Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific ...challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order oftens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most ofthe above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.
Aims
Aggressive meningioma remains incurable with neither chemo‐ nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving ...the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression.
Methods
Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression‐free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked‐down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM‐Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)‐pretreated or control IOMM‐Lee cells were implanted subcutaneously in nude mice.
Results
FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of β‐catenin, cyclin D1, p21, interleukin‐8, vascular endothelial growth factor‐A, PLAU, and epithelial‐to‐mesenchymal transition‐related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model.
Conclusions
Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.
Given observed initial conditions, how well do coupled atmosphere-ocean models predict precipitation climatology with 1-month lead forecast? And how do the models' biases in climatology in turn ...affect prediction of seasonal anomalies? We address these questions based on analysis of 1-month lead retrospective predictions for 21 years of 1981-2001 made by 13 state-of-the-art coupled climate models and their multi-model ensemble (MME). The evaluation of the precipitation climatology is based on a newly designed metrics that consists of the annual mean, the solstitial mode and equinoctial asymmetric mode of the annual cycle, and the rainy season characteristics. We find that the 1-month lead seasonal prediction made by the 13-model ensemble has skills that are much higher than those in individual model ensemble predictions and approached to those in the ERA-40 and NCEP-2 reanalysis in terms of both the precipitation climatology and seasonal anomalies. We also demonstrate that the skill for individual coupled models in predicting seasonal precipitation anomalies is positively correlated with its performances on prediction of the annual mean and annual cycle of precipitation. In addition, the seasonal prediction skill for the tropical SST anomalies, which are the major predictability source of monsoon precipitation in the current coupled models, is closely link to the models' ability in simulating the SST mean state. Correction of the inherent bias in the mean state is critical for improving the long-lead seasonal prediction. Most individual coupled models reproduce realistically the long-term annual mean precipitation and the first annual cycle (solstitial mode), but they have difficulty in capturing the second annual (equinoctial asymmetric) mode faithfully, especially over the Indian Ocean (IO) and Western North Pacific (WNP) where the seasonal cycle in SST has significant biases. The coupled models replicate the monsoon rain domains very well except in the East Asian subtropical monsoon and the tropical WNP summer monsoon regions. The models also capture the gross features of the seasonal march of the rainy season including onset and withdraw of the Asian-Australian monsoon system over four major sub-domains, but striking deficiencies in the coupled model predictions are observed over the South China Sea and WNP region, where considerable biases exist in both the amplitude and phase of the annual cycle and the summer precipitation amount and its interannual variability are underestimated.
Development of advanced high energy density lithium ion batteries is important for promoting electromobility. Making electric vehicles attractive and competitive compared to conventional automobiles ...depends on the availability of reliable, safe, high power, and highly energetic batteries whose components are abundant and cost effective. Nickel rich LiNi x Co y Mn 1−x−y O 2 layered cathode materials ( x > 0.5) are of interest because they can provide very high specific capacity without pushing charging potentials to levels that oxidize the electrolyte solutions. However, these cathode materials suffer from stability problems. We discovered that doping these materials with tungsten (1 mol%) remarkably increases their stability due to a partial layered to cubic (rock salt) phase transition. We demonstrate herein highly stable Li ion battery prototypes consisting of tungsten-stabilized Ni rich cathode materials ( x > 0.9) with specific capacities >220 mA h g -1 . This development can increase the energy density of Li ion batteries more than 30% above the state of the art without compromising durability.
Stent-assisted coiling of intracranial aneurysms requires antiplatelet therapy, typically aspirin and clopidogrel to prevent thromboembolic complications. There is a substantial concern that ...tirofiban may increase the risk of hemorrhage when used as an antiplatelet premedication in ruptured intracranial aneurysms. Our aim was to evaluate the safety and efficacy of intravenous tirofiban administration, instead of oral dual antiplatelet agents, as an antiplatelet premedication for stent-assisted coiling in patients with acutely ruptured intracranial aneurysms.
We conducted a retrospective review of a data base containing a consecutive series of patients who underwent stent-assisted coiling for acutely ruptured intracranial aneurysms between March 2010 and January 2015. Intravenous tirofiban was administered to all patients before stent-assisted coiling, instead of premedication with loading doses of aspirin or clopidogrel.
Forty patients with 41 aneurysms received intravenous tirofiban and underwent stent-assisted coiling. None of the patients had a newly developed intracerebral hemorrhage, subarachnoid hemorrhage, or intraventricular hemorrhage. Intraprocedural aneurysmal rupture occurred in 2 patients (5%). Cerebral infarction developed in 2 patients (5%). Ventriculostomy-related hemorrhage was seen in 2 of 10 patients in whom ventriculostomy was performed before or after coiling. Thirty-four (85%) patients had a good outcome (Glasgow Outcome Score of 4 or 5) at the time of discharge, but 1 patient died of cardiac arrest. None of the patients developed thrombocytopenia, retroperitoneal, gastrointestinal, or genitourinary bleeding related to tirofiban administration.
In our study, tirofiban showed a low risk of symptomatic hemorrhagic or thromboembolic complications. Tirofiban may offer a safe and effective alternative as an antiplatelet premedication during stent-assisted coiling of acutely ruptured intracranial aneurysms.
In this study, an IgG-degrading enzyme derived from
Streptococcus pyogenes
(IdeS) that cleaves human IgG into F(ab′)
2
and Fc fragments reduced or eliminated donor-specific antibodies and permitted ...HLA-incompatible renal transplantation.
An organic field‐effect transistor (OFET) memory device based on pentacene is fabricated using an additional poly(α‐methyl styrene) gate dielectric layer (PαMS, see figure) that has charge‐trapping ...ability (an electret). The device has excellent non‐volatile OFET memory characteristics, believed to originate from the stored charges in PαMS layer and transferred from the semiconductor to the polymeric gate electret.
BACKGROUND: An excess of intra‐abdominal fat is observed frequently in dogs with hyperadrenocorticism (HAC). Adipokine dysregulation is a possible cause of complications related to visceral obesity, ...but little information is available on adipokine in dogs with naturally occurring HAC. OBJECTIVES: To examine the differences in the circulating adipokines concentrations in overweight dogs with and without pituitary‐dependent HAC (PDH). ANIMALS: Thirty healthy dogs and 15 client‐owned dogs with PDH. METHODS: Case–controlled observational study, which enrolled 15 overweight dogs diagnosed with PDH and 30 otherwise healthy dogs of similar body condition score. Nine of 15 dogs with PDH were treated with low‐dose trilostane twice daily and reassessed after treatment. RESULTS: The serum leptin (P < .0001) and insulin (P < .0001) concentrations were significantly higher in the PDH group (leptin, 22.8 ± 8.8 mean ± SD; insulin, 9.1 ± 6.1) than the healthy group (leptin, 4.9 ± 3.7; insulin, 1.9 ± 0.9). However, there were no significant differences in the adiponectin, resistin, tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, IL‐10, and IL‐18 levels between the 2 groups. In the PDH group, the serum cortisol concentrations had a linear association with the leptin concentrations, and there were significant decreases in the leptin (P = .0039) and insulin (P = .0039) levels after trilostane treatment. However, the leptin and insulin levels remained higher after trilostane treatment than in healthy control dogs with similar body condition score. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypercortisolemia in dogs with PDH might upregulate the circulating leptin levels. However, a large population‐based study will be necessary to determine whether the upregulation of leptin is involved directly with the complications caused by HAC.
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.
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