SUMMARY
Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We ...investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)‐γ, inflammatory cytokines interleukin (IL)‐1, IL‐6 and IL‐12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)‐α, anti‐inflammatory cytokine IL‐10, Th1 cytokine IL‐2 and Th2 cytokine IL‐4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL‐8, monocyte chemoattractant protein‐1 (MCP‐1), and Th1 chemokine IFN‐γ‐inducible protein‐10 (IP‐10). Corticosteroid reduced significantly IL‐8, MCP‐1 and IP‐10 concentrations from 5 to 8 days after treatment (all P < 0·001). Together, the elevation of Th1 cytokine IFN‐γ, inflammatory cytokines IL‐1, IL‐6 and IL‐12 and chemokines IL‐8, MCP‐1 and IP‐10 confirmed the activation of Th1 cell‐mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
The effect of displacement and humidity on fretting-induced instability of electrical contact resistance (Rc) was studied. A fretting tester was used to examine Rc in partial and gross slip modes. ...Under the partial slip regime the contact failure was susceptible to the displacement and moisture effectively increased contact stability, which was pronounced at smaller displacements. In the gross slip mode, however, humidity effect was relatively small. The early contact failure at low humidity was attributed to the wear debris agglomeration within the sliding interface, suggesting a high propensity of electrical contact failure at dry conditions.
•The effect of humidity and displacement on fretting induced electrical contact failure was studied.•Humidity effect was pronounced at small displacements due to effective removal of debris.•Premature contact failure was found at low humidity and with large displacements.•Moisture reduced wear debris pileup, producing a smooth contact area with more electrical junctions.•Our results suggested a high propensity of electrical contact failure at dry conditions.
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.
The present study aimed to determine the isoform‐specific role of the NADPH oxidases (NOX) in the endothelium‐mediated vascular dysfunction associated with ageing. Endothelium‐dependent intraluminal ...flow‐ and acetylcholine (ACh)‐induced vasodilatation in human skeletal muscle feed arteries (SMFAs) of young (24 ± 1 years, n = 16), middle aged (45 ± 1 years, n = 18) and old (76 ± 2 years, n = 21) subjects was assessed in vitro with and without the inhibition of NOX1 (ML090), NOX2 (gp91) and NOX4 (plumbagin). To identify the role of nitric oxide (NO) bioavailability in these responses, NO synthase blockade (l‐NG‐monomethyl arginine citrate) was utilized. SMFA NOX1, NOX2 and NOX4 protein expression was determined by western blotting. Age related endothelium‐dependent vasodilatory dysfunction was evident in response to flow (young: 69 ± 3; middle aged: 51 ± 3; old: 27 ± 3%, P < 0.05) and ACh (young: 89 ± 2; middle aged: 72 ± 3; old: 45 ± 4%, P < 0.05). NOX1 inhibition had no effect on SMFA vasodilatation, whereas NOX2 inhibition restored flow‐ and ACh‐induced vasodilatation in the middle aged and the old SMFAs (middle aged + gp91: 69 ± 3; 86 ± 3, old + gp91: 65 ± 5; 83 ± 2%, P < 0.05) and NOX4 inhibition tended to restore these vasodilatory responses in these two groups, but neither achieved statistical significance (P ≈ 0.06). l‐NG‐monomethyl arginine citrate negated the restorative effects of NOX2 and NOX4 blockade. Only NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function (r = 0.48 to 0.93, P < 0.05). NOX2 and, to a lesser extent, NOX4 appear to play an important, probably NO‐mediated, role in age‐related endothelial dysfunction.
Key points
The present study aimed to determine the isoform‐specific role of the NADPH oxidases (NOX) in the endothelium‐mediated vascular dysfunction associated with ageing.
Age related endothelium‐dependent vasodilatory dysfunction was evident in skeletal muscle feed arteries in response to both flow and acetylcholine.
NOX2 inhibition (gp91) restored endothelium‐dependent vasodilatation in the middle aged and the old skeletal muscle feed arteries, and NOX4 inhibition (plumbagin) tended to restore these vasodilatory responses in these two groups. Nitric oxide synthase inhibition negated the restorative effects of NOX2 and NOX4 blockade.
NOX2 and NOX4 protein expression was significantly greater in the two older groups and inversely related to vascular function.
NOX2 and, to a lesser extent, NOX4 appear to play an important, probably nitric oxide‐mediated, role in age‐related endothelial dysfunction and could be important therapeutic targets to maintain vascular health with ageing.
figure legend This study aimed to determine the isoform‐specific role of NADPH oxidase (NOX) in the endothelium‐mediated vascular dysfunction associated with ageing. NOX2 inhibition using NOX2 inhibitor (gp91) restored flow‐ and acetylcholine‐induced vasodilatation in the middle aged and the old skeletal muscle feed arteries, and NOX4 inhibition using NOX 4 inhibitor (plumbagin) tended to restore these vasodilatory responses in these two groups. NOX2 and, to a lesser extent, NOX4 appear to play an important, probably nitric oxide‐mediated, role in age‐related endothelial dysfunction. Created with BioRender.com.
Particulate matter (PM) air pollution has gradually become a widespread problem in East Asia. PM may cause unfamiliar inflammatory responses, oxidative stress, and pulmonary tissue damage, and a ...comprehensive understanding of the underlying mechanisms is required in order to develop effective anti-inflammatory agents. In this study, fine dust collected from Beijing, China (CPM) (size < PM13 with majority < PM2.5) was evaluated for its oxidative stress- and inflammation-inducing effects, which cause cell damage, in A459 human lung epithelial cells. Oxidative stress was marked by an increase in intracellular ROS levels and the production of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and heme oxygenase-1 (HO-1). Upon induction of oxidative stress, a marked increase was observed in the expression of key inflammatory mediators such as COX-2 and PGE2 and the pro-inflammatory cytokines TNF-α and IL-6 via NF-kB and MAPK pathways. Cellular damage was marked by a reduction in viability, increased lactate dehydrogenase (LDH) release, formation of apoptotic and necrotic bodies, accumulation of sub-G1 phase cells, and DNA damage. Apoptosis was found to be mediated via the activation of caspases through the mitochondria-mediated pathway. Fucosterol, purified from the brown alga Sargassum binderi (Sonder ex J. Agardh) by bio-assay-guided fractionation and purification, exhibited potential therapeutic effects against CPM-induced detrimental effects. Further studies could focus on developing fucosterol, in forms such as steroidal inhalers, against PM-induced pulmonary tissue inflammation.
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•Fine dust air pollution is a major reason of pulmonary complications in East Asia.•Dust particles induce oxidative stress and inflammation damaging the lung epithelial cells.•Fucosterol suppressed the dust induced cell damage by inhibiting oxidative stress and inflammation.•Fucosterol may have beneficial effects in alleviating adverse respiratory effects of air pollution.
Key points
The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age‐related vascular ...dysfunction.
Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial‐dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels.
Adropin incubation restored age‐related endothelial‐dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age‐dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression.
Additional evidence of a mechanistic link between declining adropin and age‐related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin‐induced eNOS‐mediated vasodilatation with ageing.
Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing.
The present study aimed to determine the impact of advancing age on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age‐related vascular dysfunction. Adropin protein expression and vasodilatory capacity was assesed in SMFAs from Young (27 ± 2 years, n = 10), Middle Aged (54 ± 2 years, n = 10) and Old (75 ± 2 years, n = 16) subjects. Endothelial‐dependent vasodilatation, with and without adropin incubation, was assessed in response to flow‐induced shear stress and ACh. Both SMFA adropin protein expression and endothelial‐dependent vasodilatory function exhibited a progressive, age‐related, reduction (Flow: Y: 65 ± 3%; Middle Aged: 36 ± 3%; Old: 15 ± 2%; ACh: Young: 63 ± 2%, Middle Aged: 34 ± 3%; Old: 23 ± 3%, P < 0.05). There was a strong positive correlation between SMFA adropin protein expression and both flow (r = 0.81, P < 0.05) and ACh (r = 0.78, P < 0.05). Adropin incubation in the Middle Aged and Old SMFAs restored the vasodilatory response to flow (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 47 ± 3%, P < 0.05) and ACh (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 49 ± 2%, P < 0.05). A mechanistic link between adropin and nitric oxide (NO) biovavailabilty was supported by (i) increased phosphorylated endothelial NO synthase (eNOS)/eNOS protein expression with adropin incubation only in the Middle Aged and Old SMFAs; (ii) eNOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression and (iii) a progressive increase in the magnitude of effect of adropin‐induced eNOS‐mediated vasodilatation with advancing age. Adropin could be a novel therapeutic target for facilitating the restoration of endothelial function via increased NO bioavailability, with advancing age.
Key points
The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age‐related vascular dysfunction.
Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial‐dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels.
Adropin incubation restored age‐related endothelial‐dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age‐dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression.
Additional evidence of a mechanistic link between declining adropin and age‐related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin‐induced eNOS‐mediated vasodilatation with ageing.
Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing.
Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 ...yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s
·mg
and CI+II: 12.4 ± 0.8 pmol·s
·mg
, P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s
·mg
and CI+II: 8.3 ± 0.5 pmol·s
·mg
) and old (CI: 7.2 ± 0.4 pmol·s
·mg
and CI+II: 7.6 ± 0.5 pmol·s
·mg
) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age r = -0.56 (CI), r = -0.7 (CI+II), and r = 0.4 (CII), P < 0.05. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = -0.71, P < 0.05). As CS activity was inversely correlated with age ( r = -0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s
·mg
·U CS
, P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s
·mg
·U CS
, respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.
Context. The Vista Variables in the Via Lactea (VVV) ESO Public Survey is a variability survey of the Milky Way bulge and an adjacent section of the disk carried out from 2010 on ESO Visible and ...Infrared Survey Telescope for Astronomy (VISTA). The VVV survey will eventually deliver a deep near-IR atlas with photometry and positions in five passbands (ZYJHK sub(S)) and a catalogue of 1-10 million variable point sources - mostly unknown - that require classifications. Aims. The main goal of the VVV Templates Project, which we introduce in this work, is to develop and test the machine-learning algorithms for the automated classification of the VVV light-curves. As VVV is the first massive, multi-epoch survey of stellar variability in the near-IR, the template light-curves that are required for training the classification algorithms are not available. In the first paper of the series we describe the construction of this comprehensive database of infrared stellar variability. Methods. First, we performed a systematic search in the literature and public data archives; second, we coordinated a worldwide observational campaign; and third, we exploited the VVV variability database itself on (optically) well-known stars to gather high-quality infrared light-curves of several hundreds of variable stars. Results. We have now collected a significant (and still increasing) number of infrared template light-curves. This database will be used as a training-set for the machine-learning algorithms that will automatically classify the light-curves produced by VVV. The results of such an automated classification will be covered in forthcoming papers of the series.
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