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BACKGROUND: In the RESCUE BT (Endovascular Treatment With versus Without Tirofiban for Stroke Patients with Large Vessel Occlusion) trial, enrollment in extended time window was based on non-contrast computed tomography. To assess whether perioperative intravenous tirofiban would further enhance the clinical benefit of endovascular therapy in the RESCUE BT trial according to advanced imaging criteria based on current American Heart Association/American Stroke Association (AHA/ASA) guidelines. METHODS: This is a secondary analysis of the RESCUE BT trial. Patients who were eligible for endovascular thrombectomy in the 6-hour window and met the criteria of the DAWN or DEFUSE 3 trials in the extended window according to the AHA/ASA guidelines were analyzed. The primary outcome was the distribution of the 90-day modified Rankin Scale (mRS) scores. Safety outcomes included the incidence of symptomatic intracranial hemorrhage (sICH) within 48 hours and 90-day mortality. RESULTS: A total of 652 patients (319 in tirofiban group and 333 in placebo group) who meeting the AHA/ASA guidelines were included in this analysis, with median (IQR) age of 68 (58-75) years, 278 (42.6%) were women. The median 90-day mRS score was 3 (IQR, 1-4) in the tirofiban group, and 3 (IQR, 1-4) in the placebo group. The adjusted common odds ratio (OR) for a lower level of disability with tirofiban than with placebo was 1.08 (95% confidence interval [CI], 0.83-1.42). The incidence of sICH (10.1% versus 6.3%; adjusted OR 1.70; [95% CI, 0.95-3.04]) was not significantly different between groups. However, intravenous tirofiban might be associated with lower disability level (adjusted common OR, 1.74 [95% CI, 1.14-2.65]; P=0.01) in patients with large artery atherosclerosis. CONCLUSIONS: There was no significant difference in the severity of disability at 90 days with intravenous tirofiban compared to placebo in patients who underwent endovascular therapy according to AHA/ASA guidelines. We observed potential benefits of tirofiban in patients with large artery atherosclerosis, but there was an increased risk of sICH in patients with cardioembolism stroke.
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BACKGROUND: Previous trials confirmed the benefit of endovascular treatment (EVT) in acute large core stroke, but the effect of EVT on outcomes in these patients based on noncontrast computed tomography (NCCT) in real-world clinical practice was unclear. The aim of this study was to explore the effect of EVT versus standard medical treatment (SMT) in patients with large ischemic core stroke defined as Alberta Stroke Program Early CT Score (ASPECTS) ≤5 based on NCCT alone. MATERIALS AND METHODS: Patients with acute large core stroke at 38 Chinese centers between November 2021 and February 2023 were reviewed from a prospectively maintained database. The primary outcome was favorable functional outcome [modified Rankin Scale score (mRS), 0-3] at 90 days. Safety outcomes included 48 h symptomatic intracerebral hemorrhage (sICH) and 90-day mortality. RESULTS: Of 745 eligible patients recruited at 38 stroke centers between November 2021 and February 2023, 490 were treated with EVT+SMT and 255 with SMT alone. One hundred and eighty-one (36.9%) in the EVT group achieved favorable functional independence versus 48 (18.8%) treated with SMT only [adjusted risk ratio (RR), 1.86; 95% CI: 1.43-2.42, P <0.001; adjusted risk difference (RD), 13.77; 95% CI: 7.40-20.15, P <0.001]. The proportion of sICH was significantly higher in patients undergoing EVT (13.3 vs. 2.4%; adjusted RR, 5.17; 95% CI: 2.17-12.32, P <0.001; adjusted RD, 10.10; 95% CI: 6.12-14.09, P <0.001). No significant difference of mortality between the groups was observed (41.8 vs. 49.0%; adjusted RR, 0.91; 95% CI: 0.77-1.07, P =0.24; adjusted RD, -5.91; 95% CI: -12.91-1.09, P =0.1). CONCLUSION: Among patients with acute large core stroke based on NCCT in real-world, EVT is associated with better functional outcomes at 90 days despite of higher risk of sICH. Rates of procedure-related complications were relatively higher in the EVT+SMT group.
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Procedimentos Endovasculares , Humanos , Masculino , Feminino , Procedimentos Endovasculares/efeitos adversos , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Estudos de Coortes , Tomografia Computadorizada por Raios X , AVC Isquêmico/terapia , AVC Isquêmico/mortalidade , AVC Isquêmico/diagnóstico por imagem , Estudos Retrospectivos , Idoso de 80 Anos ou mais , China/epidemiologiaRESUMO
Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the ß-catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin-proteasome pathway by promoting the interaction of E3 ubiquitin-protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/ß-catenin-dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/ß-catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.
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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.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Peroxidação de Lipídeos , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Glutationa/metabolismo , Linhagem Celular TumoralRESUMO
OBJECTIVE: To evaluate the non-inferiority of endovascular treatment (EVT) alone versus intravenous thrombolysis (IVT) followed by EVT and to assess its heterogeneity across prespecified subgroups. METHODS: We pooled data from two trials (SKIP in Japan; DEVT in China). Individual patient data were pooled to assess outcomes and heterogeneity of treatment effect. The primary outcome was functional independence (modified Rankin Scale score 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and 90-day mortality. RESULTS: We included 438 patients (217 EVT alone; 221 combined IVT+EVT). The meta-analysis failed to demonstrate the non-inferiority of EVT alone over combined IVT+EVT in achieving 90-day functional independence (56.7% vs 51.6%; adjusted common odds ratio (cOR)=1.27, 95% CI 0.84 to 1.92, pnon-inferiority=0.06). Effect sizes favoring EVT alone were present with stroke onset to puncture time longer than 180 min (cOR=2.28, 95% CI 1.18 to 4.38, pinteraction ≤180 vs >180 min=0.02) and intracranial internal carotid artery ICA occlusions (for ICA cOR=3.04, 95% CI 1.10 to 8.43, pinteraction ICA vs MCA=0.08). The rates of sICH (6.5% vs 9.0%; cOR=0.77, 95% CI 0.37 to 1.61) and 90-day mortality (12.9% vs 13.6%; cOR=1.05, 95% CI 0.58 to 1.89) were comparable. CONCLUSIONS: The cumulative data of these two recent Asian trials failed to unequivocally demonstrate the non-inferiority of EVT alone over combined IVT+EVT. However, our study suggests a potential role for more individualized decision-making. Specifically, Asian patients with stroke onset to EVT longer than 180 min, as well as those with intracranial ICA occlusions and those with atrial fibrillation might have better outcomes with EVT alone than with combined IVT+EVT.
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Arteriopatias Oclusivas , Isquemia Encefálica , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Isquemia Encefálica/terapia , Procedimentos Endovasculares/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas , Distribuição Aleatória , Acidente Vascular Cerebral/terapia , Trombectomia , Terapia Trombolítica , Resultado do Tratamento , Ensaios Clínicos como AssuntoRESUMO
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.
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Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Apoptose/genética , Linfócitos T/metabolismo , Proteínas Quinases Dependentes de 3-FosfoinositídeoRESUMO
The inert atmosphere in chemical looping (CL) technology can considerably inhibit the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans during the thermal treatment of polyvinyl chloride plastic (PVC) waste. In this study, PVC was innovatively converted to dechlorinated fuel gas via CL gasification under a high reaction temperature (RT) and the inert atmosphere by applying an unmodified bauxite residue (BR) as both a dechlorination agent and oxygen carrier. The dechlorination efficiency reached 49.98% at an oxygen ratio of only 0.1. Furthermore, a moderate RT (750 °C in this study) and an increased oxygen ratio enhanced the dechlorination effect. The highest dechlorination efficiency (92.12%) was achieved at an oxygen ratio of 0.6. Iron oxides in BR improved the generation of syngas from CL reactions. The yields of the effective gases (CH4, H2, and CO) increased by 57.13% to 0.121 Nm3/kg with an increase in oxygen ratio from 0 to 0.6. A high RT improved the production of the effective gases (an 809.39% increase to 0.344 Nm3/kg from 600 to 900 °C). Energy-dispersive spectroscopy and X-ray diffraction were used to study the mechanism, and formation of NaCl and Fe3O4 was observed on the reacted BR, indicating the successful adsorption of Cl and its capability as an oxygen carrier. Therefore, BR eliminated Cl in situ and enhanced the generation of value-added syngas, thereby achieving efficient PVC conversion.
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Oxigênio , Dibenzodioxinas Policloradas , Gases , Temperatura Alta , Cloreto de PolivinilaRESUMO
Isovitexin (ISO) is a glycosylated flavonoid obtained from Asian rice that has been reported to have anti-inflammatory effect. However, the effects of ISO on colitis have not been reported. In the present study, we aimed to explore the protective effects of isovitexin on colitis using the dextran sodium sulfate (DSS)-induced model. In vitro, the protective mechanism was investigated in TNF-α-stimulated IEC cells. Inflammatory cytokines were measured by ELISA. The signaling pathways were measured by Western blot analysis. ISO attenuated DSS-induced colitis through reducing body weight loss and colonic histological changes. Also, the levels of TNF-α and IL-1ß induced by DSS were inhibited by ISO. The MPO activity induced by DSS was attenuated by ISO. In vitro, ISO inhibited IL-6 and IL-1ß production in TNF-α-stimulated cells. ISO increased the expression of tight junction proteins ZO-1 and occludin. Also, ISO inhibited TNF-α-induced NF-κB activation. In addition, ISO was found to increase the expression of aryl hydrocarbon receptor (AhR). And inhibition of AhR by its antagonist CH223191 could reverse these effects of ISO. ISO inhibited DSS-induced colitis in mice through suppressing inflammation and preserving intestinal barrier integrity through activating AhR. ISO may be useful as a potential therapeutic agent for colitis.
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Colite Ulcerativa , Colite , Animais , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colite Ulcerativa/tratamento farmacológicoRESUMO
Bacterial infections remain a major cause of morbidity worldwide due to drug resistance of pathogenic bacteria. Photodynamic therapy (PDT) has emerged as a promising approach to overcome this drug resistance. However, existing photosensitizers (PSs) are broad-spectrum antibacterial agents that dysregulate the microflora balance resulting in undesirable side effects. Herein, we synthesized a series of aggregation-induced emission (AIE)-active PSs with a lipophilic cationic AIE core with varying charges, named TBTCP and its derivatives. The association of the difference in their molecular charge with the antibacterial effects was systemically investigated. Among the derivatives presented, TBTCP-SF with the electronegative sulfonate group nulled its ability to bind to and ablate Gram-positive (G+) or Gram-negative (G-) bacteria. TBTCP-QY modified by electropositive quaternary ammonium facilitated binding and augmented the photodynamic antibacterial activity for both G+ and G- bacteria. TBTCP-PEG with hydrophilic neutral ligands selectively bound and inactivated G+ bacteria. Under white-light illumination, TBTCP-PEG ablated 99.9% methicillin-resistant Staphylococcus aureus (MRSA) and promoted wound healing in MRSA-infected mice, eliminating MRSA infection both in vitro and in vivo. Our work provides unprecedented insight into the utility of AIE-active PSs for highly targeted and efficient photodynamic ablation of either G+ or G- bacteria that can be translated to next-generation antibacterial materials.
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Staphylococcus aureus Resistente à Meticilina , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes/química , Fotoquimioterapia/métodos , Antibacterianos/química , LuzRESUMO
BACKGROUND: Predicting mortality in stroke patients using information available before endovascular treatment (EVT) is an essential component for supporting clinical decision-making. Although the mortality rate of acute basilar artery occlusion (ABAO) after EVT has reached 40%, few studies have focused on predicting mortality in these individuals. Thus, we aimed to develop and validate a machine learning-based mortality prediction tool based on preoperative information for ABAO patients receiving EVT. METHODS: The derivation cohort comprised patients from southern provinces of China in the BASILAR registry. The model (POSITIVE: Predicting mOrtality of baSilar artery occlusion patIents Treated wIth EVT) was trained and optimized using a fivefold cross-validation method in which hyperparameters were selected and fine-tuned. This model was retrospectively tested in patients from the northern provinces of China from the BASILAR registry. A prospective test of POSITIVE was performed on consecutive patients from two hospitals between January 2020 and June 2022. RESULTS: Extreme gradient boosting was employed to construct the POSITIVE model, which achieved the best predictive performance among the eight machine learning algorithms and showed excellent discrimination (area under the curve (AUC) 0.83, 95% confidence interval (95% CI) 0.80 to 0.87) and calibration (Hosmer-Lemeshow test, P>0.05) in the development cohort. AUC yielded by the POSITIVE model for the retrospective test was 0.79 (95% CI 0.71 to 0.85), higher than that obtained by traditional models. Prospective comparisons showed that the POSITIVE model achieved the highest AUC (0.82, 95% CI 0.74 to 0.90) among all prediction models. CONCLUSION: We developed a machine learning algorithm and retrospective and prospective testing with multicentric cohorts, which exhibited a solid predictive performance and may act as a convenient reference to guide decision-making for ABAO patients. The POSITIVE model is presented online for user-friendly access.
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Algoritmos , Artéria Basilar , Humanos , Estudos Retrospectivos , Área Sob a Curva , Aprendizado de MáquinaRESUMO
OBJECTIVE: Progesterone receptor membrane component 2 (PGRMC2) belongs to the membrane-associated progesterone receptor family, which regulates multiple pathophysiological processes. However, the role of PGRMC2 in ischemic stroke remains unexplored. The present study sought to determine the regulatory role of PGRMC2 in ischemic stroke. METHODS: Male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO). The protein expression level and localization of PGRMC2 were examined by western blotting and immunofluorescence staining. The gain-of-function ligand of PGRMC2 (CPAG-1, 45 mg/kg) was intraperitoneally injected into sham/MCAO mice, and brain infarction, blood-brain barrier (BBB) leakage, and sensorimotor functions were evaluated by magnetic resonance imaging, brain water content, Evans blue extravasation, immunofluorescence staining, and neurobehavioral tests. The astrocyte and microglial activation, neuronal functions, and gene expression profiles were revealed by RNA sequencing, qPCR, western blotting, and immunofluorescence staining after surgery and CPAG-1 treatment. RESULTS: Progesterone receptor membrane component 2 was elevated in different brain cells after ischemic stroke. Intraperitoneal delivery of CPAG-1 reduced infarct size, brain edema, BBB leakage, astrocyte and microglial activation, and neuronal death, and improved sensorimotor deficits after ischemic stroke. CONCLUSION: CPAG-1 acts as a novel neuroprotective compound that could reduce neuropathologic damage and improve functional recovery after ischemic stroke.
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Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Masculino , Camundongos , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/patologia , Isquemia Encefálica/metabolismo , Mutação com Ganho de Função , Infarto da Artéria Cerebral Média/patologia , AVC Isquêmico/patologia , Camundongos Endogâmicos C57BL , Receptores de Progesterona/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
The huge amount of plastic waste accumulated in landfills has caused serious microplastic (MP) pollution to the soil environment, which has become an urgent issue in recent years. It is challenging to deal with the non-biodegradable MP pollutants in actual soil from landfills. In this study, a coaxial dielectric barrier discharge (DBD) system was proposed to remediate actual MP-contaminated landfill soil due to its strong oxidation capacity. The influence of carrier gas type, applied voltage, and air flow rate was investigated, and the possible degradation pathways of MP pollutants were suggested. Results showed the landfill soil samples contained four common MP pollutants, including polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyvinyl chloride (PVC) with sizes ranging from 50 to 1500 µm. The MP pollutants in the soil were rapidly removed under the action of reactive oxygen species (ROS) generated by DBD plasma. Under the air flow rate of 1500 mL min-1, the maximum remediation efficiency represented by mass loss reached 96.5% after 30 min treatment. Compared with nitrogen, when air was used as the carrier gas, the remediation efficiency increased from 41.4% to 81.6%. The increased applied voltage from 17.5 to 24.1 kV could also promote the removal of MP contaminants. Sufficient air supply was conducive to thorough removal. However, when the air flow rate reached 1500 mL min-1 and continued to rise, the final remediation efficiency would be reduced due to the shortened residence time of ROS. The DBD plasma treatment proposed in this study showed high energy efficiency (19.03 mg kJ-1) and remediation performance (96.5%). The results are instructive for solving MP pollution in the soil environment.
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Poluentes Ambientais , Recuperação e Remediação Ambiental , Microplásticos , Plásticos , Espécies Reativas de Oxigênio , Instalações de Eliminação de Resíduos , SoloRESUMO
BACKGROUND: The effects of secondary collateral compensation on outcomes remain unclear in patients with acute basilar artery occlusion (BAO) after endovascular treatment (EVT). This study aimed to evaluate the benefits of the anastomosis between the posterior inferior cerebellar artery (PICA) and the superior cerebellar artery (SCA) in BAO after EVT. METHODS: This cohort study was conducted using data from the Endovascular Treatment for Acute Basilar Artery Occlusion Study Registry. Patients with acute BAO and treated with EVT were included. The primary outcome was a modified Rankin Scale score of 0-2 at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage (SICH) and 90-day mortality. RESULTS: Of the 646 patients included in the study, 196 (30.3%) patients had a PICA-SCA anastomosis. The PICA-SCA anastomosis was significantly associated with independent functional outcome at 90 days (67/196 (34.2%) vs 109/450 (24.2%), adjusted OR (aOR) 1.80 (95% CI 1.13 to 2.86), p=0.01) and was significantly associated with a decreased rate of SICH (40/442 (9.0%) vs 5/193 (2.6%), aOR 0.29 (95% CI 0.11 to 0.76), p=0.01). No significant difference was found between PICA-SCA anastomosis and 90-day mortality (219/450 (48.7%) vs 80/196 (40.8%), aOR 0.72 (95% CI 0.48 to 1.08), p=0.11). Subgroup analysis showed that the association between independent functional outcome and PICA-SCA anastomosis was strongest in patients with middle BAO (27/77 (35.1%) vs 22/118 (18.6%), aOR 2.64 (95% CI 1.13 to 6.15), p=0.03). CONCLUSIONS: The PICA-SCA anastomosis is significantly associated with better functional outcomes in patients with acute BAO after EVT, especially in those with middle BAO.
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Arteriopatias Oclusivas , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Artéria Basilar/diagnóstico por imagem , Artéria Basilar/cirurgia , Estudos de Coortes , Resultado do Tratamento , Estudos Retrospectivos , Procedimentos Endovasculares/efeitos adversos , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/cirurgia , Arteriopatias Oclusivas/etiologia , Trombectomia/efeitos adversos , Hemorragia Cerebral/etiologia , Acidente Vascular Cerebral/cirurgiaRESUMO
BACKGROUND: Locked-in syndrome (LiS) is a rare and devastating condition in patients with acute basilar artery occlusion. However, the benefits of endovascular treatment (EVT) for LiS remain unclear. OBJECTIVE: To assess the outcomes associated with EVT and identify the factors associated with outcomes of LiS. METHODS: We used the data of the Endovascular Treatment for Acute Basilar Artery Occlusion Study Registry (BASILAR) from 47 tertiary stroke centers in China. The included patients had LiS and received EVT or standard medical treatment (SMT) alone. The primary outcome was improvement in the modified Rankin Scale (mRS) score at 90 days. RESULTS: Among the 120 patients with LiS, 92 (76.7%) received EVT and 28 (23.3%) received SMT. Compared with SMT, EVT was associated with improved mRS score (common OR (cOR)=2.68 (95% CI 1.16 to 6.20); p=0.02) and decreased mortality (aOR=0.35 (95% CI 0.13 to 0.90); p=0.03). Moreover, the benefit of EVT for LiS was sustained for at least 1 year (p=0.008). Higher baseline posterior circulation Alberta Stroke Prognosis Early CT Score (pc-ASPECTS, aOR=2.04 (95% CI 1.34 to 3.10); p<0.001) and absence of pneumonia (aOR=0.26 (95% CI 0.08 to 0.90); p=0.03) were significantly associated with favorable functional outcome at 90 days in patients who received EVT, while lower pc-ASPECTS (aOR=0.52 (95% CI 0.36 to 0.76); p<0.001) was associated with increased 90-day mortality. CONCLUSIONS: This study found that EVT was associated with favorable functional outcomes and decreased mortality among patients with LiS. Baseline pc-ASPECTS and pneumonia were independent predictors of outcomes.
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Arteriopatias Oclusivas , Procedimentos Endovasculares , Síndrome do Encarceramento , Acidente Vascular Cerebral , Humanos , Trombectomia/efeitos adversos , Síndrome do Encarceramento/etiologia , Resultado do Tratamento , Acidente Vascular Cerebral/terapia , Artéria Basilar , Arteriopatias Oclusivas/etiologia , Procedimentos Endovasculares/efeitos adversosRESUMO
Introduction: Gastric cancer (GC) is one of the most common malignant tumors worldwide. Single-cell sequencing technology can achieve an accurate and unbiased assessment of cell heterogeneity. Therefore, it is necessary to explore the molecular characteristics of GC-related malignant cells at a single-cell resolution. Methods: Single-cell RNA sequencing GC profiles were collected from the Gene Expression Omnibus database. Moreover, feature gene sets of metabolic pathways and hypoxia signals were collected from the Molecular Signatures Database. The marker genes of specific cell types were collected from the published literature and CellMarker database. The R package InferCNV was used to calculate the copy-number variations of cells and to identify real cancer cells. The weighted relative pathway activity algorithm was used to evaluate the differences in metabolic activity between cell types. Results: Our study found that cancer epithelial cells exhibited individual differences in molecular features and showed metabolic heterogeneity. Oxidative phosphorylation and glycolytic pathway activity were the major contributors to the metabolic heterogeneity of cancer epithelial cells. Furthermore, we used the hypoxia signaling pathway to indirectly evaluate the oxygen content of cells and found that hypoxia contributed to the heterogeneity of cancer epithelial cells. Finally, functional identification of genes co-expressed with HIF1A showed that the reprogramming of the oxidative stress response contributed to the tumor malignant progression. Conclusions: This study described hypoxia-induced metabolic reprogramming of GC at a single-cell level, partially addressing the lack of insight into the heterogeneity of cancer cell metabolism when using traditional sequencing technology.
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Medicago falcata L. is an important legume forage grass with strong drought resistant, which could be utilized as an important gene pool in molecular breed of forage grass. In this study, M. falcata seedlings were treated with 400 mM mannitol to simulate drought stress, and the morphological and physiological changes were investigated, as well as the transcriptome changes of M. falcata seedlings at different treatment time points (0 h, 2 h, 6 h, 12 h, 24 h, 36 h and 48 h). Transcriptome analyses revealed four modules were closely related with drought response in M. falcata by WGCNA analysis, and four ERF transcription factor genes related with drought stress were identified (MfERF053, MfERF9, MfERF034 and MfRAP2.1). Among them, MfERF053 was highly expressed in roots, and MfERF053 protein showed transcriptional activation activity by transient expression in tobacco leaves. Overexpression of MfERF053 in Arabidopsis improved root growth, number of lateral roots and fresh weight under drought, salt stress and exogenous ABA treatments. Transgenic Arabidopsis over-expressing MfERF053 gene grew significantly better than the wild type under both drought stress and salt stress when grown in soil. Taken together, our strategy with transcriptome combined WGCNA analyses identified key transcription factor genes from M. falcata, and the selected MfERF053 gene was verified to be able to enhance drought and salt resistance when over-expressed in Arabidopsis.
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Doxorubicin (DOX) is a widely used first-line antitumor agent; however, acquired drug resistance and side effects have become the main challenges to effective cancer therapy. Herein, DOX is loaded into iron-rich metal-organic framework/tannic acid (TA) nanocomplex to form a tumor-targeting and acid-activatable drug delivery system (MOF/TA-DOX, MTD). Under the acidic tumor microenvironment, MTD simultaneously releases DOX and ferrous ion (Fe2+) accompanied by degradation. Apart from the chemotherapeutic effect, DOX elevates the intracellular H2O2 levels through cascade reactions, which will be beneficial to the Fenton reaction between the Fe2+ and H2O2, to persistently produce hydroxyl radicals (â¢OH). Thus, MTD efficiently mediates chemodynamic therapy (CDT) and remarkably enhances the sensitivity of chemotherapy. More encouragingly, the cancer cell killing efficiency of MTD is up to ~86% even at the ultralow equivalent concentration of DOX (2.26 µg/mL), while the viability of normal cells remained >88% at the same concentration of MTD. Taken together, MTD is expected to serve as drug-delivery nanoplatforms and â¢OH nanogenerators for improving chemo/chemodynamic synergistic therapy and reducing the toxic side effects.
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BACKGROUND: Higher extended Thrombolysis In Cerebral Infarction (eTICI) grades are associated with better clinical outcomes after endovascular treatment (EVT) for proximal intracranial occlusion of the anterior circulation. However, the relationship between eTICI grade and outcomes after EVT in patients with acute basilar artery occlusion (BAO) remains unclear. We aimed to explore which eTICI category was the cut-off correlating with better clinical outcomes in patients with BAO undergoing EVT. METHODS: We included patients treated via EVT from the BASILAR study. Multivariable logistic regression analyses were performed to assess the impact of eTICI grades on 90-day favorable functional outcomes, defined as a modified Rankin Scale (mRS) score of 0-3. Other outcomes were functional independence (mRS 0-2), all-cause mortality, and symptomatic intracranial hemorrhage. RESULTS: Among 647 patients treated with EVT, 127 (19.6%), 128 (24.5%), 110 (21.1%), and 282 (54%) patients achieved eTICI grades of 0-2a, 2b, 2c, and 3, respectively. Compared with eTICI grades 0-2a, higher rates of favorable functional outcomes (adjusted OR (aOR) 2.96, 95% CI 1.33 to 6.57, and aOR 7.40, 95% CI 3.63 to 15.09, respectively) were observed for grades 2c and 3, not 2b (aOR 1.93, 95% CI 0.86 to 4.36). The risks of mortality and symptomatic intracranial hemorrhage were also lower for eTICI grades 2c and 3 than for grades 0-2a. CONCLUSIONS: An eTICI grade of 2c/3 may be a target for successful reperfusion after EVT in patients with acute BAO; however, further studies with larger sample sizes and clinical trials are needed.
Assuntos
Arteriopatias Oclusivas , Procedimentos Endovasculares , Acidente Vascular Cerebral , Arteriopatias Oclusivas/terapia , Artéria Basilar/diagnóstico por imagem , Angiografia Cerebral , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Infarto Cerebral/terapia , Procedimentos Endovasculares/efeitos adversos , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/etiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/terapia , Trombectomia , Terapia Trombolítica , Resultado do TratamentoRESUMO
BACKGROUND: The best anesthetic management strategy for patients with acute large vessel occlusion treated with mechanical thrombectomy (MT) remains uncertain. Most studies have focused on anterior-circulation stroke caused by large artery occlusion. Nevertheless, limited data are available on the appropriate choice of anesthetic for acute basilar artery occlusion (BAO). We aimed to investigate the effect of anesthetic method on clinical outcomes in patients with BAO undergoing MT. METHODS: Patients undergoing MT for acute BAO in the BASILAR registry (Acute Basilar Artery Occlusion Study) were included. We divided patients into three groups according to the anesthetic technique used during MT: general anesthesia (GA), local anesthesia (LA), and conscious sedation (CS). Propensity score matching was performed to achieve baseline balance. RESULTS: 639 patients were included. GA was used in 257 patients (40.2%), LA was used in 250 patients (39.1%), and CS was used in 132 patients (20.7%). After 1:1 matching, favorable outcome, mortality, and hemorrhagic transformation rates, as well as modified Rankin Scale (mRS) score at 90 days, did not differ between the GA, LA, and CS groups. CONCLUSIONS: The choice of anesthetic strategy, GA, LA, or CS, did not affect the clinical outcomes of patients with acute BAO treated with MT in the BASILAR registry.
Assuntos
Anestésicos , Arteriopatias Oclusivas , Procedimentos Endovasculares , Acidente Vascular Cerebral , Arteriopatias Oclusivas/etiologia , Artéria Basilar , Procedimentos Endovasculares/métodos , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Resultado do TratamentoRESUMO
Cystic fibrosis (CF) is a rare autosomal recessive disease with only one pathogenic gene cystic fibrosis transmembrane conductance regulator (CFTR). To identify the potential pathogenic mutations in a Chinese patient with CF, we conducted Sanger sequencing on the genomic DNA of the patient and his parents and detected all 27 coding exons of CFTR and their flanking intronic regions. The patient is a compound heterozygote of c.2909G > A, p.Gly970Asp in exon 18 and c.1210-3C > G in cis with a poly-T of 5T (T5) sequence, 3 bp upstream in intron 9. The splicing effect of c.1210-3C > G was verified via minigene assay in vitro, indicating that wild-type plasmid containing c.1210-3C together with T7 sequence produced a normal transcript and partial exon 10-skipping-transcript, whereas mutant plasmid containing c.1210-3G in cis with T5 sequence caused almost all mRNA to skip exon 10. Overall, c.1210-3C > G, the newly identified pathogenic mutation in our patient, in combination with T5 sequence in cis, affects the CFTR gene splicing and produces nearly no normal transcript in vitro. Moreover, this patient carries a p.Gly970Asp mutation, thus confirming the high-frequency of this mutation in Chinese patients with CF.