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Objective: Small extracellular vesicle (sEV)‐mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs. Subjects and Methods: Fifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p‐AKT/vacuolar protein sorting‐associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells. Results: The size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B. Conclusion: Downregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs. [ABSTRACT FROM AUTHOR]

To control the meshing performance of hypoid gear drive, current local conjugate theory and local synthesis method establish a relationship between the relative motion and local geometrical properties of the mating surfaces at one reference point. Theoretically, both local conjugate theory and local synthesis method cannot ensure the contact performance on the entire tooth surface resulting in uncontrolled contact pattern and undesirable transmission error. A global synthesis approach consisting of a machine-tool settings calculation model, a tooth contact analysis model, a meshing quality assessment function, and a swarm intelligence algorithm are proposed. The direction, area, and shape of the contact pattern and the amplitude of the intersection of two adjacent transmission error curves are taken as the evaluation indexes. Three curvatures of the design pitch cone of the pinion are taken as the control variables. A global selection space is then established within the reasonable range of the curvatures. An improved multiple population genetic algorithm is employed to find the optimal set of the curvatures to achieve the target values of the evaluation indexes. To avoid the edge contact and corner contact condition, a feasible region is defined on tooth surface and the contact patterns on the gear and pinion surfaces are all confined within the area. The optimized contact patterns obtained by the loaded tooth contact analysis method are similar to those obtained by the proposed approach, thus demonstrating the effectiveness of this methodology. The main novelty of this approach is to translate the derivation of the mathematical relation between the curvatures of the mating surfaces and the contact properties to solving a multi-objective optimization problem of the meshing quality indexes by the intelligence algorithm. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC), the most commonly diagnosed malignancy, is also the second leading cause of cancer-related deaths. Although tremendous efforts have been achieved to improve the early detection of PC, it is still urgent to find out novel markers and therapeutic targets for PC patients. Homeobox protein MOX-1 (MEOX1) is found to be ectopically expressed in human cancers. This study aims to test the hypothesis that MEOX1 gene silencing might suppress the proliferation and invasion of LNCaP cells in PC.Materials and Methods: Microarray analysis was conducted to screen PC-related differentially expressed gene. MEOX1 was silenced to detect the relationship between silenced MEOX1 and cell proliferation, migration, apoptosis, and invasion. Expression of MEOX1, Bcl-2, p53, and Bax in LNCaP cells was determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Cell proliferation, colony formation rate, cell migration, invasion, cell cycle, and apoptosis were detected respectively.Results: MEOX1 gene was found to be expressed highly in PC tissues. After MEOX1 was silenced in LNCaP cells, the mRNA and protein expression of Bcl-2 decreased while the mRNA and protein expressions of p53 and Bax increased. Additionally, cell proliferation, migration, and invasion were reduced while cell apoptosis was increased by MEOX1, and MEOX1 gene silencing was revealed to inhibit cell proliferation and decrease tumorigenic ability of LNCaP cells in nude mice.Conclusion: Taken together, MEOX1 gene silencing could decrease the proliferation and increase apoptosis of LNCaP cells, and so it is expected to be a therapeutic target for PC. [ABSTRACT FROM AUTHOR]

Summary: Background: The purposes of this study were three‐fold: (i) to determine the contribution of known genes to the causation of a broad‐spectrum of pediatric drug‐resistant epilepsy (DRE), (ii) to compare the diagnostic yield and cost among different next‐generation sequencing (NGS) approaches, and especially (iii) to assess how NGS approaches can benefit patients by improving diagnosis and treatment efficiency. Methods: This study enrolled 273 pediatric DRE patients with no obvious acquired etiology. Seventy‐four patients underwent whole‐exome sequencing (WES), 141 patients had epilepsy‐related gene panel testing, and another 58 patients had clinical WES gene panel testing. We obtained these patients' seizure and hospitalization frequency by periodic follow‐up phone calls and outpatient visits. Results: Genetic diagnosis was achieved in 86 patients (31.5%) and involved 93 likely disease‐causing mutations in 33 genes. In this study, the detection rates of the epilepsy‐related gene panel, the clinical WES gene panel, and WES were 32.6% (46/141), 44.8% (26/58), and 17.3% (13/74), respectively. Moreover, 34 patients accepted corrective therapy according to their mutant genes, after which 52.9% (18/34) became seizure‐free and 38.2% (13/34) achieved seizure reduction. In the end, patients with either positive or negative genetic results had significantly fewer hospitalization incidents (times/half year) than before (positive genetic results group 0.58 ± 1.14 vs 0.10 ± 0.26; negative genetic results group 0.72 ± 1.65 vs 0.12 ± 0.33). Conclusions: These results offer further proof that NGS approaches represent powerful tools for establishing a definitive diagnosis. Moreover, this study indicated how NGS can improve treatment efficacy and reduce hospitalization in children with DRE. [ABSTRACT FROM AUTHOR]