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.
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.
Cell surface sialylation is associated with tumor cell invasiveness in many cancers. Glioblastoma is the most malignant primary brain tumor and is highly infiltrative. ST3GAL1 sialyltransferase gene ...is amplified in a subclass of glioblastomas, and its role in tumor cell self-renewal remains unexplored.
Self-renewal of patient glioma cells was evaluated using clonogenic, viability, and invasiveness assays. ST3GAL1 was identified from differentially expressed genes in Peanut Agglutinin-stained cells and validated in REMBRANDT (n = 390) and Gravendeel (n = 276) clinical databases. Gene set enrichment analysis revealed upstream processes. TGFβ signaling on ST3GAL1 transcription was assessed using chromatin immunoprecipitation. Transcriptome analysis of ST3GAL1 knockdown cells was done to identify downstream pathways. A constitutively active FoxM1 mutant lacking critical anaphase-promoting complex/cyclosome (APC/C-Cdh1) binding sites was used to evaluate ST3Gal1-mediated regulation of FoxM1 protein. Finally, the prognostic role of ST3Gal1 was determined using an orthotopic xenograft model (3 mice groups comprising nontargeting and 2 clones of ST3GAL1 knockdown in NNI-11 8 per group and NNI-21 6 per group), and the correlation with patient clinical information. All statistical tests on patients' data were two-sided; other P values below are one-sided.
High ST3GAL1 expression defines an invasive subfraction with self-renewal capacity; its loss of function prolongs survival in a mouse model established from mesenchymal NNI-11 (P < .001; groups of 8 in 3 arms: nontargeting, C1, and C2 clones of ST3GAL1 knockdown). ST3GAL1 transcriptomic program stratifies patient survival (hazard ratio HR = 2.47, 95% confidence interval CI = 1.72 to 3.55, REMBRANDT P = 1.92 x 10⁻⁸; HR = 2.89, 95% CI = 1.94 to 4.30, Gravendeel P = 1.05 x 10⁻¹¹), independent of age and histology, and associates with higher tumor grade and T2 volume (P = 1.46 x 10⁻⁴). TGFβ signaling, elevated in mesenchymal patients, correlates with high ST3GAL1 (REMBRANDT gliomacor = 0.31, P = 2.29 x 10⁻¹⁰; Gravendeel gliomacor = 0.50, P = 3.63 x 10⁻²⁰). The transcriptomic program upon ST3GAL1 knockdown enriches for mitotic cell cycle processes. FoxM1 was identified as a statistically significantly modulated gene (P = 2.25 x 10⁻⁵) and mediates ST3Gal1 signaling via the (APC/C)-Cdh1 complex.
The ST3GAL1-associated transcriptomic program portends poor prognosis in glioma patients and enriches for higher tumor grades of the mesenchymal molecular classification. We show that ST3Gal1-regulated self-renewal traits are crucial to the sustenance of glioblastoma multiforme growth.
This study evaluated the capacity of 23 multidrug-resistant (MDR) clinical isolates of Acinetobacter baumannii to adhere to respiratory epithelial cell surfaces and to form biofilm on a polystyrene ...surface. All 23 A. baumannii isolates were capable of adhering efficiently to respiratory epithelial cells, and biofilm production was positively associated with epithelial cell adhesiveness (r 0.80, p <0.0001). In the presence of the chelating agent EDTA, biofilm formation was markedly reduced. Cell adhesiveness and biofilm formation were significantly higher in isolates carrying the blaPER-1 gene as compared with isolates without this extended-spectrum β-lactamase gene (p <0.005 and p <0.001, respectively). Further examination by RT-PCR showed a positive correlation between the level of expression of the blaPER-1 gene and the level of biofilm formation (r 0.89, p <0.0001) and cell adhesiveness (r 0.74, p <0.006). Overall, the study demonstrated a high capacity of clinical isolates of MDR A. baumannii to form biofilm and to adhere to respiratory epithelial cells. This feature, combined with multidrug resistance, might contribute to the survival of these organisms and their dissemination in the hospital environment.
Nano-structured silicon is an attractive alternative anode material to conventional graphite in lithium-ion batteries. However, the anode designs with higher silicon concentrations remain to be ...commercialized despite recent remarkable progress. One of the most critical issues is the fundamental understanding of the lithium-silicon Coulombic efficiency. Particularly, this is the key to resolve subtle yet accumulatively significant alterations of Coulombic efficiency by various paths of lithium-silicon processes over cycles. Here, we provide quantitative and qualitative insight into how the irreversible behaviors are altered by the processes under amorphous volume changes and hysteretic amorphous-crystalline phase transformations. Repeated latter transformations over cycles, typically featured as a degradation factor, can govern the reversibility behaviors, improving the irreversibility and eventually minimizing cumulative irreversible lithium consumption. This is clearly different from repeated amorphous volume changes with different lithiation depths. The mechanism behind the correlations is elucidated by electrochemical and structural probing.
Abstract Introduction To assess if parameters in intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) can be used to evaluate early renal fibrosis in a mouse model of diabetic ...nephropathy. Materials & methods In a population of 38 male CD1 mice (8 weeks old, 20–30 g), streptozotocin induced diabetes was created in 20 mice via a single intraperitoneal injection of streptozotocin at 150 mg/kg, while 18 mice served as control group. IVIM parameters were acquired at 0, 12 and 24 weeks after injection of streptozotocin using a range of b values from 0 to 1200 s/mm2 . DTI parameters were obtained using 12 diffusion directions and lower b values of 0, 100 and 400 s/mm2 . DTI and IVIM parameters were obtained using region of interests drawn over the renal parenchyma. Histopathological analysis of the right kidney was performed in all mice. Results were analyzed using an unpaired t -test with P < 0.05 considered statistically significant. Results Renal cortex fractional anisotropy (FA) was significantly lower in the diabetes group at week 12 as compared with the control group. Renal cortex apparent diffusion coefficient and tissue diffusivity were significantly higher in the diabetes group at week 12 compared with the control group at 12 weeks. Blood flow was significantly decreased at the renal medulla at 24 weeks. Histopathological analysis confirmed fibrosis in the diabetes group at 24 weeks. Conclusion FA is significantly reduced in diabetic nephropathy. FA might serve a potential role in the detection and therapy monitoring of early diabetic nephropathy.
Summary Purpose Data on the association between body mass index (BMI) and risk of knee osteoarthritis (KOA) are sparse for Asian populations who are leaner than Western populations. We evaluated the ...association between BMI and risk of total knee replacement (TKR) due to severe KOA among Chinese in Singapore. Methods We used data from the Singapore Chinese Health Study (SCHS), a population-based prospective cohort of 63,257 Chinese men and women, aged 45–74 years at enrollment from 1993 to 1998. Information on height, weight, diet and lifestyle factors were obtained via in-person interviews. TKR cases for severe KOA were identified via linkage with the nationwide hospital discharge database through 2011. Cox regression and weighted least squares regression were used in the analysis. Results The mean BMI among cohort participants was 23.1 kg/m2 , and more than two-thirds had BMI below 25 kg/m2 . A total of 1649 had TKR attributable to severe KOA. Risk of TKR increased in a strong dose-dependent manner with increasing BMI throughout the 15–32 kg/m2 range and became less clear at BMI >32 kg/m2 . In the BMI range 16–27 kg/m2 , there was a 27% increase in TKR risk for each unit increase in BMI ( P for trend < 0.001). Compared to BMI 19–20 kg/m2 , the risk estimates of TKR were all statistically significant with increasing unit of BMI ≥21 kg/m2 . Results were similar for men and women. Conclusion Our results provided evidence for a constant mechanical mechanism underlying BMI and KOA initiation and/or progression.
AbstractContentBurnout is common amongst palliative care clinicians. Resilience helps to reduce burnout, compassion fatigue and is associated with longevity in palliative care. ObjectivesWe aimed to ...study palliative care clinicians who have remained in the field for longer than 10 years to deepen our understanding on their views on burnout and resilience. Patients and MethodsWe conducted a qualitative study using semi-structured interviews and purposive sampling on 18 palliative care clinicians – 5 doctors, 10 nurses and 3 social workers who worked in various palliative care settings (hospital palliative care team, home hospice and inpatient hospice). The mean age of the interviewees was 52 years old and the mean number of years practicing palliative care was 15.7 years (ranging from 10 -25 years). The interviews were recorded verbatim, transcribed and analysed using a grounded theory approach. Results4 major themes emerged from our analysis – Struggling, Changing Mindset, Adapting and Resilience (SCAR). Intervening conditions such as self-awareness, reflection, and evolution were also important factors. The core phenomenon of our study was that of ‘Transformational Growth’ – a process which palliative care clinicians have to go through before they achieve resilience. We also further classified resilience into both personal and collective resilience. ConclusionOur findings highlight the evolving process of transformational growth which palliative care clinicians must repeatedly undergo as they strive towards sustained resilience and longevity. It also stresses the importance of taking individual and collective responsibility towards building a culture of personal and team resilience.
Aims/hypothesis
Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome ...proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes.
Methods
Four groups of male C57BLKS/J
db
/
m
and
db
/
db
mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks.
Results
The
db
/
db
mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1–PGC-1α signalling and of the key downstream effectors, the PPARα–oestrogen-related receptor (ERR)-1α–sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)–Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1–PGC-1α signalling and the downstream effectors, PPARα–ERR-1α–SREBP1.
Conclusions/interpretation
The results suggest that resveratrol prevents diabetic nephropathy in
db
/
db
mice by the phosphorylation of AMPK and activation of SIRT1–PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
PDF
