Spinel Co3O4, comprising two types of cobalt ions: one Co2+ in the tetrahedral site (Co2+ Td) and the other two Co3+ in the octahedral site (Co3+ Oh), has been widely explored as a promising oxygen ...evolution reaction (OER) catalyst for water electrolysis. However, the roles of two geometrical cobalt ions toward the OER have remained elusive. Here, we investigated the geometrical-site-dependent OER activity of Co3O4 catalyst by substituting Co2+ Td and Co3+ Oh with inactive Zn2+ and Al3+, respectively. Following a thorough in operando analysis by electrochemical impedance spectroscopy and X-ray absorption spectroscopy, it was revealed that Co2+ Td site is responsible for the formation of cobalt oxyhydroxide (CoOOH), which acted as the active site for water oxidation.
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that ...epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.
Background
Whether non–vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear.
Methods and Results
In this ...nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity‐score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43–0.69), 0.82 (0.68–0.98), and 0.81 (0.67–0.97); major bleeding, 0.41 (0.31–0.53), 0.65 (0.53–0.80), and 0.58 (0.46–0.72); and all‐cause mortality, 0.58 (0.51–0.66), 0.61 (0.54–0.68), and 0.57 (0.51–0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low‐dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10–15 mg once daily), respectively. Similar to all‐dose NOACs, all low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard‐dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 0.31–0.65), major bleeding (0.29 0.18–0.46), and mortality (0.23 0.17–0.31) than warfarin.
Conclusions
All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real‐world practice among Asians with nonvalvular atrial fibrillation. All low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard‐dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin.
Abstract Background It is unclear whether the non–vitamin K antagonist oral anticoagulant agents rivaroxaban and dabigatran are superior to warfarin for efficacy and safety outcomes in Asians with ...nonvalvular atrial fibrillation (NVAF). Objectives The aim of this study was to compare the risk for thromboembolic events, bleeding, and mortality associated with rivaroxaban and dabigatran versus warfarin in Asians with NVAF. Methods A nationwide retrospective cohort study was conducted of consecutive patients with NVAF taking rivaroxaban (n = 3,916), dabigatran (n = 5,921), or warfarin (n = 5,251) using data collected from the Taiwan National Health Insurance Research Database between February 1, 2013 and December 31, 2013. The propensity score weighting method was used to balance covariates across study groups. Patients were followed until the first occurrence of any study outcome or the study end date (December 31, 2013). Results A total of 3,425 (87%) and 5,301 (90%) patients were taking low-dose rivaroxaban (10 to 15 mg once daily) and dabigatran (110 mg twice daily), respectively. Compared with warfarin, both rivaroxaban and dabigatran significantly decreased the risk for ischemic stroke or systemic embolism (p = 0.0004 and p = 0.0006, respectively), intracranial hemorrhage (p = 0.0007 and p = 0.0005, respectively), and all-cause mortality (p < 0.0001 and p < 0.0001, respectively) during the short follow-up period. In comparing the 2 non–vitamin K antagonist oral anticoagulant agents with each other, no differences were found regarding risk for ischemic stroke or systemic embolism, intracranial hemorrhage, myocardial infarction, or mortality. Rivaroxaban carried a significantly higher risk for hospitalization for gastrointestinal bleeding than dabigatran (p = 0.0416), but on-treatment analysis showed that the risk for hospitalized gastrointestinal bleeding was similar between the 2 drugs (p = 0.5783). Conclusions In real-world practice among Asians with NVAF, both rivaroxaban and dabigatran were associated with reduced risk for ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality without significantly increased risk for acute myocardial infarction or hospitalization for gastrointestinal bleeding compared with warfarin.
High entropy oxide (HEO) is a new class of lithium‐ion battery anode with high specific capacity and excellent cyclability. The beauty of HEO lies in the unique tailorable properties with respect to ...tunable chemical composition, which enables the use of infinite element combinations to develop new electrode materials. This study synthesizes a series of Co‐free spinel‐type HEOs via a facile hydrothermal method. Based on quaternary medium‐entropy (CrNiMnFe)3O4, the fifth elements of V, Mg, and Cu are added, and their ability to form single‐phase HEOs is investigated. It is demonstrated that the chemical composition of HEOs is critical to the phase purity and corresponding charge–discharge performance. The oxygen vacancy concentration seems to be decisive for the rate capability and reversibility of the HEO electrodes. An inactive spectator element is not necessary for achieving high cyclability, given that the phase purity of the HEO is wisely controlled. The single‐phase (CrNiMnFeCu)3O4 shows a great high‐rate capacity of 480 mAh g−1 at 2000 mA g−1 and almost no capacity decay after 400 cycles. Its phase transition behavior during the lithiation/delithiation process is characterized with operando X‐ray diffraction. A (CrNiMnFeCu)3O4||LiNi0.8Co0.1Mn0.1O2 cell is constructed with 590 Wh kg−1 (based on electrode materials) gravimetric energy density.
A series of Co‐free spinel‐type HEO anodes are fabricated via a facile hydrothermal method. Chemical composition of HEOs is critical to phase purity and oxygen vacancies. Entropy stabilization effects sustain the crystalline framework and electrode reversibility. An inactive spectator element is not needed for the high cyclability of HEO electrodes. A (CrNiMnFeCu)3O4||LiNi0.8Co0.1Mn0.1O2 cell shows an energy density of 590 Wh kg−1.
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis ...factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.
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•TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation•Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization•CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination•Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy
Lim et al. show that inflammation increases PD-L1 expression in tumors through TNF-α-mediated activation of NF-κB, leading to transactivation of CSN5. CSN5 reduces PD-L1 ubiquitination and stabilizes it. Inhibition of CSN5 cooperates with anti-CTLA4 to enhance anti-tumor T cell function and reduce tumor growth.
Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like ...breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2
in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2
in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.
The risk factors of diabetic retinopathy (DR) were investigated extensively in the past studies, but it remains unknown which risk factors were more associated with the DR than others. If we can ...detect the DR related risk factors more accurately, we can then exercise early prevention strategies for diabetic retinopathy in the most high-risk population. The purpose of this study is to build a prediction model for the DR in type 2 diabetes mellitus using data mining techniques including the support vector machines, decision trees, artificial neural networks, and logistic regressions.
Experimental results demonstrated that prediction performance by support vector machines performed better than the other machine learning algorithms and achieved 79.5% and 0.839 in accuracy and area under the receiver operating characteristic curve using percentage split (i.e., data set divided into 80% as trainning and 20% as test), respectively. Evaluated by three-way data split scheme (i.e., data set divided into 60% as training, 20% as validation, and 20% as independent test), our method obtained slightly lower performance compared to percentage split, which suggested that three-way data split is a better way to evaluate the real performance and prevent overestimation. Moreover, we incorporated approaches proposed in previous studies to evaluate our data set and our prediction performance outperformed the other previous studies in most evaluation measures. This lends support to our assumption that appropriate machine learning algorithms combined with discriminative clinical features can effectively detect diabetic retinopathy.
Our method identifies use of insulin and duration of diabetes as novel interpretable features to assist with clinical decisions in identifying the high-risk populations for diabetic retinopathy. If duration of DM increases by 1 year, the odds ratio to have DMR is increased by 9.3%. The odds ratio to have DR is increased by 3.561 times for patients who use insulin compared to patients who do not use insulin. Our results can be used to facilitate development of clinical decision support systems for clinical practice in the future.
The aim of this study is to evaluate the sex-related differences on the risks of perioperative and late outcomes for adult acute aortic dissection (AAD) patients following surgical management.
By ...using Taiwan National Health Insurance Research Database, totally 1,410 female and 3,432 male patients were identified to first-ever receive type A AAD open surgery or type B AAD stenting treatment from 2004 to 2013. We assessed the sex-related difference on outcomes, including in-hospital mortality, all-cause mortality, aortic death, redo aortic surgery, ischemic stroke, and depression during the follow-up period. The analysis was done separately for type A and type B surgeries.
On average, female patients diagnosed with AAD were older than males. There was no significant sex difference of in-hospital mortality or all-cause mortality for both type A open and type B stent surgeries. The risk of redo aortic surgery was significantly greater in males than females (7.8% vs. 4%; unadjusted subdistribution hazard ratio SHR 0.51, 95% CI 0.38-0.69) for type A open surgery, but not for type B stent surgery. Noticeably, the risk of newly-diagnosed depression was significantly greater in females than males (8% vs. 5.1%; unadjusted SHR 1.6, 95% CI 1.24-2.06) for type A open surgery, but not for type B stent surgery.
No significant sex-related difference was found for the in-hospital mortality or accumulative all-cause mortality. However, there were more redo aortic surgeries for males and more postoperative depression for females in type A AAD population.
Background Liver cirrhotic patients with nonvalvular atrial fibrillation have been excluded from randomized clinical studies regarding oral anticoagulants for stroke prevention. Whether non-vitamin K ...antagonist oral anticoagulants ( NOAC s) are superior to warfarin for these patients remains unclear. Methods and Results This nationwide retrospective cohort study, with data collected from the Taiwan National Health Insurance Research Database, enrolled 2428 liver cirrhotic patients with nonvalvular atrial fibrillation taking apixaban (n=171), dabigatran (n=535), rivaroxaban (n=732), or warfarin (n=990) from June 1, 2012, to December 31, 2016. We used propensity score-based stabilized weights to balance covariates across study groups. Patients were followed until the occurrence of an event or the end date of study. The NOAC group (n=1438) showed risk of ischemic stroke/systemic embolism and intracranial hemorrhage comparable to that of the warfarin group (n=990) after adjustment. The NOAC group showed significantly lower risk of gastrointestinal bleeding (hazard ratio: 0.51 95% CI, 0.32-0.79; P=0.0030) and all major bleeding (hazard ratio: 0.51 95% CI, 0.32-0.74; P=0.0003) compared with warfarin group. Overall, 90% (n=1290) of patients were taking a low-dose NOAC (apixaban 2.5 mg twice daily, rivaroxaban 10-15 mg daily, or dabigatran 110 mg twice daily). The subgroup analysis indicated that both dabigatran and rivaroxaban showed lower risk of all major bleeding than warfarin. The advantage of lower gastrointestinal and all major bleeding with NOACs over warfarin is contributed by those subgroups with either nonalcoholic or nonadvanced liver cirrhosis. Conclusions NOACs have a risk of thromboembolism comparable to that of warfarin and a lower risk of major bleeding among liver cirrhotic Asian patients with nonvalvular atrial fibrillation. Consequently, thromboprophylaxis with low-dose NOAC s may be considered for such patients.
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