Summary
Background Nationwide data on the epidemiology of dermatomyositis (DM) and polymyositis (PM) were limited.
Objectives This study was to estimate the incidence, occurrence of cancer and ...mortality of DM and PM in Taiwan.
Methods Both the register of critical illness of the Taiwan National Health Insurance Research Dataset and the National Death Registry of Taiwan were used to calculate estimates of the incidence, cancer association, and mortality of DM and PM between 2003 and 2007.
Results A total of 803 DM and 500 PM cases were identified between 2003 and 2007. Mean age at diagnosis was 44·0 ± 18·3 years for DM and 49·2 ± 15·9 years for PM. The overall annual incidences of DM and PM were 7·1 (95% CI 6·6–7·6) and 4·4 (95% CI 4·0–4·8) cases per million population. The incidence of both DM and PM increased with age and reached a peak at age 50–59 years. One hundred and eleven (13·8%) patients with DM and 31 (6·2%) patients with PM had cancers. The diagnosis of most cancers was made after the diagnoses of DM (n = 71; 64·0%) and PM (n = 21; 67·7%). Overall, the standardized incidence ratios (SIR) for cancer were 5·36 (4·12–6·87) and 1·80 (1·10–2·79) among patients with DM and PM; however, during the first year, SIRs for cancer were 24·55 (95% CI 18·62–31·79) and 9·17 (95% CI 14·82–15·93) in patients with DM and PM, respectively. The most common types of cancer were nasopharyngeal cancer for men and breast cancer for women. Patients with DM and PM had standardized mortality ratios of 7·68 (6·41–9·01) and 5·29 (4·28–6·48).
Conclusion This study reports robust estimates of important aspects of the epidemiology of both DM and PM in Taiwan. This highlights the rarity of these diseases, and their associated cancer risks and increased mortality.
Satellite aerosol optical depth (AOD) has been used to assess population exposure to fine particulate matter (PM2.5). The emerging high-resolution satellite aerosol product, Multi-Angle ...Implementation of Atmospheric Correction (MAIAC), provides a valuable opportunity to characterize local-scale PM2.5 at 1-km resolution. However, non-random missing AOD due to cloud/snow cover or high surface reflectance makes this task challenging. Previous studies filled the data gap by spatially interpolating neighboring PM2.5 measurements or predictions. This strategy ignored the effect of cloud cover on aerosol loadings and has been shown to exhibit poor performance when monitoring stations are sparse or when there is seasonal large-scale missingness. Using the Yangtze River Delta of China as an example, we present a Multiple Imputation (MI) method that combines the MAIAC high-resolution satellite retrievals with chemical transport model (CTM) simulations to fill missing AOD. A two-stage statistical model driven by gap-filled AOD, meteorology and land use information was then fitted to estimate daily ground PM2.5 concentrations in 2013 and 2014 at 1km resolution with complete coverage in space and time. The daily MI models have an average R2 of 0.77, with an inter-quartile range of 0.71 to 0.82 across days. The overall model 10-fold cross-validation R2 (root mean square error) were 0.81 (25μg/m3) and 0.73 (18μg/m3) for year 2013 and 2014, respectively. Predictions with only observational AOD or only imputed AOD showed similar accuracy. Comparing with previous gap-filling methods, our MI method presented in this study performed better with higher coverage, higher accuracy, and the ability to fill missing PM2.5 predictions without ground PM2.5 measurements. This method can provide reliable PM2.5 predictions with complete coverage that can reduce bias in exposure assessment in air pollution and health studies.
•Fused satellite data, chemical transport model simulations and ground measurements•Improved the annual coverage of PM2.5 prediction by about two-fold•Provided PM2.5 predictions with complete-coverage high-accuracy at 1-km resolution•Corrected sampling bias in exposure assessment due to non-random missingness in AOD
This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic ...circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner.
Summary
Background
Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral ...cutaneous melanoma (NAM) in Asians are not well understood.
Objectives
To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma.
Methods
We performed comprehensive genomic profiling of 409 cancer‐associated genes, using next‐generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs.
Results
Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild‐type (triple‐WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell‐cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell‐cycle aberrations were independent prognostic factors of melanoma‐specific survival.
Conclusions
This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians.
What's already known about this topic?
Mutation frequencies of driver genes vary between melanoma subtypes.
Acral melanoma is the most common subtype of melanoma in Asians.
KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype
What does this study add?
NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment.
Melanomas with cell‐cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration.
What is the translational message?
Cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival.
These observations should be explored further for future drug development.
Linked Comment: Johansson. Br J Dermatol 2020; 182:1085.
Plain language summary available online
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET ...inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Microbial metabolites, produced in the intestine, have significant effects on inflammatory diseases throughout the body. Short-chain fatty acids (SCFAs) have protective effects on experimental ...autoimmune encephalitis (EAE) responses but the detailed roles of SCFAs and their receptors in regulating autoimmune CNS inflammation have been unclear. SCFAs metabolically regulate T cells and change the phenotype of antigen presenting cells to efficiently induce IL-10
regulatory T cells. In line with the overall protective effect, blood levels of major SCFAs, such as acetate, propionate and butyrate, are significantly decreased in long-term active progressive multiple sclerosis (MS) patients. Importantly, SCFAs can induce CD4
effector T cells, which are highly inflammatory when transferred into mice, suggesting that the direct effect of SCFAs on T cells can even be pro-inflammatory in the CNS. In contrast to the moderate protective effect of SCFAs, mice deficient in GPR41 or GPR43 are more resistant to EAE pathogenesis. Thus, despite the overall protective function of SCFAs, SCFAs and their receptors have the potential to regulate autoimmune CNS inflammation both positively and negatively.
Abstract
Surface acoustic waves are commonly used in classical electronics applications, and their use in quantum systems is beginning to be explored, as evidenced by recent experiments using ...acoustic Fabry–Pérot resonators. Here we explore their use for quantum communication, where we demonstrate a single-phonon surface acoustic wave transmission line, which links two physically separated qubit nodes. Each node comprises a microwave phonon transducer, an externally controlled superconducting variable coupler, and a superconducting qubit. Using this system, precisely shaped individual itinerant phonons are used to coherently transfer quantum information between the two physically distinct quantum nodes, enabling the high-fidelity node-to-node transfer of quantum states as well as the generation of a two-node Bell state. We further explore the dispersive interactions between an itinerant phonon emitted from one node and interacting with the superconducting qubit in the remote node. The observed interactions between the phonon and the remote qubit promise future quantum-optics-style experiments with itinerant phonons.
Summary Background A common approach for tissue regeneration is cell delivery, for example by direct transplantation of stem or progenitor cells. An alternative, by recruitment of endogenous cells, ...needs experimental evidence. We tested the hypothesis that the articular surface of the synovial joint can regenerate with a biological cue spatially embedded in an anatomically correct bioscaffold. Methods In this proof of concept study, the surface morphology of a rabbit proximal humeral joint was captured with laser scanning and reconstructed by computer-aided design. We fabricated an anatomically correct bioscaffold using a composite of poly-ε-caprolactone and hydroxyapatite. The entire articular surface of unilateral proximal humeral condyles of skeletally mature rabbits was surgically excised and replaced with bioscaffolds spatially infused with transforming growth factor β3 (TGFβ3)-adsorbed or TGFβ3-free collagen hydrogel. Locomotion and weightbearing were assessed 1–2, 3–4, and 5–8 weeks after surgery. At 4 months, regenerated cartilage samples were retrieved from in vivo and assessed for surface fissure, thickness, density, chondrocyte numbers, collagen type II and aggrecan, and mechanical properties. Findings Ten rabbits received TGFβ3-infused bioscaffolds, ten received TGFβ3-free bioscaffolds, and three rabbits underwent humeral-head excision without bioscaffold replacement. All animals in the TGFβ3-delivery group fully resumed weightbearing and locomotion 3–4 weeks after surgery, more consistently than those in the TGFβ3-free group. Defect-only rabbits limped at all times. 4 months after surgery, TGFβ3-infused bioscaffolds were fully covered with hyaline cartilage in the articular surface. TGFβ3-free bioscaffolds had only isolated cartilage formation, and no cartilage formation occurred in defect-only rabbits. TGFβ3 delivery yielded uniformly distributed chondrocytes in a matrix with collagen type II and aggrecan and had significantly greater thickness (p=0·044) and density (p<0·0001) than did cartilage formed without TGFβ3. Compressive and shear properties of TGFβ3-mediated articular cartilage did not differ from those of native articular cartilage, and were significantly greater than those of cartilage formed without TGFβ3. Regenerated cartilage was avascular and integrated with regenerated subchondral bone that had well defined blood vessels. TGFβ3 delivery recruited roughly 130% more cells in the regenerated articular cartilage than did spontaneous cell migration without TGFβ3. Interpretation Our findings suggest that the entire articular surface of the synovial joint can regenerate without cell transplantation. Regeneration of complex tissues is probable by homing of endogenous cells, as exemplified by stratified avascular cartilage and vascularised bone. Whether cell homing acts as an adjunctive or alternative approach of cell delivery for regeneration of tissues with different organisational complexity warrants further investigation. Funding New York State Stem Cell Science; US National Institutes of Health.
A new series of metal-free organic chromophores (TPA-TTAR-A (1), TPA-T-TTAR-A (2), TPA-TTAR-T-A (3), and TPA-T-TTAR-T-A (4)) are synthesized for application in dye-sensitized solar cells (DSSC) based ...on a donor-π-bridge-acceptor (D−π–A) design. Here a simple triphenylamine (TPA) moiety serves as the electron donor, a cyanoacrylic acid as the electron acceptor and anchoring group, and a novel tetrathienoacene (TTA) as the π-bridge unit. Because of the extensively conjugated TTA π-bridge, these dyes exhibit high extinction coefficients (4.5–5.2 × 104 M–1 cm–1). By strategically inserting a thiophene spacer on the donor or acceptor side of the molecules, the electronic structures of these TTA-based dyes can be readily tuned. Furthermore, addition of a thiophene spacer has a significant influence on the dye orientation and self-assembly modality on TiO2 surfaces. The insertion of a thiophene between the π-bridge and the cyanoacrylic acid anchoring group in TPA-TTAR-T-A (dye 3) promotes more vertical dye orientation and denser packing on TiO2 (molecular footprint = 79 Å2), thus enabling optimal dye loading. Using dye 3, a DSSC power conversion efficiency (PCE) of 10.1% with V oc = 0.833 V, J sc = 16.5 mA/cm2, and FF = 70.0% is achieved, among the highest reported to date for metal-free organic DSSC sensitizers using an I–/I3 – redox shuttle. Photophysical measurements on dye-grafted TiO2 films reveal that the additional thiophene unit in dye 3 enhances the electron injection efficiency, in agreement with the high quantum efficiency.
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