Kindlin-2 controls angiogenesis through modulating Notch1 signaling.

Kindlin-2 is critical for development and homeostasis of key organs, including skeleton, liver, islet, etc., yet its role in modulating angiogenesis is unknown. Here, we report that sufficient KINDLIN-2 is extremely important for NOTCH-mediated physiological angiogenesis. The expression of KINDLIN-2 in HUVECs is significantly modulated by angiogenic factors such as vascular endothelial growth factor A or tumor necrosis factor α. A strong co-localization of CD31 and Kindlin-2 in tissue sections is demonstrated by immunofluorescence staining. Endothelial-cell-specific Kindlin-2 deletion embryos die on E10.5 due to hemorrhage caused by the impaired physiological angiogenesis. Experiments in vitro show that vascular endothelial growth factor A-induced multiple functions of endothelial cells, including migration, matrix proteolysis, morphogenesis and sprouting, are all strengthened by KINDLIN-2 overexpression and severely impaired in the absence of KINDLIN-2. Mechanistically, we demonstrate that KINDLIN-2 inhibits the release of Notch intracellular domain through binding to and maintaining the integrity of NOTCH1. The impaired angiogenesis and avascular retinas caused by KINDLIN-2 deficiency can be rescued by DAPT, an inhibitor of γ-secretase which releases the intracellular domain from NOTCH1. Moreover, we demonstrate that high glucose stimulated hyperactive angiogenesis by increasing KINDLIN-2 expression could be prevented by KINDLIN-2 knockdown, indicating Kindlin-2 as a potential therapeutic target in treatment of diabetic retinopathy. Our study for the first time demonstrates the significance of Kindlin-2 in determining Notch-mediated angiogenesis during development and highlights Kindlin-2 as the potential therapeutic target in angiogenic diseases, such as diabetic retinopathy.

New opportunities for RGD-engineered metal nanoparticles in cancer.

The advent of nanotechnology has opened new possibilities for bioimaging. Metal nanoparticles (such as gold, silver, iron, copper, etc.) hold tremendous potential and offer enormous opportunities for imaging and diagnostics due to their broad optical characteristics, ease of manufacturing technique, and simple surface modification. The arginine-glycine-aspartate (RGD) peptide is a three-amino acid sequence that seems to have a considerably greater ability to adhere to integrin adhesion molecules that exclusively express on tumour cells. RGD peptides act as the efficient tailoring ligand with a variety of benefits including non-toxicity, greater precision, rapid clearance, etc. This review focuses on the possibility of non-invasive cancer imaging using metal nanoparticles with RGD assistance.

A case report on Mycobacterium houstonense infection after total hip arthroplasty.

BACKGROUND: Mycobacterium houstonense is a category of rapidly growing mycobacteria that is gram-positive, acid-fast, polycrystalline, and non-spore-forming. There have been few reports of human infection caused by Mycobacterium houstonense worldwide. CASE PRESENTATION: We present a case of chronic periprosthetic joint infection caused by Mycobacterium houstonense in an elderly female patient. The patient developed signs of infection after undergoing total hip arthroplasty. Despite receiving antibiotic treatment and revision surgery, the signs of infection recurred repeatedly. Multiple bacterial cultures during the treatment period were negative. Later, we identified the pathogenic bacteria Mycobacterium houstonense through mNGS testing, isolated the bacteria from the ultrasonically centrifuged fluid of the prosthesis and obtained drug sensitivity results. Finally, we performed a revision surgery and treated the patient with moxifloxacin and clindamycin. After treatment, the patient did not show signs of infection recurrence during 24 months of follow-up. CONCLUSION: Through a relevant literature search, we believe that Mycobacterium houstonense may show higher sensitivity to amikacin and quinolone antibiotics. Additionally, clarifying occult infection sources through methods such as gene testing will improve the diagnosis and treatment of periprosthetic joint infection.

Machine learning based on eye-tracking data to identify Autism Spectrum Disorder: A systematic review and meta-analysis.

BACKGROUND: Machine learning has been widely used to identify Autism Spectrum Disorder (ASD) based on eye-tracking, but its accuracy is uncertain. We aimed to summarize the available evidence on the performances of machine learning algorithms in classifying ASD and typically developing (TD) individuals based on eye-tracking data. METHODS: We searched Medline, Embase, Web of Science, Scopus, Cochrane Library, IEEE Xplore Digital Library, Wan Fang Database, China National Knowledge Infrastructure, Chinese BioMedical Literature Database, VIP Database for Chinese Technical Periodicals, from database inception to December 24, 2021. Studies using machine learning methods to classify ASD and TD individuals based on eye-tracking technologies were included. We extracted the data on study population, model performances, algorithms of machine learning, and paradigms of eye-tracking. This study is registered with PROSPERO, CRD42022296037. RESULTS: 261 articles were identified, of which 24 studies with sample sizes ranging from 28 to 141 were included (n = 1396 individuals). Machine learning based on eye-tracking yielded the pooled classified accuracy of 81 % (I2 = 73 %), specificity of 79 % (I2 = 61 %), and sensitivity of 84 % (I2 = 61 %) in classifying ASD and TD individuals. In subgroup analysis, the accuracy was 88 % (95 % CI: 85-91 %), 79 % (95 % CI: 72-84 %), 71 % (95 % CI: 59-91 %) for preschool-aged, school-aged, and adolescent-adult group. Eye-tracking stimuli and machine learning algorithms varied widely across studies, with social, static, and active stimuli and Support Vector Machine and Random Forest most commonly reported. Regarding the model performance evaluation, 15 studies reported their final results on validation datasets, four based on testing datasets, and five did not report whether they used validation datasets. Most studies failed to report the information on eye-tracking hardware and the implementation process. CONCLUSION: Using eye-tracking data, machine learning has shown potential in identifying ASD individuals with high accuracy, especially in preschool-aged children. However, the heterogeneity between studies, the absence of test set-based performance evaluations, the small sample size, and the non-standardized implementation of eye-tracking might deteriorate the reliability of results. Further well-designed and well-executed studies with comprehensive and transparent reporting are needed to determine the optimal eye-tracking paradigms and machine learning algorithms.

Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin.

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.

Enhanced MFC sensor performances and extracellular electron transport efficiency mediated by biochar and underlying biochemical mechanisms.

To explore the application of biosensor in real-time monitoring of composite heavy metal polluted wastewater in view of the low performance of MFC sensor, this study used sodium alginate to immobilize biochar to the anode of MFC biosensor, and conducted a study on the sensor performance and related biological processes. The results showed that under the optimal HRT conditions, the output power of the MFC-sensor (BC-300) was 0.432 W/m3 after biochar modification, which was much higher than the highest power density of CG and BC-0 of 0.117 and 0.088 W/m3. The correlation coefficient was greater than that of the control group at the plating wastewater concentration of 0.1-1.0 M and had a wider detection range, and the time to recover the output voltage was 1/3 of that of the control group. The biochar significantly promoted the sensitivity, interference resistance, recovery and anti-interference performance of the MFC-sensor. The intrinsic mechanism was that the composition and structure of biochar lead to a 1.53 fold increase in the abundance of electrogenic microorganisms and the abundance of functional genes such as cytochrome c (MtrABC, CymA, Cox, etc.) and flavin (riba, Rib B, gdh, ushA, IDH, etc.) increased by about 1.03-3.20 times, which promoted the shift of electrons from intracellular to extracellular receptors and significantly improved the electron transfer and the energy metabolism efficiency. The results of this study can provide a reference for the application of MFCsensor to the detection of complex heavy metal effluents.

The identification and validation of EphA7 hypermethylation, a novel biomarker, in cervical cancer.

BACKGROUND: Aberrant methylation of EphA7 has been reported in the process of carcinogenesis but not in cervical cancer. Therefore, an integration study was performed to explore the association between EphA7 hypermethylation and cervical cancer and validate the potential value of EphA7 hypermethylation in the diagnosis of cervical cancer. METHODS: We performed an integration study to identify and validate the association between EphA7 methylation and cervical cancer. First, data on EphA7 methylation and expression in cervical cancer were extracted and analyzed via bioinformatics tools. Subsequently, CRISPR-based methylation perturbation tools (dCas9-Tet1/DNMT3a) were constructed to further demonstrate the association between DNA methylation and EphA7 expression. Ultimately, the clinical value of EphA7 methylation in cervical cancer was validated in cervical tissues and Thinprep cytologic test (TCT) samples by methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP), respectively. RESULTS: Pooled analysis showed that EphA7 promoter methylation levels were significantly increased in cervical cancer compared to normal tissues (P < 0.001) and negatively correlated with EphA7 expression. These prediction results were subsequently confirmed in cell lines; moreover, CRISPR-based methylation perturbation tools (dCas9-Tet1/DNMT3a) demonstrated that DNA methylation participates in the regulation of EphA7 expression directly. Consistent with these findings, the methylation level and the positive rate of EphA7 gradually increased with severity from normal to cancer stages in TCT samples (P < 0.01). CONCLUSIONS: EphA7 hypermethylation is present in cervical cancer and is a potential biomarker for the diagnosis of cervical cancer.

Genomic Analysis and Molecular Characteristics in Carbapenem-Resistant Klebsiella pneumoniae Strains.

Klebsiella pneumoniae is an important bacterium and responsible for both infections acquired in hospital and community because of its multidrug resistance and the virulence. The aim of this research was to investigate clonal lineages, antibiotic resistance profiles, and virulence factors of the hospital isolated carbapenem-resistant strains. Fifty carbapenem-resistant isolates were phenotypically confirmed extended-spectrum beta-lactamases ESBLs producers. MLST analysis revealed 94% sequence type 11. These isolates mainly belonged to three clones according to the PFGE DNA patterns. PFGE patterns have good discrimination than ST profiles. One isolate, K. pneumoniae KPX, undergoing whole-genome sequencing comprised one circular chromosome and four circular plasmids. This isolate harbored a variety of antimicrobial resistance and virulence determinants. The closest relative of K. pneumoniae KPX was another ST11 clinical isolate recovered Sichuan. In addition, KPC-2 (98.0%), SHV-11 (98.0%), TEM-1 (76.0%), CTX-M (76.0%), oqxB1(66%), qnrS (70%), Int1 (42.0%), sul1 (82.0%), sul2 (96.0%), iutA (88%), iucC(10%), and rmpA2 (100%) genes were presented in multiple drug-resistant isolates. The dataset presented in this study provided the genomic and epidemiological analysis of carbapenem-resistant K. pneumoniae in hospital settings. Antimicrobial-resistant profiles suggested the presence of significant selective antibiotic pressure. Appropriate surveillance is essential to the development of effective control strategies in the prevention of nosocomial infection.

Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478.

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, Kd, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 µM for A549; 14.29 µM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

LncRNA MALAT1/miR-320a axis is associated with exercise-induced improvement of endothelial dysfunction in obese children.

BACKGROUND: Endothelial dysfunction commonly occurs in obese children, leading to increased risk of cardiovascular diseases. Exercise has protective effects against endothelial dysfunction through regulating some noncoding RNAs. This study aimed to investigate the relationship of long noncoding RNA MALAT1 and microRNA-320a (miR-320a) with the exercise-induced improvement of endothelial dysfunction in obese children. METHODS: Sixty obese children were included in this study, and 40 cases received a 12-week exercise training. The morphological and blood indices before and after exercise were recorded and compared, and the endothelial dysfunction was evaluated by examining the levels of VCAM-1, ICAM-1, E-selectin, IL-6 and TNF-α using ELISA kits. The expression of noncoding RNAs was assessed using Real-Time quantitative PCR. Endothelial cells were used to explore the effects of MALAT1 and miR-320a on endothelial function. RESULTS: The 12-well exercise training decreased the levels of VCAM-1, ICAM-1 and E-selectin, and inhibited MALAT1 but promoted miR-320a expression in obese children. The expression of MALAT1 and miR-320a was correlated with the changes of morphological and blood indices in obese children, and their correlations with endothelial dysfunction markers were obtained. Additionally, MALAT1 overexpression or miR-320a reduction led to inhibited proliferation and increased inflammation in HUVECs. CONCLUSION: All the data revealed that exercise has significantly protective effects against endothelial dysfunction, and can regulate the expression of the MALAT1/miR-320a axis. MALAT1 and miR-320a were correlated with endothelial dysfunction, indicating that the MALAT1/miR-320a axis may be related with the alleviating effects of exercise on endothelial function in obese children.

SOX14 hypermethylation as a tumour biomarker in cervical cancer.

BACKGROUND: The association between SOX14 and cancer has been reported. The aim of this study was to identify and validate the potential value of SOX14 methylation in the early detection of cervical cancer. METHODS: First, we extracted the data for SOX14 methylation and expression within cervical cancer from The Cancer Genome Atlas (TCGA) database and analysed them via UALCAN, Wanderer, MEXPRESS and LinkedOmics. Subsequently, according to the bioinformatics findings, primers and probes were designed for the most significantly differentiated methylation CpG site and synthesized for methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP) to verify SOX14 methylation in both cervical tissuses and liquid-based cell samples. Eventually, the clinical diagnostic efficacy of SOX14 methylation in the normal, cervical intraepithelial neoplasia, and cancer groups was analysed by ROCAUC. RESULTS: Pooled analysis demonstrated that SOX14 methylation levels were significantly increased in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) compared to normal tissues (P < 0.001). Both the verification and validation cohorts indicated that the methylation level and the positive rate of SOX14 gradually increased with increasing severity from normal to cancer samples (P < 0.01). When the cut-off value was set as 128.45, the sensitivity and specificity of SOX14 hypermethylation in the diagnosis of cervical cancer were 94.12 and 86.46%, respectively. When taken as a screening biomarker (>CINII), the sensitivity was 74.42% and the specificity was 81.48%, with a cut-off value of 10.37. CONCLUSION: SOX14 hypermethylation is associated with cervical cancer and has the potential to be a molecular biomarker for the screening and early diagnosis of cervical cancer.

Association of High-Mobility Group Box 1 (HMGB1) Gene Polymorphisms with Susceptibility and Better Survival Prognosis in Chinese Han Neonatal Necrotizing Enterocolitis.

BACKGROUND High-mobility group box 1 (HMGB1) plays a crucial role in a variety of diseases, including neonatal necrotizing enterocolitis (NEC). The purpose of this study was to investigate the association of HMGB1 gene single-nucleotide polymorphisms (SNPs) with susceptibility and survival prognosis in Chinese Han neonates with NEC. MATERIAL AND METHODS The HMGB1 gene rs1360485, rs1045411, and rs2249825 site SNPs were genotyped in all participants. The mRNA expression of serum HMGB1 was examined using quantitative reverse transcription-polymerase chain reaction. The correlation of the HMGB1 rs1360485 SNP with NEC neonatal survival prognosis was evaluated by univariate analysis and logistic multivariate regression analysis. RESULTS The TC and CC genotype and C allele distribution frequencies of the rs1360485 SNP were lower in the NEC group, and the differences were statistically significant (all P<0.05). Individuals carrying the TC and CC genotype or C allele had a low risk of being affected by NEC. However, the genotype and allele distributions of rs1045411 and rs2249825 were not significantly different between the patient and control groups (P>0.05). NEC neonates with HMGB1 gene rs1360485 site mutations had lower mRNA levels of serum HMGB1 than those with rs1360485 site wild-type, and the rs1360485 genotypes TC and CC could independently predict better survival outcomes in NEC neonates. CONCLUSIONS This study demonstrated that the rs1360485 SNP of the HMGB1 gene is associated with susceptibility of NEC in neonates, and the rs1360485 genotypes TC and CC may affect HMGB1 expression and are associated with the survival prognosis of neonates with NEC.

Red Blood Cell Distribution Width as a Predictive Marker for Coronary Artery Lesions in Patients with Kawasaki Disease.

This study aimed to investigate the association between red blood cell distribution width (RDW) and the risk of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). A total of 1355 patients who met the diagnostic criteria for KD were reviewed between January 2018 and December 2019, including 636 patients with CALs and 719 patients without CALs. Blood samples for RDW were obtained at admission (before intravenous immunoglobulin treatment). A logistic regression analysis was performed, and a receiver operating characteristic curve was constructed to determine the prognostic value of RDW standard deviation (RDW-SD) and RDW coefficient of variation (RDW-CV). The study was registered at www.chictr.org.cn , No.: ChiCTR 2000040980. The results showed that RDW-SD increased in patients with complete KD and CALs compared with patients with complete KD without CALs (39 fL vs. 38 fL, respectively; p = 0.000). RDW-CV in patients with complete KD and CALs was significantly higher compared with patients with completed KD without CALs (p = 0.000). Further multivariate logistic regression analysis revealed that RDW-SD was an independent marker of CALs in patients with complete KD (p = 0.001), but no association was found between RDW-CV and CALs. The area under the curve of RDW-SD for predicting CALs in patients with complete KD was 0.606 (95% confidence interval 0.572-0.640; p = 0.000) with a sensitivity and specificity of 61% and 55%, respectively, when the optimal cut-off value of RDW-SD was 38.5 fL. RDW-CV increased in patients with incomplete KD and CALs compared with patients without CALs (13.55% vs 13.3%, respectively; p = 0.004), and multivariate logistic regression analysis revealed that RDW-CV was an independent marker of CALs in patients with incomplete KD (p = 0.021). The area under the curve of RDW-CV for predicting CALs in patients with incomplete KD was 0.597 (95% confidence interval 0.532-0.661; p = 0.004) with a sensitivity and specificity of 40% and 77%, respectively, when the optimal cut-off value of RDW-SD was 13.85%. Conclusion: RDW can be used as an independent predictive marker of CALs in patients with KD, but the type of KD should be considered. RDW-SD was an independent marker of CALs in patients with complete KD, while RDW-CV was a predictor of incomplete KD.

New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment.

The similarity of spatial structure between radicicol and matrine urged us to perform conformation modification of matrine, followed by L-shaped matrine derivatives, 6, 12, 21a-h and 22a-h were originally designed, synthesized and evaluated for Hsp90N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90N with∣ΔTm∣ > 3, meanwhile, MTT assay also revealed these compounds displayed potent anticancer activity with IC50 values below 25 µM against HepG2, HeLa and MDA-MB-231 cells lines. Then, compound 22g with a high ΔTm = 10.92 was chosen as a representative to perform further mechanism study. It can induce cell apoptosis, arrest the cell cycle at the S phase and decrease the expression level of Hsp90 in Hela cell. These results originally provided targeted modification strategy for matrine derivatives to serve as Hsp90 inhibitors for cancer therapy.

Case-Control Study of Endovascular Thrombectomy in a Canadian Stroke Center.

BACKGROUND: Although the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke caused by intracranial anterior circulation large vessel occlusion (LVO) is proven, demonstration of local effectiveness is critical for health system planning and resource allocation because of the complexity and cost of this treatment. METHODS: Using our prospective registry, we identified all patients who underwent EVT for out-of-hospital LVO stroke from February 1, 2013 through January 31, 2017 (n = 44), and matched them 1:1 in a hierarchical fashion with control patients not treated with EVT based on age (±5 years), prehospital functional status, stroke syndrome, severity, and thrombolysis administration. Demographics, in-hospital mortality, discharge disposition from acute care, length of hospitalization, and functional status at discharge from acute care and at follow-up were compared between cases and controls. RESULTS: For EVT-treated patients (median age 66, 50% women), the median onset-to-recanalization interval was 247 min, and successful recanalization was achieved in 30/44 (91%). Alteplase was administered in 75% of cases and 57% of controls (p = 0.07). In-hospital mortality was 11% among the cases and 36% in the control group (p = 0.006); this survival benefit persisted during follow-up (p = 0.014). More EVT patients were discharged home from acute care (50% vs. 18%, p = 0.002). Among survivors, there were nonsignificant trends in favor of EVT for median length of hospitalization (14 vs. 41 days, p = 0.11) and functional independence at follow-up (51% vs. 32%, p = 0.079). CONCLUSION: EVT improved survival and decreased disability. This demonstration of single-center effectiveness may help facilitate expansion of EVT services in similar health-care jurisdictions.

Étude cas-témoin portant sur la thrombectomie endovasculaire dans un centre canadien de prise en charge des AVC. Contexte : Bien qu'on ait prouvé l'efficacité de la thrombectomie endovasculaire dans le cas d'accidents ischémiques cérébraux aigus causés par l'occlusion de grosses artères affectant la circulation antérieure intracrânienne, la démonstration de son efficacité sur le terrain est essentielle à la planification du réseau la santé et à l'allocation des ressources en raison de la complexité de ce traitement et des coûts qui y sont associés. Méthodes : À l'aide d'un registre prospectif, nous avons identifié tous les patients ayant bénéficié (n = 44), du 1er février 2013 au 31 janvier 2017, d'une thrombectomie endovasculaire à la suite d'un AVC survenu en dehors d'un établissement de la santé, AVC causé par l'occlusion de grosses artères. De manière hiérarchique, nous avons fait correspondre nos patients dans un rapport de 1 à 1 à nos témoins non traités par thrombectomie endovasculaire, et ce, en nous basant sur leur âge (± 5 ans), sur leur situation fonctionnelle avant d'être admis, sur les signes cliniques et la gravité de leur AVC, et sur l'administration d'un traitement thrombolytique. Nous avons également comparé leurs caractéristiques démographiques, leur taux de mortalité hospitalière, les modalités d'obtention d'un congé des soins intensifs, la durée de leur hospitalisation et leur situation fonctionnelle au moment de quitter les soins intensifs et à l'occasion d'un suivi. Résultats : Dans le cas de nos patients traités par thrombectomie endovasculaire (âge médian : 66 ans ; 50 % de femmes), l'intervalle médian entre les premiers signes d'un AVC et la recanalisation a été de 247 minutes. Fait à souligner, une recanalisation réussie a été accomplie dans 30 cas sur 44 (91 %). L'altéplase a été administré dans 75 % des cas et chez 57 % des témoins (p = 0,07). En ce qui concerne le taux de mortalité hospitalière, il a été de 11 % parmi tous nos cas et de 36 % chez nos témoins (p = 0,006) ; À noter que cet avantage en termes de survie a persisté au moment des suivis (p = 0,014). Plus de patients traités par thrombectomie endovasculaire ont obtenu leur congé des soins intensifs et sont revenus à la maison (50 % contre 18 % ; p = 0,002). Parmi les survivants à ces AVC, on a noté des tendances non significatives en faveur des patients traités par thrombectomie endovasculaire pour ce qui est de la durée médiane d'hospitalisation (14 jours contre 41 jours ; p = 0,11) et de l'autonomie fonctionnelle au moment des suivis (51 % contre 32 % ; p = 0,079). Conclusion : En somme, la thrombectomie endovasculaire a permis d'améliorer le taux de survie des patients ainsi que leur niveau d'autonomie fonctionnelle. Effectuée dans un seul établissement hospitalier, cette démonstration de l'efficacité de ce traitement pourrait contribuer à faciliter l'essor des traitements de thrombectomie endovasculaire dans d'autres systèmes de santé similaires.

A Cost-Utility Analysis of Endovascular Thrombectomy in a Real-World Setting.

OBJECTIVE: Endovascular thrombectomy (EVT) is efficacious for ischemic stroke caused by proximal intracranial large-vessel occlusion involving the anterior cerebral circulation. However, evidence of its cost-effectiveness, especially in a real-world setting, is limited. We assessed whether EVT ± tissue plasminogen activator (tPA) was cost-effective when compared with standard care ± tPA at our center. METHOD: We identified patients treated with EVT ± tPA after the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing computed tomography to recanalization times trial from our prospective stroke registry from February 1, 2013 to January 31, 2017. Patients admitted before February 2013 and treated with standard care ± tPA constitute the controls. The sample size was 88. Cost-effectiveness was assessed using the net monetary benefit (NMB). Differences in average costs and quality-adjusted life years (QALYs) were estimated using the augmented inverse probability weighted estimator. We accounted for sampling and methodological uncertainty in sensitivity analyses. RESULTS: Patients treated with EVT ± tPA had a net gain of 2.89 [95% confidence interval (CI): 0.93-4.99] QALYs at an additional cost of $22,200 (95% CI: -28,902-78,244) per patient compared with the standard care ± tPA group. The NMB was $122,300 (95% CI: -4777-253,133) with a 0.85 probability of being cost-effective. The expected savings to the healthcare system would amount to $321,334 per year. CONCLUSION: EVT ± tPA had higher costs and higher QALYs compared with the control, and is likely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY.

Analyse coût-efficacité de la thrombectomie endovasculaire dans un contexte réel. Objectif : La thrombectomie endovasculaire (TE) est efficace dans le cas d'accidents ischémiques cérébraux (AIC) causés par une occlusion proximale de l'artère cérébrale antérieure. Toutefois, les preuves d'un bon rapport coût-efficacité, particulièrement dans le cadre d'une pratique réelle, demeurent limitées. Nous avons ainsi évalué au sein de notre établissement dans quelle mesure la thrombectomie endovasculaire jumelée à un traitement au moyen d'un activateur tissulaire du plasminogène (t-PA) étaient davantage rentables en comparaison avec des soins usuels également jumelés à un traitement de t-PA. Méthodes : En consultant nos registres prospectifs, nous avons identifié des patients traités par une thrombectomie endovasculaire jumelée à un traitement de t-PA après avoir subi, du 1er février 2013 au 31 janvier 2017, un traitement endovasculaire destiné à un petit AVC central et ischémique à occlusion proximale avec un accent mis sur la minimisation du temps de recanalisation par tomodensitométrie. Les patients hospitalisés avant février 2013 et auxquels des soins usuels avaient été prodigués de concert avec l'administration d'un t-PA ont fait partie de notre groupe témoin. Au total, notre échantillon était formé de 88 patients. Nous avons évalué le rapport coût-efficacité au moyen du concept d'avantage monétaire net (AMN). Nous avons également estimé les différences en ce qui concerne les coûts moyens et l'indicateur QALY (quality-adjusted life years) en faisant appel à un estimateur pondéré par l'inverse de la probabilité inverse (augmented inverse probability weighted estimator). Enfin, nous avons tenu compte de l'incertitude de notre échantillonnage et de nos choix méthodologiques dans nos analyses de sensibilité. Résultats : Les patients traités par thrombectomie endovasculaire et l'administration d'un t-PA ont donné à voir un gain net de 2,89 années selon l'indicateur QALY (IC 95 % : 0,93 ­ 4,99) pour un coût additionnel de 22 200 $ (IC 95 % : −28,902 ­ 78,244) par patient si on les compare à notre groupe témoin. L'AMN s'est quant à lui élevé à 122 300 $ (IC 95 % : −4 777 ­ 253 133), sa probabilité d'être rentable atteignant 0,85. À cet égard, les économies annuelles pour le système de soins de santé pourraient atteindre les 321 334 $. Conclusion : Il appert que la thrombectomie endovasculaire jumelée à un traitement de t-PA entraînent des coûts plus élevés et un meilleur indicateur QALY en comparaison avec notre groupe témoin. Il est probable qu'une telle approche soit rentable en vertu d'un seuil de disposition à payer (willingness-to-pay threshold) avoisinant les 50 000 $ par année selon le QALY.

The Effect of Umbilical Cord Mesenchymal Stem Cells Combined with Tetramethylpyrazine Therapy on Ischemic Brain Injury: A Histological Study.

BACKGROUND: Relatively poor survival and differentiation performance of umbilical cord mesenchymal stem cells (ucMSCs) limits its application of transplantation. The purpose of this study was to investigate the combined effect of ucMSCs and tetramethylpyrazine (TMP) on the histological therapy of ischemia stroke. METHODS: Using a middle cerebral artery occlusion (MCAO) model, we sought to determine the therapeutic effects of ucMSCs combined with TMP on ischemic stroke in rats. 1 × 106 ucMSCs was intracerebral transplanted after 24 hours and TMP (50 mg/kg) was injected intraperitoneally every day. After 7 days, the brain tissues were subjected to infarct weight measurement and preparation for 2,3,5-triphenyltetrazolium chloride (TTC) staining, HE staining, and immunohistochemical analysis. RESULTS: The results showed that TMP combined with ucMSCs treatment significantly decreased the neurological deficit score, as well as the cerebral infarct ratio (from 16.33±3.35 to 7.67±1.19%) compared to TMP or ucMSCs treated alone. Moreover, TMP+ucMSCs treatment improved the morphological architecture of the infarct zone, dramatically up-regulated the expression of α-tubulin and nestin, and down-regulated GFAP and IL-1 expression. CONCLUSIONS: These data suggest that ucMSCs combined with TMP are able to exert therapeutic effects following ischemic injury by improving neurogenesis, inhibiting inflammation, and ameliorating histological damage. This may therefore be a promising future treatment for ischemic stroke.

Smad Ubiquitination Regulatory Factor 1 (Smurf1) Promotes Thyroid Cancer Cell Proliferation and Migration via Ubiquitin-Dependent Degradation of Kisspeptin-1.

BACKGROUND/AIMS: Thyroid cancer is the most common malignancy in human endocrine system. Smad ubiquitination regulatory factor 1 (Smurf1) is an E3 ubiquitin-protein ligase in ubiquitin-proteasome pathway (UPP) system. This study aimed to investigate the effects of Smurf1 on thyroid cancer proliferation and metastasis, as well as underlying potential mechanism. METHODS: The expression levels of Smurf1 in thyroid tumor tissues and thyroid cancer cells were detected by western blotting and qRT-PCR. Then, the effects of up-regulation or down-regulation of Smurf1 on thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were measured using trypan blue exclusion assay, two-chamber migration (invasion) assay, cell colony formation assay and Guava Nexin assay, respectively. The ubiquitination of kisspeptin-1 (KISS-1) was assessed by protein ubiquitination assay. Finally, the effects of KISS-1 overexpression on activity of nuclear factor-kappa B (NF-κB) signaling pathway, as well as thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were also detected, respectively. RESULTS: Smurf1 was highly expressed in thyroid tumor tissues and thyroid cancer cells. Up-regulation of Smurf1 promoted the viability, migration, invasion and proliferation of thyroid cancer cells. Knockdown of Smurf1 had opposite effects. Moreover, smurf1 promoted the ubiquitination of KISS-1. Overexpression of KISS-1 inactivated NF-κB pathway, suppressed thyroid cancer cell viability, migration, invasion and proliferation, and induced cell apoptosis. CONCLUSION: Up-regulation of Smurf1 exerted important roles in thyroid cancer formation and development by promoting thyroid cancer proliferation and metastasis. The ubiquitin-dependent degradation of KISS-1 induced by Smurf1 and the activation of NF-κB signaling pathway might be involved in this process. Smurf1 could be an effective therapy target and biomarker for thyroid cancer treatment.

Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up-regulation of Vegfr3 gene expression in lymphatic endothelial cells.

Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.

Pretreatments with injured microenvironmental signals altered the characteristics of human umbilical cord mesenchymal stem cells.

OBJECTIVE: Human umbilical cord mesenchymal stem cells (hUCMSCs) have renoprotective effects but the influence of the microenvironment on characteristics of hUCMSCs has not been well studied. Here, we investigate the effects of injury conditions on properties of hUCMSCs. RESULTS: hUCMSCs were treated in vitro under conditions mimicking the injury microenvironment of acute kidney injury. Cells stimulated with factor-treated medium proliferated slowly at first but quickly afterwards their morphology subsequently changed from spindle to stellate shape. Increased number of cells with strong expression of thymine-1 (Thy-1) or α-smooth muscle actin (α-SMA) was detected at 1 or 2 weeks after stimulation. Hepatocyte growth factor (HGF) level markedly increased after culture for 6 h under hypoxia condition. The expressions of HGF and insulin growth factor-1 (IGF-1) were significantly up-regulated from 0.22 ± 0.03 to 0.9 ± 0.02 and 0.07 ± 0.03 to 0.19 ± 0.01 in H/R-treated hUCMSCs respectively. Co-culture with injured renal tubular epithelial cells significantly promoted the expression of HGF (1.19 ± 0.21) and IGF-1 (0.24 ± 0.03) in hUCMSCs. CONCLUSION: The characteristics of hUCMSCs change in response to inured conditions, which may enhance the efficacy of stem cell therapy and provide novel strategies in maximizing biological and functional properties of hUCMSCs.