Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

Structures of the SARS-CoV-2 nucleocapsid and their perspectives for drug design.

COVID-19, caused by SARS-CoV-2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N- and C-terminal domains (N-NTD and N-CTD) of SARS-CoV-2 N protein, at 1.8 and 1.5 Å resolution, respectively. Both structures show conserved features from other CoV N proteins. The binding sites targeted by small molecules against HCoV-OC43 and MERS-CoV, which inhibit viral infection by blocking the RNA-binding activity or normal oligomerization of N protein, are relatively conserved in our structure, indicating N protein is a promising drug target. In addition, certain areas of N-NTD and N-CTD display distinct charge distribution patterns in SARS-CoV-2, which may alter the RNA-binding modes. The specific antigenic characteristics are critical for developing specific immune-based rapid diagnostic tests. Our structural information can aid in the discovery and development of antiviral inhibitors against SARS-CoV-2 in the future.

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.

Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy.

Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.

[Pathogenesis of ferroptosis on chronic kidney disease and traditional Chinese medicine intervention: a review].

Chronic kidney disease(CKD) is an insidious disease that has become a significant global public health issue due to its high incidence rate, low awareness, low diagnostic rate, poor prognosis, and high medical costs. Recent studies have shown that CKD development is associated with varying degrees of ferroptosis features. Traditional Chinese medicine(TCM) can regulate iron metabolism, lipid peroxidation, antioxidant systems to inhibit ferroptosis and delay the progression of CKD. Consequently, the intervention mechanism of ferroptosis has become one of the focuses of CKD research. TCM has thousands of years of traditional experience and wisdom. It focuses on the overall regulation of human body functions and can stimulate the body's disease resistance and recovery capabilities, which has certain advantages in treating CKD. However, there is currently a lack of comprehensive articles on the application of TCM in intervening ferroptosis to treat CKD and the pathogenesis of ferroptosis in CKD. Therefore, this article summarizes the latest research progress both domestically and internationally, briefly introduces the main mechanisms of ferroptosis, and systematically reviews the relationship between ferroptosis and CKD. The article integrates TCM theories related to ferroptosis in CKD, including "deficiency" "stasis" "phlegm turbidity" and "toxins" and summarizes the research status of active ingredients and herbal formulas in intervening ferroptosis to treat CKD. By considering ferroptosis from a new perspective, this article aims to provide new targets and directions for the application of TCM in treating CKD.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke.

BACKGROUND: In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. METHODS: We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. RESULTS: Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. CONCLUSIONS: In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.).

Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC-derived small extracellular vesicles (MSC-sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC-sEV on DCs in allergic diseases remain unclear. MSC-sEV were prepared from the induced pluripotent stem cells (iPSC)-MSCs by anion-exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte-derived DCs were generated and cultured in the presence of MSC-sEV to differentiate the so-called sEV-immature DCs (sEV-iDCs) and sEV-mature DCs (sEV-mDCs), respectively. The phenotypes and the phagocytic ability of sEV-iDCs were analyzed by flow cytometry. sEV-mDCs were co-cultured with isolated CD4+ T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated. We demonstrated that MSC-sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA-DR, but had no effects on mDCs with these markers. However, MSC-sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti-IL-10 monoclonal antibody or IL-10Rα blocking antibody, we identified that sEV-mDCs suppressed the Th2 immune response by reducing the production of IL-4, IL-9, and IL-13 via IL-10. Furthermore, sEV-mDCs increased the level of Treg cells. Our study identified that mDCs treated with MSC-sEV inhibited the Th2 responses, providing novel evidence of the potential cell-free therapy acting on DCs in allergic airway diseases.

Silencing of novel TtVtg6-like induced ovarian cell apoptosis in ancient chelicerate Tachypleus tridentatus.

Vitellogenin (Vtg) serves as the precursor of yolk protein and exhibits widespread distribution in tissues, including in the ovary of both vertebrates and invertebrates. Vtg plays a critical role in facilitating oocyte maturation and embryonic development following oviposition. In this study, we have successfully elucidated the complete transcript sequence of TtVtg6-like from an ancient chelicerate Tachypleus tridentatus. The TtVtg6-like transcript encompassed a length of 4887 bp and encoded 1629 amino acids residues. Notably, TtVtg6-like was found to contain 25 exons. Furthermore, the molecular weight and isoelectric point of TtVtg6-like were determined to be 191.6 KDa and 6.73, respectively. Subsequent mRNA expression analysis demonstrated the specific expression of TtVtg6-like in ovary and yellow connective tissue. In addition, TtVtg6-like was located and distributed in both ovary and yellow connective tissue. Intriguingly, employing an siRNA approach to silence TtVtg6-like resulted in a decrease in TtVtg6-like transcription levels. Concomitantly, TtVtg6-like silencing led to increase production of ROS, ultimately resulting in DNA damage and cell apoptosis within the ovarian primary cell. The induction of apoptosis ovarian primary cells due to TtVtg6-like silencing was further corroborated through TUNEL assay and flow cytometry analysis. Overall, our findings underscore the significance of TtVtg6-like in ovarian cell development, revealing its potential association with ovarian cell apoptosis. Consequently, the insights gained from this study contribute to the future exploration of vitellogenesis and ovarian development in T. tridentatus.

Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3.

PURPOSE: Pellino3, an ubiquitin E3 ligase, prevents the formation of the death-induced signaling complex in response to TNF-α by targeting receptor-interacting protein kinase 1 (RIPK1), and bioinformatics analysis predicted an interaction between Pellino3 and caspofungin, a common antifungal drug used in clinics. This study aimed to explore the effect of caspofungin on brain injury in ischemic stroke and the underlying mechanisms. METHODS: Ischemic stroke injury was induced in Sprague Dawley rats by occlusion of the middle cerebral artery (MCA) for 2 h, followed by 24 h reperfusion. PC12 cells were deprived of both oxygen and glucose for 8 h and then were cultured for 24 h with oxygen and glucose to mimic an ischemic stroke in vitro. RESULTS: Animal experiments showed brain injury (increase in neurological deficit score and infarct volume) concomitant with a downregulation of Pellino3, a decreased ubiquitination of RIPK1, and an up-regulation of necroptosis-associated proteins [RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), p-RIPK1, p-RIPK3, and p-MLKL]. Administration of caspofungin (6 mg/kg, i.m.) at 1 h and 6 h after ischemia significantly improved neurological function, reduced infarct volume, up-regulated Pellino3 levels, increased RIPK1 ubiquitination, and down-regulated protein levels of RIPK1, p-RIPK1, p-RIPK3, and p-MLKL. PC12 cells deprived of oxygen/glucose developed signs of cellular injury (LDH release and necroptosis) concomitant with downregulation of Pellino3, decreased ubiquitination of RIPK1, and elevated necroptosis-associated proteins. These changes were reversed by overexpression of Pellino3. CONCLUSION: We conclude that Pellino3 has an important role in counteracting necroptosis via ubiquitination of RIPK1 and caspofungin can suppress the brain cell necroptosis in ischemic stroke through upregulation of Pellino3.

Perioperative care based on roy adaptation model in elderly patients with benign prostatic hyperplasia: impact on psychological well-being, pain, and quality of life.

PURPOSE: This study aimed to assess the impact of perioperative care based on the Roy Adaptation Model (RAM) on psychological well-being, postoperative pain, and health-related quality of life (HRQoL) in elderly patients with benign prostatic hyperplasia (BPH) undergoing transurethral resection of the prostate (TURP). METHODS: A total of 160 elderly patients diagnosed with BPH between June 2021 and June 2022 and scheduled for TURP were randomly assigned to either the routine care group (n = 80) or the RAM group (n = 80). The RAM group received standard care supplemented with interventions based on the RAM model. Negative emotions measured by the Hospital Anxiety and Depression Scale (HADS), pain intensity by the Visual Analog Scale (VAS), and HRQoL by the 36-Item Short Form Health Survey (SF-36) were measured at the preoperative visit (T0), at 30 days (T1), and at 3 months of (T2) follow­up. RESULTS: Repeated measures ANOVA revealed significant differences in psychological well-being, postoperative pain intensity, and HRQoL within both the routine care and RAM groups across the three time points. Holm-Sidak's multiple comparisons test confirmed significant differences between each time point for both groups. The RAM intervention led to significant reductions in anxiety and depression levels, alleviation of postoperative pain intensity, and improvements in various domains of HRQoL at T1 and T2 compared to routine care. CONCLUSION: Incorporating the RAM model into perioperative care for elderly patients undergoing TURP for BPH has shown promising results in improving psychological well-being, reducing postoperative pain intensity, and enhancing HRQoL.

Anticancer activity of oleanolic acid and its derivatives modified at A-ring and C-28 position.

Oleanolic acid (OA) is a five-ring triterpenoid compound, which is widely present in plants. Due to a wide range of pharmacological activities, oleanolic acid has attracted more and more attention. However, oleanolic acid is insoluble in water and has low bioavailability, which limits its clinical application. In this review, we focus on summarizing the anti-cancer activity and mechanism of the A ring or C-28 carboxyl modified derivatives of OA since 2015, to determine the strength of its anti-cancer effectiveness and evaluate whether it could be used as a clinical anti-cancer drug.

LncRNA SNHG16 promotes colorectal cancer cell proliferation, migration, and epithelial-mesenchymal transition through miR-124-3p/MCP-1.

Colorectal cancer (CRC) has been the third leading cause of cancer-associated deaths. LncRNA SNHG16 is reported to be involved in metastasis of CRC cells. However, the mechanism by which SNHG16 regulates CRC progression is poorly understood. The proliferation of CRC cells was examined by MTT. Wound healing and transwell assay were used to measure migration and invasion ability. RT-qPCR and western blot were used to examine gene expression. Immunofluorescence was conducted to evaluate the EMT of CRC cells. Luciferase reporter assay were used to confirm direct interaction between miR-124-3p and SNHG16 or MCP-1. The interaction between miR-124-3p and SNHG16 was detected by RIP and RNA pull down assay. H&E staining was used to test the histomorphological changes of hepatic metastatic nodules. Finally, xenograft tumor experiment was utilized to determine tumor growth in vivo. SNHG16 and miR-124-3p were dysregulated in human colorectal tumors or cells. Knockdown of SNHG16 led to attenuate cell proliferation, migration, invasion, and EMT of CRC cells. And xenograft tumor experiment showed that SNHG16 might influence tumor growth. In contrast, miR-124-3p exerted the antitumor effects. Knockdown of miR-124-3p can reverse the effect of sh-SNHG16 on CRC cells. miR-124-3p could directly bind to SNHG16 or MCP-1. More importantly, MCP-1 acts as a critical effector mediating the role of SNHG16/ miR-124-3p in CRC cells. In summary, our data suggest that SNHG16 plays a contributory role in proliferation, migration, and EMT of CRC cells via miR-124-3p/MCP-1 axis, which offers a rationale for targeting SNHG16 and developing therapeutic drugs to treat CRC.

Effect of Occlusion Site on the Safety and Efficacy of Intravenous Alteplase Before Endovascular Thrombectomy: A Prespecified Subgroup Analysis of DIRECT-MT.

BACKGROUND AND PURPOSE: Recent trials showed thrombectomy alone was comparable to bridging therapy in patients with anterior circulation large vessel occlusion eligible for both intravenous alteplase and endovascular thrombectomy. We performed this study to examine whether occlusion site modifies the effect of intravenous alteplase before thrombectomy. METHODS: This is a prespecified subgroup analysis of a randomized trial evaluating risk and benefit of intravenous alteplase before thrombectomy (DIRECT-MT [Direct Intra-Arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals]). Among 658 randomized patients, 640 with baseline occlusion site information were included. The primary outcome was the score on the modified Rankin Scale at 90 days. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by occlusion location (internal carotid artery versus M1 versus M2). We report the adjusted common odds ratio for a shift toward better outcome on the modified Rankin Scale after thrombectomy alone compared with combination treatment adjusted for age, the National Institutes of Health Stroke Scale score at baseline, the time from stroke onset to randomization, the modified Rankin Scale score before stroke onset, and collateral score per the DIRECT-MT statistical analysis plan. RESULTS: The overall adjusted common odds ratio was 1.08 (95% CI, 0.82-1.43) with thrombectomy alone compared with combination treatment, and there was no significant treatment-by-occlusion site interaction (P=0.47). In subgroups based on occlusion location, we found the following adjusted common odds ratios: 0.99 (95% CI, 0.62-1.59) for internal carotid artery occlusions, 1.12 (95% CI, 0.77-1.64) for M1 occlusions, and 1.22 (95% CI, 0.53-2.79) for M2 occlusions. No treatment-by-occlusion site interactions were observed for dichotomized modified Rankin Scale distributions and successful reperfusion (extended thrombolysis in Cerebral Infarction score ≥2b) before thrombectomy. Differences in symptomatic hemorrhage rate were not significant between occlusion locations (internal carotid artery occlusion: 7.02% in bridging therapy versus 7.14% for thrombectomy alone, P=0.97; M1 occlusion: 5.06% versus 2.48%, P=0.22; M2 occlusion: 9.09% versus 4.76%; P=0.78). CONCLUSIONS: In this prespecified subgroup of a randomized trial, we found no evidence that occlusion location can inform intravenous alteplase decisions in endovascular treatment eligible patients directly presenting at endovascular treatment capable centers. Future studies are needed to confirm our findings. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03469206.

Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction.

Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing TH 2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin- ) cells. PBMCs and Lin- cells were cocultured with induced pluripotent stem cell-derived MSCs (iPSC-MSCs) under the stimulation of epithelial cytokines IL-25 and IL-33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS-ICOSL pathway. iPSC-MSCs successfully decreased the high levels of IL-13, IL-9, and IL-5 in PBMCs in response to IL-25, IL-33, and the high percentages of IL-13+ ILC2s and IL-9+ ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC-MSCs. However, iPSC-MSCs were found directly to enhance ILC2 levels and functions via ICOS-ICOSL interaction in Lin- cells and pure ILC2s. iPSC-MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS-ICOSL interaction. The MSC-induced Treg cells then suppressed ILC2s by secreting IL-10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS-ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders.

Effects of endovascular treatment and prognostic factors for recovery of oculomotor nerve palsy caused by posterior communicating artery aneurysms: a multi-center retrospective analysis.

BACKGROUND: Oculomotor nerve palsy (ONP) may result from posterior communicating artery (PcomA) aneurysms. We aimed to evaluate the resolution of ONP after endovascular treatment with the intention of clarifying predictors of nerve recovery in a relatively large series. METHODS: A total of 211 patients with ONP caused by PcomA aneurysms underwent endovascular coiling between May 2010 and December 2020 in four tertiary hospitals. We evaluated the demographics, clinical characteristics, aneurysm morphology parameters and ONP resolution to analyze the predictors of ONP recovery using univariate and multivariate analyses. RESULTS: At the last available clinical follow-up, ONP resolution was complete in 126 (59.7%) patients, partial in 73 (34.6%) patients, and no recovery in 12 (5.7%) patients. The median resolution time after endovascular treatment was 55 days (interquartile range: 40-90 days). In multivariate analysis, degree of ONP (incomplete palsy) on admission (OR 5.396; 95% CI 2.836-10.266; P < 0.001), duration of ONP (≤ 14 days) before treatment (OR 5.940; 95% CI 2.724-12.954; P < 0.001) were statistically significant predictors of complete recovery of ONP. In the subgroup analysis of patients with unruptured aneurysms, aspirin showed a higher complete recovery rate in univariate analysis (OR 2.652; 95% CI 1.057-6.656; P = 0.038). CONCLUSION: Initial incomplete ONP and early management might predict better recovery of ONP after endovascular treatment.

Platelet count and clinical outcomes among ischemic stroke patients with endovascular thrombectomy in DIRECT-MT.

OBJECTIVES: The prognostic role of baseline platelet count (PLT) in acute ischemic stroke patients with large vessel occlusion undergoing endovascular thrombectomy is unclear. Whether PLT modifies alteplase treatment effect on clinical outcome in those patients is also uncertain. METHODS: We derived data from a multicenter randomized clinical trial (DIRECT-MT) comparing intravenous alteplase before endovascular treatment vs. endovascular treatment only. The 654 patients with available PLT data were included. Primary outcome was the ordinal modified Rankin Scale (mRS) score evaluated at 90 days. We also assessed various secondary and safety outcomes. RESULTS: After adjusting for confounding factors, patients in the top tertile of PLT had a significantly lower risk of a worse shift in the distribution of mRS score (Odds Ratio: 0.671, 95% Confidence Interval: 0.473-0.953, p for trend=0.025), major disability and death (Odds Ratio: 0.617, 95% Confidence Interval: 0.393-0.97, p for trend=0.037) as well as death (Odds Ratio: 0.544, 95% Confidence Interval: 0.313-0.947, p for trend=0.031), respectively, compared with the bottom one. Among patients in the bottom tertile of PLT, combination therapy was associated with a better imaging outcome of eTICI score of 2b, 2c or 3 on final angiogram (Odds Ratio: 3.23, 95% Confidence Interval: 1.49-7.002) with a marginally significant interaction effect. CONCLUSIONS: Participants with higher baseline PLT had a decreased risk of poor functional outcomes. Low baseline PLT modified alteplase treatment effect on the eTICI score on final angiogram. Combination therapy was beneficial for patients with low baseline PLT to have a better reperfusion status.

Mechanism and Kinetics of Methane Combustion. Part II: Potential Energy Surface for Hydrogen-Abstraction Reaction of CH4 + O(3P).

Methane combustion plays an important role in various fields such as combustion chemistry and atmospheric chemistry of the stratosphere. Highly accurate study of its initial reaction remains a key challenge. Here, through extensive studies with a state-of-the-art ab initio and neural network method, we present a potential energy surface of the O(3P) + CH4 → OH + CH3 reaction on the ground state 13A and the first excited state 23A. In this work, the energies of 10 167 points covering all important regions are obtained with state-averaged complete active space self-consistent field calculations and then fitted using the Levenberg-Marquardt algorithm with a root-mean-square error of 0.391 and 0.442 kcal/mol for the 13A and 23A states, respectively. This study explores the characteristics of the radical van der Waals (VdW) complex and reveals a detailed mechanism of the methane combustion initial reaction. Within the scope of this mechanism, this surface gives a fairly accurate description of the regions around the saddle point, conical intersection, and vdW wells in the entrance for efficient computational simulations. As a theoretical study on a prototypical polyatomic reaction, it is hopeful that this work will modify our understanding of the primary process in hydrocarbon combustion.

Multicore Fiber Bending Sensors with High Sensitivity Based on Asymmetric Excitation Scheme.

Bending sensing was realized by constructing a tapered four-core optical fiber (TFCF) sensor. The four-core fiber (FCF) between the fan-in and fan-out couplers was tapered and the diameter became smaller, so that the distance between the four cores arranged in a square became gradually smaller to produce supermodes. The two ends of the TFCF were respectively connected to the fan-in and fan-out couplers so that the individual cores in the FCF could link to the separate single-mode fibers. A broadband light source (superluminescent diodes (SLD)) spanning 1250-1650 nm was injected into any one of the four cores, and the orientation was thus determined. In the tapering process, the remaining three cores gradually approached the excitation core in space to excite several supermodes based on the tri-core structure first, and then transited to the quadruple-core structure. The field distributions of the excited supermodes were asymmetric due to the corner-core excitation scheme, and the interference thus resulted in a higher measurement sensitivity. When the diameter of the TFCF was 7.5 µm and the tapered length was 2.21 mm, the sensitivity of the bending sensor could reach 16.12 nm/m-1.