Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the ...therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively.
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
NCT02746796.
Summary
Background
Asthma in the elderly (aged ≥ 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late‐onset asthma. Recent studies ...suggest staphylococcal enterotoxin IgE (SE‐IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late‐onset elderly asthma.
Objective
We aimed to examine the associations of SE‐IgE sensitization with late‐onset asthma in the elderly, using a database of elderly asthma cohort study.
Methods
A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE‐IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12‐month follow‐up period.
Results
At baseline, serum SE‐IgE concentrations were significantly higher in patients with asthma than in controls median 0.16 (interquartile range 0.04–0.53) vs. 0.10 (0.01–0.19), P < 0.001. Elderly asthma patients with high SE‐IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE‐IgE levels. In multivariate logistic regression analyses, the associations between serum SE‐IgE concentrations and severe asthma were significant, independently of covariables SE‐IgE‐high (≥ 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86–30.03, P = 0.005. Multiple correspondence analyses also showed that high serum SE‐IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together.
Conclusions and Clinical Relevance
This is the first report on the significant associations of SE‐IgE sensitization with late‐onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late‐onset eosinophilic asthma in the elderly.
Fully dense PLA blocks were manufactured by 3D-printing, depositing a polymer filament in a single direction via the fusion deposition method (FDM). Specimens were cut from printed blocks using ...conventional machining and were used to perform tension, compression and fracture experiments along different material directions. The elasto-plastic material response was found to be orthotropic and characterised by a strong tension-compression asymmetry; the material was tougher when loaded in the extrusion direction than in the transverse direction. The response of the unidirectional, 3D-printed material was compared to that of homogeneous injection-moulded PLA, showing that manufacturing by 3D-printing improves toughness; the effects of an annealing thermal cycle on the molecular structure and the mechanical response of the material were assessed.
Display omitted
•3D-printed PLA displays an elasto-plastic, orthotropic mechanical response with a strong tension/compression asymmetry.•The material is tougher when tested in the extrusion direction (KIC=5MPam) than in the transverse direction (KIC=4MPam).•Manufacturing by 3D-printing results in higher toughness than manufacturing by injection-moulding (KIC=3MPam).•Annealing at a temperature below Tg has negligible effect on crystallinity and stiffness but reduces the strength 10 to 30%.
SETTING: Multicentre study.OBJECTIVE: To define the clinical characteristics of patients with tuberculosis (TB) destroyed lung due to past TB.DESIGN: We reviewed patients with TB-destroyed lung ...between May 2005 and June 2011.RESULTS: A total of 595 patients from 21 hospitals
were enrolled. The mean age was 65.63 ± 0.47 (mean ± standard error); 60.5% were male. The mean number of lobes involved was 2.59 ± 0.05. Pleural thickening was observed in 54.1% of the patients. Mean forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1),
FEV1/FVC, bronchodilator response and number of exacerbations per year were respectively 2.06 ± 0.03 l (61.26% ± 0.79), 1.16 ± 0.02 l (49.05% ± 0.84), 58.03% ± 0.70, 5.70% ± 0.34, and 0.40 ± 0.04. The number of lobes involved was
significantly correlated with FVC and FEV1, and with the number of exacerbations per year. Use of long-acting muscarinic antagonists or long-acting beta-2 agonists plus inhaled corticosteroids resulted in bronchodilatory effects. Multivariable regression analysis showed that age,
initial FEV1 (%) and number of exacerbations during follow-up were independent factors affecting change in FEV1.CONCLUSION: Decreased lung function with exacerbation, and progressive decline of FEV1 were observed in patients with TB-destroyed lung.
Summary
Background
Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre‐sized vesicles into the extracellular milieu, but it remains to be ...determined whether bacteria‐derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases.
Objective
To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma.
Methods
Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV.
Results
Repeated intranasal application of indoor‐dust‐induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50–200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer‐membrane component of Gram‐negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV‐reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis.
Conclusion & Clinical Relevance
Indoor dust EV, especially derived from Gram‐negative bacteria, is a possible causative agent of neutrophilic airway diseases.
Medium Mn steels have been actively investigated due to their excellent balance between material cost and mechanical properties. The steels possess a single α′ martensite phase in hot and cold rolled ...states and multiphases after intercritical annealing. Many studies have focused on investigating the influences of chemical composition and annealing conditions on the microstructure, particularly the grain size and retained γ (γ
R
), and on the tensile properties. The steels exhibit high strength and good ductility due to transformation induced plasticity occurring in γ
R
, whose volume fraction is approximately 0·2-0·4. The present review summarises the important results of previous studies about the effects of both intercritical annealing conditions and alloying elements on the microstructure and tensile properties of medium Mn steels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Incidence of hip fracture increased in Korean populations over age 50 between 2008 and 2012, and the number of fractures was predicted to increase by 1.4 times by 2025. This is important ...information for public health planning.
Introduction
The purposes of this study were to evaluate the trends in the incidence and mortality of hip fracture between 2008 and 2012 and predict the number of hip fractures in Korea through 2025 using nationwide claims data.
Methods
The data managed by the National Health Insurance Service were used to identify the hip fractures in patients aged >50 years between 2008 and 2012. Projections of hip fractures were conducted using the Poisson distribution from 2016 to 2025 in Korea.
Results
The incidence of hip fractures (per 100,000) increased by 14.1 % over the 5 years of the study, by 15.8 % in women and 10.9 % in men; the older age group showed a steep rise and shift in the incidence from 2008 to 2012. The cumulative mortality rates at 1 year after hip fractures were 17.2 % (3575/20,849) in 2008 and 16.0 % (4547/28,426) in 2012. Overall standardized mortality ratios (SMRs) for hip fracture were higher in men (11.93) than in women (11.22) and were higher than those in the general population in all age groups. In 2016, the total number of hip fractures was estimated to increase an overall of 1.4 times by 2025.
Conclusions
The incidence of hip fracture continues to increase, and the related mortality is still high, although it has decreased over time. The socioeconomic burden of hip fracture is expected to increase in Korea along with the increased estimated number of fractures. Nationwide strategies should include attempts to reduce the future socioeconomic burdens of hip fractures.
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.
We present microlensing events in the 2015 Korea Microlensing Telescope Network (KMTNet) data and our procedure for identifying these events. In particular, candidates were detected with a novel ..."completed-event" microlensing event-finder algorithm. The algorithm works by making linear fits to a grid of point-lens microlensing models. This approach is rendered computationally efficient by restricting u0 to just two values (0 and 1), which we show is quite adequate. The implementation presented here is specifically tailored to the commission-year character of the 2015 data, but the algorithm is quite general and has already been applied to a completely different (non-KMTNet) data set. We outline expected improvements for 2016 and future KMTNet data. The light curves of the 660 "clear microlensing" and 182 "possible microlensing" events that were found in 2015 are presented along with our policy for their public release.
We report the discovery of a giant planet in the OGLE-2017-BLG-1522 microlensing event. The planetary perturbations were clearly identified by high-cadence survey experiments despite the relatively ...short event timescale of tE ∼ 7.5 days. The Einstein radius is unusually small, θE = 0.065 mas, implying that the lens system either has very low mass or lies much closer to the microlensed source than the Sun, or both. A Bayesian analysis yields component masses and source-lens distance , implying that this is a brown-dwarf/Jupiter system that probably lies in the Galactic bulge, a location that is also consistent with the relatively low lens-source relative proper motion = 3.2 0.5 mas yr−1. The projected companion-host separation is , indicating that the planet is placed beyond the snow line of the host, i.e., asl ∼ 0.12 au. Planet formation scenarios combined with the small companion-host mass ratio q ∼ 0.016 and separation suggest that the companion could be the first discovery of a giant planet that formed in a protoplanetary disk around a brown-dwarf host.
PDF
