Zoonotic coronavirus (CoV) infections, such as those responsible for the current severe acute respiratory syndrome-CoV 2 (SARS-CoV-2) pandemic, cause grave international public health concern. In ...infected cells, the CoV RNA-synthesizing machinery associates with modified endoplasmic reticulum membranes that are transformed into the viral replication organelle (RO). Although double-membrane vesicles (DMVs) appear to be a pan-CoV RO element, studies to date describe an assortment of additional CoV-induced membrane structures. Despite much speculation, it remains unclear which RO element(s) accommodate viral RNA synthesis. Here we provide detailed 2D and 3D analyses of CoV ROs and show that diverse CoVs essentially induce the same membrane modifications, including the small open double-membrane spherules (DMSs) previously thought to be restricted to gamma- and delta-CoV infections and proposed as sites of replication. Metabolic labeling of newly synthesized viral RNA followed by quantitative electron microscopy (EM) autoradiography revealed abundant viral RNA synthesis associated with DMVs in cells infected with the beta-CoVs Middle East respiratory syndrome-CoV (MERS-CoV) and SARS-CoV and the gamma-CoV infectious bronchitis virus. RNA synthesis could not be linked to DMSs or any other cellular or virus-induced structure. Our results provide a unifying model of the CoV RO and clearly establish DMVs as the central hub for viral RNA synthesis and a potential drug target in CoV infection.
Objective
To evaluate drug survival, effectiveness, pharmacokinetics, immunogenicity, and safety in daily practice after transitioning treatment from original reference infliximab (Remicade REM) to a ...biosimilar infliximab (CT‐P13 Remsima; Inflectra) in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
Methods
Of the initial 222 REM‐treated patients, 192 agreed to transition to CT‐P13 and were included in this multicenter prospective cohort study. Changes in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and changes in the CRP levels, infliximab trough levels, and anti‐infliximab antibody levels were assessed after 6 months, and adverse events (AEs) were documented. Drug survival and prognostic factors were analyzed using Kaplan‐Meier and Cox regression analyses.
Results
During 6 months follow‐up, 24% of the patients (n = 47) discontinued CT‐P13. Thirty‐seven patients restarted REM, 7 switched to another biologic drug, and 3 continued without a biologic drug. The DAS28‐CRP remained stable from baseline to month 6, with a mean ± SD score of 2.2 ± 0.9 at baseline to 2.2 ± 0.8 at 6 months (difference of 0.0 95% confidence interval (95% CI) –0.1, 0.2). The BASDAI increased from a mean ± SD of 3.8 ± 2.0 at baseline to 4.3 ± 2.1 at 6 months (difference of +0.5 95% CI 0.1, 0.9). The CRP levels, infliximab trough levels, and anti‐infliximab antibody levels did not change. Just prior to CT‐P13 discontinuation, the DAS28‐CRP components tender joint count and patient's global assessment of disease activity, as well as the BASDAI were increased compared to baseline. The most frequently reported AEs were arthralgia, fatigue, pruritus, and myalgia. A shorter REM infusion interval (hazard ratio: 0.77 95% CI 0.62, 0.95) at baseline was predictive of discontinuing CT‐P13.
Conclusion
In our cohort, one‐fourth of patients discontinued CT‐P13 during 6 months of follow‐up, mainly due to an increase in the subjective features of the tender joint count and the patient's global assessment of disease activity and/or subjective AEs, possibly explained by nocebo effects and/or incorrect causal attribution effects.
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 notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated ...in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
To provide an observational basis for the Intergovernmental Panel on Climate Change projections of a slowing Atlantic meridional overturning circulation (MOC) in the 21st century, the Overturning in ...the Subpolar North Atlantic Program (OSNAP) observing system was launched in the summer of 2014. The first 21-month record reveals a highly variable overturning circulation responsible for the majority of the heat and freshwater transport across the OSNAP line. In a departure from the prevailing view that changes in deep water formation in the Labrador Sea dominate MOC variability, these results suggest that the conversion of warm, salty, shallow Atlantic waters into colder, fresher, deep waters that move southward in the Irminger and Iceland basins is largely responsible for overturning and its variability in the subpolar basin.
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in ...sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Iron (Fe) is an essential trace element for marine life. Extremely low Fe concentrations limit primary production and nitrogen fixation in large parts of the oceans and consequently influence ocean ...ecosystem functioning. The importance of Fe for ocean ecosystems makes Fe one of the core chemical trace elements in the international GEOTRACES program. Despite the recognized importance of Fe, our present knowledge of its supply and biogeochemical cycle has been limited by mostly fragmentary datasets. Here, we present highly accurate dissolved Fe (DFe) values measured at an unprecedented high intensity (1407 samples) along the longest full ocean depth transect (17,500 kilometers) covering the entire western Atlantic Ocean. DFe measurements along this transect unveiled details about the supply and cycling of Fe. External sources of Fe identified included off-shelf and river supply, hydrothermal vents and aeolian dust. Nevertheless, vertical processes such as the recycling of Fe resulting from the remineralization of sinking organic matter and the removal of Fe by scavenging still dominated the distribution of DFe. In the northern West Atlantic Ocean, Fe recycling and lateral transport from the eastern tropical North Atlantic Oxygen Minimum Zone (OMZ) dominated the DFe-distribution. Finally, our measurements showed that the North Atlantic Deep Water (NADW), the major driver of the so-called ocean conveyor belt, contains excess DFe relative to phosphate after full biological utilization and is therefore an important source of Fe for biological production in the global ocean.
We present five new satellites of the Milky Way discovered in Sloan Digital Sky Survey (SDSS) imaging data, four of which were followed up with either the Subaru or the Isaac Newton Telescopes. They ...include four probable new dwarf galaxies--one each in the constellations of Coma Berenices, Canes Venatici, Leo, and Hercules--together with one unusually extended globular cluster, Segue 1. We provide distances, absolute magnitudes, half-light radii, and color-magnitude diagrams for all five satellites. The morphological features of the color-magnitude diagrams are generally well described by the ridge line of the old, metal-poor globular cluster M92. In the past two years, a total of 10 new Milky Way satellites with effective surface brightness k sub(u) 28 mag arcsec super(-2) have been discovered in SDSS data. They are less luminous, more irregular, and apparently more metal-poor than the previously known nine Milky Way dwarf spheroidals. The relationship between these objects and other populations is discussed. We note that there is a paucity of objects with half-light radii between 640 and 6100 pc. We conjecture that this may represent the division between star clusters and dwarf galaxies.
Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. ...However, the effect of vitamin K on vascular calcification is unknown.
The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD.
In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated–uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables.
We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: −0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: −0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (−205.6 pmol/L; 95% CI: −255.8, −155.3 pmol/L). No adverse events were reported.
MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.
Abstract Blood kinetics and tissue distribution of 20, 80 and 110 nm silver nanoparticles were investigated in rats up to 16 days after intravenous administration once daily for 5 consecutive days. ...Following both single and repeated injection, silver nanoparticles disappeared rapidly from the blood and distributed to all organs evaluated (liver, lungs, spleen, brain, heart, kidneys and testes) regardless of size. The 20 nm particles distributed mainly to liver, followed by kidneys and spleen, whereas the larger particles distributed mainly to spleen followed by liver and lung. In the other organs evaluated, no major differences between the sizes were observed. Size-dependent tissue distribution suggests size-dependent toxicity and health risks. Repeated administration resulted in accumulation in liver, lung and spleen, indicating that these organs may be potential target organs for toxicity after repeated exposure. A physiologically based pharmacokinetic (PBPK) model for nanoparticles which describes the kinetics of silver nanoparticles was developed. Model parameter values were estimated by fitting to data. No clear relation between parameter values and corresponding particle diameters became apparent.
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