Search

Centromere dysfunctions leading to numerical chromosome alterations are believed to be closely related to human cancers. As a centromere-specific protein, centromere protein A (CENP-A) replaces the histone H3 in centromeres and is therefore considered a key factor of centromere identity. Researches have shown that CENP-A is overexpressed in many types of human cancers. However, the behavior and function of CENP-A in tumorigenesis have not yet been systematically summarized. In this article, we describe the pleiotropic roles of CENP-A in human cells. Moreover, we provide a comprehensive review of the current knowledge on the relationship between aberrant expression and ectopic localization of CENP-A and tumorigenesis, and the mechanism of the ectopic deposition of CENP-A in cancers. Furthermore, we note that some oncogenic viruses can modulate the expression and localization of this centromere protein along with its chaperone. At last, we also discuss the therapeutic potential of targeting CENP-A for cancer therapy.

Objectives The aim of this study was to investigate the genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in China to identify predominant lineages and their associations with clinical data and antimicrobial resistance profiles. Methods We performed a national prevalence study of patients with S. aureus infections in 22 tertiary hospitals in China from 2015 to 2017. Clinical data from patients and the antimicrobial phenotypes were collected for each isolate. Genome sequencing was performed on a proportion of isolates and a phylogenetic analysis was undertaken. Genotypic and phenotypic β-lactam susceptibilities were compared. Results A total of 1900 patients with S. aureus infections were included, of which 40% involved MRSA. Community-associated MRSA (CA-MRSA) infections were 24% of the total isolates. Genomic data showed that more than three-quarters of the MRSA were from three dominant lineages CC239 (25%, 116/471), CC5 (21%, 96/471) and CC59 (33%, 154/471) with CC59 accounting for more than half of the CA-MRSA isolates. Penicillin susceptibility genomic features were observed in 53% (251/470) of MRSA, including almost all of the CC59 (152/154) lineage, and 96% (242/251) of these isolates demonstrated in vitro susceptibility to penicillin or amoxicillin combined with clavulanic acid. Phylogenetic analysis indicated that the CC59 lineage can be divided into six lineages with all Asian CC59 isolates likely arising from an ancestral Mainland China lineage. Conclusions This study showed a high prevalence of CA-MRSA in China, largely due to the widespread presence of CC59. As almost all isolates in this lineage possess genetic variants leading to increased β-lactam susceptibility, we suggest that to improve antibiotic stewardship combinations of penicillins and β-lactamase inhibitors should be included in the antibiotic susceptibility testing panels used to inform treatment decisions and research undertaken on this combination therapy.

In this study, we investigated the associations between cadmium (Cd) and lead (Pb) co-exposure, and serum ion levels in two populations living near a mining/smelting area and a nature reserve (control area), respectively. A total of 445 participants were included in this study. Their blood cadmium (BCd), blood lead (BPb), and serum ion levels were determined, and the association between exposure levels and serum ion levels was analyzed. The exposure levels of subjects living in the polluted area were significantly higher (p

The aetiology of gastric cancer is still unclear butThis protocol of systematic review and meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols statement guidelines. PubMed, Embase, Web of Science and Cochrane Library databases will be systematically searched from inception to March 2022 for eligible studies. No language limitations were imposed. The studies will be downloaded into the EndNote V.X9 software and duplicates will be removed. Two review authors independently screened the full text against the inclusion criteria, extracted the data from each included study by using a piloted data extraction form and conducted risk of bias assessment, resolving disagreement by discussion. Results will be synthesised narratively in summary tables, using a random-effect bivariate model, and we fit a hierarchical summary receiver operating characteristic curve.This systematic review will include data extracted form published studies, therefore, does not require ethics approval. The results of this study will be submitted to a peer-reviewed journal.CRD42021282616.

Staphylococcus capitis, which causes bloodstream infections in neonatal intensive care units, is a common cause of healthcare-associated infections. Thus, a standardized high-resolution typing method to document the transmission and dissemination of multidrug-resistantS. capitisisolates is required. We aimed to establish a core genome multilocus sequence typing (cgMLST) scheme to surveilS. capitis. The cgMLST scheme was defined based on primary and validation genome sets and tested with outbreaks of linezolid-resistant isolates and a validation set. Phylogenetic analysis was performed to investigate the population structure and compare it with the result of cgMLST analysis. TheS. capitispopulation consists of 1 dominant, NRCS-A, and 4 less common clones. In this work, a multidrug-resistant clone (L clone) with linezolid resistance is identified. With the features of type III SCCmecand multiple copies of mutations of G2576T and C2104T in the 23S rRNA, the L clone has been spreading silently across China.

Spinal cord injury (SCI) will lead to irreversible damage of sensory and motor function of central nervous system, which seriously affects patient's quality of life. A variety of nerve engineering materials carrying various stem cells and cell growth factors had used to promote the repair of SCI, but they could not mimic the actual matric niche at spinal cord to promote cell proliferation and differentiation. Thus, developing novel biomaterial providing better niche of spinal cord is a new strategy to treat the severe SCI. In this study, we constructed porcine spinal cord decellularized matrix scaffold (SC-DM) with biocompatibility to load engineered basic fibroblast growth factor-overexpressing human umbilical cord mesenchymal stromal cells (bFGF-HUCMSCs) for treating SCI. The continuously released bioactive bFGF factors from grafted bFGF-HUCMSCs and three-dimensional niche by SC-DM promoted the differentiation of endogenous stem cells into neurons with nerve conduction function, leading a markedly motor function recovery of SCI. These results indicated that the functional bFGF-HUCMSCs/SC-DM scaffold provided more suitable matric niche for nerve cells, that would be a promising strategy for the clinical application of SCI.

Breast cancer (BC) is the most frequently invasive malignancy and the leading cause of tumor-related mortality among women worldwide. Cancer metastasis is a complex, multistage process, which eventually causes tumor cells to colonize and grow at the metastatic site. Distant organ metastases are the major obstacles to the management of advanced BC patients. Notably, exosomes are defined as specialized membrane-enclosed extracellular vesicles with specific biomarkers, which are found in a wide variety of body fluids. Recent studies have demonstrated that exosomes are essential mediators in shaping the tumor microenvironment and BC metastasis. The transferred tumor-derived exosomes modify the capability of invasive behavior and organ-specific metastasis in recipient cells. BC exosomal components, mainly including noncoding RNAs (ncRNAs), proteins, lipids, are the most investigated components in BC metastasis. In this review, we have emphasized the multifaceted roles and mechanisms of tumor-derived exosomes in BC metastasis based on these important components. The underlying mechanisms mainly include the invasion behavior change, tumor vascularization, the disruption of the vascular barrier, and the colonization of the targeted organ. Understanding the significance of tumor-derived exosomal components in BC metastasis is critical for yielding novel routes of BC intervention.

Acute pancreatitis (AP) is a pancreatic inflammatory disease that varies greatly in course and severity. To further the understanding of the pathology of AP, we carried out data-independent acquisition-based proteomic analyses using proteins extracted from the plasma of patients with severe acute pancreatitis (SAP) (experimental group) and healthy volunteers (control group). Compared to the control group, there were 35 differentially expressed proteins (DEPs) in the plasma of patients with SAP. Of those, the expression levels for 6 proteins were significantly increased, and 29 proteins were significantly decreased. Moreover, six candidate biomarkers—VWF, ORM2, CD5L, CAT, IGLV3-10, and LTF—were matched as candidate biomarkers of the disease severity of AP. The area under the receiver operating characteristic of 0.903 (95% CI: 0.839, 0.967) indicated that this combination of these six candidate biomarkers had a good prediction accuracy for predicting the severity of AP. Our study provides specific DEPs that may be useful in the diagnosis and prognosis of SAP, which suggests new theoretical bases for the occurrence and development of SAP and offers potential novel treatment strategies for SAP.

Hepatocellular carcinoma (HCC) is the most common primary human liver malignancy with high mortality. Liver cancer stem cells (CSCs) have been demonstrated to contribute to the recurrence, metastasis and drug resistance of liver cancer. Human HCC cohort analysis indicated that the epigenetic regulator polycomb chromobox homologue 4 (CBX4) was overexpressed in human HCC. Moreover, we found that CBX4 expression was significantly higher in CD44+ CD133+ Hep3B CSCs. Functionally, we demonstrated that CBX4 regulated cell proliferation, self-renewal, and metastasis ability of Hep3B CSCs. Bioinformatics analysis predicted that CBX4 was a direct target of microRNA-6838-5p (miR-6838-5p), which was further confirmed by luciferase reporter assay. MiR-6838-6p was down-regulated in HCC tumors and overexpression of miR-6838-5p attenuated the malignant traits of human liver CSCs in vitro. In addition, we found that miR-6838-5p/CBX4 axis modulates the biological properties of human liver CSCs via regulating ERK signaling. Overexpression of miR-6838-5p suppressed Hep3B xenograft tumor growth in vivo, while CBX4 overexpression abrogated the suppression effect, restored the angiogenesis, epithelial-to-mesenchymal transition (EMT), and ERK signaling in Hep3B tumor. In summary, our findings suggest that miR-6838-5p/CBX4 axis regulates liver tumor development and metastasis, which could be utilized as potential therapeutic target for HCC treatment.

Background Effective therapeutics to stop or reverse liver fibrosis have not emerged, because these potential agents cannot specifically target activated hepatic stellate cells (aHSCs) or are frequently toxic to parenchymal cells. Human umbilical cord mesenchymal stem cell (Huc-MSC)-derived exosomes show promise in nanomedicine for the treatment of liver fibrosis. However, systemic injection showed that unmodified exosomes were mainly taken up by the mononuclear phagocyte system. The discovery of ligands that selectively bind to a specific target plays a crucial role in clinically relevant diagnostics and therapeutics. Herein, we aimed to identify the targeting peptide of aHSCs by screening a phage-displayed peptide library, and modify Huc-MSC-derived exosomes with the targeting peptide. Results In this study, we screened a phage-displayed peptide library by biopanning for peptides preferentially bound to HSC-T6 cells. The identified peptide, HSTP1, also exhibited better targeting ability to aHSCs in pathological sections of fibrotic liver tissues. Then, HSTP1 was fused with exosomal enriched membrane protein (Lamp2b) and was displayed on the surface of exosomes through genetic engineering technology. The engineered exosomes (HSTP1-Exos) could be more efficiently internalized by HSC-T6 cells and outperformed both unmodified exosomes (Blank-Exos) and Lamp2b protein overexpressed exosomes (Lamp2b + Exos) in enhancing the ability of exosomes to promote HSC-T6 reversion to a quiescent phenotype. In vivo results showed HSTP1-Exos could specifically target to the aHSC region after intravenous administration, as demonstrated by coimmunofluorescence with the typical aHSCs marker α-SMA, and enhance the therapeutic effect on liver fibrosis. Conclusion These results suggest that HSTP1 is a reliable targeting peptide that can specifically bind to aHSCs and that HSTP1-modified exosomes realize the precise treatment for aHSCs in complex liver tissue. We provide a novel strategy for clinical liver fibrosis therapy. Graphical Abstract

Fosfomycin has gained attention as a combination therapy for methicillin-resistant

Radish (Raphanus sativus L.) is rich in specific glucosinolates (GSLs), which benefit human health and special flavor formation. Although the basic GSLs metabolic pathway in Brassicaceae plants is clear, the regulating mechanism for specific glucosinolates content in radish fleshy taproots is not well understood. In this study, we discovered that there was a significant difference in the GSLs profiles and the content of various GSLs components. Glucoraphasatin (GRH) is the most predominant GSL in radish taproots of different genotypes as assessed by HPLC analysis. Further, we compared the taproot transcriptomes of three radish genotypes with high and low GSLs content by employing RNA-seq. Totally, we identified forty-one differentially expressed genes related to GSLs metabolism. Among them, thirteen genes (RsBCAT4, RsIPMDH1, RsMAM1a, RsMAM1b, RsCYP79F1, RsGSTF9, RsGGP1, RsSUR1, RsUGT74C1, RsST5b, RsAPK1, RsGSL-OH, and RsMYB28) were significantly higher co-expressed in the high content genotypes than in low content genotype. Notably, correlation analysis indicated that the expression level of RsMYB28, as an R2R3 transcription factor directly regulating aliphatic glucosinolate biosynthesis, was positively correlated with the GRH content. Co-expression network showed that RsMYB28 probably positively regulated the expression of the above genes, particularly RsSUR1, and consequently the synthesis of GRH. Moreover, the molecular mechanism of the accumulation of this 4-carbon (4C) GSL in radish taproots was explored. This study provides new perspectives on the GSLs accumulation mechanism and genetic improvements in radish taproots.

Background Lack of forward-viewing endoscopy experience impairs training in endoscopic retrograde cholangiopancreatography (ERCP). We evaluated the effect of ERCP mechanical simulator (EMS) practice on ERCP performance by surgical trainees. Patients and methods 12 surgical trainees without endoscopy experience were randomly allocated to non-EMS (n = 6) programs or to EMS (n = 6) programs with coaching and 20 hours of supervised EMS practice. All trainees then received supervised hands-on clinical ERCP training. Trainers provided verbal instructions and hands-on assistance, and took over if cannulation was not achieved by 20 minutes. Blinded trainers rated clinical performance. Results Each group performed 150 clinical ERCPs. Biliary cannulation success was significantly higher in the EMS vs. the non-EMS group (P = 0.006), with shorter mean times (in minutes) for intubation, cannulation, and completion (all P Conclusions EMS practice shortens the ERCP early learning curve of inexperienced surgical trainees, improves clinical success in selective biliary cannulation, and may reduce complications.

The authors sought to determine the efficacy of periumbilical fat block grafting to the orbital retro-orbicularis oculi fat (ROOF) layer to correct sunken-upper eyelids in Asians. All patients complained about upper-eyelid hollowness and a variety of deformities. Invasive double-eyelid procedures were performed, and periumbilical fat blocks were grafted for these patients. The core procedure of this approach was to make a separation between the orbicularis oculi muscle and septum to expose the retro-orbicularis oculi fat (ROOF) and fixate the fat grafts to the desired region of ROOF. From February 2018 to October 2019, the novel technique was performed on 38 Chinese patients (76 eyes) in our department. After follow-up of 6–15 months, 35 patients (92%) showed satisfactory aesthetic results with approximately 20–40% fat absorption rate. No cases required a second procedure. Periumbilical scars remained hidden within the umbilicus area. Periumbilical fat grafting in the ROOF of the sunken upper eyelid can both fill the depression and help correct over-wide double eyelid. 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 .

Purpose To determine the genetic characteristics of the Chinese epidemic ST5-SCCmec II-t311 methicillin-resistant Staphylococcus aureus (MRSA) clone and to investigate the transmission characteristics of the cfr-positive plasmid. Methods The complete genome of SR153 was sequenced. Genomic comparison with MRSA strains of other lineages was performed. The cfr-positive plasmid was investigated and compared with other cfr-positive plasmids from different origins and different areas. Results The cfr-positive MRSA strain SR153 was a Chinese epidemic ST5-SCCmec II-t311 strain. It clustered much closer to the Japanese ST5-SCCmec II clone than to the European and American ST5-SCCmec II clones. The genome of SR153 contains one circular chromosome and three plasmids. It harbors the genomic islands νSaα, νSaβ, νSaγ, ΦSa1 and ΦSa3, the pathogenicity island νSa4, and genes encoding virulence factors such as tst and many enterotoxins. The SR153 genome also contains several resistance genes and mutations, such as ermA, aadD, spc, aacA-aphD, lnuA, tetK, blaZ and mutations in grlA and gyrA. SR153 harbors a cfr-positive plasmid, pSR01, which is highly similar to pSX01 from a Staphylococcus xylosus of pig origin from Henan Province. pSR01 was also highly similar to pXWZ from a Staphylococcus capitis and pLRSA417 from S. aureus. Both were obtained from geographically separated hospitals in Zhejiang Province. Conclusions SR153, which clustered closely to the Japanese ST5-SCCmec II clone, is more resistant than N315. A pSR01-like cfr-positive plasmid was widespread among different Staphylococcus species of both human and animal origin in different hospitals and areas.

BACKGROUND Different types of periampullary diverticulum (PAD) may differentially affect the success of endoscopic retrograde cholangiopancreatography (ERCP) cannulation, but the clinical significance of the two current PAD classifications for cannulation is limited. AIM To verify the clinical value of our newly proposed PAD classification. METHODS A new PAD classification (Li-Tanaka classification) was proposed at our center. All PAD patients with native papillae who underwent ERCP from January 2012 to December 2017 were classified according to three classification systems, and the effects of various types of PAD on ERCP cannulation were compared. RESULTS A total of 3564 patients with native papillae were enrolled, including 967 (27.13%) PAD patients and 2597 (72.87%) non-PAD patients. In the Li-Tanaka classification, type I PAD patients exhibited the highest difficult cannulation rate (23.1%, P = 0.01), and type II and IV patients had the highest cannulation success rates (99.4% in type II and 99.3% in type IV, P < 0.001). In a multivariable-adjusted logistic model, the overall successful cannulation rate in PAD patients was higher than that in non-PAD patients [odds ratio (OR) = 1.87, 95% confidence interval (CI): 1.04-3037, P = 0.037]. In addition, compared to the non-PAD group, the difficulty of cannulation in the type I PAD group according to the Li-Tanaka classification was greater (OR = 2.04, 95%CI: 1.13-3.68, P = 0.004), and the successful cannulation rate was lower (OR = 0.27, 95%CI: 0.11-0.66, P < 0.001), while it was higher in the type II PAD group (OR = 4.44, 95%CI: 1.61-12.29, P < 0.01). CONCLUSION Among the three PAD classifications, the Li-Tanaka classification has an obvious clinical advantage for ERCP cannulation, and it is helpful for evaluating potentially difficult and successful cannulation cases among different types of PAD patients.

Objectives: To determine the molecular characteristics of a sequence type 338 community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strain and the relationship among MRSA strains from various lineages and areas. Methods: Whole-genome sequencing, genomic comparison, antimicrobial susceptibility testing, and hemolysis analysis were performed to identify the resistance determinants and virulence factors of strain ZY05 and the relationships among CC59 clones. Results: MRSA strain ZY05 was resistant to tetracycline, erythromycin, and clindamycin, and the resistance genes erm(B) and tet(K) were detected in the genome. ZY05 harbors the genomic islands νSaα, νSaβ, νSaγ, and ΦSa2, the pathogenicity island νSa1, and virulence factors such as Panton–Valentine leukocidin, phenol-soluble modulins, alpha-hemolysin, enterotoxin B, enterotoxin K, and enterotoxin Q, which are the same as those present in ST59 strains. In addition, the virulence potential of ST338 did not differ from that of ST59. This strain contains the staphylococcal cassette chromosome mec (SCCmec) type VT, a distinct SCCmec type previously reported from Taiwan. The results of core genome multilocus sequence typing (cgMLST) analysis showed that the gene distances between ST59 and ST338 were close among CC59 isolates, while strains from Taiwan were identical to isolates from the Chinese mainland with respect to these two sequence types. Conclusions: The ST338 strain ZY05, which has a close genetic relationship to ST59 strains, is multidrug-resistant and highly virulent. Strains of two identical lineages, ST59 and ST338, from Taiwan and the Chinese mainland may have the same genetic background. Keywords: CA-MRSA, ST338, ST59, Whole-genome sequencing, China

Previous research suggests that heavy metals may be associated with increased susceptibility to

Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (ICsub50/sub = 23 nM) against EGFRsupL858R/T790M/supand displayed about 21-fold inhibitory activity decrease against EGFRsupwt/sup. Under hypoxia, JT21 exhibited more significant proliferation inhibitory activities against H1975 cells (ICsub50/sub = 7.39 ± 2.20 nM) and HCC827 cells (ICsub50/sub = 5.88 ± 0.85 nM) than that of AZD9291, which was about 5 times more effective than normoxia activities. Meanwhile, the weak inhibition effects on A549 and BEAS-2B cells suggested JT21 might be a selective inhibitor for EGFR mutations with low toxicity. Furthermore, JT21 could induce apoptosis of H1975 cells under hypoxia and showed good bio-reductive property.

In this study, we evaluated the ceftobiprole (BPR) susceptibilities of 472 methicillin-resistant Staphylococcus aureus (MRSA) isolates, and investigated the mechanisms underlying BPR resistance.For all MRSA isolates, BPR MIC was determined by agar dilution. We sequenced the BPR-resistant isolates through Illumina short- and MinION long-read sequencing. We also selected MRSA isolates of ST5, ST59, and ST239, and exposed them to increasing BRP concentrations. The isolated mutants developing BPR resistance were sequenced.A total of 471 MRSA isolates were susceptible to BPR, with MICs ranging from 0.25 to 2 mg/L. Compared with HA-MRSA isolates (MICBPR showed significant antibacterial activity against MRSA isolates in China; however, the emergence of a BPR-resistant isolate before its launch was a cause for concern. Multiple genes and pathways are potentially involved in the development of BPR resistance in MRSA, and our data demonstrated the role of nanopore-sequencing in revealing the tandem repeat-mediated resistance mechanism in MRSA.

Background Although Helicobacter pylori (Hp) as high risk factor for gastric cancer have been investigated from human trial, present data is inadequate to explain the effect of Hp on the changes of metabolic phenotype of gastric cancer in different stages. Purpose Herein, plasma of human superficial gastritis (Hp negative and positive), early gastric cancer and advanced gastric cancer analyzed by UPLC-HDMS metabolomics can not only reveal metabolic phenotype changes in patients with gastric cancer of different degrees (30 Hp negative, 30 Hp positive, 20 early gastric cancer patients, and 10 advanced gastric cancer patients), but also auxiliarily diagnose gastric cancer. Results Combined with multivariate statistical analysis, the results represented biomarkers different from Hp negative, Hp positive, and the alterations of metabolic phenotype of gastric cancer patients. Forty-three metabolites are involved in amino acid metabolism, and lipid and fatty acid metabolism pathways in the process of cancer occurrence, especially 2 biomarkers glycerophosphocholine and neopterin, were screened in this study. Neopterin was consistently increased with gastric cancer progression and glycerophosphocholine tended to consistently decrease from Hp negative to advanced gastric cancer. Conclusion This method could be used for the development of rapid targeted methods for biomarker identification and a potential diagnosis of gastric cancer.

Chronic exposure to environmental cadmium (Cd) and lead (Pb) may have adverse effects on the human health. In this study, we aimed to determine the primary and interactive effects of Cd and Pb exposure on liver function in residents near a mining and smelting area in northwestern China. A total of 451 subjects were recruited, from which blood samples were collected to determine the levels of Cd, Pb, and liver function indices. Additionally, the association between the levels of exposure markers and liver function indices was analysed. Cd and Pb levels were significantly higher in subjects living in the polluted area than in those living in the non-polluted reference area. The liver function levels of subjects in the polluted area were poor compared with those in the reference area. In addition, Cd and Pb levels in the blood were positively associated with gamma glutamyl transpeptidase (GGT) levels and negatively associated with direct bilirubin (DBil) levels. Cd and Pb may be risk factors for abnormal liver function. The risk of abnormal liver function was higher in subjects with moderate Cd and Pb levels, high Cd levels, high Pb levels, and high Cd and Pb levels than in those with low Cd and Pb levels. Our data show that exposure to Cd and/or Pb can cause abnormal liver function. Cd and Pb may have an antagonistic effect on liver function, and high Cd exposure alone has a more profound effect on abnormal liver function compared with co-exposure to Pb and Cd.

Exposure to both cadmium (Cd) and lead (Pb) can promote systemic inflammation. However, the effects of combined exposure to environmental levels of Cd and Pb on systemic immune inflammation have not been fully clarified. A total of 486 subjects (313 women and 173 men) living in either a control area or heavy metal-polluted area were included. Blood Cd and Pb and immune inflammation biomarkers were determined, including the eosinophil-lymphocyte ratio (ELR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and systemic immune-inflammation index (SII); moreover, the associations between exposure markers and systemic inflammation markers were analysed. The exposure levels in the polluted area were significantly higher than those in the control area. The NLR, PLR, and SII of subjects in the polluted area were higher and the LMR was lower than in the control area. Blood Pb and Cd levels are associated with elevated or decreased immune inflammation biomarkers in subjects from the exposed and control areas. Furthermore, co-exposure to both Cd and Pb was divided into high, middle, and low exposure groups. The subjects in the high co-exposure group displayed higher levels of ELR, NLR, and SII compared with the middle and low co-exposure group, and LMR levels displayed the opposite trend. Our data demonstrate that Cd and Pb co-exposure is associated with systemic immune inflammation, and the immune inflammatory response is aggravated with an increased co-exposure to Cd and Pb.

BACKGROUND Patients with severe aortic stenosis who have comorbidities that prevent general anesthesia and open cardiothoracic surgery are candidates for transcatheter aortic valve implantation (TAVI). However, TAVI can result in patient mortality following the procedure. This systematic review of the literature and meta-analysis aimed to determine the relationship between preoperative anemia and postoperative mortality in patients following TAVI. MATERIAL AND METHODS PubMed, EMBASE, the Cochrane Library, and the Web of Science were systematically searched from their inception to February 2019 for relevant published studies that included patients with bicuspid aortic valve stenosis and tricuspid aortic valve stenosis who underwent TAVI and who had preoperative data on hemoglobin levels. The pooled odds ratios (OR) and 95% confidence interval (CI) were calculated using a random-effects generic inverse variance method. RESULTS Six published studies that involved 6,406 patients with aortic stenosis were included in the meta-analysis. There was no significant difference observed for the final pooled result for patients with and without anemia for the short-term 30-day postoperative mortality (OR, 1.34; 95% CI, 0.77-2.35). However, long-term mortality rates were significantly worse in patients with preoperative anemia compared with those without anemia (OR, 1.77; 95% CI, 1.34-2.35). CONCLUSIONS Systematic review of the literature and meta-analysis showed that pre-procedural anemia reduced long-term mortality following TAVI. This finding supports the need to correct preoperative anemia in patients with aortic stenosis to improve patient outcome following TAVI.

In recent years, because the formation mechanism of double eyelids in Asians is still controversial, many techniques for double-eyelid plasty have been developed. However, the removal of large amounts of pretarsal tissue and the obvious scars in those techniques make patients dissatisfied with the appearance. Thus, we have devised a novel surgical approach named the kiss technique. The method is to create a physiological double-eyelid fold on the basis of the formation mechanism of double-eyelid creases. From January 2017 to March 2019, the novel blepharoplasty was performed on 386 Chinese patients (769 eyes) in our department. Patients were evaluated at 3–24 months after surgery. Instead of dividing the orbital septum all the way to the orbital margin both medially and laterally, all that is required is to dissect the pretarsal orbicularis oculi muscle inferiorly to the lower border of the tarsus and to incise the pretarsal extension of the aponeurosis to expose the white line. Then, the white line is sutured to the orbicularis oculi muscle. Finally, the skin incisions are sutured interruptedly, and a vivid fold is created. The general satisfaction rate was 97.5%. The edema period for most patients ended within 2 weeks. The scars became unnoticeable after 3–6 months. Disappearance of the fold was not found in any case. The kiss technique is a simple and effective method, which can not only create a natural double crease but also reduce the complications of double-eyelid surgery. 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.

Endoscopic sphincterotomy is the established treatment for common bile duct stones. Balloon dilation offers an alternative. Prolonged dilation (300 s) with a 10 mm diameter balloon decreases the occurrence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We aimed to determine the optimal duration of dilation for combined endoscopic sphincterotomy and balloon dilation for the removal of common bile duct stones.We did a multicentre, single-blinded, randomised controlled trial at 15 tertiary surgical centres in China. Eligible patients (≥18 years) with native papilla and common bile duct stones (≤1·5 cm in size and2 cm in diameter) undergoing ERCP were randomly assigned (1:1:1:1:1) to receive balloon dilation for 0, 30, 60, 180, or 300 s after deep bile duct cannulation. Randomisation was done by an independent statistician using a computer-generated randomisation list with a block size of ten, stratified by centre. Patients and outcome assessors, but not endoscopists and investigators, were masked to treatment allocation. Balloon dilation was done with controlled radial expansion balloons according to common bile duct stone size. Stones were removed using stone retrieval balloons or baskets. The primary endpoint was overall frequency of post-ERCP pancreatitis. The primary efficacy analysis and safety analyses were done in the modified intention-to-treat population, which included all randomly assigned patients with successful cannulation, but excluded those who withdrew consent after randomisation. This study was registered with ClinicalTrials.gov, number NCT02510495, and is complete.Between July 29, 2015, and Dec 1, 2017, 3721 consecutive patients with common bile duct stones were recruited, 1718 of whom were excluded. The remaining 2003 patients underwent a small (3-5 mm) endoscopic sphincterotomy. 83 patients withdrew consent after the ERCP procedure, thus 1920 patients were included in the modified intention-to-treat analysis (0 s [n=371], 30 s [n=384], 60 s [n=388], 180 s [n=390], and 300 s [n=387]). Overall, post-ERCP pancreatitis occurred in 199 (10%) of 1920 patients (44 [12%] patients in the 0 s group, 28 [7%] in the 30 s group, 32 [8%] in the 60 s group, 36 [9%] in the 180 s group, and 59 [15%] in the 300 s group). Prolonged dilation (300 s) significantly increased the occurrence of post-ERCP pancreatitis compared with shorter balloon dilation (p=0·002). The frequency of post-ERCP pancreatitis was significantly lower in the 30, 60, and 180 s groups than in the 300 s group (relative risk [RR] 0·48, 95% CI 0·31-0·73; p=0·0005 vs the 30 s group; 0·54, 0·36-0·81; p=0·003 vs the 60 s group; 0·61, 0·41-0·89; p=0·01 vs the 180 s group). The frequency of post-ERCP pancreatitis was significantly higher in the 0 s group than the 30 s group (RR 1·62, 1·04-2·56; p=0·03). No difference in stone extraction (all ≥90%) was observed between groups. Following ERCP, 90 (5%) of 1920 patients had acute cholangitis, 14 (1%) had acute cholecystitis, and five (1%) had gastrointestinal bleeding, with no significant differences between groups. One (1%) patient had Stapfer II perforation, which resolved spontaneously with conservative treatment.A balloon dilation time of 30 s for combined endoscopic sphincterotomy and balloon dilation reduced the frequency of post-ERCP pancreatitis and was determined to be the optimum dilation time for the removal of common bile duct stones.National Natural Science Foundation of China, Gansu Competitive Foundation Projects for Technology Development and Innovation.

BACKGROUND Early gastric cancer (EGC), compared with advanced gastric cancer (AGC), has a higher 5-year survival rate. However, due to the lack of typical symptoms and the difficulty in diagnosing EGC, no effective biomarkers exist for the detection of EGC, and gastroscopy is the only detection method. AIM To provide new biomarkers with high specificity and sensitivity through analyzed the differentially expressed microRNAs (miRNAs) in EGC and AGC and compared them with those in benign gastritis (BG). METHODS We examined the differentially expressed miRNAs in the plasma of 30 patients with EGC, AGC, and BG by miRNA chip analysis. Then, we analyzed and selected the significantly different miRNAs using bioinformatics. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) confirmed the relative transcription level of these miRNAs in another 122 patients, including patients with EGC, AGC, Helicobacter pylori (H. pylori)-negative gastritis (Control-1), and H. pylori-positive atrophic gastritis (Control-2). To establish a diagnostic model for the detection of plasma miRNA in EGC, we chose miRNAs that can be used to determine EGC and AGC from Control-1 and Control-2 and miRNAs in EGC from all other groups. RESULTS Among the expression profiles of the miRNA chips in the three groups in the discovery set, of 117 aberrantly expressed miRNAs, 30 confirmed target prediction, whereas 14 were included as potential miRNAs. The RT-qPCR results showed that 14 potential miRNAs expression profiles in the two groups exhibited no differences in terms of H. pylori-negative gastritis (Control-1) and H. pylori-positive atrophic gastritis (Control-2). Hence, these two groups were incorporated into the Control group. A combination of four types of miRNAs, miR-7641, miR-425-5p, miR-1180-3p and miR-122-5p, were used to effectively distinguish the Cancer group (EGC + AGC) from the Control group [area under the curve (AUC) = 0.799, 95% confidence interval (CI): 0.691-0.908, P < 0.001]. Additionally, miR-425-5p, miR-24-3p, miR-1180-3p and miR-122-5p were utilized to distinguish EGC from the Control group (AUC = 0.829, 95%CI: 0.657-1.000, P = 0.001). Moreover, the miR-24-3p expression level in EGC was lower than that in the AGC (AUC = 0.782, 95%CI: 0.571-0.993, P = 0.029), and the miR-4632-5p expression level in EGC was significantly higher than that in AGC (AUC = 0.791, 95%CI: 0.574-1.000, P = 0.024). CONCLUSION The differentially expressed circulatory plasma miR-425-5p, miR-1180-3p, miR-122-5p, miR-24-3p and miR-4632-5p can be regarded as a new potential biomarker panel for the diagnosis of EGC. The prediction and early diagnosis of EGC can be considerably facilitated by combining gastroscopy with the use of these miRNA biomarkers, thereby optimizing the strategy for effective detection of EGC. Nevertheless, larger-scale human experiments are still required to confirm our findings.

BACKGROUND Gastric cancer is a common gastrointestinal tumor. The incidence and mortality of gastric cancer are very high. Therefore, it is important to study targeted drugs. Recent studies found long chain non-coding RNA (lncRNAs) and microRNAs (miRNAs) were abnormal in gastric cancer. MATERIAL AND METHODS We collected adjacent normal and cancer tissues of gastric cancer patients and measured HOTAIR, miR-454-3p, STAT3, and Cyclin D1 expression and analyzed the correlation with clinical status. We also measured AGS and SGC7901 cells proliferation rate of different groups by MTT assay, and we evaluated AGS and SGC7901 cell apoptosis and cell cycle by flow cytometry. In addition, we assessed the relative proteins expressions by WB assay. Finally, we explored the correlation between miR-454-3p and STAT3 by use of double luciferase reporter. RESULTS lncRNA HOTAIR was negatively correlated with miR-454-3p expression in gastric cancer tissues. lncRNA HOTAIR knockdown suppressed AGS and SGC7901, which are gastric cancer cell lines that promote cell proliferation by increasing cell apoptosis and keeping the cell cycle in G1 phase. In further mechanism research, we found that the STAT3 and Cyclin D1 proteins expressions were suppressed by lncRNA HOTAIR down-regulation in AGS and SGC7901 cells. CONCLUSIONS Our results suggest that lncRNA HOTAIR knockdown stimulates miR-454-3p expression to inhibit gastric cancer growth by depressing STAT3/Cyclin D1 activity.

We identified 2 methicillin-resistant Staphylococcus aureus strains of sequence type 398 from surgical site infections in China. Genetic analysis and clinical data from these strains suggested that they were human-related but sporadic. Hemolysis analysis and mouse-skin infection models indicated a high virulence potential for these strains.

Objective Atrial septal defect, secundum (ASD Ⅱ, OMIM: 603642 ) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive. Methods and results Using whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant Arg1822_Glu1823dup co-segregated with the disease in this family with autosomal dominant inheritance. The insertion variant located in the coiled-coil domain of the MYH6 protein, which is highly conserved across homologous myosin proteins and species. In transfected myoblast C2C12 cell lines, the MYH6 Arg1822_Glu1823dup variant significantly impaired myofibril formation and increased apoptosis but did not significantly reduce cell viability. Furthermore, molecular simulations revealed that the Arg1822_Glu1823dup variant impaired the myosin α-helix, increasing the stability of the coiled-coil myosin dimer, suggesting that this variant has an effect on the coiled-coil domain self-aggregation. These findings indicate that Arg1822_Glu1823dup variant plays a crucial role in the pathogenesis of ASD II. Conclusion Our findings expand the spectrum of MYH6 variations associated with familial ASD II and may provide a molecular basis in genetic counseling and prenatal diagnosis for this Chinses family.

Currently, the mechanism of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) transmission mechanism is unclear; however, it must be considered in conjunction with asymptomatic S. aureus strains colonization dynamics. This epidemiological study aimed to determine the role of the household in CA-MRSA transmission in China. Five patients with culture-confirmed CA-MRSA infection and five control patients were recruited from the Sir Run Run Shaw Hospital in Zhejiang, China, between December 2019 and January 2020. The household members of the patients, their pets, and environmental surfaces were sampled and screened for MRSA colonization. Mass spectrometry identification and antimicrobial susceptibility testing were performed on the MRSA isolates. Whole-genome sequencing and core genome multilocus sequence typing (cgMLST) were performed to determine the origin and transmission of the MRSA isolates in the households. Overall, 14 S. aureus-positive specimens (14.1%, 14/99) were obtained from the five households of patients with CA-MRSA infections, of which 12 (85.7%) were MRSA. The overall positivity of MRSA was 12.1% (12/99) among the samples from the CA-MRSA households, while no MRSA isolates were detected in the five control households. Most MRSA isolates belonged to epidemic CA-MRSA clones, such as ST59 (15/35, 42.9%) and ST508 (15/35, 42.9%). The cgMLST results confirmed that MRSA was transmitted among patients, contacts, and pets in the households and was present on environmental surfaces in the CA-MRSA patients' households. In conclusion, the study revealed that the home environment was an important MRSA reservoir. Therefore, focusing on MRSA decolonization in patients alone is not sufficient for infection control of CA-MRSA.

Tang and colleagues show that a half-life-extended IL-10-Fc fusion protein acts directly on terminally exhausted PD1(+)TIM-3(+)CD8(+) T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. Treatment of tumor-bearing mice with IL-10-Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures. T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8(+) tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8(+) tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

Diabetic skin ulcer is one of the severe complications of diabetes mellitus, which has a high incidence and may cause death or disability. Platelet-rich plasma (PRP) is widely used in the treatment of diabetic wounds due to the effect of growth factors (GFs) derived from it. However, the relatively short half-life of GFs limits their applications in clinics. In addition, the presence of a large amount of proteases in the diabetic wound microenvironment results in the degradation of GFs, which further impedes angiogenesis and diabetic wound healing. In our study, we fabricated a self-healing and injectable hydrogel with a composite of chitosan, silk fibroin, and PRP (CBPGCTS-SF@PRP) for promoting diabetic wound healing. CBPGCTS-SF@PRP could protect PRP from enzymatic hydrolysis, release PRP sustainably, and enhance the chemotaxis of mesenchymal stem cells. The results showed that it could promote the proliferation of repair cells in vitro. Moreover, it could enhance wound healing by expediting collagen deposition, angiogenesis, and nerve repair in a type 2 diabetic rat model and a rat skin defect model. We hope that this study will offer a new treatment for diabetic nonhealing wounds in clinics.

Glioma stem cell (GSC)-derived extracellular vesicles (EVs) can mediate the communication between GSCs and microglia. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in GSCs, EVs, and supernatant was detected by real-time PCR. The direct targeting between MALAT1 and miR-129-5p, miR-129-5p, and HMGB1 were tested with luciferase reporter analysis. The expression and secretion of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α were determined in lipopolysaccharide-stimulated microglia or miR-129-5p inhibitor transferred to microglia exposed to GSC EVs or EVs derived from siMALAT1 pre-transferred GSCs. MALAT1 was enriched in GSC EVs compared with GSCs, and up-regulated MALAT1 was also observed in microglia upon GSC EVs incubation. The relative expression and secretion of IL-6, IL-8, and TNF-α in lipopolysaccharide-stimulated microglia were up-regulated in the GSC supernatant group, which could be reversed by dimethyl amiloride (DMA) (EV secretion inhibitor) co-administration or si-MALAT1 pre-transfection of GSCs. Luciferase reporter assay testified the direct binding of MALAT1 and miR-129-5p, miR-129-5p, and HMGB1, and si-MALAT1 could up-regulate miR-129-5p expression and down-regulate HMGB1 expression in microglia cells. The concentration of IL-6, IL-8, and TNF-α in lipopolysaccharide-stimulated microglia exposed to EVs from siMALAT1 transfected GSCs could be up-regulated by miR-129-5p inhibition. EVs lncRNA MALAT1 released from GSCs could modulate the inflammatory response of microglia after lipopolysaccharide stimulation through regulating the miR-129-5p/HMGB1 axis.

The diverse distribution and functions of regulatory T cells (Tregs) ensure tissue and immune homeostasis; however, it remains unclear which factors can guide distribution, local differentiation, and tissue context-specific behavior in Tregs. Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings, the underlying mechanisms that reprogram transcriptome in Tregs are unknown. In the past decade, metabolic machineries have been revealed as a new regulatory circuit, known as immunometabolic regulation, to orchestrate activation, differentiation, and functions in a variety of immune cells, including Tregs. Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions, it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs. The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmunity with minimizing side effects. This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies.

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by increased pulmonary artery pressure which if left untreated, can lead to poor quality of life and ultimately death. It is a group of conditions and includes idiopathic PAH, familial/hereditary PAH and associated PAH. The condition has been studied for many years and its association with the immune system and in particular autoimmunity has been investigated. The mechanisms for the pathobiology of PAH are unclear although research has highlighted the role of adaptive and innate immune systems in its development. Diagnostics and therapeutic approaches range from cytokine treatments to the use of immunomodulating drugs, although there is still scope for improvements in the field. This article discusses the mechanisms linked to PAH, its association with other conditions and recent therapeutic interventions.

Background This study was performed to elucidate the changing epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in a Chinese teaching hospital. Methods We performed whole-genome sequencing and phylogenetic analysis on MRSA isolates recovered at Sir Run Run Shaw Hospital (SRRSH) from 2013 to 2015. MRSA isolates underwent susceptibility testing, resistance determinant screening, virulence assays and clinical data analysis. Results A total of 292 MRSA infections were identified during the study period. Of these, most belonged to sequence type (ST) 5 (51.4%; 150 of 292) and ST59 (23.3%; 68 of 292). The proportion of ST5 MRSA decreased from 68.3% in 2013 to 32.1% in 2015, and the proportion of ST59 MRSA increased from 8.9% to 41.0%. Core-genome phylogenetic analysis revealed that ST59 MRSA isolates exhibited wider genotypic diversity than ST5 MRSA isolates in both healthcare-onset and community-onset groups. Minimum spanning trees showed that a cluster of ST5 MRSA was circulating at SRRSH, whereas the ST59 MRSA infections were mostly sporadic. ST59 MRSA caused 45.2% of the 93 skin and soft-tissue infection cases and displayed lower levofloxacin (11.8%) and ciprofloxacin (19.1%) resistance rates than the ST239 and ST5 MRSA isolates. ST59 healthcare-onset MRSA displayed enhanced virulence in the skin infection model and hemolysis assays. Notably, these isolates had virulence levels similar to those of classic community-associated MRSA strains. Conclusions ST59 MRSA strains with high virulence potential have been replacing ST5 MRSA in predominance in SRRSH and causing nosocomial infections. Whole-genome sequencing is a powerful tool to monitor changes in the epidemiology of MRSA in hospitals.

The aim of this study was to compare the different responses to hypocrellin B (HB)-mediated sonodynamic treatment between human gastric adenocarcinoma cell line SGC7901 and SGC7901/ADR. Tumor cells in culture dishes (35-mm diameter) were exposed to planar ultrasound at an intensity of 0.5 W/cm2 for 60 s combined with/without 2.5 μM HB. Cell viability was determined by MTT and Guava ViaCount assay. Production of reactive oxygen species (ROS) and destabilization of the mitochondrial membrane potential were assessed by flow cytometry. Apoptosis was analyzed using annexin-PE/7-amino-actinomycin D staining. The cell membrane integrity was estimated by isothiocyanate–dextran (FD500) uptake assay. Ultrastructural alterations on the membrane surface were observed by scanning electron microscopy. The membrane fluidity was also compared between the two cell lines using spectrophotometry. Compared with SGC7901 cells, HB-mediated sonodynamic therapy (HB-SDT) showed higher cytotoxic in SGC7901/ADR cells at the same treatment doses. Abundant intracellular ROS, a decrease in the mitochondrial membrane potential, and an increased rate of apoptosis were detected in the SDT group of both cell lines, wherein SGC7901/ADR cells showed a much more higher rate. Cell membrane permeability was remarkably enhanced after HB-SDT application. In addition, relatively severe cell damage was observed under scanning electron microscopy after HB-SDT treatment in SGC7901/ADR cells compared with SGC7901 cells. These results suggest that HB-SDT could induce apoptosis in SGC7901 and SGC7901/ADR cells via production of ROS. SGC7901/ADR was found to be more sensitive to HB-SDT than SGC7901 cells under the same experimental condition. Meanwhile, a noteworthy difference in cell membrane injury between SGC7901 and SGC7901/ADR cells was detected. The decreased membrane fluidity in SGC7901/ADR cells may be one of the reasons for its increased membrane damage.

Objective Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Recently, long non-coding RNAs (lncRNAs) were found to be critical modulators in the CRC progression. The aim of this study is to investigate the potential roles of lncRNA P73 antisense RNA 1T (TP73-AS1) in CRC development and progression. Methods Quantitative real-time PCR (qRT-PCR) was performed to determine relevant gene expression levels; western blot was performed to determine protein expression levels; CCK-8, colony formation, wound healing and Transwell invasion assays were used to determined CRC cell proliferation, migration and invasion; in vivo tumor growth was assessed in xenograft mice model. Results TP73-AS1 was up-regulated in both CRC tissues and CRC cell lines. Overexpression of TP73-AS1 was associated with metastasis and advanced clinical stages in CRC patients. Overexpression of TP73-AS1 promoted CRC cell growth, proliferation, migration and invasion in vitro; and knockdown of TP73-AS1 significantly inhibited CRC cell growth, proliferation, migration and invasion in vitro as well as tumor growth in vivo. Bioinformatics analysis and luciferase reporter assay indicated that TP73-AS1 could bind directly with miR-194, and TP73-AS1 negatively regulated the expression of miR-194 in CRC cells. Further study indicated that miR-194 negatively regulated the downstream target of transforming growth factor alpha (TGFα) via targeting its 3' untranslated region, and TP73-AS1 positively regulated the expression of TGFα in CRC cells. Moreover, overexpression of miR-194 suppressed CRC cell proliferation and invasion, and attenuated the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion. Silence of TGFα inhibited CRC cell proliferation and invasion, and also reversed the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion. Conclusions this study demonstrated that TP73-AS1 regulated CRC progression by acting as a competitive endogenous RNA to sponge miR-194 to modulate the expression of TGFα.

Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice. In vitro studies in SIRT6-KO hepatocytes exhibited similar results. In contrast, SIRT6 upregulation alleviated liver damage during hepatic I/R injury. Our study demonstrated for the first time that SIRT6 upregulation effectively protects against hepatic I/R injury. The underlying mechanisms involve the maintenance of oxidative homeostasis and mitochondrial function, which subsequently inhibit the inflammatory responses and MAPK signaling, and finally attenuate apoptosis and autophagy related hepatocyte death. These results suggest that the activation of SIRT6 exerts multifaceted protective effects during hepatic I/R injury, which can provide a novel therapeutic target for hepatic I/R injury.

Sequence type 88 community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strain SR434, isolated from an outpatient with skin and soft tissue infection, was subjected to whole genome sequencing, antimicrobial susceptibility testing, mouse skin infection model and hemolysis analysis to identify its virulence and resistance determinants. MRSA strain SR434 is resistant to clindamycin, erythromycin and fosfomycin. Four plasmids with resistance genes were identified in this strain, including a 20,658bp blaZ-carrying plasmid, a 2473bp ermC-carrying plasmid, a 2622bp fosB7-carrying plasmid (86% identity with plasmid in a ST2590 MRSA strain) and a 4817bp lnuA-carrying plasmid (99% identity with pLNU4 from bovine coagulase-nagetive Staphylococci). This strain contains staphylococcal cassette chromosome mec type IV and does not contain arginine catabolic mobile element or Panton-Valentine-Leukocidin. SR434 harbors genomic islands νSaα, νSaβ, νSaγ and ΦSa3 and pathogenicity islands νSa2 that carries genes encoding toxic shock syndrome toxin 1, superantigen enterotoxin C and superantigen enterotoxin L. Mouse skin infection model results show that SR434 had similar virulence potential causing invasive skin infection as a PVL-negative epidemic Korea clone HL1 (ST72). CA-MRSA strain of ST88 lineage might be a great concern for its high virulence. PVL has limited contribution to virulence phenotype among this lineage.

SERPINA1/AAT/α-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1E342K/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury. Both proteasome and macroautophagy/autophagy pathways are responsible for disposal of SERPINA1E342K/ATZ after it accumulates in the ER. However, the mechanisms by which SERPINA1E342K/ATZ is selectively degraded by autophagy remain unknown. Here, we showed that ER membrane-spanning ubiquitin ligase (E3) SYVN1/HRD1 enhances the degradation of SERPINA1E342K/ATZ through the autophagy-lysosome pathway. We found that SYVN1 promoted SERPINA1E342K/ATZ, especially Triton X 100-insoluble SERPINA1E342K/ATZ clearance. However, the effect of SYVN1 in SERPINA1E342K/ATZ clearance was impaired after autophagy inhibition, as well as in autophagy-related 5 (atg5) knockout cells. On the contrary, autophagy induction enhanced SYVN1-mediated SERPINA1E342K/ATZ degradation. Further study showed that SYVN1 mediated SERPINA1E342K/ATZ ubiquitination, which is required for autophagic degradation of SERPINA1E342K/ATZ by promoting the interaction between SERPINA1E342K/ATZ and SQSTM1/p62 for formation of the autophagy complex. Interestingly, SYVN1-mediated lysine 48 (K48)-linked polyubiquitin chains that conjugated onto SERPINA1E342K/ATZ might predominantly bind to the ubiquitin-associated (UBA) domain of SQSTM1 and couple the ubiquitinated SERPINA1E342K/ATZ to the lysosome for degradation. In addition, autophagy inhibition attenuated the suppressive effect of SYVN1 on SERPINA1E342K/ATZ cytotoxicity, and the autophagy inducer rapamycin enhanced the suppressive effect of SYVN1 on SERPINA1E342K/ATZ-induced cell apoptosis. Therefore, this study proved that SYVN1 enhances SERPINA1E342K/ATZ degradation through SQSTM1-dependent autophagy and attenuates SERPINA1E342K/ATZ cytotoxicity.

B23, a multifunctional nucleolar protein, is overexpressed in numerous cancers and is associated with tumorigenesis. However, the clinical significance and potential role of B23 in bladder urothelial carcinoma remains to be elucidated. The present study observed that the mRNA and protein expression levels of B23 were increased in bladder cancer cells and tissues. The overexpression of B23 contributed to tumorigenesis and was associated with poor prognosis in bladder cancer patients. Silencing of B23 by short hairpin RNA inhibited tumor cell growth and colony formation. In addition, knockdown of B23 suppressed the phosphorylation of extracellular signal‑regulated kinase (ERK), resulting in the inactivation of the ERK signaling pathway. Therefore, the present study indicated that B23 promotes bladder cancer cell growth via activation of the ERK signaling pathway and is a novel potential biomarker for the diagnosis and prognosis of bladder cancer.

Background Multidrug resistance (MDR) of breast cancer is a major obstacle in chemotherapy of cancer treatments. Recently the anti-tumor effects of Chlorin e6 (Ce6) mediated photodynamic therapy (Ce6-PDT) were reported in skin cancer and hepatoma in vitro. However, its therapeutic potential in killing human breast cancer especially those with MDR and the differences between MCF-7 and MCF-7/ADR after PDT treatment has not been fully investigated. Methods MTT assay was used to measure cell survival rate of MCF-7 cells and MCF-7/ADR cells. Intracellular reactive oxygen species (ROS) generation was measured by monitoring the fluorescence intensity of dichlorofluorescein (DCF) by flow cytometry. Nuclear morphology changes and DNA damage in both MCF-7 and MCF-7/ADR after Ce6-PDT were analyzed by hochest33342 staining and comet assay. Western blot and monodansylcadaverine (MDC) staining were used to monitor autophagic response in MCF-7/ADR. Results Ce6-PDT induced cell viability decrease, intracellular ROS generation, and DNA damage in concentration-dependent and cell-specific manner, and MCF-7 was more sensitive to Ce6-PDT than MCF-7/ADR cells at the same PDT condition. PDT treatment could trigger cell death via apoptosis in MCF-7 cells but autophagic cell death in MCF-7/ADR cells. Conclusion These results suggested that MCF-7 was more sensitive to Ce6-PDT than MCF-7/ADR, and PDT treatment could trigger apoptotic response in MCF-7 cells, but stimulate autophagic response in MCF-7/ADR cells.

In this study, we investigated the fosfomycin susceptibility rates among different methicillin-resistant Staphylococcus aureus (MRSA) clones. A total of 293 MRSA isolates obtained from Sir Run Run Shaw hospital during 2013-2015 were tested for fosfomycin susceptibility. The overall fosfomycin resistance rate among these MRSA isolates was 53.2%. Although 91.9% of the ST5 MRSA isolates (MIC50>1,024 mg/L) were resistant to fosfomycin, no fosfomycin-resistant isolate was found among the 69 ST59 MRSA isolates (MIC50/90, 0.5/4 mg/L). The fosfomycin resistance rate among the MRSA isolates recovered from skin and soft tissue infections was 19.1%, which was lower than the rates detected among MRSA isolates from other types of invasive infections. The fosfomycin resistance rate in community-onset MRSA was 30.2%, which was lower than that detected in healthcare-associated MRSA of 70.7%. One MRSA isolate had the fosB7 gene, whereas most (127/156) of the fosfomycin-resistant MRSA isolates had deletions in glpT genes. These findings highlight the importance of monitoring the fosfomycin susceptibility in MRSA isolates for epidemiological purposes.

Background Autologous fat injection is a procedure aimed at eliminating grave defects in the skin surface by subcutaneous injection of the patient's fatty tissue. Fat embolism is a rare but severe complication of this procedure, especially cerebral infarction. It is first reported by Thaunat in 2004. Methods were presented to the hospital with sudden unconsciousness and left limb weakness in 24 hours after facial fat injection. Brain computed tomography and magnetic resonance imaging were performed immediately after admission. Frontal temporoparietal decompressive craniectomy plus multiple treatments scheduled for patients. Pictures and videos were taken during follow-up. Figures are edited with Adobe Photograph CS6. Results Patients were diagnosed with extensive cerebral infarction of the right hemisphere through the middle cerebral artery or facial-intracranial branches. Conclusion Routine cosmetic procedures of facial fat injections could cause devastating and even fatal complications to patients. The small volume of fat grafts can be inserted through the internal carotid artery or go through the communicating branches between the facial artery and the intracranial artery into the brain.

As an electrophilic nitroalkene fatty acid, nitro-oleic acid (OA-NO2) exerts multiple biological effects that contribute to anti-inflammation, anti-oxidative stress, and antiapoptosis. However, little is known about the role of OA-NO2in peritoneal fibrosis. Thus, in the present study, we examined the effects of OA-NO2on the high glucose (HG)-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs) and evaluated the morphological and immunohistochemical changes in a rat model of peritoneal dialysis-related peritoneal fibrosis. In in vitro experiments, we found that HG reduced the expression level of E-cadherin and increased Snail, N-cadherin, and α-smooth muscle actin expression levels in HPMCs. The above-mentioned changes were attenuated by pretreatment with OA-NO2. Additionally, OA-NO2also inhibited HG-induced activation of the transforming growth factor-β1/Smad signaling pathway and NF-κB signaling pathway. Meanwhile, OA-NO2inhibited HG-induced phosphorylation of Erk and JNK. The results from the in vivo experiments showed that OA-NO2notably relieved peritoneal fibrosis by decreasing the thickness of the peritoneum; it also inhibited expression of transforming growth factor-β1, α-smooth muscle actin, N-cadherin, and vimentin and enhanced expression of E-cadherin in the peritoneum. Collectively, these results suggest that OA-NO2inhibits the HG-induced epithelial-mesenchymal transition in HPMCs and attenuates peritoneal dialysis-related peritoneal fibrosis.

Background Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid ( FA ) transport. Pigment epithelial‐derived factor ( PEDF ) is an important regulator in lipid metabolism. We hypothesized that PEDF is involved in endothelium‐mediated FA uptake under hyperlipidemic conditions. Methods and Results Circulating PEDF levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum PEDF levels were confirmed in both wild‐type and apolipoprotein E–deficient mice fed a long‐term high‐fat diet. Apolipoprotein E–deficient/PEDF‐deficient mice were generated by crossing PEDF‐deficient mice with apolipoprotein E–deficient mice, and then mice were fed with 24, 36, or 48 weeks of high‐fat diet. Greater increases in body fat and plasma lipids were displayed in PEDF ‐deficient mice. In addition, PEDF deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno‐associated virus encoding PEDF exerted opposite effects. Mechanistically, PEDF inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor‐1 and neuropilin‐1), and FA transport proteins 3 and 4, to suppress endothelial FA uptake, whereas PEDF deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation. Conclusions Decreasing expression of PEDF aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial FA uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.

Streptococcus pneumoniae (S. pneumoniae) is the main conditional pathogen of acute respiratory infection in infants, children, and older adults worldwide. It was great significant to identify the epidemic characteristics of serotypes and antibiotic susceptibility for the prevention and treatment of S. pneumoniae diseases. This research assessed the serotype distribution and the minimum inhibitory concentrations (MICs) of S. pneumoniae isolated from pediatric patients to provide information on the epidemiology and antibiotic resistance of S. pneumoniae in Kunming, China. A total of 140 S. pneumoniae isolates were collected from pediatric patients at Kunming Children’s Hospital from January 2016 to October 2017. Serotype identification was done by Quellung reaction and multiplex polymerase chain reaction. MICs were determined by E-test. 140 isolates distributed in 13 types of serotypes. The top-three prevalent serotypes were 19F, 19A, and 6B. The immunization coverage rate of 13-valent pneumococcal conjugate vaccine (PCV) was relatively higher and should be introduced into the vaccination program in the region. MIC50 of penicillin, ceftriaxone, and levofloxacin was 1 μg/mL. MIC50 for meropenem and vancomycin was 0.38 μg/mL. MIC90 of penicillin, ceftriaxone, and levofloxacin was 1.5 μg/mL and that of meropenem and vancomycin was 0.5 μg/mL. The MIC90 of erythromycin was > 256 μg/mL. In summary, S. pneumoniae had low resistance rates to penicillin, ceftriaxone, levofloxacin, vancomycin, and meropenem, and these antibiotics could be the first-line agents for children with pneumococcal infections in Kunming.