Muscone alleviates neuronal injury via increasing stress granules formation and reducing apoptosis in acute ischemic stroke.

As the main bioactive component of musk, muscone has been reported to have marked protective effects in treating acute ischemic stroke (AIS). However, the specific anti-stroke mechanism of muscone still needs further research. In the current investigation, the PC12 cells OGD/R and the rat transient MCAO/R models were utilized as the AIS models. Serum hepatic and renal functional indexes (ALT, AST, BUN, and Cr) and cell viability were determined to select the appropriate muscone concentrations for in vitro and in vivo experiments. TTC, Hematoxylin and eosin (H&E), and Live/Dead staining were utilized to evaluate the protective effects of muscone in injured tissues and cells. Western blotting analysis, TUNEL staining, propidium iodide, and annexin V staining were applied to detect the anti-apoptotic effect of muscone. Double-label immunofluorescence staining of T-cell intracellular antigen-1 (TIA1) and Ras-GAP SH3 domain-binding protein 1 (G3BP1) was performed to observe whether muscone regulated the SG formation level. Molecular docking, TIA1 silencing and TIA1 overexpression experiments were employed to investigate the molecular mechanism underlying the regulation of SG formation by muscone. The 2, 3, 5-Triphenyl-tetrazolium chloride (TTC) staining and live/dead staining showed the AIS injury level of MCAO/R rat and the OGD/R PC12 cells were attenuated by muscone administration. The muscone significantly minimized the apoptosis rate in MCAO/R rats and OGD/R PC12 cells following flow cytometry analysis, western blotting analysis, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The double-label immunofluorescence staining data revealed that muscone promoted the SG formation level in OGD/R PC12 cells and the cortex MCAO/R rats. The results of molecular docking, TIA1 silencing and TIA1 overexpression experiments revealed that muscone could bind to TIA1 protein and regulate its expression level, thereby promoting the formation of stress granules and exerting a protective effect against AIS injury. This study indicated that the significant protective effect of muscone in reducing apoptosis levels might be via promoting SG formation under AIS conditions. This study further explores the therapeutic effect and anti-apoptosis mechanism of muscone in AIS, which may provide a potential candidate drug for the clinical treatment of AIS injury.

Prospective, multi-center post-marketing surveillance cohort study to monitor the safety of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Chinese girls and women aged 9 to 45 years, 2018-2020.

Following the approval of Cervarix for the immunization of girls and women in China against high-risk human papillomavirus types 16 and 18, a non-interventional post-authorization safety study was performed. A multi-center prospective cohort study assessed safety following Cervarix vaccination of Chinese girls and women aged 9-45 years between 31 May 2018 and 3 December 2020. Adverse events following immunization (AEFIs), potential immune-mediated diseases (pIMDs), and pregnancy-related outcomes were collected up to 12 months from the third immunization or 24 months from the first immunization, whichever came first. Among 3,013 women who received 8,839 Cervarix doses, 167 (5.5%) reported ≥ 1 any AEFI, and 22 (0.7%) reported 40 serious AEFIs. During the 30 days after each dose, 147 women (4.9%) reported 211 medically attended AEFIs, including 3 serious AEFIs reported by 1 woman (0.03%). One woman reported a pIMD. Cervarix was inadvertently administered to 65 women (2.2%) within 60 days before conception or during pregnancy. Of these women, 34 (52.3%) gave birth to live infant(s) with no apparent congenital anomalies, and 1 (1.5%) woman gave birth to a live infant with a congenital anomaly. No serious AEFIs or pIMDs were considered to be related to the vaccination. In Chinese women aged 9-45 years, immunization with the Cervarix three-dose schedule was well tolerated. Overall, no safety concerns were identified, although rare adverse events may have been missed due to the study sample size.Clinical trial registration: NCT03438006.

Infection with high-risk human papillomavirus is a prerequisite for cervical cancerCervarix is a human papillomavirus-16/18 AS04-adjuvanted vaccineMulti-centre prospective cohort study to monitor safety of Cervarix immunisationSafety was monitored in 3,013 girls/women aged 9­45 years in China (8,839 doses)Cervarix was well tolerated, and no safety concerns were identified.

Development and validation of the risk score for estimating suicide attempt in patients with major depressive disorder.

Early identification of high-risk patients with Major depressive disorder (MDD) having suicide attempts (SAs) is essential for timely targeted and tailored psychological interventions and medications. This study aimed to develop and validate a web-based dynamic nomogram as a personalized predictor of SA in MDD patients. A dynamic nomogram was developed using data collected from 1718 patients in China. The dynamic model was established based on a machine learning-based regression technique in the training cohort. We validated the nomogram internally using 1000 bootstrap replications. The nomogram performance was assessed using estimates of discrimination (via the concordance index) and calibration (calibration plots). The nomogram incorporated five predictors, including Hamilton anxiety rating scale (odds ratio [OR]: 1.255), marital status (OR: 0.618), clinical global impressions (OR: 2.242), anti-thyroid peroxidase antibodies (OR: 1.002), and systolic pressure levels (OR: 1.037). The model demonstrated good overall discrimination (Harrell's C-index = 0.823). Using decision curve analysis, this model also demonstrated good clinical applicability. An online web server was constructed ( https://odywong.shinyapps.io/PRSM/ ) to facilitate the use of the nomogram. Based on these results, our study developed a nomogram to predict SA in MDD patients. The application of this nomogram may help for patients and clinicians to make decisions.

Development, validation, and visualization of a novel nomogram to predict stroke risk in patients.

Background: Stroke is the second leading cause of death worldwide and a major cause of long-term neurological disability, imposing an enormous financial burden on families and society. This study aimed to identify the predictors in stroke patients and construct a nomogram prediction model based on these predictors. Methods: This retrospective study included 11,435 participants aged >20 years who were selected from the NHANES 2011-2018. Randomly selected subjects (n = 8531; 75%) and the remaining subjects comprised the development and validation groups, respectively. The least absolute shrinkage and selection operator (LASSO) binomial and logistic regression models were used to select the optimal predictive variables. The stroke probability was calculated using a predictor-based nomogram. Nomogram performance was assessed by the area under the receiver operating characteristic curve (AUC) and the calibration curve with 1000 bootstrap resample validations. Decision curve analysis (DCA) was performed to evaluate the clinical utility of the nomogram. Results: According to the minimum criteria of non-zero coefficients of Lasso and logistic regression screening, older age, lower education level, lower family income, hypertension, depression status, diabetes, heavy smoking, heavy drinking, trouble sleeping, congestive heart failure (CHF), coronary heart disease (CHD), angina pectoris and myocardial infarction were independently associated with a higher stroke risk. A nomogram model for stroke patient risk was established based on these predictors. The AUC (C statistic) of the nomogram was 0.843 (95% CI: 0.8186-0.8430) in the development group and 0.826 (95% CI: 0.7811, 0.8716) in the validation group. The calibration curves after 1000 bootstraps displayed a good fit between the actual and predicted probabilities in both the development and validation groups. DCA showed that the model in the development and validation groups had a net benefit when the risk thresholds were 0-0.2 and 0-0.25, respectively. Discussion: This study effectively established a nomogram including demographic characteristics, vascular risk factors, emotional factors and lifestyle behaviors to predict stroke risk. This nomogram is helpful for screening high-risk stroke individuals and could assist physicians in making better treatment decisions to reduce stroke occurrence.

Snap25 attenuates neuronal injury via reducing ferroptosis in acute ischemic stroke.

Due to the limited clinical treatment options for acute ischemic stroke (AIS), there is still an urgent requirement for in-depth research on the pathogenesis of AIS and the development of efficient therapeutic approaches and agents. Literature reports reveal that ferroptosis may play an important role in the pathogenesis of AIS. However, the specific mechanism and the molecular target of action of ferroptosis in AIS injury remains unclear. In this study, we constructed AIS rat and PC12 cell models. We applied RNAi-mediated knockdown and gene overexpression technologies to investigate whether Snap25 (Synaptosome-associated protein 25 kDa) can regulate the level of AIS damage by interfering with the level of ferroptosis in AIS. The in vivo and in vitro results revealed that the level of ferroptosis significantly increased in the AIS model. Snap25 gene overexpression significantly inhibited the ferroptosis level and decreased the AIS damage and OGD/R injury level in the model group. Snap25 silencing exacerbated the ferroptosis level and aggravated OGD/R injury in PC12 cells. The overexpression and silencing of Snap25 can significantly affect the expression level of ROS, suggesting that the regulatory effect on the ROS level may be an important factor in regulating ferroptosis in AIS by Snap25. In conclusion, the findings of this study suggested that Snap25 has a protective effect against ischemia/reperfusion injury by reducing ROS levels and ferroptosis levels. This study further confirmed the involvement of ferroptosis in the process of AIS injury and explored the regulatory mechanism of Snap25 on the ferroptosis level in AIS, which could provide a promising therapeutic target for ischemic stroke treatment.

Moxibustion treatment for Parkinson's disease: study protocol for a randomized controlled trial.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder and seriously affects quality of life globally. Moxibustion is widely used to treat neurodegenerative diseases in the clinic and has achieved a beneficial clinical effect. However, strict control and high-quality randomized controlled trials are still lacking. Therefore, this trial aims to evaluate the clinical efficacy and safety of moxibustion in patients with PD and preliminarily explore the underlying mechanism. METHODS: This is a randomized, single-blind and placebo-controlled trial design in which 70 eligible participants will be randomly divided into a moxibustion group and a sham moxibustion group. Baihui (DU20) and Sishenchong (EX-HN1) are selected for both groups. The treatment will be performed for 30 min per session, two sessions a week for 8 weeks. The mean change in MDS-UPDRS scores (including MDS-UPDRS II, III subscale scores and total scores) from baseline to the observation points will be the primary outcome. The secondary outcomes will include scores on the Parkinson's Disease Questionnaire-39 (PDQ-39), Fatigue Severity Scale (FSS), Parkinson Disease Sleep Scale (PDSS), Montreal Cognitive Assessment (MoCA), and Self-Rating Depression Scale (SDS) as well as the Wexner constipation score. All the above outcomes will be assessed at 4 and 8 weeks. Laboratory blood biochemical analysis and functional magnetic resonance imaging (fMRI) will be conducted at baseline and at the end of treatment to explore the potential mechanisms of moxibustion in regulating PD. DISCUSSION: In conclusion, the results of this trial will reveal whether moxibustion is effective for treating motor and nonmotor symptoms in PD. This trial will also preliminarily explore the underlying mechanism of the regulatory effect of moxibustion in PD, which will contribute to providing a theoretical basis for the treatment of PD. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2000029745. Registered on 9 August 2021.

Single-cell transcriptomic analysis of tumor heterogeneity and intercellular networks in human urothelial carcinoma.

BACKGROUND: Heterogeneity of tumor cells and the tumor microenvironment (TME) is significantly associated with clinical outcomes and treatment responses in patients with urothelial carcinoma (UC). Comprehensive profiling of the cellular diversity and interactions between malignant cells and TME may clarify the mechanisms underlying UC progression and guide the development of novel therapies. This study aimed to extend our understanding of intra-tumoral heterogeneity and the immunosuppressive TME in UC and provide basic support for the development of novel UC therapies. METHODS: Seven patients with UC were included who underwent curative surgery at our hospital between July 2020 and October 2020. We performed single-cell RNA sequencing (scRNA-seq) analysis in seven tumors with six matched adjacent normal tissues and integrated the results with two public scRNA-seq datasets. The functional properties and intercellular interactions between single cells were characterized, and the results were validated using multiplex immunofluorescence staining, flow cytometry, and bulk transcriptomic datasets. All statistical analyses were performed using the R package with two-sided tests. Wilcoxon-rank test, log-rank test, one-way analysis of variance test, and Pearson correlation analysis were used properly. RESULTS: Unsupervised t-distributed stochastic neighbor embedding clustering analysis identified ten main cellular subclusters in urothelial tissues. Of them, seven urothelial subtypes were noted, and malignant urothelial cells were characterized with enhanced cellular proliferation and reduced immunogenicity. CD8 + T cell subclusters exhibited enhanced cellular cytotoxicity activities along with increased exhaustion signature in UC tissues, and the recruitment of CD4 + T regulatory cells was also increased in tumor tissues. Regarding myeloid cells, coordinated reprogramming of infiltrated neutrophils, M2-type polarized macrophages, and LAMP3 + dendritic cells contribute to immunosuppressive TME in UC tissues. Tumor tissues demonstrated enhanced angiogenesis mediated by KDR + endothelial cells and RGS5 + /ACTA2 + pericytes. Through deconvolution analysis, we identified multiple cellular subtypes may influence the programmed death-ligand 1 (PD-L1) immunotherapy response in patients with UC. CONCLUSION: Our scRNA-seq analysis clarified intra-tumoral heterogeneity and delineated the pro-tumoral and immunosuppressive microenvironment in UC tissues, which may provide novel therapeutic targets.

Screening and Verification of Reference Genes for Analysis of Gene Expression in Garlic (Allium sativum L.) under Cold and Drought Stress.

The principal objective of this study was to screen and verify reference genes appropriate for gene expression evaluation during plant growth and development under distinct growth conditions. Nine candidate reference genes were screened based on garlic transcriptome sequence data. RT-qPCR was used to detect the expression levels of the aforementioned reference genes in specific tissues under drought and cold stress. Then, geNorm, NormFinder, BestKeeper, and ReFinder were used to consider the consistency of the expression levels of candidate reference genes. Finally, the stress-responsive gene expression of ascorbate peroxidase (APX) was quantitatively evaluated to confirm the chosen reference genes. Our results indicated that there were variations in the abundance and stability of nine reference gene transcripts underneath cold and drought stress, among which ACT and UBC-E2 had the highest transcript abundance, and 18S rRNA and HIS3 had the lowest transcript abundance. UBC and UBC-E2 were the most stably expressed genes throughout all samples; UBC and UBC-E2 were the most stably expressed genes during cold stress, and ACT and UBC were the most stably expressed genes under drought stress. The most stably expressed genes in roots, pseudostems, leaves, and cloves were EF1, ACT, HIS3, UBC, and UBC-E2, respectively, while GAPDH was the most unstable gene during drought and cold stress conditions and in exclusive tissues. Taking the steady reference genes UBC-E2, UBC, and ACT as references during drought and cold stress, the reliability of the expression levels was further demonstrated by detecting the expression of AsAPX. Our work thereby offers a theoretical reference for the evaluation of gene expression in garlic in various tissues and under stress conditions.

Dietary vitamin E intake and risk of Parkinson's disease: a cross-sectional study.

Objective: Current evidence on the association between dietary vitamin E intake and the risk of Parkinson's disease (PD) is limited. The aim of the study was to explore the association of dietary vitamin E intake with PD in the United States among adults over 40 years. Methods: We conducted a cross-sectional study with data collected from National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. A total of the sample of 13,340 participants were included. To identify the different characteristics of the participants, we utilized propensity score matching (PSM) to reduce the effects of selection bias and confounding variables. Weighted univariate and multivariable logistic regression were used to examine the association between dietary vitamin E intake and PD before and after matching. Then, restricted cubic spline (RCS) was used to visually describe the possible non-linear relationships. Finally, we employed the subgroup analysis to further investigate the relationship between dietary vitamin E intake and PD. Results: According to the weighted univariate and multivariable logistic regression analysis, vitamin E intake was inversely associated with the risk of PD before and after matching. The results of RCS analysis revealed no non-linear inverse relationship between vitamin E intake and PD before and after matching. The subgroup analysis showed that age may influence the negative association between vitamin E and PD (P < 0.05 for interaction). Conclusion: Among participants over 40 years of age, vitamin E intake was negatively associated with the risk of PD. Our data may support the supplementation of vitamin E to be used as an intervention strategy for the occurrence of PD.

Effectiveness of varicella vaccination during an outbreak in a large one-dose-vaccinated population in Shanghai.

Emergency vaccination (EV) is used as effective postexposure prophylaxis (PEP) to control varicella outbreaks within 3-5 days. However, the advantages of a second dose of varicella vaccine (VarV) in students who had received one dose before an outbreak and the potential benefits of EV at more than 5 days after exposure have not been fully evaluated. This study evaluated the vaccine effectiveness (VE) of EV in preventing disease development during a varicella outbreak in Shanghai, China, in 2020. Questionnaires were used to obtain student demographic information, clinical manifestations, varicella history, vaccination status, and willingness to receive EV. The VE of EV was calculated as [1-relative risk (RR)] ×100%. Among the 1455 students included in this study, 31 cases were identified, resulting in an overall attack rate of 2.13%. There were 6 cases in unvaccinated students and 25 cases in one-dose-vaccinated students. A total of 788 students received one EV dose. The attack rates were 6.38% (6/94), 4.26% (19/446), 2.82% (2/71), and 0.56% (4/717) among unvaccinated students, students who received 1 dose of VarV, and students who received EV with the 1st and 2nd dose of VarV, respectively. Compared to that in unvaccinated students, the VE of EV with the 2nd dose of VarV was 88% (95% CI 49% to 97%). EV should be performed as soon as possible after exposure. Nevertheless, vaccination is still recommended at more than 5 days post exposure to control varicella outbreaks.

Chronic Cerebral Hypoperfusion Aggravates Parkinson's Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism.

Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson's disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and Morris water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of α-Syn and Aß in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson's disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.

Engineered exosomes for targeted delivery of miR-187-3p suppress the viability of hemangioma stem cells by targeting Notch signaling.

Background: Infantile hemangioma (IH) is the most common benign vascular tumor of infancy and is proposed to arise from hemangioma stem cells (HemSCs). Therapies for IH include oral beta-blockers, surgery, and the delivery of novel therapeutic agents, such as bioactive microRNAs (miRNAs). However, in the extracellular environment, miRNA is easily hydrolyzed by RNase. miR-187-3p has previously been confirmed to promote or inhibit various malignancies, but its role in the development and progression of IH remains unclear. Methods: In this study, engineered exosomes (E-exos) were exploited to deliver miR-187-3p into HemSCs. The E-exos were generated by introducing miR-187-3p mimics into human adipose mesenchymal stem cell-derived exosomes (hAMSC-exos) via electroporation. The expression and secretion of miR-187-3p were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blot analysis, transmission electron microscopy (TEM), and dynamic light scattering (DLS) were used to characterize the exosomes. The effects of the E-exos on HemSC viability were examined using the tube formation assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Western blot analysis was used to evaluate the effects of E-exos on Notch-1, Notch-4, and Jagged-1 expression in HemSCs. Results: E-exos did not differ significantly from hAMSC-exos in terms of morphology, particle size, or surface markers. E-exos could be internalized by HemSCs, and the course of cellular uptake of E-exos was time dependent. After 12 hours of treatment, E-exos significant inhibited tube formation. Notch signaling was also inhibited by miR-187-3p loading by E-exos. E-exos showed excellent inhibitory effects against HemSC proliferation via Notch signaling. Conclusions: This study provides a foundation for using hAMSC-exos to optimize current clinical options to facilitate IH treatment and deliver therapeutic agents in the future.

Initial symptoms of vertebrobasilar artery occlusions and the outcomes after endovascular treatment.

BACKGROUND: Acute vertebrobasilar artery occlusion (VBAO) is a devastating disease in stroke patients. This study was aimed to identify the initial symptoms of patients with acute VBAO receiving endovascular treatment and determine its associations with clinical outcomes. METHODS: Patients with VBAO receiving endovascular treatment at 21 stroke centres in China were recruited for this derivation cohort A data-driven approach of latent class analysis was applied to identify distinct symptom typologies of VBAO patients. Multivariable binary and ordinary logistic regressions were used to evaluate the associations between symptom subtypes and clinical outcomes. RESULTS: A total of 548 patients were analysed in this study. Four distinct subgroups were defined: the vestibular symptom group (32.8%), anterior circulation mimic group (26.5%), non-specific symptom group (14.8%) and severe VBAO symptom group (25.9%). Compared with severe VBAO symptoms, non-specific symptoms were independently associated with higher rates of favourable outcome and functional independence at the 3 months [odds ratio (OR) 2.46, 95% confidence interval (CI) 1.15-5.28; OR 3.46, 95% CI 1.54-7.79]and 1 year follow-up (OR 2.25, 95% CI 1.05-4.82; OR 2.69, 95% CI 1.22-5.92), and better functional improvement (shift in mRS score) at the 3 months (OR 2.05, 95% CI 1.15-3.67). CONCLUSION: We identified four distinctive subtypes based on the initial symptoms of VBAO patients. Severe VBAO symptoms were associated with poor outcomes while non-specific and vestibular symptoms were indicators of a favourable outcome.

Circular RNA Signatures of Human Healing and Nonhealing Wounds.

Venous ulcers (VUs) have complex and obscure pathogenicity, and effective VU therapies are still lacking. Circular RNAs (circRNAs) have emerged as powerful gene regulators with important roles in health and disease. In this study, we used paired total RNA and small RNA sequencing to profile circRNAs, protein-coding mRNAs, and microRNAs expression in a unique collection of clinical samples: healthy skin and acute wounds at inflammatory and proliferative phases and wound-edge VU biopsies. We unravel a dynamically changed expression pattern of circRNAs during human skin repair and their abnormal expression signature in VU, which are presented as a searchable web resource (www.xulandenlab.com/humanwounds-circrna). We analyzed the coexpression relationship between the circRNAs and mRNAs with weighted correlation network analysis and constructed circRNA‒mRNA‒microRNA networks. This allowed us to expose the regulatory networks specific to the inflammatory and proliferative phases of wound repair and VU, the biological processes the circRNAs may regulate, and the circRNAs that could sponge microRNAs in human wounds. Importantly, we found that hsa-CHST15_0003 and hsa-TNFRSF21_0001, two circRNAs upregulated in VU, hampered epidermal keratinocyte migration while promoting proliferation by modulating gene networks underpinning these cellular processes. This study paves the way to decipher the functional significance of circRNAs in tissue repair.

Successful Sclerotherapy for Cervicofacial Macrocystic Lymphatic Malformations Using Polidocanol and Pingyangmycin Combined Foam Sclerosants.

Background: Sclerotherapy is the first-line therapeutic method for lymphatic malformations (LMs). This retrospective cohort study evaluated the effectiveness and safety of a novel combined foam sclerosant: polidocanol and pingyangmycin foam (PPF), for treating cervicofacial macrocystic LMs. Methods and Results: From July 2018 to October 2020, 51 patients with cervicofacial macrocystic LMs were enrolled in this study. All patients received intralesional 3% polidocanol or PPF injections. The outcome was evaluated regarding demographic and clinical characteristics, degree of treatment response, and post-treatment complications. Overall, 16 patients (31.4%) underwent PPF sclerotherapy. All these patients (100%) showed remarkable reduction in lesion size within three sessions. Excellent responses were shown in 88.5% of these patients within three sessions, which is higher than single polidocanol sclerotherapy (80%). The average sessions (duration) of PPF sclerotherapy were 2.5, which was significantly shorter than the single foam sclerotherapy (p < 0.05). Treatment duration was significantly associated with age, lesion location, lesion size, and number of cysts (p < 0.05). No severe complications were noted in this study. Local or systemic complications, such as swelling and mild fever occurred but subsided without any specific treatment. Conclusions: PPF is a safe, and effective combined foam sclerosant for the treatment of cervicofacial macrocystic LMs. This combined foam can improve treatment response and reduce treatment duration compared with a single sclerosant. It can be broadly used if further large-scale clinical trials verify its efficacy and safety.

Influence of renal impairment on clinical outcomes after endovascular recanalization in vertebrobasilar artery occlusions.

BACKGROUND: Renal impairment (RI) is associated with worse outcomes in the treatment of intravenous thrombolysis and emergent endovascular treatment (EVT) in anterior circulation stroke. The objective of this study was to investigate the association of RI with short-term and long-term outcomes in patients with vertebrobasilar artery occlusions (VBAO) who received EVT. METHODS: Consecutive patients with VBAO receiving EVT involving 21 stroke centers were retrospectively included. Multivariate regression analyses were used to evaluate the association of RI with mortality and symptomatic intracranial hemorrhage (sICH) during the hospital stay, and also mortality, favorable functional outcome (modified Rankin Scale (mRS) score of 0-3), and functional improvement (shift in mRS score) at 3 months and 1 year follow-up. The association between RI and the risk of recurrent stroke was evaluated with multivariate competing-risk regression analyses. RESULTS: After adjustment for potential confounders, RI was independently associated with sICH (OR 3.30, 95% CI 1.55 to 7.18), as well as mortality (OR 2.54, 95% CI 1.47 to 4.38; OR 3.07, 95% CI 1.72 to 8.08), favorable functional outcome (OR 0.33, 95% CI 0.17 to 0.66; OR 0.25, 95% CI 0.12 to 0.51), and functional improvement (OR 0.45, 95% CI 0.28 to 0.74; OR 0.35, 95% CI 0.21 to 0.60) at 3 months and 1 year follow-up, respectively, but RI was not associated with in-hospital mortality. Additionally, there was no significant association between RI and recurrent stroke within 1 year. CONCLUSIONS: Our findings suggest that RI is associated with a higher risk of sICH in hospital and a decrease in survival, favorable functional outcome, and functional improvement at 90 days and 1 year follow-up. TRIAL REGISTRATION NUMBER: URL: http://www.chictr.org.cn/; Unique identifier: ChiCTR2000033211.

Integrated Bioinformatics Analysis of Potential mRNA and miRNA Regulatory Networks in Mice With Ischemic Stroke Treated by Electroacupuncture.

Background: The complicated molecular mechanisms underlying the therapeutic effect of electroacupuncture (EA) on ischemic stroke are still unclear. Recently, more evidence has revealed the essential role of the microRNA (miRNA)-mRNA networks in ischemic stroke. However, a systematic analysis of novel key genes, miRNAs, and miRNA-mRNA networks regulated by EA in ischemic stroke is still absent. Methods: We established a middle cerebral artery occlusion (MCAO) mouse model and performed EA therapy on ischemic stroke mice. Behavior tests and measurement of infarction area were applied to measure the effect of EA treatment. Then, we performed RNA sequencing to analyze differentially expressed genes (DEGs) and functional enrichment between the EA and control groups. In addition, a protein-protein interaction (PPI) network was built, and hub genes were screened by Cytoscape. Upstream miRNAs were predicted by miRTarBase. Then hub genes and predicted miRNAs were verified as key biomarkers by RT-qPCR. Finally, miRNA-mRNA networks were constructed to explore the potential mechanisms of EA in ischemic stroke. Results: Our analysis revealed that EA treatment could significantly alleviate neurological deficits in the affected limbs and reduce infarct area of the MCAO model mice. A total of 174 significant DEGs, including 53 upregulated genes and 121 downregulated genes, were identified between the EA and control groups. Functional enrichment analysis showed that these DEGs were associated with the FOXO signaling pathway, NF-kappa B signaling pathway, T-cell receptor signaling pathway, and other vital pathways. The top 10 genes with the highest degree scores were identified as hub genes based on the degree method, but only seven genes were verified as key genes according to RT-qPCR. Twelve upstream miRNAs were predicted to target the seven key genes. However, only four miRNAs were significantly upregulated and indicated favorable effects of EA treatment. Finally, comprehensive analysis of the results identified the miR-425-5p-Cdk1, mmu-miR-1186b-Prc1, mmu-miR-434-3p-Prc1, and mmu-miR-453-Prc1 miRNA-mRNA networks as key networks that are regulated by EA and linked to ischemic stroke. These networks might mainly take place in neuronal cells regulated by EA in ischemic stroke. Conclusion: In summary, our study identified key DEGs, miRNAs, and miRNA-mRNA regulatory networks that may help to facilitate the understanding of the molecular mechanism underlying the effect of EA treatment on ischemic stroke.

"Ballistic" waves among chemically oscillating micromotors.

Coordinating a group of chemically powered micromotors holds great importance in potential applications that involve a large population in a complex environment, yet information transmission at a population scale remains challenging. To this end, we demonstrate how propagating waves emerge among a population of spontaneously oscillating micromotors that dash toward a direction prescribed by their Janus orientations (termed a "ballistic" wave). Moreover, chemical communication among these micromotors enables the tuning of the speed and frequency of individual micromotors and their waves, by varying the population density or the viscosity of the medium.

Exosome-derived miR-196b-5p facilitates intercellular interaction in infantile hemangioma via down-regulating CDKN1B.

BACKGROUND: Though infantile hemangioma (IH) is a common benign vascular tumor, its pathogenesis remains unclear. This study explored the function of hemangioma-derived stem cells (HemSCs) derived exosomes, which exerted an intercellular effect on hemangioma-derived endothelial cells (HemECs). METHODS: First, HemSCs and HemECs were extracted and cultured. HemSCs derived exosomes (HemSCs-exos) were harvested. miRNA sequencing and target prediction were used to explore differentially expressed miRNAs and potential binding targets. After HemECs were co-cultured with HemSCs-exos, a series of in vitro assays were then performed including cell counting kit-8 (CCK-8) assay, cell apoptosis assay, cell cycle assay and tube formation assay to evaluate proliferation, angiogenesis abilities, etc. qRT-PCR and Western blot were conducted to detect the expression level of target genes and proteins. RESULTS: After co-culturing with HemSCs-exos, proliferation, and angiogenesis abilities of HemECs were enhanced, while apoptosis and cell cycle arrest rate were decreased. MiR-196b-5p was observed to be significantly highly expressed in HemSCs-exos. CDKN1B was identified as the binding target of miR-196b-5p. HemECs' proliferation and angiogenesis abilities were elevated when co-cultured with exosomes from HemSCs transfected with miR-196b-5p mimic. In addition, apoptosis rate declined, and lower cells were arrested in G0/G1 phases. Cyclin E, bcl-2 were significantly highly expressed, whereas p27, Bax expression were significantly down-regulated. The positive effect of miR-196b-5p in HemSCs-exos was dramatically reversed when HemECs were transfected with oe-CDKN1B. CONCLUSIONS: The current study found a novel intercellular interaction between IH cells. Briefly, exosome-derived miRNA-196b-5p in HemSCs could facilitate proliferation and angiogenesis abilities, and attenuate apoptosis and cell cycle repression rate of HemECs by directly binding with CDKN1B.

Oral atenolol treatment for infantile hemangiomas: clinical analysis of 133 consecutive patients.

BACKGROUND: Infantile hemangiomas (IHs) are the most frequently occurring pediatric lesions. Oral propranolol has been shown to be safe and effective in infants with IHs. Side effects such as sleep disturbances have been associated with propranolol. Atenolol is a hydrophilic, selective ß1-blocker and therefore may be not associated with side effects attributable to ß2-adrenergic receptor blockade and lipophilicity. However, the efficacy of atenolol in the treatment of IHs is poorly understood. The aim of this study was to evaluate the efficacy of atenolol in the treatment of proliferating IHs in a clinical cohort including 133 consecutive patients. METHODS: In this study, we enrolled 133 patients diagnosed as proliferating IHs from the routine clinical and referral practices of the authors. The procedures followed were in accordance with the ethical standards of the Institute Review Board of Shanghai Ninth People's Hospital and Helsinki Declaration. Clinical characteristics, including demographic data and clinical morphology, were collated. Responses to oral atenolol therapy were graded as: excellent, good, fair and poor. According to the reaction to atenolol treatment, additional medications or therapy were used for IH patients to achieve satisfactory clinical results. RESULTS: In this study, 128 (96.2%) of 133 IH patients responded to oral atenolol, and the response rate (RR) was significantly different for different ages of patients (P<0.05), with the youngest patients having the highest RR. The mean time of treatment was 4.9 months. Forty-one patients who exhibited residual hyperpigmentation or telangiectasia were further treated with timolol maleate cream (n=32) or pulsed dye laser (n=9). All the 41 patients showed positive response. No life-threatening complications were noted during and after oral atenolol. Only 4 (3.0%) of 133 patients developed minor complications including diarrhea. No agitation and bronchospasm were noted in our study. CONCLUSIONS: This study demonstrated that atenolol was effective in the treatment of IHs. Compared to propranolol, atenolol seems to have a similar effect on IHs. Furthermore, atenolol seems to be less frequently associated with potentially life-threatening side effects.