454 GS‐FLX platform.
Results
Metagenomics showed that bacteria composition was positively correlated with EV composition. Samples from patients with CRS had greater bacterial abundance and lower diversity, both from bacteria and the EV portion of samples, compared with non‐CRS samples. At each phylogenetic level, Bacteroidetes decreased while Proteobacteria increased in the CRS group at the phylum level. At the genus level, Prevotella spp. decreased in the CRS group, while Staphylococcus spp. increased from both bacteria and EV. Moreover, Staphylococcus aureus and its secreting EV compositions were higher in samples from CRS with polyps compared with CRS without polyps.
Conclusions
These results suggest that patients with CRS have altered nasal microbiota and decreased diversity in bacterial compositions as well as increased S. aureus abundance in those patients with polyps.
This national survey was undertaken to propose the classification of extranodal natural killer (NK)/T-cell lymphoma (NTCL) subtypes and to clarify a clinical heterogeneity.
Two hundred and eighty ...patients newly diagnosed as NTCL were enrolled from 22 Korean medical centers. Two subsets were compared: one involving the upper aerodigestive tract (UAT) and another involving the non-upper aerodigestive tract (NUAT) region, which comprises the skin, gastrointestinal tract, and liver or soft tissues. Clinical prognostic factors, survival outcomes, and independent predictors for survival were compared between each subset.
NUAT-NTCL (59 patients) had significantly higher proportions of disseminated disease, aggressive biologic features, and unfavorable host reactions compared with UAT-NTCL (221 patients). NUAT-NTCL had shortened 5-year overall survival (OS) (22% versus 41%, P = 0.001). Ann Arbor staging, the International Prognostic Index, and the NTCL prognostic index failed to predict the OS of NUAT-NTCL, but did predict the OS in UAT-NTCL. Independent predictors for OS by multivariate analyses differed between each subset. In the NUAT subset, extranodal sites and regional nodes predicted the OS, while Ann Arbor staging, age, performance status, and lactate dehydrogenase level predicted the OS in the UAT subset.
NUAT-NTCL may represent a distinctive disease entity in terms of clinical factors, independent predictors, and survival outcomes.
Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close, producing a bright flare in ultraviolet and X-ray spectral regions from ...stellar debris that forms an accretion disk around the black hole. The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies, but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Summary
Several patients with chronic kidney disease (CKD) have deteriorated bone status. Estimation of bone status using DXA has limitations especially in patients with CKD accompanying aortic ...calcifications. Quantitative CT and the trabecular bone score could be more accurate methods to estimate bone status for patients with CKD and vascular calcifications.
Introduction
It remains unclear whether dual-energy absorptiometry (DXA) is appropriate for the assessment of bone status in patients with chronic kidney disease (CKD), a disease that impacts bone health. The aims of this study were to compare DXA and central quantitative computed tomography (cQCT) and to evaluate bone status in patients with pre-dialysis CKD.
Methods
This retrospective study included 363 healthy control subjects whose bone mineral density (BMD) was evaluated with DXA and 117 CKD patients whose BMD was evaluated using both cQCT and DXA. Diagnostic discordance was assessed between the lumbar spine (LS) and femur neck (FN) from DXA or between two modalities. The trabecular bone score (TBS) was extracted from DXA images. The volume of abdominal aortic calcification (AAC) was calculated using CT images from cQCT.
Results
Using LS DXA T-score, osteoporosis was less common in the CKD group than in controls. Patients with normal LS BMD using DXA were reclassified into osteopenia or osteoporosis using cQCT in CKD patients. Among discordant subjects between FN and LS in DXA, a higher BMD of LS was more common in CKD patients than in controls. CKD patients had lower TBS than controls despite having the same diagnosis using DXA. AAC volume negatively correlated with BMD from cQCT and with TBS but not with BMD from DXA.
Conclusions
TBS and cQCT could accurately assess bone status in CKD patients since DXA may overestimate LS BMD, likely due to an increased AAC volume.
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