Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

Genome-wide identification and expression analysis of the glycosyl hydrolase family 1 genes in Medicago sativa revealed their potential roles in response to multiple abiotic stresses.

Glycoside hydrolase family 1 (GH1) ß-glucosidases (BGLUs), are encoded by a large number of genes, which participate in the development and stress response of plants, particularly under biotic and abiotic stresses through the activation of phytohormones. However, there are few studies systematically analyzing stress or hormone-responsive BGLU genes in alfalfa. In this study, a total of 179 BGLU genes of the glycoside hydrolase family 1 were identified in the genome of alfalfa, and then were classified into five distinct clusters. Sequence alignments revealed several conserved and unique motifs among these MsBGLU proteins. Many cis-acting elements related to abiotic stresses and phytohormones were identified in the promoter of some MsBGLUs. Moreover, RNA-seq and RT-qPCR analyses showed that these MsBGLU genes exhibited distinct expression patterns in response to different abiotic stress and hormonal treatments. In summary, this study suggests that MsBGLU genes play crucial roles in response to various abiotic stresses and hormonal responses, and provides candidate genes for stress tolerance breeding in alfalfa.

Integrated physiological, metabolomic, and transcriptomic analyses elucidate the regulation mechanisms of lignin synthesis under osmotic stress in alfalfa leaf (Medicago sativa L.).

Alfalfa, an essential forage crop known for its high yield, nutritional value, and strong adaptability, has been widely cultivated worldwide. The yield and quality of alfalfa are frequently jeopardized due to environmental degradation. Lignin, a constituent of the cell wall, enhances plant resistance to abiotic stress, which often causes osmotic stress in plant cells. However, how lignin responds to osmotic stress in leaves remains unclear. This study explored the effects of osmotic stress on lignin accumulation and the contents of intermediate metabolites involved in lignin synthesis in alfalfa leaves. Osmotic stress caused an increase in lignin accumulation and the alteration of core enzyme activities and gene expression in the phenylpropanoid pathway. We identified five hub genes (CSE, CCR, CADa, CADb, and POD) and thirty edge genes (including WRKYs, MYBs, and UBPs) by integrating transcriptome and metabolome analyses. In addition, ABA and ethylene signaling induced by osmotic stress regulated lignin biosynthesis in a contradictory way. These findings contribute to a new theoretical foundation for the breeding of high-quality and resistant alfalfa varieties.

Value of intravenous thrombolysis in endovascular treatment for large-vessel anterior circulation stroke: individual participant data meta-analysis of six randomised trials.

BACKGROUND: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. METHODS: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986. FINDINGS: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly. INTERPRETATION: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment. FUNDING: Stryker and Amsterdam University Medical Centers, University of Amsterdam.

Modulation of Buried Interface by 1-(3-aminopropyl)-Imidazole for Efficient Inverted Formamidinium-Cesium Perovskite Solar Cells.

Considering the direct influence of substrate surface nature on perovskite (PVK) film growth, buried interfacial engineering is crucial to obtain ideal perovskite solar cells (PSCs). Herein, 1-(3-aminopropyl)-imidazole (API) is introduced at polytriarylamine (PTAA)/PVK interface to modulate the bottom property of PVK. First, the introduction of API improves the growth of PVK grains and reduces the Pb2+ defects and residual PbI2 present at the bottom of the film, contributing to the acquisition of high-quality PVK film. Besides, the presence of API can optimize the energy structure between PVK and PTAA, which facilitates the interfacial charge transfer. Density functional theory (DFT) reveals that the electron donor unit (R-C ═ N) of the API prefers to bind with Pb2+ traps at the PVK interface, while the formation of hydrogen bonds between the R-NH2 of API and I- strengthens the above binding ability. Consequently, the optimum API-treated inverted formamidinium-cesium (FA/Cs) PSCs yields a champion power conversion efficiency (PCE) of 22.02% and exhibited favorable stability.

Laser-Ignited Lipid Peroxidation Nanoamplifiers for Strengthening Tumor Photodynamic Therapy Through Aggravating Ferroptotic Propagation and Sustainable High Immunogenicity.

Photodynamic therapy (PDT) is extensively investigated for tumor therapy in the clinic. However, the efficacy of PDT is severely limited by the tissue penetrability of light, short effective half-life and radius of reactive oxygen species (ROS), and the weak immunostimulatory effect. In this study, a glutathione (GSH)-activatable nano-photosensitizer is developed to load with arachidonic acid (AA) and camouflage by erythrocyte membrane, which serves as a laser-ignited lipid peroxidation nanoamplifier (MAR). The photosensitive effect of MAR is recovered accompanied by the degradation in the tumor microenvironment and triggers the peroxidation of AA upon laser excitation. Interestingly, it aggravates the propagation of ferroptosis among cancer cells by driving the continuous lipid peroxidation chain reactions with the participation of the degradation products, ferrous ions (Fe2+), and AA. Consequently, even the deep-seated tumor cells without illumination also undergo ferroptosis owing to the propagation of ferroptotic signal. Moreover, the residual tumor cells undergoing ferroptosis still maintain high immunogenicity after PDT, thus continuously triggering sufficient tumor-associated antigens (TAAs) release to remarkably promote the anti-tumor immune response. Therefore, this study will provide a novel "all-in-one" nano-photosensitizer that not only amplifies the damaging effect and expands the effective range of PDT but also improves the immunostimulatory effect after PDT.

Doping of ZnO Electron Transport Layer with Organic Dye Molecules to Enhance Efficiency and Photo-Stability of the Non-Fullerene Organic Solar Cells.

The solution-processed zinc oxide (ZnO) electron transport layer (ETL) always exhibits ubiquitous defects, and its photocatalytic activity is detrimental for the organic solar cell (OSC) to achieve high efficiency and stability. Herein, an organic dye molecule, PDINN-S is introduced, to dope ZnO, constructing a hybrid ZnO:PDINN-S ETL. This hybrid ETL exhibits improved electron mobility and conductivity, particularly post-light exposure. The catalytic activity of ZnO is also effectively suppressed.Consequently, the efficiency and photo-stability of inverted non-fullerene OSCs are synergistically enhanced. The devices based on PM6:Y6/PM6:BTP-eC9 active layer with ZnO:PDINN-S as ETL give impressive power conversion efficiencies (PCEs) of 16.78%/17.59%, significantly higher than those with pure ZnO as ETL (PCEs = 15.31%/16.04%). Moreover, ZnO:PDINN-S-based device shows exceptional long-term stability under continuous AM 1.5G illumination (T80 = 1130 h) , overwhelming the reference device (T80 = 455 h). In addition, Incorporating PDINN-S into ZnO alleviate mechanical stress within the inorganic lattice, making ZnO:PDINN-S ETL more suitable for the fabrication of flexible devices. Overall, doping ZnO with organic dye molecules offers an innovative strategy for developing multifunctional and efficient hybrid ETL of the non-fullerene OSCs with excellent efficiency and photo-stability.

Predictors of outcome in large vessel occlusion stroke patients with intravenous tirofiban treatment: a post hoc analysis of the RESCUE BT clinical trial.

OBJECTIVE: The aim of this study was to investigate the factors influencing good outcomes in patients receiving only intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke. METHODS: Post hoc exploratory analysis using the RESCUE BT trial identified consecutive patients who received intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke in 55 comprehensive stroke centers from October 2018 to January 2022 in China. RESULTS: A total of 521 patients received intravenous tirofiban, 253 of whom achieved a good 90-day outcome (modified Rankin Scale [mRS] 0-2). Younger age (adjusted odds ratio [aOR]: 0.965, 95% confidence interval [CI]: 0.947-0.982; p < 0.001), lower serum glucose (aOR: 0.865, 95%CI: 0.807-0.928; p < 0.001), lower baseline National Institutes of Health Stroke Scale (NIHSS) score (aOR: 0.907, 95%CI: 0.869-0.947; p < 0.001), fewer total passes (aOR: 0.791, 95%CI: 0.665-0.939; p = 0.008), shorter punctures to recanalization time (aOR: 0.995, 95%CI:0.991-0.999; p = 0.017), and modified Thrombolysis in Cerebral Infarction (mTICI) score 2b to 3 (aOR: 8.330, 95%CI: 2.705-25.653; p < 0.001) were independent predictors of good outcomes after intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke. CONCLUSION: Younger age, lower serum glucose level, lower baseline NIHSS score, fewer total passes, shorter punctures to recanalization time, and mTICI scores of 2b to 3 were independent predictors of good outcomes after intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke. CHINESE CLINICAL TRIAL REGISTRY IDENTIFIER: ChiCTR-IOR-17014167.

The impact of stress hyperglycemia ratio on short-term and long-term outcomes for acute basilar artery occlusion underwent endovascular treatment.

BACKGROUND: Stress hyperglycemia ratio (SHR) reflects a true acute hyperglycemic state during acute basilar artery occlusion (ABAO). We aimed to investigate the association between SHR and short-term and long-term outcomes in patients with ABAO receiving endovascular treatment (EVT). METHODS: We selected patients treated with EVT from the BASILAR study, a nationwide prospective registry. A total 250 patients with documented glucose and glycated hemoglobin (HbA1C) values at admission were included. SHR was calculated as the ratio of glucose/HbA1C. All 250 patients completed 90 days of follow-up and 234 patients (93.6%) completed 1 year of follow-up. The primary outcome was the favorable outcome defined as modified Rankin Scale (mRS) score ≤ 3 at 90 days. Safety outcomes included mortality at 90 days and 1 year, and intracranial hemorrhage. RESULTS: Among the 250 patients included, patients with higher tertiles of SHR were associated with decreased odds of a favorable functional outcome at 90 days (adjusted OR, 0.26; 95% CI, 0.12-0.56; P = 0.001 and adjusted OR, 0.37; 95% CI, 0.18-0.80; P = 0.01; respectively) and 1 year (adjusted OR, 0.34; 95% CI, 0.16-0.73; P = 0.006 and adjusted OR, 0.38; 95% CI, 0.18-0.82; P = 0.01; respectively) after adjusting for confounding covariates. The mortality was comparable across tertiles of SHR groups at 90 days and 1 year. CONCLUSIONS: Our study showed that SHR was associated with a decreased probability of favorable functional outcome both at 90 days and 1 year after EVT in patients with ABAO. The relationship was more pronounced in non-diabetes patients. TRIAL REGISTRATION: Clinical Trial Registry Identifier: ChiCTR1800014759 (November 12, 2013).

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

Effect of Imaging Selection Paradigms on Endovascular Thrombectomy Outcomes in Patients With Acute Ischemic Stroke.

BACKGROUND: The effect of imaging selection paradigms on endovascular thrombectomy outcomes in patients with acute ischemic stroke with large vessel occlusion remains uncertain. The study aimed to assess the effect of basic imaging (noncontrast computed tomography with or without computed tomographic angiography) versus advanced imaging (magnetic resonance imaging or computed tomography perfusion) on clinical outcomes following thrombectomy in patients with stroke with large vessel occlusion in the early and extended windows using a pooled analysis of patient-level data from 2 pivotal randomized clinical trials done in China. METHODS: This post hoc analysis used data from 1182 patients included in 2 multicenter, randomized controlled trials in China that evaluated adjunct therapies to endovascular treatment for acute ischemic stroke (Direct Endovascular Treatment for Large Artery Anterior Circulation Stroke performed from May 20, 2018, through May 2, 2020, and Intravenous Tirofiban Before Endovascular Treatment in Stroke from October 10, 2018, through October 31, 2021). Patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery (M1/M2 segments) were categorized according to baseline imaging modality (basic versus advanced) as well as treatment time window (early, 0-6 hours versus extended, 6-24 hours from last known well to puncture). The primary outcome was the proportion of patients with functional independence (modified Rankin Scale score of 0-2) at 90 days. Multivariable Poisson regression analysis was performed to determine the association between imaging selection modality and outcomes after endovascular treatment at each time windows. RESULTS: A total of 1182 patients were included in this cohort analysis, with 648 in the early (471 with basic imaging versus 177 advanced imaging) and 534 in the extended (222 basic imaging versus 312 advanced imaging) time window. There were no differences in 90-day functional independence between the advanced and basic imaging groups in either time windows (early window: adjusted relative risk, 0.99 [95% CI, 0.84-1.16]; P=0.91; extended window: adjusted relative risk, 1.00 [95% CI, 0.84-1.20]; P=0.97). CONCLUSIONS: In this post hoc analysis of 2 randomized clinical trial pooled data involving patients with large vessel occlusion stroke, an association between imaging selection modality and clinical or safety outcomes for patients undergoing thrombectomy in either the early or extended windows was not detected. Our study adds to the growing body of literature on simpler imaging paradigms to assess thrombectomy eligibility across both the early and extended time windows. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.

WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia.

WDR54 has been recently identified as a novel oncogene in colorectal and bladder cancers. However, the expression and function of WDR54 in T-cell acute lymphoblastic leukemia (T-ALL) were not reported. In this study, we investigated the expression of WDR54 in T-ALL, as well as its function in T-ALL pathogenesis using cell lines and T-ALL xenograft. Bioinformatics analysis indicated high mRNA expression of WDR54 in T-ALL. We further confirmed that the expression of WDR54 was significantly elevated in T-ALL. Depletion of WDR54 dramatically inhibited cell viability and induced apoptosis and cell cycle arrest at S phase in T-ALL cells in vitro. Moreover, knockdown of WDR54 impeded the process of leukemogenesis in a Jurkat xenograft model in vivo. Mechanistically, the expression of PDPK1, phospho-AKT (p-AKT), total AKT, phospho-ERK (p-ERK), Bcl-2 and Bcl-xL were downregulated, while cleaved caspase-3 and cleaved caspase-9 were upregulated in T-ALL cells with WDR54 knockdown. Additionally, RNA-seq analysis indicated that WDR54 might regulate the expression of some oncogenic genes involved in multiple signaling pathways. Taken together, these findings suggest that WDR54 may be involved in the pathogenesis of T-ALL and serve as a potential therapeutic target for the treatment of T-ALL.

Clinical Predictors for Early Mortality of Patients with Acute Basilar Artery Occlusion.

BACKGROUND: Acute ischemic stroke due to basilar artery occlusion (BAO) is associated with the highest mortality in patients with large vessel occlusion. This study aimed to identify modifiable risk factors of early mortality in patients with BAO. METHODS AND RESULTS: This was a cohort study of consecutive patients with BAO admitted to 47 stroke centers in China between January 2014 and May 2019. The primary outcome was all-cause mortality within 7 days after hospitalization. Of 829 patients, 164 died (0-3 days: 115; 4-7 days: 49) within 7 days after hospitalization. Among pre- and periprocedural variables, higher admission National Institutes of Health Stroke Scale (NIHSS, adjusted OR, 1.06, 95% CI: 1.04-1.09; p < 0.001), lower admission posterior circulation-Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS, adjusted OR, 0.88, 95% CI: 0.79-0.98; p = 0.02), lower Basilar Artery on Computed Tomography Angiography score (BATMAN, adjusted OR, 0.84, 95% CI: 0.76-0.93; p = 0.001), and recanalization failure (adjusted OR, 2.99, 95% CI: 2.04-4.38; p < 0.001) were independently associated with a higher risk of early mortality. Herniation (adjusted OR, 2.84, 95% CI: 1.52-5.30; p = 0.001) is an independent postprocedural predictor of early mortality. In patients dying ≤3 days, higher NIHSS (p < 0.001), lower pc-ASPECTS (p = 0.01), lower BATMAN (p = 0.004), recanalization failure (p < 0.001), herniation (p = 0.001), gastrointestinal hemorrhage (p = 0.046), and absence of pneumonia (p < 0.001) were independent predictors of early mortality. Higher NIHSS (p = 0.01), recanalization failure (p < 0.001), and pneumonia (p = 0.03) were independently associated with early mortality between 4 and 7 days. CONCLUSIONS: Recanalization failure, herniation, gastrointestinal hemorrhage, and pneumonia are potentially modifiable risk factors for early mortality in basilar artery occlusion.

Turbulent Taylor-Couette flow of dilute polymeric solutions: a 10-year retrospective.

This retrospective aims to present a coherent history of important findings in direct numerical simulations and experiments in turbulent Taylor-Couette (TC) flow of dilute polymeric solutions in the last decade. Specifically, the sequence of flow transitions due to a continuous increase of fluid elasticity from classical Newtonian, to inertially and in turn to elastically dominated, and finally to the inertialess purely elastic turbulence, is presented. In each elastically modified flow state, the drag modification, coherent flow structures, velocity and elastic stress statistics, mechanism of turbulent kinetic energy production, spectral features as well as the self-sustaining cycles of turbulence, are discussed. Finally, to provide a broader perspective, an overview of important similarities and differences between elastically induced turbulence in prototypical curvilinear and rectilinear shear flows including the curvature-free limit of TC flow, namely, the spanwise-rotating plane Couette flow, is presented. This article is part of the theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (part 1)'.

High Conductivity, Semiconducting, and Metallic PEDOT:PSS Electrode for All-Plastic Solar Cells.

Plastic electrodes are desirable for the rapid development of flexible organic electronics. In this article, a plastic electrode has been prepared by employing traditional conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) and plastic substrate polyethersulfone (PES). The completed electrode (Denote as HC-PEDOT:PSS) treated by 80% concentrated sulfuric acid (H2SO4) possesses a high electrical conductivity of over 2673 S/cm and a high transmittance of over 90% at 550 nm. The high conductivity is attributed to the regular arrangement of PEDOT molecules, which has been proved by the X-ray diffraction characterization. Temperature-dependent conductivity measurement reveals that the HC-PEDOT:PSS possesses both semiconducting and metallic properties. The binding force and effects between the PEDOT and PEI are investigated in detail. All plastic solar cells with a classical device structure of PES/HC-PEDOT:PSS/PEI/P3HT:ICBA/EG-PEDOT:PSS show a PCE of 4.05%. The ITO-free device with a structure of Glass/HC-PEDOT:PSS/Al4083/PM6:Y6/PDINO/Ag delivers an open-circuit voltage (VOC) of 0.81 V, short-circuit current (JSC ) of 23.5 mA/cm2, fill factor (FF) of 0.67 and a moderate power conversion efficiency (PCE) of 12.8%. The above results demonstrate the HC-PEDOT:PSS electrode is a promising candidate for all-plastic solar cells and ITO-free organic solar cells.

One-Year Outcome After Endovascular Treatment for Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: The BASILAR registry, a nationwide prospective nonrandomized study conducted in China, enrolled consecutive patients with acute basilar artery occlusion receiving endovascular treatment or conventional-treatment from January 2014 to May 2019. This article aimed to report the results of clinical follow-up at one year among these patients. METHODS: The primary outcome was the modified Rankin Scale at one year, assessed as a common odds ratio using ordinal logistic regression analysis adjusted for prespecified prognostic factors. Secondary outcomes included the modified Rankin Scale-based outcome group at one year (0-1, 0-2, or 0-3) and all-cause death. RESULTS: Of the 829 patients enrolled in the original BASILAR registry, one-year data were available for 785 patients (94.7%). The distribution of outcomes on the modified Rankin Scale favored endovascular treatment over conventional-treatment (adjusted common odds ratio, 4.50 [95% CI, 2.81-7.29]; P<0.001). The cumulative one-year mortality rate was 54.6% in the endovascular treatment group versus 83.5% in the conventional-treatment group (adjusted odds ratio, 4.36 [95% CI, 2.69-7.29]; P<0.001). CONCLUSIONS: The beneficial effect of endovascular treatment on functional outcome at one year in patients with acute basilar artery occlusion is similar to that reported at 90 days in the original study. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1800014759.

Tumor promoter TPA activates Wnt/ß-catenin signaling in a casein kinase 1-dependent manner.

The tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) has been defined by its ability to promote tumorigenesis on carcinogen-initiated mouse skin. Activation of Wnt/ß-catenin signaling has a decisive role in mouse skin carcinogenesis, but it remains unclear how TPA activates Wnt/ß-catenin signaling in mouse skin carcinogenesis. Here, we found that TPA could enhance Wnt/ß-catenin signaling in a casein kinase 1 (CK1) ε/δ-dependent manner. TPA stabilized CK1ε and enhanced its kinase activity. TPA further induced the phosphorylation of LRP6 at Thr1479 and Ser1490 and the formation of a CK1ε-LRP6-axin1 complex, leading to an increase in cytosolic ß-catenin. Moreover, TPA increased the association of ß-catenin with TCF4E in a CK1ε/δ-dependent way, resulting in the activation of Wnt target genes. Consistently, treatment with a selective CK1ε/δ inhibitor SR3029 suppressed TPA-induced skin tumor formation in vivo, probably through blocking Wnt/ß-catenin signaling. Taken together, our study has identified a pathway by which TPA activates Wnt/ß-catenin signaling.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

Sulfur-Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/ß-Catenin Signaling.

The sulfur-coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS, which contain C,N and S,S (dithione) chelating ligands, were found to inhibit breast cancer tumorigenesis and metastasis by targeting Wnt/ß-catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induces the degradation of LRP6, thereby decreasing the protein levels of DVL2, ß-catenin and activated ß-catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate the stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti-tumor and anti-metastasis effects in mouse xenograft models through the blockage of Wnt/ß-catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.

CDDO-Me Elicits Anti-Breast Cancer Activity by Targeting LRP6 and FZD7 Receptor Complex.

Aberrant activation of the Wnt/ß-catenin pathway leads to the development of multiple cancers, including breast cancer. Development of therapeutic agents against this signaling pathway is an urgent need. In this study, we found that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) could inhibit Wnt/ß-catenin signaling mainly through targeting the low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed that CDDO-Me mediated the degradation of FZD7 in an LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and FZD7 and reduced the levels of phosphorylated Disheveled (DVL) 2 and active ß-catenin, resulting in the downregulation of Wnt target genes and several cancer stem cell (CSC) marker genes. In a murine xenograft bearing mouse mammary tumor virus (MMTV)-Wnt1-driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth and was accompanied by reduced expression of phosphorylated and total LRP6, phosphorylated and unphosphorylated DVL2, active ß-catenin, several Wnt target genes, and CSC marker genes. Collectively, the results of our study present that CDDO-Me is a potent Wnt/ß-catenin signaling inhibitor that may be a promising therapeutic agent against breast cancer. SIGNIFICANCE STATEMENT: Blocking the membrane receptor complex consisting of low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 may help developing therapeutic approaches for cancers, including breast cancers. Our study indicates that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) can inhibit Wnt/ß-catenin signaling by inducing the ubiquitination and degradation of LRP6/FZD7 membrane receptor complex via a lysosomal pathway. We also found that the ectodomain of LRP6 is essential for CDDO-Me-induced FZD7 degradation. Defining CDDO-Me as a novel inhibitor of Wnt/ß-catenin signaling, our results provide insight into the mechanism of its anticancer activity.