Summary
Background
B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic ...rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways.
Objective
We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation.
Methods
We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody‐secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT‐PCR.
Results
NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein–Barr virus‐induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody‐secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro.
Conclusions and Clinical Relevance
Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC‐mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell‐targeted therapies may provide new treatment options for CRSwNP.
Summary
Background
Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is ...excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐PA) in NPs. As t‐PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐PA would be a potential new strategy for the treatment of NPs.
Objective
The objective of this study was to determine whether short‐chain fatty acids (SCFAs) can induce t‐PA in airway epithelial cells via their known receptors GPR41 and GPR43.
Methods
We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein‐coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t‐PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA.
Results
Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐PA expression from two‐ to tenfolds. The strongest inducer of t‐PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t‐PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t‐PA by SCFAs was dependent upon both GPR41 and GPR43.
Conclusions and Clinical Relevance
Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
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.
Although the existence of metabolically healthy obese (MHO) individuals has been recognized, little is known regarding metabolic health status in these subjects over time. Thus, we evaluated ...longitudinal changes in metabolic parameters among MHO subjects compared with metabolically healthy, normal-weight (MHNW) subjects.
A cohort study was performed on 2599 Korean men, 30-59 years of age, with no evidence of fatty liver disease on ultrasound and no traits of metabolic syndrome at baseline. BMI was categorized based on criteria for Asian population. Study participants were followed annually or biennially between 2002 and 2009. At each visit, the fatty liver on ultrasound was assessed and metabolic abnormalities were measured. Parametric Cox models and a pooled logistic regression models were used to evaluate the relationships of BMI with incident metabolic abnormalities.
During 9647.1 person-years of follow-up, 1673 participants developed metabolic abnormalities. After adjusting for age, smoking, alcohol intake and exercise, higher baseline BMI categories predicted increased incidences of metabolic abnormalities in a dose-response manner. The hazard ratios (95% confidence intervals) for hypertriglyceridemia, prediabetes, pre-hypertension, low high-density lipoprotein-cholesterol, fatty liver, elevated high sensitivity-C reactive protein, elevated homeostasis model assessment of insulin resistance, any metabolic abnormality and metabolic syndrome among the MHO subjects compared with the MHNW subjects were 1.51 (1.23-1.85), 1.43 (1.19-1.72), 1.79 (1.45-2.22), 1.80 (1.30-2.49), 2.69 (2.19-3.31), 1.39 (1.16-1.67), 2.90 (2.31-3.62), 1.68 (1.45-1.93) and 1.84(1.02-3.30), respectively.
In this study, MHO individuals showed higher incidences of metabolic abnormalities compared with MHNW individuals. This suggests that initially MHO individuals undergo adverse metabolic changes associated with obesity over time.
ABSTRACT
Neptunian Trojans (NTs), trans-Neptunian objects in 1:1 mean-motion resonance with Neptune, are generally thought to have been captured from the original trans-Neptunian protoplanetary disc ...into co-orbital resonance with the ice giant during its outward migration. It is possible, therefore, that the colour distribution of NTs is a constraint on the location of any colour transition zones that may have been present in the disc. In support of this possible test, we obtained g, r, and i-band observations of 18 NTs, more than doubling the sample of NTs with known visible colours to 31 objects. Out of the combined sample, we found ≈4 objects with g –i colours of >1.2 mags placing them in the very red (VR) category as typically defined. We find, without taking observational selection effects into account, that the NT g – i colour distribution is statistically distinct from other trans-Neptunian dynamical classes. The optical colours of Jovian Trojans and NTs are shown to be less similar than previously claimed with additional VR NTs. The presence of VR objects among the NTs may suggest that the location of the red to VR colour transition zone in the protoplanetary disc was interior to 30 – 35 au.
Background
Chronic rhinosinusitis (CRS) is a disease characterized by inflammation of the nasal mucosa and paranasal sinuses. This inflammation may result in part from decreased epithelial barrier ...and innate immune responses, leading to frequent bacterial and fungal colonization. The objectives of this study were to investigate the expression of innate immune proteins of the palate lung and nasal epithelium clone (PLUNC) family in patients with CRS.
Methods
Nasal tissue samples were collected from control subjects and CRS patients with and without nasal polyps. Expression of the members of the PLUNC family was analyzed by real‐time PCR. Expression of SPLUNC1 and LPLUNC2 proteins was analyzed by ELISA, immunoblot, and immunohistochemical analysis.
Results
Levels of mRNA for most of the members of the PLUNC family were profoundly reduced in nasal polyps (NPs) compared to uncinate tissue from control subjects or patients with CRS. LPLUNC2 and SPLUNC1 proteins were decreased in NPs of patients with CRS compared to uncinate tissue from control subjects. Immunohistochemical data revealed that within submucosal glands of sinonasal tissues, SPLUNC1 and LPLUNC2 were differentially expressed, in serous and mucous cells, respectively. The decrease in the expression of these molecules is probably explained by a decrease in the number of glands in NPs as revealed by correlations with levels of the glandular marker lactoferrin.
Conclusions
Decreased SPLUNC1 and LPLUNC2 in NPs reflect a profound decrease in the number of submucosal glands. Decreased glands may lead to a localized defect in the production and release of glandular innate defense molecules.
Vertically aligned perfectly hexagonal-shaped ZnO nanoprisms have been grown on a Si(100) substrate via a noncatalytic thermal evaporation process by using metallic zinc powder in the presence of ...oxygen gas. The as-grown nanoprisms consist of ultra smooth Zn-terminated (0001) facets bounded with the {011̅0} surfaces. The as-synthesized products are single-crystalline with the wurtzite hexagonal phase and grown along the 0001 direction, as confirmed from the detailed structural investigations. The presence of a sharp and strong nonpolar optical phonon high-E2 mode at 437 cm−1 in the Raman scattering spectrum further confirms good crystallinity and wurtzite hexagonal phase for the as-grown products. The as-grown nanoprisms exhibit a strong near-band-edge emission with a very weak deep-level emission in the room-temperature and low-temperature photoluminescence measurements, confirming good optical properties for the deposited products. Moreover, systematic time-dependent experiments were also performed to determine the growth process of the grown vertically aligned nanoprisms.
Summary
Background
Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not ...been fully elucidated. Dendritic cells (DCs) are major antigen‐presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied.
Objective
The objective of this study was to characterize DC subsets in CRS.
Methods
We used real‐time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry.
Results
Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were significantly elevated in NPs (n = 29). In contrast, CD207 mRNA was not elevated in NPs. Immunohistochemistry showed that CD1c+ cells but not CD303+ cells were significantly elevated in NPs compared to control subjects or patients with CRSsNP. Flow cytometric analysis showed that CD1a+ cells in NPs might be a subset of mDC1s and that CD45+CD19−CD1c+CD11c+CD141−CD303−HLA‐DR+ mDC1s and CD45+CD19−CD11c+CD1c−CD141high HLA‐DR+ mDC2s were significantly elevated in NPs compared to UT from controls and CRSsNP, but CD45+CD11c−CD303+HLA‐DR+ pDCs were only elevated in NPs compared to control UT.
Conclusion and Clinical Relevance
Myeloid DCs are elevated in CRSwNP, especially in NPs. Myeloid DCs thus may indirectly contribute to the inflammation observed in CRSwNP.
To maximize dye absorption and improve energy conversion efficiency, we adopted a branched structure for single crystalline ZnO nanowires in dye-sensitized solar cells (DSSCs). The ZnO nanowire DSSCs ...exhibited an overall efficiency of ∼0.46%.
To maximize dye absorption and improve energy conversion efficiency, we adopted a branched structure for single crystalline ZnO nanowires in dye-sensitized solar cells (DSSCs). The high-density branched structures of these ZnO nanowires were incorporated by a two-step seeding with zinc acetate dihydrate seeds. The ZnO nanowire DSSCs exhibited an overall efficiency of ∼0.46%. This represented a 35% improvement compared to the ZnO nanowire DSSCs with pillar-shaped ZnO nanowires. Our current density–voltage (J–V) characterizations suggest that the current densities and power conversion efficiencies were improved by increasing the surface area with these branched structures of ZnO nanowires in DSSCs.
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.
PDF
