The feasibility and safety of combining atrial septal defect/patent foramen ovale and left atrial appendage closure: A systematic review and meta-analysis.

Introduction: Atrial Septal Defect/Patent Foramen Ovale (ASD/PFO) occlusion is performed to prevent paradoxical embolism and reduce the risk of recurrent ischemic stroke. Left atrial appendage (LAA) closure is used as an alternative to medical therapy of non-valvular atrial fibrillation for prevention of stroke. Multiple studies have examined performing LAA and ASD/PFO occlusion. However, the feasibility and safety of combined occlusion of the left atrial appendage and ASD/PFO are not clear, furthermore, these studies are limited by their small sample sizes and retrospective analysis. In this study, we aimed to systematically review and meta-analyze the feasibility and safety of combining left atrial appendage and ASD/PFO closure. Methods: PubMed, Web of Science, CNKI, Cochrane Library, Embase, and WanFang database were searched up to April 2022 to identify peer-reviewed human studies on assessing the feasibility, safety, and efficacy of combining left atrial appendage and ASD/PFO closure. The primary outcome was calculated: procedural feasibility outcome and procedural safety outcome. Results: A total of 10 articles, including 340 patients from multiple countries, were included in the analysis. The principal findings of our study are: compared with single LAA closure, (i) combining PFO/ASD occlusion and LAA closure had similar procedural success proportion (98.43%, 95% CI: 96.67-100.00%), (ii) similar safety event incidences developed (1.67%, 95% CI: 0.24-3.92%), subgroup analyzed safety event incidences in death was 0.00 (95% CI: 0.00-0.33%), cardiac tamponade was 0.87% (95% CI: 0.00-2.77%), device embolization was 0.00 (95% CI: 0.00-0.60%), major bleeding was 0.00 (95% CI: 0.00-0.33%), stroke was 0.00 (95% CI: 0.00-0.02%). Conclusion: Although this systematic review and meta-analysis demonstrate the technical feasibility and safety of combining closure of PFO/ASD and LAA, further studies of sufficient sample size, long-term follow-up, and rigor endpoint criteria are yet needed to fully evaluate this combination procedure for its role in clinical outcomes.

Publisher Correction: Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

A Correction to this paper has been published: https://doi.org/10.1038/s42255-021-00397-5.

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Clinical Characteristics of BRAF V600E Gene Mutation in Patients of Epilepsy-Associated Brain Tumor: a Meta-analysis.

Epilepsy-associated brain tumors (EATs) are usually slow-growing, with seizures as the primary and most dominant symptom. BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene mutations have been found in several subsets of EATs; the V600E mutation is currently believed to contribute to the intrinsic epileptogenicity and tumor growth. However, the relationship between BRAF V600E gene mutation and clinical characteristics in EAT patients is not clear. In this study, we aimed to systematically review the frequency of BRAF V600E gene mutation, as well as the relationship between BRAF V600E gene mutation and clinical characteristics, which may help with the diagnosis and treatment of EATs. Cochrane Library, PubMed, Embase, CNKI, WanFang Data, CQVIP, and SinoMed databases were searched up to October 2020 to identify peer-reviewed human studies on assessing the relationship between BRAF V600E gene mutations and clinical characteristics in EATs. The following data were calculated: the frequency of BRAF V600E mutation and clinical feature comparison between BRAF V600E mutations and wild type in EATs, such as gender, age of seizure onset, duration of epilepsy, location of tumors, and Engel outcome. A total of 12 articles were included in the analysis. Five hundred and nine patients with epilepsy-associated brain tumors were screened for the BRAF V600E gene mutation. Among them, 193 patients had the BRAF V600E mutation (34.06%, 95% CI = 0.25 to 0.43). The subgroup analyses of BRAF V600E mutation showed positive frequency of 44.76% (95% CI = 0.36 to 0.54) in ganglioglioma, 24.75% (95% CI = 0.14 to 0.37) in gysembryoplastic neuroepithelial tumor, 2.15% (95% CI = 0 to 0.19) in angiocentric glioma, and 50.16% (95% CI = 0.33 to 0.68) in pleomorphic xanthoastrocytoma. Compared with the overall frequency, the BRAF V600E positive frequency in ganglioglioma was significantly higher (P = 0.0283). We also found that BRAF V600E gene mutation was significantly associated with age at seizure onset (MD = -2.37; 95% CI = -4.33 to -0.41; P = 0.02). There was no statistical difference between BRAF V600E mutations and wild type in gender, duration of epilepsy, tumor site, and Engel outcome comparison. In conclusion, our updated and comprehensive meta-analysis based on a large number of clinical data demonstrated that BRAF V600E mutation is a specific biomarker and could be a pharmacological target for ganglioglioma patients and an exclusion diagnostic criterion for angiocentric glioma. This meta-analysis suggested the critical role of BRAF V600E mutation in the occurrence and development of EATs. Our findings help to elucidate the progression mechanisms in EATs and develop future therapeutic strategies for EATs.

Imaging of Tie2 with a Fluorescently Labeled Small Molecule Affinity Ligand.

The receptor tyrosine kinase inhibitor, Tie2, has significant roles in endothelial signaling and angiogenesis and is relevant in the pathophysiology of several diseases. However, there are relatively few small molecule probes available to study Tie2, making the evaluation of its activity in vivo difficult. Recently, it was discovered that the small molecule rebastinib (DCC-2036) is a potent Tie2 inhibitor. We hypothesized that fluorescent derivatives of rebastinib could be used as imaging agents for Tie2. On the basis of crystallography structures, we synthesized three fluorescent derivatives, which we then evaluated in both in vitro and in vivo assays. We found that the Rebastinib-BODIPY TMR (Reb-TMR) derivative has superior imaging characteristics in vitro, and we successfully labeled endothelial cells in vivo. We propose that this probe could be further used in in vivo applications for studying the role of Tie2 in disease.