Restoring long-lasting midface volume in the Asian face with a hyaluronic acid filler: A randomized controlled multicenter study.

BACKGROUND: Hyaluronic acid (HA) filler treatment is a minimally-invasive alternative to surgery to volumize the cheeks. HAVOL (Restylane® Volyme) is a flexible HA filler suited to contouring and volumizing the midface. METHODS: This randomized, evaluator-blinded, no-treatment controlled study evaluated effectiveness and safety of HAVOL for correction of midface volume deficit and midface contour deficiency in Chinese subjects. In total 111 subjects were randomized to HAVOL and 37 to no treatment (control). The primary endpoint was response, on the blinded evaluator-assessed Medicis Midface Volume Scale (MMVS), at 6 months after last injection for the treatment group and 6 months after randomization for controls, where response was defined as ≥1-point improvement from baseline on both sides of the face. RESULTS: HAVOL was superior to no treatment at 6 months, meeting the primary objective: 76% versus 8% MMVS responders, a difference of 68% (CI: 55.7%-79.4%, p < 0.0001). These effects were sustained in 51% at 12 months after last injection. A majority (≥96%) had improved aesthetic appearance of midface fullness at Month 1 (using the Global Aesthetic Improvement Scale [GAIS]), effects which remained in ≥80% up to 12 months. Volume change captured by 3D photography increased after 1 month to 3.6 mL (close to the total injected volume of 3.4 mL), and remained stable through 12 months. Over 97% reported satisfaction with results after treatment with HAVOL. Additionally, HAVOL was well tolerated, with no unanticipated related adverse events. CONCLUSIONS: This study showed that HAVOL is effective and well tolerated for midface treatment in a Chinese population.

Helicobacter pylori infection selectively attenuates endothelial function in male mice via exosomes-mediated ROS production.

Background: Substantial sex differences exist in atherosclerosis. Excessive reactive oxygen species (ROS) formation could lead to endothelial dysfunction which is critical to atherosclerosis development and progression. Helicobacter pylori (H. pylori) infection has been shown to attenuate endothelial function via exosomes-mediated ROS formation. We have demonstrated that H. pylori infection selectively increases atherosclerosis risk in males with unknown mechanism(s). The present study was to test the hypothesis that H. pylori infection impaired endothelial function selectively in male mice through exosome-mediated ROS formation. Methods and results: Age-matched male and female C57BL/6 mice were infected with CagA+ H. pylori to investigate sex differences in H. pylori infection-induced endothelial dysfunction. H. pylori infection attenuated acetylcholine (ACh)-induced endothelium-dependent aortic relaxation without changing nitroglycerine-induced endothelium-independent relaxation in male but not female mice, associated with increased ROS formation in aorta compared with controls, which could be reversed by N-acetylcysteine treatment. Treatment of cultured mouse brain microvascular endothelial cells with exosomes from H. pylori infected male, not female, mice significantly increased intracellular ROS production and impaired endothelial function with decreased migration, tube formation, and proliferation, which could be prevented with N-acetylcysteine treatment. Conclusions: H. pylori infection selectively impairs endothelial function in male mice due to exosome-mediated ROS formation.

Efficacy and Safety of Botulinum Toxin Type A for Treatment of Glabellar Lines: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Botulinum toxin type A (BoNT/A) has been used in aesthetic applications worldwide, including glabellar lines. Currently, four BoNT/A preparations were approved for the improvement of moderate-to-severe glabellar lines: onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA. DaxibotulinumtoxinA is a new form of BoNT/A drug that is developed in clinical application. We performed this network meta-analysis (NMA) to assess the efficacy and safety of all these different BoNT/A formulations for treating glabellar lines. METHODS: The investigators searched randomized controlled trials (RCTs) using the Medical Subject Headings (MeSH) terms "botulinum toxin" and "glabellar lines." We searched the relevant studies in electronic databases as following: PubMed, Elsevier, EMBASE and the Cochrane Library. The end points included the percentage of subjects with a glabellar line severity (GLS) score of none (0) or mild (1), and the percentage of subjects achieving ≥ 1-point and 2-point improvement in glabellar line severity at maximum frown at approximately month 1 by the investigators' assessment. RESULTS: All formulations of BoNT/A were far superior to placebo in efficacy. DaxibotulinumtoxinA was the only treatment that significantly increased the proportion of subjects achieving ≥ 1 point improvement in GLS score compared with other BoNT/A formulations. Moreover, daxibotulinumtoxinA was ranked the highest for the proportion of subjects achieving ≥ 2-point improvement in GLS score. No significant differences were revealed for the incidence of any adverse events (AEs) that related to treatment or drug among all BoNT/A preparations. CONCLUSION: The overall results of this NMA suggested that daxibotulinumtoxinA is a new BoNT/A preparation that may be not only more effective but also well-tolerated for the treatment of glabellar lines. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Identification of a Five-mRNA Signature as a Novel Potential Prognostic Biomarker for Glioblastoma by Integrative Analysis.

Despite the availability of advanced multimodal therapy, the prognosis of patients suffering from glioblastoma (GBM) remains poor. We conducted a genome-wide integrative analysis of mRNA expression profiles in 302 GBM tissues and 209 normal brain tissues from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project to examine the prognostic and predictive value of specific mRNAs in GBM. A total of 26 mRNAs were identified to be closely related to GBM patients' OS (p < 0.05). Utilizing survival analysis and the Cox regression model, we discovered a set of five mRNAs (PTPRN, ABCC3, MDK, NMB, and RALYL) from these 26 mRNAs that displayed the capacity to stratify patients into high- and low-risk groups with statistically different overall survival in the training set. The model of the five-mRNA biomarker signature was successfully verified on a testing set and independent sets. Moreover, multivariate Cox regression analysis revealed that the five-mRNA biomarker signature was a prognostic factor for the survival of patients with GBM independent of clinical characteristics and molecular features (p < 0.05). Gene set enrichment analysis indicated that the five-mRNA biomarker signature might be implicated in the incidence and development of GBM through its roles in known cancer-related pathways, signaling molecules, and the immune system. Moreover, consistent with the bioinformatics analysis, NMB, ABCC3, and MDK mRNA expression was considerably higher in four human GBM cells, and the expression of PTPRN and RALYL was decreased in GBM cells (p < 0.05). Our study developed a novel candidate model that provides new prospective prognostic biomarkers for GBM.

Circulating Exosomal miR-144-3p from Crohn's Disease Patients Inhibits Human Umbilical Vein Endothelial Cell Function by Targeting FN1.

Background: Crohn's disease (CD) is a chronic nonspecific inflammatory disease with unknown pathogenesis and vascular changes associated with the progression of CD. Many studies have shown that miRNAs participate in the development of CD. However, the effect of miRNAs in circulating exosomes on vascular endothelial cells in CD has not been investigated. Our study is aimed at identifying the differential miRNAs in circulating exosomes in CD and exploring their potential roles in human umbilical vein endothelial cells (HUVECs). Methods: In our study, exosomes were extracted from circulating blood to identify differential miRNAs. After in vitro transfection of HUVECs with miR-144-3p mimics and inhibitors and the corresponding controls, cell counting kit-8, wound healing, Transwell migration, and tube formation assays were performed to study the viability, migration, and angiogenesis of HUVECs. Furthermore, bioinformatics analysis was used to predict miRNA targets. Western blotting was used to determine protein expression. In addition, exogenous supplementation with the fibronectin 1 (FN1) protein rescued the effects of miR-144-3p on changes in cell function in vitro. Results: miR-144-3p was significantly increased in circulating exosomes of patients with CD compared with those in the control group. The promotion or inhibition of miR-144-3p correspondingly abolished or accelerated cell viability, migration, and angiogenesis. FN1 is a significant target of miR-144-3p, and exogenous FN1 administration improved the function of HUVECs in vitro. Conclusions: Circulating exosomal miR-144-3p from patients with active CD contributes to vascular endothelial dysfunction by affecting the gene expression of FN1. These findings suggested that circulating exosomal miR-144-3p could be a potential biological marker for CD.

Comparative study of allicin-containing quadruple therapy vs. bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection: a prospective randomized study.

BACKGROUND: Bismuth has antimicrobial activity and can improve the efficacy of triple Helicobacter pylori (H. pylori) therapy. Allicin added to conventional therapy for H. pylori infection also improves H. pylori eradication rates. Thus, this study aims to evaluate and compare the efficacy, safety and tolerability of allicin-containing quadruple therapy and bismuth-containing quadruple therapy and to investigate the factors that affect the eradication rates. METHODS: Two hundred twenty H. pylori-infected patients were included and randomly (1:1) assigned to 14-day quadruple therapy: ilaprazole (5 mg bid), doxycycline (100 mg bid), and furazolidone (100 mg bid) with an allicin soft capsule (40 mg of DATS tid) (IDFA) or colloidal bismuth tartrate (220 mg of elemental bismuth bid) (IDFB). Eradication was confirmed by urea breath tests. Symptom improvement, adverse events, and adherence were assessed by a questionnaire. RESULTS: In the intention-to-treat and per-protocol analysis, the eradication rates for IDFA and IDFB groups were 87.5% (70/80) vs. 86.3% (69/80, P = 0.815) and 91.9% (68/74) vs. 91.8% (67/73, P = 0.980) as first-line therapies; 83.3% (25/30) vs. 83.3% (25/30, P = 1) and 89.3% (25/28) vs. 88.9% (24/27, P = 1) as second-line therapies. Symptom improvement rates were 96.1% and 97.0% for IDFA and IDFB (P = 1). The adverse event rates were 10.9% in IDFA and 14.5% in IDFB groups (P = 0.418). Nausea occurred frequently in IDFB than IDFA (1.8% vs. 8.2%, P = 0.030). Smoking and sharing utensils significantly affected the efficacy. CONCLUSION: Allicin-containing quadruple therapy might be regarded as a promising alternative to bismuth-containing quadruple therapy in H. pylori eradication.

Helicobacter pylori infection selectively increases the risk for carotid atherosclerosis in young males.

BACKGROUND AND AIMS: Atherosclerosis is an important contributing factor to cardiovascular mortality. The role of Helicobacter pylori (H. pylori) infection in atherosclerosis is inconsistent and sometimes controversial. The present study aimed to determine if H. pylori infection is associated with carotid atherosclerosis. METHODS: 17,613 males and females with both carotid ultrasonic examination and 13C-urea breath test for H. pylori infection were screened by a major Chinese university hospital from March 2012 to March 2017 for the study. Baseline demographics, cardiac risk factors, and laboratory studies were obtained. After exclusion for pre-specified conditions, 12,836 individuals were included in the analysis, including 8157 men (63.5%) and 4679 women (36.5%). Analysis was also made for 5-year follow-up data of 1216 subjects (869 males and 347 females) with and without H. pylori infection for development and progression of carotid atherosclerosis. RESULTS: After adjusting for age, sex, body mass index, lipid profile, hypertension, renal function, diabetes mellitus, and smoking, H. pylori infection was found as an independent risk factor for carotid atherosclerosis in males under 50 years, but not in older males or females (odds ratio 1.229, 95% CI 1.054-1.434, p = 0.009). Follow-up data analysis showed that the incidence of carotid atherosclerosis from no atherosclerosis to detectable lesions was significantly higher in young males with persistent H. pylori infection than those without H. pylori infection (p = 0.028) after 3 years. CONCLUSIONS: These data suggest that H. pylori infection might be an important risk factor for carotid atherosclerosis in young Chinese males under 50.

miRNA-126 enhances viability, colony formation, and migration of keratinocytes HaCaT cells by regulating PI3 K/AKT signaling pathway.

Wound healing is a basic biological process including proliferation and migration of keratinocyte. The effects of microRNAs on skin wound healing remain largely unexplored. This study aimed to investigate the role of microRNA-126 (miR-126) in human skin wound healing. Relative expression of miR-126 after injury was evaluated by qRT-PCR. Cell viability, colony formation, cycle distribution, migration, and the alternation of PI3 K/AKT pathway after miR-126 knockdown or overexpression were detected, respectively. In addition, potential target gene of miR-126 was also explored by luciferase assay. Results showed that miR-126 was up-regulated during skin wound healing. Moreover, overexpression of miR-126 promoted cell proliferation and migration, whereas inhibition of miR-126 led to the opposite effects. Additionally, we discovered that PLK2, which inhibited cell viability, colony formation and migration of keratinocyte, was a target gene of miR-126. The expression of PLK2 was negatively correlated with the level of miR-126 during wound healing. Finally, we demonstrated that overexpression of miR-126 significantly increased the expression of p-AKT, p-ERK2, and PI3 K, indicating that overexpression of miR-126 activated PI3 K/AKT signaling pathway. In conclusion, our results demonstrated that miR-126 acted as a critical regulator for promoting proliferation and migration in keratinocyte during skin wound healing.

Clinical Characteristics and Prognostic Factors of Primary Splenic Angiosarcoma: A Retrospective Clinical Analysis from China.

BACKGROUND/AIMS: Primary splenic angiosarcoma is an aggressive malignancy originating from endothelial cells with a particularly poor outcome despite radical therapy. Owing to its extremely low incidence, available data for splenic angiosarcoma are limited. The present study aimed to address this limitation by presenting a thorough retrospective analysis of Chinese primary splenic angiosarcoma patients over a 53-year period (1963-2016). METHODS: To determine the characteristics of Chinese primary splenic angiosarcoma and identify factors that impact the outcomes of this histology, we retrospectively retrieved reports of 110 Chinese primary splenic angiosarcoma cases published between 1963-2012. RESULTS: In total, 61 males and 49 females diagnosed with primary splenic angiosarcoma were included in the present study. The median age at diagnosis was 50 years (range 2.5-76 years). Of these patients, 25.5% had received prior radiotherapy. The rate of splenic rupture was 59.11%. The 1-year overall survival rate was 19.1% with a median overall survival time of 8.1 months. Age, gender, and radiation history showed no correlation with survival rate. However, by univariate analysis, we found that significant adverse predictors of survival were splenic rupture before surgery and large tumor size (> 5 cm), while adjuvant chemotherapy was a favorable predictor. Furthermore, multivariate analysis revealed that splenic rupture and adjuvant chemotherapy were independent adverse and favorable predictors, respectively. CONCLUSION: Our large series describes and confirms the characteristics and poor prognosis of Chinese primary splenic angiosarcoma, thus indicating a critical role for early diagnosis and surgical intervention (prior to rupture) in management, and highlights the promising potential of adjuvant chemotherapy for improving the outcome in these cases.

Correlations of serum cystatin C and hs-CRP with vascular endothelial cell injury in patients with systemic lupus erythematosus.

BACKGROUND: To investigate the correlations of serum cystatin C and high-sensitivity C-reactive protein (hs-CRP) with vascular endothelial cell injury in patients with active systemic lupus erythematosus (SLE). METHODS: A total of 80 patients with SLE treated in our hospital from January 2016 to September 2017 were selected and randomly divided into stable-stage group (N.=40) and active-stage group (N.=40) using a random number table. The expressions of cystatin C and hs-CRP in stable and active stages were compared, and the inner diameters of brachial artery and levels of vascular endothelial growth factors in stable and active stages were also compared. The correlations of expressions of cystatin C and hs-CRP in active stage with the inner diameter of brachial artery and vascular endothelial growth factor were analyzed. At the same time, the correlation between vascular endothelial growth factor and inner diameter of brachial artery in active stage was analyzed. RESULTS: The level of cystatin C in active stage was higher than that in stable stage (P<0.05), and the expression level of hs-CRP in active stage was also higher than that in stable stage (P<0.05). The inner diameter of brachial artery in active stage was smaller than that in stable stage (P<0.05), but the level of vascular endothelial growth factor (VEGF) was higher than that in stable stage (P<0.05). The expressions of cystatin C and hs-CRP were negatively correlated with the inner diameter of brachial artery in active stage (P<0.05). The expressions of cystatin C and hs-CRP were positively correlated with VEGF in active stage (P<0.05). Moreover, there was a negative correlation between VEGF and inner diameter of brachial artery in active stage (P<0.05). CONCLUSIONS: Levels of cystatin C and hs-CRP are significantly increased in patients with active SLE, and the increase degrees are negatively correlated with the inner diameter of brachial artery under ultrasound, but positively correlated with the level of VEGF in vivo.

Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4.

Melanoma is the most common skin cancer and malignant melanoma which can cause skin cancer-related deaths. Toll-like receptor 4 (TLR4) had been reported to play an important role in melanoma, and tea polyphenol (TP) is regarded as an anticancer substance. However, the relationship between TP and TLR4 in melanoma is not well explored. Therefore, our aim is to figure out how TP has an influence on melanoma. Melanoma cell lines (B16F10 and A375) were treated with TP and lipopolysaccharides (LPS). Western blot assay was used to examine TLR4 expression, and MTT assay was conducted to assess proliferation. Wound healing assay was conducted to evaluate the migration of melanoma cells, and transwell assay was used to examine the melanoma cells' invasiveness. Besides, in vivo experiments were practiced for TP function in mice with melanoma cells. TP inhibited the proliferation, migration and invasion ability of melanoma cells, which displayed a dosage and time dependence. TLR4 was highly expressed in melanoma cells compared with normal skin cells. TP could suppress TLR4 expression both in normal melanomas and in stimulated melanomas by TLR4 agonist LPS. Suppressing TLR4 in melanomas could inhibit cell function (proliferation, migration, and invasion), and blocking the expression of 67LR could abolish TP function on TLR4. TP can inhibit melanoma (B16F10) growth in vivo.

Group 2 Innate Lymphoid Cells Are Involved in Skewed Type 2 Immunity of Gastric Diseases Induced by Helicobacter pylori Infection.

H. pylori induces a complicated local and systematic immune response and contributes to the carcinogenesis of gastric cancer. A primary type 1 immune response is evoked by H. pylori since its occurrence. However, it is not unusual that an inhibitory immunity is dominant in H. pylori-associated diseases, which are promoted by the formation of immunosuppressive microenvironment. But whether group 2 innate lymphoid cells (ILC2s) plays a critical role in H. pylori-induced skewed type 2 immunity is still unclear. In the present study, firstly, we confirmed that type 1 immunity was inhibited and type 2 immunity were undisturbed or promoted after H. pylori infection in vitro and in vivo. Secondly, GATA-3 was firstly found to be increased in the interstitial lymphocytes from H. pylori-associated gastric cancer, among them, Lin-GATA-3+ cells and Lin+GATA-3+ cells were also found to be enhanced, which indicated an important role for ILC2s in H. pylori infection. More importantly, ILC2s were found to be increased after H. pylori infection in clinical patients and animal models. In conclusion, our results indicated that ILC2-mediated innate immune response might play a potential role in dominant type 2 phenotype and immunosuppressive microenvironment in H. pylori infection.

PBX1 attributes as a determinant of connexin 32 downregulation in Helicobacter pylori-related gastric carcinogenesis.

AIM: To clarify the mechanisms of connexin 32 (Cx32) downregulation by potential transcriptional factors (TFs) in Helicobacter pylori (H. pylori)-associated gastric carcinogenesis. METHODS: Approximately 25 specimens at each developmental stage of gastric carcinogenesis [non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric carcinoma (GC)] with H. pylori infection [H. pylori (+)] and 25 normal gastric mucosa (NGM) without H. pylori infection [H. pylori (-)] were collected. After transcriptional factor array analysis, the Cx32 and PBX1 expression levels of H. pylori-infected tissues from the developmental stages of GC and NGM with no H. pylori infection were measured by real-time polymerase chain reaction (RT-PCR) and Western blot analysis. Regarding H. pylori-infected animal models, the Cx32 and PBX1 mRNA expression levels and correlation between the gastric mucosa from 10 Mongolian gerbils with long-term H. pylori colonization and 10 controls were analyzed. PBX1 and Cx32 mRNA and protein levels were further studied under the H. pylori-infected condition as well as PBX1 overexpression and knockdown conditions in vitro. RESULTS: Incremental PBX1 was first detected by TF microarray in H. pylori-related gastric carcinogenesis. The identical trend of PBX1 and Cx32 expression was confirmed in the developmental stages of H. pylori-related clinical specimens. The negative correlation of PBX1 and Cx32 was confirmed in H. pylori-infected Mongolian gerbils. Furthermore, decreased PBX1 expression was detected in the normal gastric epithelial cell line GES-1 with H. pylori infection. Enforced overexpression or RNAi-mediated knockdown of PBX1 contributed to the diminished or restored Cx32 expression in GES-1 and the gastric carcinoma cell line BGC823, respectively. Finally, dual-luciferase reporter assay in HEK293T cells showed that Cx32 promoter activity decreased by 30% after PBX1 vector co-transfection, indicating PBX1 as a transcriptional downregulator of Cx32 by directly binding to its promoters. CONCLUSION: PBX1 is one of the determinants in the Cx32 promoter targeting site, preventing further damage of gap junction protein in H. pylori-associated gastric carcinogenesis.