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Mei-Qi Xu,1,2 Yan-Li Hao,1,2 Jing-Ru Wang,1,2 Zhuo-Yue Li,1,2 Hui Li,1 Zhen-Han Feng,1,2 Hui Wang,1,2 Jing-Wen Wang,1,2 Xuan Zhang1,2 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of ChinaCorrespondence: Xuan ZhangDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing, 100191, People’s Republic of ChinaTel +86-10-82805765Fax +86-10-8280576Email xuanzhang@bjmu.edu.cnPurpose: Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo.Methods: We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated.Results: The size of ALA-PTX NPs was approximately 110.7± 1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5– 2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models.Conclusion: ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.Keywords: α-linolenic acid, α-linolenic acid-paclitaxel conjugate, α-linolenic acid-paclitaxel conjugate nanoparticles, cellular uptake, antitumor activity

Xiu-Chai Zheng,1,2,* Wei Ren,1,2,* Shuang Zhang,1,2 Ting Zhong,1,2 Xiao-Chuan Duan,1,2 Yi-Fan Yin,1,2 Mei-Qi Xu,1,2 Yan-Li Hao,1,2 Zhan-Tao Li,1,2 Hui Li,1,2 Man Liu,1,2 Zhuo-Yue Li,1,2 Xuan Zhang1,2 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China *These authors contributed equally to this work Background: In the present study, the tumor-specific, pH-responsive peptide H7K(R2)2 -modified, theranostic liposome-containing paclitaxel (PTX) and superparamagnetic iron oxide nanoparticles (SPIO NPs), PTX/SPIO-SSL-H7K(R2)2, was prepared by using H7K(R2)2 as the targeting ligand, SPIO NPs as the magnetic resonance imaging (MRI) agent, PTX as antitumor drug. Methods: The PTX/SPIO-SSL-H7K(R2)2 was prepared by a thin film hydration method. The characteristics of PTX/SPIO-SSL-H7K(R2)2 were evaluated. The targeting effect, MRI, and antitumor activity of PTX/SPIO-SSL-H7K(R2)2 were investigated detail in vitro and in vivo in human breast carcinoma MDA-MB-231 cell models. Results: Our results of in vitro flow cytometry, in vivo imaging, and in vivo MR imaging confirmed the pH-responsive characteristic of H7K(R2)2 in MDA-MB-231 cell line in vitro and in vivo. The results of in vivo MRI and in vivo antitumor activity confirmed the theranostic effect of PTX/SPIO-SSL-H7K(R2)2 in MDA-MB-231 tumor-bearing model. Conclusion: Considering all our in vitro and in vivo results, we conclude that we developed targeting modified theranostic liposome which could achieve both role of antitumor and MRI. Keywords: tumor-specific pH-responsive peptide, paclitaxel, superparamagnetic iron oxide nanoparticles, liposome, theranostic efficiency

Bin Zhang,1,* Yanli Hao,2,* Jiangyan Zhou,1,3 Fujun Jia,1 Xueli Li,1 Yi Tang,1 Huirong Zheng1 1Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Mental Health Centre, 2Department of Human Anatomy, Guang Zhou Medical University, 3Department of Psychiatry, Southern Medical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: This study evaluated the association between sleep patterns and the risk of being overweight/obese in Chinese children. Methods: A total of 3,086 children (1,608 boys and 1,478 girls) between 7 and 14 years of age and studying in primary schools were recruited as eligible study participants in this study. We collected the information about children regarding sleep patterns, body height and weight, insomnia, healthy status, time allocation of daily activities, and demographic characteristics using a parental-reported questionnaire. Results: Overweight/obese children were younger, predominantly male, and more prone to have suffered from illness in the past 12 months compared to normal-weight peers. They were also less prone to compensate for sleep deficits during weekends (47.6% vs 39.1%; χ2=11.637, P

Objective: In vitro fertilization-embryo transfer (IVF-ET) is a widely used treatment for infertility, with oocyte maturation and quality having a significant impact on oocyte fertilization, embryo development, and fetal growth. Mitochondrial transcription factor A (TFAM) is essential for maintaining the mitochondrial oxidative respiratory chain and supplying energy for oocyte development, fertilization, and embryonic development. In this study, we aimed to examine TFAM expression in women undergoing IVF-ET and assess its impact on the IVF outcomes., Methods: We recruited 85 women who underwent IVF-ET treatment for infertility. On the date of egg collection, granulosa cells were extracted from the clear follicular fluid of the first mature egg using ultrasound-guided needle aspiration. The collected granulosa cells served three purposes: (1) detecting TFAM gene expression in granulosa cells via immunocytochemistry, (2) determining TFAM mRNA expression using reverse transcription-PCR (RT-PCR), and (3) measuring TFAM protein expression through western blotting., Result: Based on the results, we found that TFAM was localized and expressed in the cytoplasm of granulosa cells, whereas no expression was detected in the nucleus. Granulosa cells exhibited a linear correlation between TFAM mRNA and TFAM protein expression. The study participants were divided into three groups using the ternary method based on relative TFAM mRNA expression thresholds of 33% and 76%: the low-expression group (n = 30), the moderate-expression group (n = 27), and the high-expression group (n = 28). When compared to the other two groups, the moderate expression group exhibited a significantly higher egg utilization rate, 2 pronucleus rate, fertilization rate, and clinical pregnancy rate (P < 0.05)., Conclusion: TFAM was detected in the cytoplasm of human ovarian granulosa cells. Women with moderate TFAM expression demonstrate enhanced outcomes in IVF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The primary objective of this study was to evaluate the efficacy and safety of pulsed field ablation in individuals diagnosed with atrial fibrillation., Methods: A total of 36 patients diagnosed with atrial fibrillation were enrolled in the pulsed field ablation group, while another 36 patients diagnosed with atrial fibrillation were included in the radiofrequency ablation group. Among the study participants, 15 patients in the pulsed field ablation group and 17 patients in the radiofrequency ablation group had persistent atrial fibrillation. Comprehensive comparisons were made between the two groups, including baseline data, underlying diseases, medication usage, intraoperative parameters, and atrial fibrillation recurrence rates at 1, 3, and 6 months during the postoperative follow-up period., Results: (1) There were no significant differences observed between the two groups concerning baseline data and antiarrhythmic drug usage (P > 0.05); (2) the effective ablation time for both left and right pulmonary veins in the pulsed field ablation group was markedly shorter compared to the radiofrequency ablation group (P < 0.001 for each vein); (3) within the pulsed field ablation group, the number of discharges, catheter operation time, and effective ablation time for the left pulmonary vein were significantly higher than those for the right pulmonary vein (P < 0.05). Conversely, in the radiofrequency ablation group, the number of discharges for the left pulmonary vein was significantly higher than that for the right pulmonary vein (P < 0.05); and (4) when comparing sinus rhythm maintenance at 1, 3, and 6 months postoperatively, no statistically significant differences were noted between the two groups for paroxysmal, persistent, and paroxysmal + persistent atrial fibrillation cases (P > 0.05)., Conclusion: During the 6-month follow-up period, pulsed field ablation demonstrated comparable efficacy to radiofrequency ablation with respect to recurrence rates for both paroxysmal and persistent atrial fibrillation. Moreover, pulsed field ablation exhibited high safety levels, excellent surgical efficiency, and a notably brief learning curve, affirming its viability as a therapeutic option for these conditions., (© 2023. The Author(s).)

Vascular dementia(VD) is a condition of cognitive impairment due to acute and chronic cerebral hypoperfusion. The available therapies for VD mainly focus on mitigating cerebral ischemia, improving cognitive function, and controlling mental behavior. Achievements have been made in the basic and clinical research on the treatment of VD with traditional Chinese medicine(TCM) active components, including Ginkgo leaf extract, puerarin, epimedium, tanshinone, and ginsenoside. Most of these components have anti-inflammatory, anti-apoptotic, anti-oxidant, and neuroprotective effects, and puerarin demonstrates excellent performance in mitigating cholinergic nervous system disorders and improving synaptic plasticity. Puerarin, ginkgetin, and epimedium are all flavonoids, while tanshinone is a diterpenoid. Puerariae Lobatae Radix, pungent in nature, can induce clear Yang to reach the cerebral orifices and has the wind medicine functions of ascending, dispersing, moving, and scurrying. Puerariae Lobatae Radix entering collaterals will dredge blood vessels to promote blood flow, and that entering the sweat pore will open the mind, which is in line with the TCM pathogenesis characteristics of VD. This study reviews the progress in the mechanism of puerarin, the main active component of Puerariae Lobatae Radix, in treating VD. Puerarin can ameliorate cholinergic nervous system disorders, reduce excitotoxicity, anti-inflammation, inhibit apoptosis, alleviate oxidative stress injury, enhance synaptic plasticity, up-regulate neuroprotective factor expression, promote cerebral circulation metabolism, and mitigate Aβ injury. The pathways of action include activating nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE), vascular endothelial growth factor(VEGF), extracellular regulated protein kinases(ERK), phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt), Janus-activating kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3), AMP-activated protein kinase(AMPK), as well as inhibiting the tumor necrosis factor α(TNF-α), transient receptor potential melastatin 2(TRPM2)/N-methyl-D-aspartate receptor(NMDAR), p38 mitogen-activated protein kinase(p38 MAPK), Toll-like receptor 4(TLR4)/nuclear factor-kappaB(NF-κB), early growth response 1(Egr-1), and matrix metalloproteinase 9(MMP-9). By reviewing the papers about the treatment of VD by puerarin published by CNKI, Wanfang, VIP, PubMed, and Web of Science in the last 10 years, this study aims to support the treatment and drug development for VD.

Bone defects have attracted increasing attention in clinical settings. To date, there have been no effective methods to repair defective bones. Balsa wood aerogels are considered as an excellent source of chemicals for chemical modification to facilitate the in situ immobilization of zeolitic imidazolate framework-8. Furthermore, dexamethasone has received considerable attention for bone tissue engineering. In this study, for the first time, a simple but effective one-pot method for developing a novel zeolitic imidazolate framework-8 with different concentrations of dexamethasone was developed. These findings illustrate that the novel scaffold has a significant positive impact on osteogenic differentiation in vitro and repairs defects in vivo , suggesting that it can be used in bone tissue engineering.

The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p -values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes. Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines. Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xie, Huang, Hao, Yu, Zhang, Wei, Gao, Wang and Zeng.)

Objective To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior, glia activation and pro-inflammatory cycokines, and Tau phosphorylation of a new Alzheimer's disease (AD) mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation, and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice ( PSEN1 G378E/WT ; Tyrobp +/- ) and the homozygous hybrid mice ( PSEN1 G378E/G378E ; Tyrobp -/- ). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed, the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and ELISA to measure the levels of pro-inflammatory cytokines. Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in PSEN1 G378E mutation mouse model prevented the deterioration of learning behavior, decreased the numbers of microglia and astrocytes, and the levels of interleukin-6, interleukin-1β and tumor necrosis factor- α in the hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice ( PSEN1 G378E/G378E ; Tyrobp -/- mice) compared with PSEN1 G378E/G378E mice (all P < 0.05). Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However, the relationship between neuroinflammation processes involving microglia and astrocyte activation, and release of pro-inflammatory cytokines, and p-Tau pathology needs further study.

As an emerging pollutant to the environment, microplastics have received widespread attention worldwide. The Loess Plateau, as one of the major agricultural production areas in China, has various land use types, but how the abundance and morphological patterns of microplastics differ among soils under different land use types remains unclear. In this study, we collected soils from three different land use types:croplands, apple orchards, and landfills in the Wangdonggou Catchment. Microplastics were separated and extracted using a modified density centrifugation method, and the abundance, composition, and morphological characteristics of the soil were analyzed and characterized using a laser infrared imaging system. The results showed that the average abundance of microplastics in the Wangdonggou Catchment was 4715 n·kg -1 , mainly composed of PET, PU, and alkyd varnish(ALK), respectively accounting for 30.39%, 29.58%, and 8.42%. More than 80% of the microplastics were fragmented, and more than 60% of the microplastics were of a size ≤ 50 μm. The average abundance of microplastics varied significantly among land use types:cropland soil (7550 n·kg -1 )>apple orchard soil (3440 n·kg -1 )>landfill soil (2283 n·kg -1 ). The average area, width, height, eccentricity, circularity, and other morphological characteristics of microplastics in apple orchard soil were significantly different from those in the cropland and landfill soil.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 μM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg -1  · d - 1 , ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC 50 value of 2.46 μM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Accurately predicting the survival prospects of patients suffering from pancreatic adenocarcinoma (PAAD) is challenging. In this study, we analyzed RNA matrices of 182 subjects with PAAD based on public datasets obtained from The Cancer Genome Atlas (TCGA) as training datasets and those of 63 subjects obtained from the Gene Expression Omnibus (GEO) database as the validation dataset. Genes regulating the metabolism of PAAD cells correlated with survival were identified. Furthermore, LASSO Cox regression analyses were conducted to identify six genes ( XDH , MBOAT2 , PTGES , AK4 , PAICS , and CKB ) to create a metabolic risk score. The proposed scoring framework attained the robust predictive performance, with 2-year survival areas under the curve (AUCs) of 0.61 in the training cohort and 0.66 in the validation cohort. Compared with the subjects in the low-risk cohort, subjects in the high-risk training cohort presented a worse survival outcome. The metabolic risk score increased the accuracy of survival prediction in patients suffering from PAAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Huang, Fang, Liang, Hao, Zhang, Xie, Wang, Tan and Zeng.)

Recently we identified the VRC01-like antibody DRVIA7(A7) from an HIV-1 B' subtype-infected individual (DRVI01) with broad neutralization activity, and almost all viruses from the individual were resistant to both VRC01 and A7 lineage antibodies. Here, we identified and characterized a panel of HIV-1 variants with resistance to VRC01 and A7 using site-directed mutagenesis and swapping amino acid fragments of gp120. Site-directed mutagenesis revealed that E279D/R282K/N460A/T464N of gp120 from DRVI01 produced VRC01-susceptible variants. Multiple mutations significantly increased the neutralization sensitivity to VRC01. Residues N464 located at the tip of the V5 loop were considered irrelevant to the neutralization of VRC01. For DRVI01-derived viruses, the single N464T change fully produced VRC01-resistant variants; conversely, a single T464N mutation generated VRC01-susceptible variants. Alanine scanning revealed that the N464 residue plays a vital role in binding with VRC01. Neutralizing assays against A7 lineage antibodies showed that DRVI01-derived viruses with multiple mutations could be neutralized by A7 lineage antibodies with different neutralizing breadths. Combining the changes in loops D and V5 produced variants that were totally sensitive variants to A7 lineage antibodies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To solve the poor sustainability of electroactive stimulation in clinical therapy, a strategy of combining a piezoelectric BaTiO 3 -coated Ti6Al4V scaffold and low-intensity pulsed ultrasound (LIPUS) was unveiled and named here as piezodynamic therapy. Thus, cell behavior could be regulated phenomenally by force and electricity simultaneously. First, BaTiO 3 was deposited uniformly on the surface of the three-dimensional (3D) printed porous Ti6Al4V scaffold, which endowed the scaffold with excellent force-electricity responsiveness under pulsed ultrasound exposure. The results of live/dead staining, cell scanning electron microscopy, and F-actin staining showed that cells had better viability, better pseudo-foot adhesion, and more muscular actin bundles when they underwent the piezodynamic effect of ultrasound and piezoelectric coating. This piezodynamic therapy activated more mitochondria at the initial stage that intervened in the cell cycle by promoting cells' proliferation and weakened the apoptotic damage. The quantitative real-time polymerase chain reaction data further confirmed that the costimulation of the ultrasound and the piezoelectric scaffolds could trigger adequate current to upregulated the expression of osteogenic-related genes. The continuous electric cues could be generated by the BaTiO 3 -coated scaffold and intermittent LIPUS stimulation; thereon, more efficient bone healing would be promoted by piezodynamic therapy in future treatment.

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H 2 O 2 , siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to analyze the biological effects of circ-0079593 and its potential mechanism in the progression of melanoma., Patients and Methods: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was carried out to detect circ-0079593 expression in melanoma tissue samples and cell lines, and the relationship between circ-0079593 expression and prognosis of patients with melanoma was analyzed based on collected clinical information. Then, the melanoma cell line stably overexpressing circ-0079593 was constructed using lentiviral stable transfection technique, and then, Cell Counting Kit-8 (CCK-8) and transwell assays were carried out to detect the proliferation rate, migration, as well as invasion abilities of melanoma cells, respectively. In addition, the potential binding targets of circ-0079593 were searched through bioinformatics analysis, and the results were verified by Dual-Luciferase assay., Results: It was found that, in comparison with the normal control group, circ-0079593 showed a significantly high expression in melanoma tissues and cell lines, which predicted a poor prognosis of melanoma patients. In vitro experiments showed that the overexpression of circ-0079593 remarkably enhanced proliferation rate, as well as invasion ability of melanoma cells. Moreover, bioinformatics data analysis revealed that there exist binding sites of microRNA-433 both in circ-0079593 and EGFR. Meanwhile, the results of the Luciferase assay confirmed that circ-0079593 probably bound to microRNA-433, as an endogenous competitive RNA (ceRNA), to regulate EGFR expression. At last, cell reverse experiments demonstrated that the overexpression of microRNA-433 could attenuate the capacity of melanoma cells to proliferate and migrate, while simultaneous overexpression of circ-0079593 partially restored those cell functions., Conclusions: In melanoma, circ-0079593 may serve as a cancer-promoting gene to accelerate the rates of cell proliferation and migration, which may exert its effects by elevating EGFR expression by binding to microRNA-433.

Cattle encephalon glycoside and ignotin (CEGI) injection is a compound preparation formed by a combination of muscle extract from healthy rabbits and brain gangliosides from cattle, and it is generally used as a neuroprotectant in the treatment of central and peripheral nerve injuries. However, there is still a need for high-level clinical evidence from large samples to support the use of CEGI. We therefore carried out a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in which we recruited 319 patients with acute cerebral infarction from 16 centers in China from October 2013 to May 2016. The patients were randomized at a 3:1 ratio into CEGI (n = 239; 155 male, 84 female; 61.2 ± 9.2 years old) and placebo (n = 80; 46 male, 34 female; 63.2 ± 8.28 years old) groups. All patients were given standard care once daily for 14 days, including a 200 mg aspirin enteric-coated tablet and 20 mg atorvastatin calcium, both taken orally, and intravenous infusion of 250-500 mL 0.9% sodium chloride containing 40 mg sodium tanshinone IIA sulfonate. Based on conventional treatment, patients in the CEGI and placebo groups were given 12 mL CEGI or 12 mL sterile water, respectively, in an intravenous drip of 250 mL 0.9% sodium chloride (2 mL/min) once daily for 14 days. According to baseline National Institutes of Health Stroke Scale scores, patients in the two groups were divided into mild and moderate subgroups. Based on the modified Rankin Scale results, the rate of patients with good outcomes in the CEGI group was higher than that in the placebo group, and the rate of disability in the CEGI group was lower than that in the placebo group on day 90 after treatment. In the CEGI group, neurological deficits were decreased on days 14 and 90 after treatment, as measured by the National Institutes of Health Stroke Scale and the Barthel Index. Subgroup analysis revealed that CEGI led to more significant improvements in moderate stroke patients. No drug-related adverse events occurred in the CEGI or placebo groups. In conclusion, CEGI may be a safe and effective treatment for acute cerebral infarction patients, especially for moderate stroke patients. This study was approved by the Ethical Committee of Peking University Third Hospital, China (approval No. 2013-068-2) on May 20, 2013, and registered in the Chinese Clinical Trial Registry (registration No. ChiCTR1800017937)., Competing Interests: None

Recent years have witnessed the rise of graphene and its applications in various electronic devices. Specifically, featuring excellent flexibility, transparency, conductivity, and mechanical robustness, graphene has emerged as a versatile material for flexible electronics. In the past decade, facilitated by various laser processing technologies, including the laser-treatment-induced photoreduction of graphene oxides, flexible patterning, hierarchical structuring, heteroatom doping, controllable thinning, etching, and shock of graphene, along with laser-induced graphene on polyimide, graphene has found broad applications in a wide range of electronic devices, such as power generators, supercapacitors, optoelectronic devices, sensors, and actuators. Here, the recent advancements in the laser fabrication of graphene-based flexible electronic devices are comprehensively summarized. The various laser fabrication technologies that have been employed for the preparation, processing, and modification of graphene and its derivatives are reviewed. A thorough overview of typical laser-enabled flexible electronic devices that are based on various graphene sources is presented. With the rapid progress that has been made in the research on graphene preparation methodologies and laser micronanofabrication technologies, graphene-based electronics may soon undergo fast development., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In recent years, mesh structures have attracted significant interest for structural and functional applications. However, the mechanical strength and energy absorption ability of uniform mesh structured materials degrade with density. To address this challenge, we propose the concept of functionally graded mesh structures. The objective of the proposed research is to fundamentally understand the compressive behavior of graded mesh structures. The compression-compression fatigue behavior of functionally graded Ti-6Al-4V mesh structure under identical bulk stress condition is studied here. During cyclic deformation, it was observed that the local stress distribution in the struts was not uniform because of inhomogeneous mechanical properties of the constituents. Fatigue cracks first initiated in the lowest strength constituent, and then propagated until structural failure occurred. However, no obvious damage was observed in other constituents during the entire process. In contrast with iso-strain state, the fatigue life of graded structure is mainly determined by the constituent with the lowest strength., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the highly selective autoimmune injury of small intrahepatic bile ducts. Studies reported that the cholangiocytes from PBC patients expressed significantly higher levels of both receptor activator of nuclear factor-kappa B (RANK) and its ligand RANKL. However, the accurate role of RANK/RANKL axis in PBC remains unclear., Methods: Forty patients with PBC were enrolled according to the inclusion criteria. The biochemical parameters (alkaline phosphatase, ALP; gamma-glutamyltransferase, GGT; alanine aminotransferase, ALT; aspartate transaminase, AST; total bilirubin, TB) were collected at baseline and followed-up after 6 months of treatment with ursodeoxycholic acid (UDCA, 15 mg/kg d). Stages of PBC were diagnosed based on liver biopsy histopathology according to Nakanuma's criteria. RANK expression in hepatic tissues was detected by immunohistochemistry. The cellular immunofluorescence method was used to locate the distribution of RANK in the human intrahepatic biliary epithelial cells (HIBECs) cultured in vitro. HIBECs were treated with RANKL at a concentration of 100 ng/ml or transfected with RANK-overexpressing lentivirus (LV-RANK). CCK-8 assay and cell cycle assay were used to detect the cell proliferation. Real-time PCR was used to detect the expression of IL-6, E-cadherin, VCAM, ICAM-1, TNF-α, and CD80., Results: RANK expression in liver biopsies from early PBC patients (stage I + stage II) was significantly lower than that from advanced PBC patients (stage III + stage IV) (1.7 ± 0.63 vs. 2.3 ± 0.45 scores, P < 0.05). High-RANK patients seemed to have better response to UDCA than low-RANK patients (88.9% vs. 40.9%, P < 0.05). The baseline biochemical parameters between the two groups were comparable. The decline percentages of ALP and GGT after UDCA treatment were more obvious in high-RANK patients than those in low-RANK patients (53.90% ± 9.82% vs. 23.93% ± 6.24%, P < 0.05; 74.11% ± 7.18% vs. 48.00% ± 8.17%, P < 0.05, respectively). HIBECs proliferation was significantly inhibited after treatment of RANKL or transfection with LV-RANK. Increased expression of IL-6 and E-cadherin was observed in HIBECs treated with RANKL or LV-RANK., Conclusion: The overall hepatic RANK expression was associated with disease severity and biochemical response in PBC patients. Activation of RANK/RANKL signaling pathway inhibited cholangiocytes proliferation in vitro. Our study suggested that RANK/RANKL pathway might be a potential target of immunotherapy of PBC based on its involvement in the occurrence and development of the disease.

Background: Reverse intertrochanteric fractures are usually initially treated with closed reduction. However, sometimes these fractures are not amenable to closed reduction and require open reduction. To date, few studies have been conducted on predictors of and reduction techniques for irreducible reverse intertrochanteric fractures. Therefore, this study aimed to summarize the displacement patterns of irreducible reverse intertrochanteric fractures and corresponding reduction techniques, and explore predictors of irreducibility., Methods: We reviewed 1174 cases of trochanteric fractures treated in our hospital from January 2006 to October 2018, 113 of which were reverse intertrochanteric fractures. An irreducible fracture was determined according to intra-operative fluoroscopy imaging after closed manipulation. Fractures were assessed for displacement patterns, radiographic features of irreducibility, and reduction techniques. Logistic regression analysis was performed on potential predictors for irreducibility, including gender, age, body mass index, AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification, and radiographic features., Results: Seventy-six irreducible fractures were identified, accounting for 67% of reverse intertrochanteric fractures. Six patterns of fracture displacement after closed manipulation were identified; the most common pattern was medial displacement and posterior sagging of the femoral shaft relative to the head-neck fragment. Multivariate logistic regression analysis identified three predictors of irreducibility: a medially displaced femoral shaft relative to the head-neck fragment on the anteroposterior (AP) view (odds ratio [OR], 8.00; 95% confidence interval [CI], 3.04-21.04; P < 0.001), a displaced lesser trochanter (OR, 3.61; 95% CI, 1.35-9.61; P = 0.010), and a displaced lateral femoral wall (OR, 2.92; 95% CI, 1.02-8.34; P = 0.046)., Conclusions: A high proportion of reverse intertrochanteric fractures are not amenable to closed reduction. Six patterns of fracture displacement after closed manipulation were identified. Different reduction techniques are required for different displacement patterns. Predictors of irreducibility include a medially displaced femoral shaft relative to the head-neck fragment on the AP view, a displaced lesser trochanter, and a displaced lateral femoral wall. These patients warrant special consideration in terms of recognition and management.

The present study aimed to investigate whether the single nucleotide polymorphisms (SNPs) rs2010963 and rs833061 in vascular endothelial growth factor (VEGF) gene is correlated with the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women, as a preliminary study. This case-control study comprised 118 women with PCOS and 130 healthy women as controls. Genotyping of the two polymorphisms within the VEGF gene 5'-untranslated region and promoter region were performed using polymerase chain reaction ligase detection reaction method. The data showed that there was a significant difference in the genotype and allele distribution of the rs2010963 polymorphism between the PCOS group and the control group ( p  = .020 and .033, respectively). The women carrying the C allele (G/C + C/C genotype) had a lower risk of PCOS compared with the women with G/G genotype [odds ratio (OR = 0.55; 95% confidence interval (CI) = 0.33-0.91]. Our study shows for the first time that the rs2010963 polymorphism may be associated with a risk of PCOS in Northern Chinese women.

Background and Aims: Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations, while the viral-chemical etiology along with molecular mechanisms of HCC pathogenesis remains largely unknown. This study aimed to determine expression profile and prognostic value of HER-2/neu, STAT3 and SOCS3 in HCC., Methods: Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to evaluate the expression of HER-2/neu, STAT3 and SOCS3 in HCC tissues and adjacent normal tissues collected from 176 HCC patients., Results: HER-2/neu and STAT3 levels were higher and SOCS3 expression was lower in HCC tissues than in adjacent normal tissues. HER-2/neu, STAT3 and SOCS3 levels were associated with histological grade, tumor diameter, TNM stage, vascular invasion, lymph node metastasis and distant metastasis in HCC. SOCS3 expression was negatively associated with HER-2/neu and STAT3 expression. HCC patients with higher HER-2/neu and STAT3 levels had shorter overall, disease-free and disease-specific survival, whereas the opposite was found in patients with higher SOCS3 expression. In Cox regression analysis, tumor size, TNM stage, and STAT3 expression were identified as independent prognostic factors of HCC., Conclusion: Taken together, these observations suggest that HER-2/neu, STAT3 and, SOCS3 are related to the aggressive tumor behavior and STAT3 has potential value as a prognostic factor for HCC., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Myocardial ischemia and reperfusion injury (MIRI) includes major drawbacks, such as excessive formation of free radicals and also overload of calcium, which lead to cell death, tissue scarring, and remodeling. The current study aims to explore whether KRT1 silencing may ameliorate MIRI via the Notch signaling pathway in mouse models. Myocardial tissues were used for the determination of the positive rate of KRT1 protein expression, apoptosis of myocardial cells, creatine kinase (CK) and lactate dehydrogenase (LDH) expression, expression of related biomarkers as well as myocardial infarction area. The transfected myocardial cells were treated with KRT1-siRNA, Jagged1, and DAPT (inhibitor of Notch-1 signaling pathway). The expression of KRT1, NICD, Hes1, Bcl-2, and Bax protein was detected. The MTT assay was applied for cell proliferation and flow cytometry was used for cell apoptosis. Mice with MIRI had a higher positive rate of KRT1 protein expression, apoptosis of myocardial cells, CK and LDH expression, myocardial infarction area, increased expression of MDA, NO, SDH, IL-1, IL-6, TNF-α, CRP, KRT1, Bax protein, CK, and LDH, and decreased expression of SOD, NICD, Hes1, and Bcl-2. The downregulation of KRT1 led to decreased expression of KRT1 and Bax protein, increased expression of NICD, Hes1, and Bcl-2, decreased cell apoptosis, and improved cell proliferation. The inhibition of the Notch signaling pathway leads to reduced expression of Bax, increased expression of NICD, Hes1, and Bcl 2, and also decreased cell apoptosis and increased cell proliferation. Our data conclude that KRT1 silencing is able to make MIRI better by activating the Notch signaling pathway in mice., (© 2018 Wiley Periodicals, Inc.)

The original version of this Article omitted the author Kuan Wang, who is from the 'College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan' and 'Nanyang Environment & Water Research Institute, Nanyang Technological University, Singapore 637141, Singapore.'Also, the author S.H. Lim was incorrectly given as L.S. Hoi and A. Larsson was incorrectly given as A. Larson.The "Author contributions" was amended to reflect the authorship changes. It previously read 'Y.Z.S., C.-W.Q., and A.Q.L. jointly conceived the idea. Y.Z.S., S.X., Y.Z., J.B.Z., W.S., J.H.W., T.N.C., Z.C.Y., Y.L.H., B.L., P.H.Y., D.P.T., and C.-W.Q. performed the numerical simulations and theoretical analysis. Y.Z.S., S.X., and L.K.C. did the fabrication and experiments of particle hopping, biomolecule binding and flow cytometry. A.L. and L.S.H. did the SPR experiments. S.X., Y.Z.S., Y.Z., C.-W.Q., Y.-Y.C., L.K.C., T.H.Z., and A.Q.L. prepared the manuscript. S.X., Y.Z., C.-W.Q., and A.Q.L. supervised and coordinated all the work. All authors commented on the manuscript.' The correct version states 'B.L., K. W., P.H.Y.' instead of 'B.L., P.H.Y.' and 'S.H.L.' in place of 'L.S.H.'This has been corrected in both the PDF and HTML versions of the Article.

Nucleus-targeting drug delivery systems (NTDDs) deliver chemotherapeutic agents to nuclei in order to improve the efficacy of anti-tumour therapy. Histone H1 (H1) plays a key role in establishing and maintaining higher order chromatin structures and could bind to cell membranes. In the present study, we selected H1 as a target to prepare a novel H1-mediated NTDD. Low molecular weight heparin (LMHP) and doxorubicin (DOX) were combined to form LMHP-DOX. Then, a novel NTDD consisting of LMHP-DOX nanoparticles (LMHP-DOX NPs) was prepared by self-assembly. The characteristics of LMHP-DOX and LMHP-DOX NPs were investigated. Histone H1 high-expressive prostate cancer PC-3M cell line was selected as the cell model. Cellular uptake, and the in vitro and in vivo anti-tumour activity of LMHP-DOX NPs were evaluated on H1 high-expressive human prostate cancer PC-3M cells. Our results indicated that intact LMHP-DOX NPs mediated by H1 could be absorbed by H1 high-expressive PC-3M cells, escape from the lysosomes to the cytoplasm, and localize in the perinuclear region via H1-mediated, whereby DOX could directly enter the cell nucleus and quickly increase the concentration of DOX in the nuclei of H1 high-expressive PC-3M cells to enhance the apoptotic activity of cancer cells. The anti-coagulant activity of LMHP-DOX NPs was almost completely diminished in rat blood compared with that of LMHP, indicating the safety of LMHP-DOX NPs. Compared to traditional NTDD strategies, LMHP-DOX NPs avoid the complicated modification of nucleus-targeting ligands and provide a compelling solution for the substantially enhanced nuclear uptake of chemotherapeutic agents for the development of more intelligent NTDDs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Deregulated expression of miRNAs contributes to the development of acute myeloid leukemia (AML). miR-504-3p, one of these miRNAs, has been found have upregulated expression in various human malignancies. Our present study aimed to detect the expression of miR-504-3p and its biological effect in AML., Patients and Methods: Real-time quantitative PCR was applied to evaluate the expression level of miR-504-3p in AML cell lines and the serum from AML cases. The correlations between miR-504-3p and AML patients' clinicopathological characteristics, as well as AML patients' overall survival, were statistically assessed. Moreover, we investigated the effect of miR-504-3p knockdown on AML cells by CCK-8, Transwell assays and flow cytometry, in vitro. The Western blot, RT-PCR and luciferase reporter assay were performed to evaluate the relationship between miR-504-3p and its downstream target genes. Finally, the biological function of MTHFD2 was also analyzed., Results: The expression levels of miR-504-3p were significantly down-regulated in the serum of AML patients and cell lines, and its low expression was positively associated with advanced clinical stages and poor prognosis of AML patients. Functional assays indicated that overexpression of miR-504-3p leads to AML cell growth arrest, invasion and migration inhibition, and elevated rates of apoptosis. We also found that miR-504-3p regulated the expression of MTHFD2 by binding to its 3'-UTR, and knockdown of MTHFD2 significantly suppressed AML cells proliferation, migration and invasion, and promoted apoptosis., Conclusions: Our findings provide important evidence that supports the role of miR-504-3p as a tumor suppressor in AML via the inhibition of MTHFD2 expression.

Background: 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX) is a paclitaxel (PTX) bioreductive prodrug synthesized by our lab. We hypothesize that NPPA-PTX can self-assemble to form nanoparticles (NPs)., Materials and Methods: In the present research, the theoretical partition coefficient (XlogP) and Hansen solubility parameters of NPPA-PTX were calculated. NPPA-PTX nanoparticles prepared by NPPA-PTX and DSPE-PEG (NPPA-PTX:DSPE-PEG =1:0.1, w/w) (NPPA-PTX@PEG NPs) were prepared and characterized. The cellular uptake, in vitro antitumor activity, in vivo targeting effect, tumor distribution, in vivo antitumor activity, and safety of NPPA-PTX@PEG NPs were investigated., Results: Our results indicate that NPPA-PTX can self-assemble to form NPPA-PTX@PEG NPs. Both the cellular uptake and safety of NPPA-PTX@PEG NPs were higher than those of Taxol. NPPA-PTX@PEG NPs could target tumor tissues by a passive targeting effect. In tumor tissues, NPPA-PTX@PEG NPs could completely transform into active PTX. The in vivo antitumor activity of NPPA-PTX@PEG NPs was confirmed in MDA-MB-231 tumor-bearing nude mice., Conclusion: The bioreductive prodrug NPPA-PTX could self-assemble to form NPs. The safety and antitumor activity of NPPA-PTX@PEG were confirmed in our in vitro and in vivo experiments. The NPPA-PTX@PEG NPs developed in this study could offer a new way of preparing bioreductive prodrug, self-assembled NPs suitable for antitumor therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

BACKGROUND Since the use of human umbilical cord Wharton's Jelly derived mesenchymal stromal cells (hWJ-MSCs) to treat sarcopenia has not been explored, we studied the effects of hWJ-MSCs in aged male C57BL/6J mice with sarcopenia induced by hindlimb suspension, and explored the potential mechanism. MATERIAL AND METHODS Hindlimb suspension was used to induce sarcopenia in 24-month-old C57BL/6J mice and green fluorescent protein-tagged hWJ-MSCs and controls were transplanted into mice via tail vein or local intramuscular injection. After hWJ-MSC transplantation, changes in whole body muscle strength and endurance, gastrocnemius muscle weight and myofiber cross-sectional area (CSA) were studied. Proliferation of skeletal muscle stem cell, apoptosis, and chronic inflammation were also investigated. RESULTS We demonstrated that whole body muscle strength and endurance, gastrocnemius muscle mass, and CSA were significantly increased in hWJ-MSC-transplanted mice than in controls (P<0.05). In hWJ-MSC-transplanted mice, apoptotic myonuclei was reduced, and BrdU and Pax-7 expression indices of gastrocnemius muscles were increased (P<0.05). Tumor necrosis factor (TNF)-α and interleukin (IL)-6 were downregulated, and IL-4 and IL-10 were upregulated (P<0.05). CONCLUSIONS hWJ-MSCs may ameliorate sarcopenia in aged male C57BL/6J mice induced by hindlimb suspension, and this may be via activation of resident skeletal muscle satellite cells, reduction of apoptosis, and less chronic inflammation.

Laryngeal cancer is a common cancer occurred in the head and neck. Irradiation sensitivity is a problem affecting the treatment of laryngeal cancer. Tanshinone IIA has been reported to play an important role in treating multiple diseases; yet, whether Tanshinone IIA can be an irradiation sensitizer has not been reported. Clonogenic assay, annexin-V/propidium iodide double-staining assay, and Cell Counting Kit-8 assay were performed to detect cell survival, proliferation, apoptosis, and viability. Mouse laryngeal cancer xenograft model was established and subjected to tumor size analysis. Tanshinone IIA treatment increased the irradiation sensitivity of laryngeal cancer cells by reducing cell survival, viability and proliferation, and increasing cell apoptosis. Tanshinone IIA treatment increased the survival period of mice in the in vivo laryngeal cancer model, evidenced by decreased growth and weight of tumors, which was possibly mediated through the JNK pathway. Tanshinone IIA increases the sensitivity to irradiation in laryngeal cancer cells and in vivo laryngeal cancer model, suggesting that Tanshinone IIA can be a therapeutic antitumor agent for treating laryngeal cancer., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Recent studies have uncovered the vital roles played by microRNAs in regulating cardiac injury. Among them, the cardiac enriched microRNA-1 (miR-1) has been extensively studied and proven to be detrimental to cardiac myocytes. Hence, the current study aimed to explore whether miR-1 affects myocardial ischemia-reperfusion injury (MIRI) in rats undergoing sevoflurane preconditioning and the underlying mechanism. After successful model establishment, rats with MIRI were transfected with mimics or inhibitors of miR-1, or siRNA against MAPK3, and then were injected with sevoflurane. A luciferase reporter gene assay was conducted to evaluate the targeting relationship between miR-1 and MAPK3. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were employed to evaluate the expressions of miR-1, MAPK3, phosphatidylinositol 3-kinase (PI3K), and Akt. Additionally, the concentration of lactate dehydrogenase (LDH) was determined. Cell apoptosis and viability were assessed using TUNEL and cell counting kit-8 assays, and the ischemic area at risk and infarct size were detected using Evans blue and triphenyltetrazolium chloride staining. MAPK3 was found to be the target gene of miR-1. miR-1 expressed at a high level whereas MAPK3 expressed at a low level in MIRI rats. Overexpressing miR-1 or silencing MAPK3 blocked the PI3K/Akt pathway to increase cell apoptosis, ischemic area at risk, and infarct area but decreased cell viability and increased LDH concentration. In contrast, miR-1 downregulation abrogated the effects induced by miR-1 mimics or siRNA against MAPK3. These findings indicate that inhibition of miR-1 promotes MAPK3 to protect against MIRI in rats undergoing sevoflurane preconditioning through activation of the PI3K/Akt pathway.

Aims: Hydrogen sulfide (H 2 S) is a novel signaling molecule with potent cytoprotective actions. In this study, we hypothesize that exogenous H 2 S may protect cardiac cells against high glucose (HG)-induced myocardial injury and inflammation with the involvement of the CIRP-MAPK signaling pathway., Main Methods: H9c2 cardiac cells cultured under HG conditions were transfected with siRNA and different inhibitor for detecting the effects of sodium hydrogen sulfide (NaHS) (a H 2 S donor) on cell biological processes. The cardiac cell viability and LDH activity were determined by CCK-8 and LDH kit. ELISA was employed to measure the levels of inflammatory factors, while 2',7'-dichlorofluorescein diacetate (DCFH-DA) to evaluate reactive oxygen species (ROS). Mitochondrial membrane potential (MMP) was identified by rhodamine 123 staining. TUNEL staining and Hoechst 33258 staining were employed to observe cardiac cell apoptosis. Besides, we determined the expression of CIRP-MAPK signaling pathway- and apoptosis-related factors by protein immunoblot analysis., Key Findings: HG culturing induced toxicity, LDH, higher level of inflammatory factors, ROS, MMP, and apoptosis in cardiac cells, attenuated the viability of cardiac cells, and activated the CIRP-MAPK signaling pathway. Notably, CIRP silencing aggravated the above condition. H 2 S or blockade of the MAPK signaling pathway reversed the above conditions induced by HG., Significance: The present study provides evidence for the protective effect of exogenous H 2 S on HG-induced myocardial injury and inflammation in H9c2 cardiac cells and suggests that the activation of CIRP-MAPK signaling pathway might be one of the mechanisms underlying the protective effect of H 2 S., (Copyright © 2018. Published by Elsevier Inc.)

Chemotherapy is one of the effective methods to treat cancer. However, the chemotherapy agents may cause a series of adverse reactions due to the nonselective characteristics that affect not only tumor cells, but also normal cells. Oral mucositis induced by chemotherapy is a common oral complication caused by chemotherapy in clinic. It brings great suffering to the patients and also interferes with the procedure of chemotherapy. Because of its high incidence in patients receiving chemotherapy and the significant influence, there are more researches on oral mucositis induced by chemotherapy which let us have further understanding of it. This review article will introduce the pathogenesis, risk factors, clinical manifestations, assessments, treatment and prevention of oral mucositis induced by chemotherapy.

Magnetic solid-phase extraction is an effective and useful technique to preconcentrate trace analytes from food samples. In this study, a magnetic trimeric chromium octahedral metal-organic framework (Fe 3 O 4 -NH 2 @MIL-101) was fabricated and characterized. Fe 3 O 4 -NH 2 @MIL-101 was applied as an adsorbent of magnetic solid-phase extraction combined with high performance liquid chromatography to effectively isolate and simultaneously determine six Sudan dyes (Para Red, Sudan I-IV, and Sudan Red 7B) from tomato sauce. Potential factors affecting the MSPE were investigated in detail, and adsorption efficiency of Fe 3 O 4 -NH 2 @MIL-101 was compared with those of conventional adsorbents, such as neutral alumina, HLB, and C 18 . The developed method facilitated the extraction with using only 3 mg of adsorbent in 2 min. In addition, enhancement factors of 50, linear range of 0.01-25 μg/mL, and detection limit (S/N = 3) of 0.5-2.5 μg/kg were obtained. The intra-day and inter-day recoveries for spiked Sudan dyes were in the range of 72.6%-92.9% and 69.6%-91.6%, respectively, with relative standard deviations of ≤9.2%., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ti-24Nb-4Zr-8Sn (Ti2448), a new β-type Ti alloy, consists of nontoxic elements and exhibits a low uniaxial tensile elastic modulus of approximately 45 GPa for biomedical implant applications. Nevertheless, the bio-corrosion resistance and biocompatibility of Ti2448 alloys must be improved for long-term clinical use. In this study, a rapid electrochemical anodization treatment was used on Ti2448 alloys to enhance the bio-corrosion resistance and bone cell responses by altering the surface characteristics. The proposed anodization process produces a unique hybrid oxide layer (thickness 50-120 nm) comprising a mesoporous outer section and a dense inner section. Experiment results show that the dense inner section enhances the bio-corrosion resistance. Moreover, the mesoporous surface topography, which is on a similar scale as various biological species, improves the wettability, protein adsorption, focal adhesion complex formation and bone cell differentiation. Outside-in signals can be triggered through the interaction of integrins with the mesoporous topography to form the focal adhesion complex and to further induce osteogenic differentiation pathway. These results demonstrate that the proposed electrochemical anodization process for Ti2448 alloys with a low uniaxial tensile elastic modulus has the potential for biomedical implant applications.

Objective: To investigate the clinical manifestations and pathological changes of benign lymphoadenosis of oral mucosa. Methods: The clinical data of 98 cases of benign lymphoadenosis of oral mucosa were analyzed. Results: The clinical manifestations of benign lymphoadenosis of oral mucosa included erosive ulcer (64%) and nodule (9%) and the rate of misdiagnosis was 98%. Neutrophil infiltration occurred in the epithelium of 51% cases and the lymphocyte was diffusely infiltrated in lamina propria of 83% cases. Conclusions: When the mucous membrane of the lamina propria is characterized by complex cell components, diffuse infiltrating lymphocytes and infiltration of neutrophils in mucosal epithelium without erosion and ulceration, it is necessary to highly suspect benign lymphoadenosis of oral mucosa. Finding the focal aggregation of lymphoid follicles or lymphocytes is helpful for the correct diagnosis.

The objective of the study described here is to fundamentally elucidate the biological response of 3D printed Ti-6Al-4V alloy mesh structures that were surface modified to introduce titania nanotubes with an average pore size of ∼80 nm via an electrochemical anodization process from the perspective of enhancing bioactivity. The bioactivity of the mesh structures were analyzed through immersion test in simulated body fluid, which confirmed the nucleation and growth of fine globular nanoscale apatite on the nanoporous titania-modified (anodized) mesh structure surface, and agglomerated apatite with fine flakes of apatite crystals on as-fabricated mesh structure surface, that were rich in calcium and phosphorous. The cellular activity of bioactive anodized mesh structure was explored in terms of cell-material interactions involving adhesion, proliferation, synthesis of extracellular and intracellular proteins, differentiation, and mineralization. Cells adhered with a sheet-like morphology on as-fabricated mesh structure, whereas, on anodized mesh structure, numerous filopodia-like cellular extensions interacting with nanotube pores were observed. The formation of a bioactive nanoscale apatite, cell-nanotube interactions as imaged via electron microscopy, higher expression of proteins (actin, vinculin, fibronectin, and alkaline phosphatase (ALP)), and calcium content points toward the determining role of anodized mesh structure in modulating osteoblasts functions. The unique combination of nanoporous bioactive titania and interconnected porous architecture of anodized titanium alloy mesh structure provided a multimodal roughness surface ranging from nano to micro to macroscale, which helps in attaining strong primary and secondary fixation of the implant device along with the pathway for supply of nutrients and oxygen to cells and tissue.

Particle trapping and binding in optical potential wells provide a versatile platform for various biomedical applications. However, implementation systems to study multi-particle contact interactions in an optical lattice remain rare. By configuring an optofluidic lattice, we demonstrate the precise control of particle interactions and functions such as controlling aggregation and multi-hopping. The mean residence time of a single particle is found considerably reduced from 7 s, as predicted by Kramer's theory, to 0.6 s, owing to the mechanical interactions among aggregated particles. The optofluidic lattice also enables single-bacteria-level screening of biological binding agents such as antibodies through particle-enabled bacteria hopping. The binding efficiency of antibodies could be determined directly, selectively, quantitatively and efficiently. This work enriches the fundamental mechanisms of particle kinetics and offers new possibilities for probing and utilising unprecedented biomolecule interactions at single-bacteria level.

Small molecule modified anticancer drug conjugates (SMMDCs) can self-assemble into nanoparticles (NPs) as therapeutic NP platforms for cancer treatment. Here we demonstrate that the XlogP and Hansen solubility parameters of paclitaxel (PTX) SMMDCs is essential for SMMDCs self-assembling into NPs. The amorphous state of PTX SMMDCs will also affect SMMDCs self-assembling into NPs. However, the antitumor activity of these PTX SMMDCs NPs decreased along with their XlogP values, indicating that a suitable XlogP value for designing the SMMDCs is important for self-assembling into NPs and for possessing antitumor activity. For higher level XlogP SMMDCs, a degradable linker should be considered in the design of SMMDCs to overcome the problem of lower antitumor activity. It is preferable that the hydrophilic groups in the SMMDCs should be present on the surface of self-assembling NPs.

Rationale: Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterized by bilateral progressive ptosis and ophthalmoplegia. Kearns -Sayre syndrome (KSS) is a multisystem disorder with PEO, cardiac conduction block, and pigmentary retinopathy. A few individuals with CPEO have other manifestations of KSS, but do not meet all the clinical diagnosis criteria, and this is called "CPEO plus.", Patient Concerns: We report a 48-year-old woman exhibiting limb weakness, ptosis, ophthalmoparesis, and cerebellar dysfunctions., Diagnoses: The patient was diagnosed as exhibiting CPEO plus syndrome., Interventions: The patient underwent clinical, genetic, histological, and histochemical analysis. She was treated orally with CoQ10, vitamin Bs, L-carnitine, and vitamin E., Outcomes: The patient's serum creatine kinase levels, electrocardiography, and nerve conduction study results were normal; an electromyogram revealed myopathic findings. Magnetic resonance imaging showed global brain atrophy, particularly in the brainstem and cerebellum areas. A muscle biopsy showed the presence of abundant ragged red fibers. Sequencing of the mitochondrial DNA from the skeletal muscle biopsy revealed C960del mutation in 12S rRNA and homozygous mutation C2835T in 16S rRNA. She took medicines on schedule, the clinical features were similar as 2 years ago., Lessons: This is the first report of 2 rRNA mutations in a patient with MRI findings showing global brain atrophy, particularly in brainstem and cerebellum areas. Early recognition and appropriate treatment is crucial. This case highlights the cerebellar ataxia can occur in CPEO plus.

Background: Perinatal transmission is the main route of hepatitis B virus (HBV) transmission. While several measures have been attempted as means of preventing perinatal HBV transmission, the optimal strategy remains inconclusive., Methods: We conducted a comprehensive search, through December 2016, for randomized controlled trials (RCTs) that compared the following measures among pregnant women with HBV infection: placebo/none, active immunoprophylaxis (hepatitis B vaccine series starting at birth [HBVac]), passive-active immunoprophylaxis (hepatitis B immunoglobulin and vaccine [HBIG+HBVac]), prenatal HBIG administration (HBIG/HBIG+HBVac), and prenatal antiviral therapy (AVT/HBIG+HBVac). Direct, indirect, and network meta-analyses were performed for all treatment comparisons., Results: Fifteen RCTs involving 2706 infants of HBV carrier mothers were eligible for analysis. Network meta-analysis demonstrated similar results as direct and indirect comparisons. HBVac alone significantly reduced the risk of hepatitis B infection in infants of HBV carrier mothers (relative risk [RR], 0.32; 95% confidence interval [CI], 0.21-0.50). The combination of immunoglobulin with vaccine is superior to vaccine alone (RR, 0.37; 95% CI, 0.20-0.67). Prenatal HBIG administration and antiviral therapy offer further advantages over current passive-active immunoprophylaxis for infants of highly viremic (HBV DNA level higher than 2 × 10 5 IU/mL) mothers (RR, 0.47; 95% CI, 0.29-0.75; and RR, 0.31; 95% CI, 0.10-0.99, respectively). There was no significant publication bias., Conclusions: Based on the universal infantile vaccination program, HBIG for infants born to HBV carrier mothers further reduces transmission. For highly viremic mothers whose children are still at risk for transmission under current immunoprophylaxis, prenatal HBIG administration or antiviral therapy in late pregnancy may be considered if more long-term evidence supports its efficacy and safety.

Objective: To determine the clinical course and perinatal transmission of chronic hepatitis B during pregnancy in a real life setting., Methods: A total of 221 singleton pregnant women with detectable HBV-DNA levels (≥10 3 copies/mL) were enrolled during January 2011 to June 2015. Forty-three high viraemic patients (≥10 6 copies/mL) received telbivudine in the 2 nd or 3 rd trimester according to their intention, while 89 high viraemic and 79 low viraemic (≥10 3 and <10 6 copies/mL) patients were the control cohorts. Primary endpoint was the pregnancy outcomes and secondary endpoint the perinatal transmission including intrauterine infection, immunoprophylaxis failure and occult infection., Results: In all, 209 patients completed pregnancy with 209 infants, while 2 in telbivudine-treated cohort had unexplained late stillbirths. Twenty-nine (70.7%) of telbivudine-treated patients and 3 (3.4%) of untreated high viraemic controls achieved undetectable HBV-DNA levels prior delivery. At 7 months postpartum, immunoprophylaxis failure was significantly lower (2.4%) in telbivudine-treated cohort, compared with 16.9% and 10.1% in untreated high and low viraemic cohorts, respectively., Conclusions: Low viraemic patients may also need antiviral therapy since they bear moderate risk for perinatal transmission of HBV. However, more multicenter, large-scale studies are required before antepartum antiviral therapy is routinely recommended in patients with detectable viral loads., (Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

An optofluidic chip is demonstrated in experiments for high-resolution and multi-range particle separation through the optically-induced microscopic vibration effect, where nanoparticles are trapped in loosely overdamped optical potential wells created with combined optical and fluidic constraints. It is the first demonstration of separating single nanoparticles with diameters ranging from 60 to 100 nm with a resolution of 10 nm. Nanoparticles vibrate with an amplitude of 3-7 μm in the loosely overdamped potential wells in the microchannel. The proposed optofluidic device is capable of high-resolution particle separation at both nanoscale and microscale without reconfiguring the device. The separation of bacteria from other larger cells is accomplished using the same chip and operation conditions. The unique trapping mechanism and the superb performance in high-resolution and multi-range particle separation of the proposed optofluidic chip promise great potential for a diverse range of biomedical applications.

Titanium alloys (Ti-6Al-4V and Ti-6Al-7Nb) are widely used for implants, which are characterized by high elastic modulus (∼110 GPa) with (α + β) structure and that may induce undesirable stress shielding effect and immune responses associated with the presence of toxic elements. In this regard, we have combined the attributes of a new alloy design and the concept of additive manufacturing to fabricate 3D scaffolds with an interconnected porous structure. The new alloy is a β-type Ti-24Nb-4Zr-8Sn (Ti2448) alloy with significantly reduced modulus. In the present study, we explore the biological response of electron beam melted low modulus Ti2448 alloy porous mesh structure through the elucidation of bioactivity and osteoblast functions. The cellular activity was explored in terms of cell-to-cell communication involving proliferation, spreading, synthesis of extracellular and intracellular proteins, differentiation, and mineralization. The formation of fine apatite-like crystals on the surface during immersion test in simulated body fluid confirmed the bioactivity of the scaffold surface, which provided the favorable osteogenic microenvironment for cell-material interaction. The combination of unique surface chemistry and interconnected porous architecture provided the desired pathway for supply of nutrients and oxygen to cells and a favorable osteogenic micro-environment for incorporation (on-growth and in-growth) of osteoblasts. The proliferation and differentiation of pre-osteoblasts and their ability to form a well mineralized bone-like extracellular matrix (ECM) by secreting bone markers (ALP, calcium, etc.) over the struts of the scaffold point toward the determining role of unique surface chemistry and 3D architecture of the Ti2448 alloy mesh structure in modulating osteoblasts functions. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 859-870, 2017., (© 2016 Wiley Periodicals, Inc.)