IMPORTANCEFor 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 MEASURESThe 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. RESULTSThe 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 ϱ)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.

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Writing Group for the BASILAR Group IMPORTANCE Several randomized clinical trials have recently established the safety and efficacy of endovascular treatment (EVT) of acute ischemic stroke in the anterior circulation. However, it remains uncertain whether patients with acute basilar artery occlusion (BAO) benefit from EVT.OBJECTIVE To evaluate the association between EVT and clinical outcomes of patients with acute BAO. DESIGN, SETTING, AND PARTICIPANTSThis nonrandomized cohort study, the EVT for Acute Basilar Artery Occlusion Study (BASILAR) study, was a nationwide prospective registry of consecutive patients presenting with an acute, symptomatic, radiologically confirmed BAO to 47 comprehensive stroke centers across 15 provinces in China between January 2014 and May 2019. Patients with acute BAO within 24 hours of estimated occlusion time were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. MAIN OUTCOMES AND MEASURESThe primary outcome was the improvement in modified Rankin Scale scores (range, 0 to 6 points, with higher scores indicating greater disability) at 90 days across the 2 groups assessed as a common odds ratio using ordinal logistic regression shift analysis, adjusted for prespecified prognostic factors. The secondary efficacy outcome was the rate of favorable functional outcomes defined as modified Rankin Scale scores of 3 or less (indicating an ability to walk unassisted) at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage and 90-day mortality.RESULTS A total of 1254 patients were assessed, and 829 patients (of whom 612 were men [73.8%]; median [interquartile] age, 65 [57-74] years) were recruited into the study. Of these, 647 were treated with standard medical treatment plus EVT and 182 with standard medical treatment alone. Ninety-day functional outcomes were substantially improved by EVT (adjusted common odds ratio, 3.08 [95% CI, 2.09-4.55]; P < .001). Moreover, EVT was associated with a significantly higher rate of 90-day modified Rankin Scale scores of 3 or less (adjusted odds ratio, 4.70 [95% CI,; P < .001) and a lower rate of 90-day mortality (adjusted odds ratio, 2.93 [95% CI, 1.95-4.40]; P < .001) despite an increase in symptomatic intracerebral hemorrhage (45 of 636 patients [7.1%] vs 1 of 182 patients [0.5%]; P < .001).CONCLUSIONS AND RELEVANCE Among patients with acute BAO, EVT administered within 24 hours of estimated occlusion time is associated with better functional outcomes and reduced mortality.

The presence of Fusobacterium nucleatum ( F. nucleatum ) in the gut is associated with the development of colorectal cancer (CRC). F. nucleatum promotes tumor development by inducing inflammation and host immune response in the CRC microenvironment. Adhesion to the intestinal epithelium by the cell surface proteins FadA, Fap2 and RadD expressed by F. nucleatum can cause the host to produce inflammatory factors and recruit inflammatory cells, creating an environment which favors tumor growth. Furthermore, F. nucleatum can induce immune suppression of gut mucosa by suppressing the function of immune cells such as macrophages, T cells and natural killer cells, contributing the progression of CRC.

The underlying mechanism of Fusobacterium nucleatum (Fn) in the carcinogenesis of colorectal cancer (CRC) is poorly understood. Here, we examined Fn abundance in CRC tissues, as well as β-catenin, TLR4 and PAK1 protein abundance in Fn positive and Fn negative CRCs. Furthermore, we isolated a strain of Fn (F01) from a CRC tissue and examined whether Fn (F01) infection of colon cancer cells activated β-catenin signaling via the TLR4/P-PAK1/P-β-catenin S675 cascade. Invasive Fn was abundant in 62.2% of CRC tissues. TLR4, PAK1 and nuclear β-catenin proteins were more abundant within Fn-positive over Fn-negative CRCs (P < 0.05). Fn and its lipopolysaccharide induced a significant increase in TLR4/P-PAK1/P-β-catenin S675/C-myc/CyclinD1 protein abundance, as well as in the nuclear translocation of β-catenin. Furthermore, inhibition of TLR4 or PAK1 prior to challenge with Fn significantly decreased protein abundance of P-β-catenin S675, C-myc and Cyclin D1, as well as nuclear β-catenin accumulation. Inhibition of TLR4 significantly decreased P-PAK1 protein abundance, and for the first time, we observed an interaction between TLR4 and P-PAK1 using immunoprecipitation. Our data suggest that invasive Fn activates β-catenin signaling via a TLR4/P-PAK1/P-β-catenin S675 cascade in CRC. Furthermore, TLR4 and PAK1 could be potential pharmaceutical targets for the treatment of Fn-related CRCs.

Aims: We aimed to measure the abundance of Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) tissues from patients and to uncover the function of this bacterium in colorectal tumor metastasis.Methods: We collected metastatic and non-metastatic CRC tissues to analyze F. nucleatum abundance. Cells were incubated with F. nucleatum or chloroquine (CQ) or were transfected with CARD3-targeting siRNA; the expression of mRNAs and proteins was then measured. CRC cells stably transfected with shRNA-luc were mixed with F. nucleatum and intravenously injected into BALB/cJ mice. APCMin/+, CARD3-/-and CARD3wt C57BL mice were given F. nucleatum; some mice were given azoxymethane (AOM) and dextran sodium sulfate (DSS).Results: F. nucleatum was abundant in CRC tissues from patients with metastasis. F. nucleatum infection increased CRC cell motility and upregulated the expression of CARD3, LC3-II, Beclin1 and Vimentin, and downregulated the expression of E-cadherin and P62 in CRC cells. These effects were attenuated by treatment with CQ, siCARD3 or both. APCMin/+ mice gavaged with F. nucleatum developed more aggressive tumors than control mice. After AOM/DSS administration, the colorectums of CARD3-/- mice had fewer tumors than those of control mice. Tumors from CARD3-/- mice had lower levels of LC3-II and Beclin1 and higher levels of P62 than those from control mice. BALB/cJ mice injected with both CT26-luc cells and F. nucleatum formed more metastases than control mice. CQ treatment, CARD3 knockdown or both reduced the ability of CT26-luc cells to form metastases in vivo.Conclusions: F. nucleatum is enriched in CRC tissues from patients with metastasis. F. nucleatum orchestrates CARD3 and autophagy to control CRC metastasis. Measuring and targeting F. nucleatum and its associated pathways will yield approaches for the prevention and treatment of CRC metastasis.

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p 5 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA-carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.The human gut is populated by hundreds of different bacterial species, some of which contribute toward the pathogenesis of a range of human diseases.1 Recently, Fusobacterium nucleatum (Fn) has been recognized as an opportunistic pathogen implicated in inflammatory diseases of the gut, including appendicitis and inflammatory bowel diseases. 2,3Current microbiome surveys of human tumors revealed an enrichment of Fn in colorectal cancer (CRC). 4-8 Moreover,accumulating evidence suggest that Fn may play a role in modulating CRC development. 4,9Many of these observations, however, were studies of the traditional adenoma (TA)-carcinoma sequence. In recent years, it's believed that up to 20% of all CRCs arise through an alternative, serrated neoplasia pathway.

Fusobacterium nucleatum (Fn) has been shown to promote colorectal cancer (CRC) development by inhibiting host anti-tumour immunity. However, the impact of Fn infection on macrophage polarization and subsequent intestinal tumour formation as well as the underlying molecular pathways has not been investigated. We investigated the impact of Fn infection on macrophage polarization in human CRCs and cultured macrophages as well as the effects on macrophage phenotype and intestinal tumour formation in Apc mice. We also examined whether macrophage-polarized activation challenged by Fn infection via a TLR4-dependent mechanism involved the IL-6/STAT3/c-MYC signalling cascade. Our data showed that macrophages are a major tumour-infiltrating immune cell type in human CRCs with Fn infection (P < 0.001). Fn infection increased M2 polarization of macrophages in vitro and in vivo, leading to intestinal tumour growth in Apc mice. Moreover, Fn infection induced high expression of TLR4, IL-6, STAT3, p-STAT3, and c-MYC in cultured macrophages challenged with Fn, which was blocked by TAK-242 pre-treatment (P < 0.05). Interestingly, c-MYC protein was mainly co-localized with CD206 M2 macrophages with Fn infection. In conclusion, we show that Fn infection increased M2 polarization of macrophages in vitro and in vivo. Furthermore, Fn infection enhanced colorectal tumour growth in a TLR4-dependent manner involving activation of the IL-6/p-STAT3/c-MYC signalling pathway. For the first time, our results indicate an immunosuppressive effect of Fn by promoting M2 polarization of macrophages through a TLR4-dependent mechanism, which may serve as a promising target for immunotherapy of Fn-related CRC.