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BackgroundStimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments.MethodsBlood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture.ResultsIncreased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion.ConclusionsThese findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

Multifunctional food packaging films were developed based on polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC), tea polyphenol (TP) and black carrot anthocyanin (CA). Results of Zeta potential, scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction showed that CA enhanced the stability of the particle dispersion system through hydrogen bonding and electrostatic interactions, promoted the compatibility between TP and PVA-CMC (PC) substrates, and enhanced the binding between the components of the films. Because of the interaction of TP and CA, PC-TP-CA films had better water resistance and water vapor barrier properties, thermal stability, antioxidant and antimicrobial properties. PC-CA and PC-TP-CA films exhibited excellent UV-blocking properties. They also showed distinct color responsiveness in the pH range of 2-13, significant sensitivity to ammonia vapor in a short period of time and excellent color stability over 20 days of storage under different conditions. When the film was applied to fish, it was found that PC-TP-CA film could extend the shelf life of fish by 1-2 days and successfully monitor the freshness of the fish in real-time. Considering all the physical and functional properties, the non-toxic and biodegradable PC-TP-CA film has excellent potential as a new multifunctional food packaging material in the future.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of gastrointestinal tract, which can develop into colorectal cancer. Triptolide (TP) is a predominant bioactive ingredient ofIn our study, we examined the function of TP in the progression of IBD.3-(4,5)dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay was used to evaluate the viability of RAW264.7 cells. Quantitative reverse transcription polymerase chain reaction assay was performed to detect the relative gene expression. Western blot was used to detect the relative protein expression. Enzyme-linked immunosorbent assay was utilized to examine the levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and IL-6.Our research demonstrated that TP restrained lipopolysaccharide (LPS)-caused activation of RAW264.7 cells, as evidenced by the reduction of PGE2, TNF-α, and IL-6, and increase of IL-10. TP treatment also restrained M1-type macrophage polarization and facilitated M2-type macrophage polarization of RAW 264.7 cells in the presence of LPS. Moreover, TP mitigated LPS-induced activation of the mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signaling in RAW264.7 cells. Further, activation of the mTOR/STAT3 signaling by MHY1485 attenuated the effect of TP in regulation of macrophage polarization in RAW264.7 cells in the presence of LPS.Overall, our results indicated that TP attenuated LPS-induced activation of RAW 264.7 macrophages by inducing M1-to-M2 repolarization

The effects of binary probiotics (Lacticaseibacillus casei CGMCC1.5956 and Lactiplantibacillus plantarum subsp. plantarum CGMCC 1.5953) in conjunction with wolfberry dietary fiber (WDF) on yogurt quality were investigated in this study. d-fructose, β-d-glucose, 6-acetyl-d-glucose, and 1-ketose in WDF significantly improved syneresis, apparent viscosity, and elastic behavior of yogurt. Binary probiotics were more suitable for fermenting WDF yogurt than single probiotics, resulting in a higher viable count (9.39 lg (CFU/mL)) and unique flavor. Binary probiotics can promote the production of tyrosol by L. casei 56 through the tyrosine metabolic pathway, thereby enhancing the resistance of L. casei 56 and L. plantarum 53 to their environment and promoting growth. Pyridine, 2,3,4,5-tetrahydro- and prenol might be responsible for the high odor scores in the sensory evaluation of WDF yogurt prepared using binary probiotics. In summary, combining binary probiotics and WDF can significantly improve yogurt quality and add value to the final product.

This study aimed to determine the impact of nutrition supplementation (whey protein, fish oil, vitamin D) and physical exercise (resistance and aerobic exercise) on muscle mass, muscle strength and fat mass among sarcopenic elderly. Participants (N = 241) with sarcopenia (aged ≥ 60 y) enrolled from 2 centers were randomized into groups undergoing nutrition supplementation (Nutr), physical exercise (Ex), nutrition combined with exercise (Nutr+Ex), or routine consultation for 12 weeks. Muscle-related indicators, grip strength as well as fat-related indicators were compared pre- and post-intervention. The per-protocol analysis showed that all indicators were significantly different between groups (P < 0.001). Further pairwise comparisons showed that compared with controls, appendicular muscle mass and grip strength were significantly higher in Nutr (P < 0.001, 95% CI: 0.578, 1.475; P < 0.001, 95% CI: 3.614∼9.118), Ex (P = 0.010, 95% CI: 0.157, 1.153; P < 0.001, 95% CI: 2.904, 8.732), and Nutr+Ex (P < 0.001, 95% CI: 0.564, 1.471; P < 0.001, 95% CI: 3.441, 8.907) groups, while fat mass was significantly lower in the Nutr (P < 0.001, 95% CI: −4.676, −2.358) and Nutr+Ex (P < 0.001, 95% CI: −4.717,−1.790) groups. When compared with Ex, fat mass decreased significantly in the Nutr (P = 0.001, 95% CI: −4.856,−1.359) and Nutr+Ex (P = 0.005, 95% CI: −4.810, −0.878) groups. The findings indicate that nutrition supplementation and physical exercise could improve muscle mass, strength and fat mass among sarcopenic elderly. Nutrition supplementation might be better at decreasing fat mass in this population. ClinicalTrials.gov registration no.: NCT02873676. Novelty: Nutrition supplementation improved muscle mass, strength and fat mass among sarcopenic elderly. Aerobic and resistance exercise improved muscle mass and strength in sarcopenic elderly. Combined nutrition supplementation and physical exercise improved muscle mass, strength and fat mass among sarcopenic elderly.

The demands for carbon fiber reinforced composites (CFRCs) are growing in the aviation industry for fuel consumption savings, despite the increasing risk of electromagnetic interference (EMI). In this work, polyacrylonitrile (PAN) sheets were prepared by electrospinning. Carbon nanofiber (CNF) sheets were obtained by the carbonization of PAN sheets. The laminate structures of the CF reinforced bismaleimide (BMI)-based composites were specially designed by introducing two thin CNF sheets in the upper and bottom plies, according to EMI shielding theory. The results showed that the introduction of CNF sheets led to a substantial increase in the EMI shielding effectiveness (SE) by 35.0% compared with CFRCs free of CNF sheets. The dominant EMI shielding mechanism was reflection. Noticeably, the introduction of CNF sheets did not impact the interlaminar shear strength (ILSS) of CFRCs, indicating that the strategy provided in this work was feasible for fabricating CFRCs with a high EMI shielding performance without sacrificing their mechanical properties. Therefore, the satisfactory EMI shielding and ILSS properties, coupled with a high service temperature, made BMI-based composites a promising candidate in some specific fields, such as high-speed aircrafts and missiles.

Background Central nervous system (CNS) hemangioblastomas are the most frequent cause of mortality in patients with Von Hippel–Lindau (VHL) disease, an autosomal dominant genetic disease resulting from germline mutations in the VHL tumor suppressor gene, with most mutations occurring in the exons. To date, there have been no reports of CNS hemangioblastoma cases related to pathogenic variants in intron 2 of VHL, which encodes a tumor suppressor protein (i.e., pVHL) that regulates hypoxia-inducible factor proteins. Case presentation We report the presence of a base substitution of c.464-1G > C and c.464-2A > G in the intron 2 of VHL causing CNS hemangioblastomas in six patients with VHL from two Chinese families. The clinical information about the two pathogentic variants has been submitted to ClinVar database. The ClinVar accession for NM_000551.3(VHL):c.464-1G > C was SCV001371687. This finding may provide a new approach for diagnosing and researching VHL-associated hemangioblastomas. Conclusions This is the first report of a pathogenic variant at intron 2 in VHL-associated hemangioblastomas. Gene sequencing showed that not only exonic but also intronic mutations can lead to the development of CNS hemangioblastomas.

To restore tissue growth without increasing the risk for cancer during aging, there is a need to identify small molecule drugs that can increase cell growth without increasing cell proliferation. While there have been numerous high-throughput drug screens for cell proliferation, there have been few screens for post-mitotic anabolic growth.A machine learning (ML)-based phenotypic screening strategy was used to discover metabolites that boost muscle growth. Western blot, qRT-PCR and immunofluorescence staining were used to evaluate myotube hypertrophy/maturation or protein synthesis. Mass spectrometry (MS)-based thermal proteome profiling-temperature range (TPP-TR) technology was used to identify the protein targets that bind the metabolites. Ribo-MEGA size exclusion chromatography (SEC) analysis was used to verify whether the ribosome proteins bound to calcitriol.We discovered both the inactive cholecalciferol and the bioactive calcitriol are amongst the top hits that boost post-mitotic growth. A large number of ribosomal proteins' melting curves were affected by calcitriol treatment, suggesting that calcitriol binds to the ribosome complex directly. Purified ribosomes directly bound to pure calcitriol. Moreover, we found that calcitriol could increase myosin heavy chain (MHC) protein translation and overall nascent protein synthesis in a cycloheximide-sensitive manner, indicating that calcitriol can directly bind and enhance ribosomal activity to boost muscle growth.Through the combined strategy of ML-based phenotypic screening and MS-based omics, we have fortuitously discovered a new class of metabolite small molecules that can directly activate ribosomes to promote post-mitotic growth.

This work concentrated on the interlaminar mechanical properties and toughening mechanism of carbon fiber-reinforced bismaleimide resin (CF/BMI) composites modified by polyacrylonitrile (PAN) nanofiber films. The PAN nanofiber films were prepared by electrospinning. End-notched flexure (ENF) and short-beam strength tests were conducted to assess the mode II fracture toughness (GIIc) and interlaminar shear strength (ILSS). The results showed that the GIIc and ILSS of PAN-modified specimens are 1900.4 J/m2 and 93.1 MPa, which was 21.4% and 5.4% higher than that of the virgin specimens (1565.5 J/m2 and 88.3 MPa), respectively. The scanning electron microscopy (SEM) images of the fracture surface revealed that the PAN nanofiber films toughen the composite on two scales. On the mesoscopic scale, the composite laminates modified by PAN formed a resin-rich layer with high strength and toughness, which made the crack propagate across the layers. At the microscopic scale, the crack propagation between two-dimensional nanofiber films led to constant pull-out and breakage of the nanofibers. As a result, the interlaminar fracture toughness of the composite laminates improved.

Due to the lack of historical data, the inability to carry out a large number of reliability tests on the machine tool, the lack of reliability information collected, and the change of the working environment of the machine tool, there are a lot of uncertainties in the machine tool. In the existing research, only unilateral uncertainty factors are usually considered, while in practical problems, random uncertainty and cognitive uncertainty exist at the same time. Therefore, in this study, the random uncertainty and cognitive uncertainty in the system are characterized by random variables, fuzzy variables, probability box variables, and interval variables. For the structural function with more variables, the dimension is reduced first, and then the reliability model of the universal generating function (UGF) is established. Taking the heavy CNC machine tool as an example, the structural reliability analysis model of the fatigue strength of the milling shaft based on the UGF is constructed. The local sensitivity analysis and global sensitivity analysis of the variables affecting the fatigue strength of the milling shaft are carried out, and the factors that have the greatest impact on the fatigue strength of the milling shaft are obtained. The case study shows the effectiveness of the method proposed in this study.

With considering sewage pipe network upgrading projects in the “villages” in cities, the optimization of construction resources and the assessment of delay risks could be achieved. Based on the schedule-cost hypothetical theory, the mathematical model with constraint indicators was established to obtain the expression of optimal resource input, and conclude the method to analyze the schedule uncertainties. The analysis showed that cyclical footage of pipe could be regarded as a relatively fixed value, and the cost can be regarded as a function that depending on the number of working teams. The optimal number of teams and the optimal schedule occurred when the minimum total cost achieved. In the case of insufficient meteorological data, the Monte Carlo simulation method and uncertainty analysis method can be applied to assess the impact of rainfall on the total construction period, correspondingly the probability of such risk could be derived. The calculation showed that the risk of overdue completion varied significantly according to the construction starting time. It was necessary to take rainfall risk into consideration and make corresponding strategies and measures.

This study aims to present the clinical characteristics and surgical treatment in patients with intracranial hemangioblastomas and to investigate risk factors for postoperative functional outcomes.Patients with intracranial hemangioblastomas who received surgical treatment in our institute between 2011 and 2020 were included. We retrospectively reviewed and analyzed the clinical characteristics, surgical treatment, and postoperative functional status. Risk factors for postoperative functional outcomes were further analyzed using univariate and multivariate analysis.We identified 48 patients with 82 intracranial hemangioblastomas resected in this study. There were 22 females and 26 males, and the mean age was 39.3 ± 15.3 years. Total resection was achieved in all the cases. After primary surgery, immediate functional status was improved in 20 patients (41.7%), stable in 9 patients (18.8%), and worsened in 19 patients (39.6%). Forty-two patients (89.4%) had favorable functional status (Karnofsky Performance Scale ≥80) at long-term follow-up. Through univariate and multivariate analysis, body mass index, number of resected tumors per operation, and intraoperative blood loss were independent risk factors for the immediate functional outcome (P = 0.006, P = 0.023, P = 0.038, respectively). Preoperative hydrocephalus was significantly associated with unfavorable long-term functional status (P = 0.047).Generally, patients can benefit from surgical removal of intracranial hemangioblastomas with favorable functional outcomes. Body mass index, number of resected tumors per operation, and intraoperative blood loss can be used as risk factors for immediate functional outcomes after surgery, and preoperative hydrocephalus for long-term functional status.

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host–virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.

The well-conserved correlation between juvenility and tissue regeneration was first discussed by Charles Darwin. Ectopic Lin28 is known to play an important role in somatic reprogramming and tissue regeneration, but endogenous Lin28’s role in tissue homeostasis and juvenility had remained unclear. Through lineage tracing, we found that a rare subset of muscle stem cells (MuSCs) expressing Lin28a can respond to acute injury by proliferating as Pax3+ or Pax7+ MuSCs, and contribute to all types of myofibers during muscle regeneration. Compared with conventional Pax7+ MuSCs, Lin28a+ MuSCs express more Pax3 and show enhanced myogenicity in vitro. In terms of the epigenetic clock, adult Lin28a+ MuSCs lie between adult Pax7+ MuSCs and embryonic Pax7+ myoblasts according to their DNA methylation profiles. We found that Lin28a+ MuSCs upregulate several embryonic limb bud mesoderm transcription factors and could maintain a juvenile state with enhanced stem cell self-renewal and stress-responsiveness in vitro and in vivo. When combined with telomerase and TP53 inhibition to biomimic mouse Lin28a+ MuSCs, we found that Lin28a can rejuvenate and dedifferentiate aged human primary myoblasts into engraftable, self-renewing MuSCs. Mechanistic studies revealed that Lin28a activated the HIF1A pathway by optimizing mitochondrial ROS (mtROS), thereby rejuvenating MuSC self-renewal and muscle regeneration. Our findings connect the stem cell factor Lin28, mtROS metabolism and stress response pathways to the process of stem cell rejuvenation and tissue regeneration.

In view of the problems of traditional repair materials for anchorage concrete of expansion joints, such as ease of damage and long maintenance cycles, the design of polyurethane concrete was optimized in this article, which could be used for rapid repair of concrete in anchorage zone of expansion joints. A new type of carbon fiber grid–polyurethane concrete system was designed, which makes the carbon fiber grid have an excellent synergistic effect with the quick-hardening and high-strength polyurethane concrete, and improved the flexural bearing capacity of the polyurethane concrete. Through the four-point bending test, the influence of the parameters such as the number of grid layers, grid width, and grid density on the flexural bearing capacity of polyurethane concrete beams was tested. The optimum preparation process parameters of carbon fiber grid were obtained to improve the flexural performance of polyurethane concrete. Compared with the Normal specimen, C-80-1’s average flexural strength increased by 47.7%, the failure strain along the beam height increased by 431.1%, and the failure strain at the bottom of the beam increased by 68.9%. The best width of the carbon fiber grid was 80 mm, and the best number of reinforcement layers was one layer. The test results show that the carbon fiber grid could improve the flexural bearing capacity of polyurethane concrete. The carbon fiber grid–polyurethane concrete system provides a new idea for rapid repair of the anchorage zone of bridge expansion joints, and solves the problems such as ease of damage and long maintenance cycles of traditional repair materials, which can be widely used in the future.

Oropharynx is the anatomical site with the highest human papillomavirus (HPV) infection in head and neck. Many studies on HPV prevalence and p16We calculated the number of new cancer cases using the Cancer Incidence in Five Continents Volume XI (CI5XI) and country-specific population in 2012 issued by the United Nations. Estimates of HPV prevalence and p16Globally the number of oropharyngeal cancer and tonsillar cancer attributable to HPV were 42,000 and 20,000 in 2012, corresponding to AFs of 42.7% and 52.7%. The number of cancer cases attributable to HPV among males was about 4-fold greater than that among females. For both oropharyngeal cancer and tonsillar cancer, AFs were higher in more developed countries. Among HPV positive oropharyngeal cancer cases, 86.7%, 87.8%, and 92.5% could have been prevented by bivalent (2v), quadrivalent (4v), and nonavalent (9v) HPV vaccines.It is worth considering the inclusion of HPV immunization in males, especially in the regions where oropharyngeal cancer is highly prevalent.

Carbon fiber-reinforced polymer (CFRP) reinforcement technology has been widely used in the reinforcement of reinforced concrete (RC) beams. At this stage, high prestressed CFRP board reinforcement is often used in actual reinforcement. However, most reinforced bridges are designed for a long time, and the design value of the protective layer is low, and it is impossible to achieve a large prestressed tension. Therefore, this paper proposes the reverse-arch method to paste the CFRP board and apply low prestress to strengthen the symmetrical RC beam. Through the three-point forward loading test, the cracking load, ultimate load, crack width, mid-span deflection, strain and failure mode of a reverse-arch method-pasted CFRP board-reinforced beam, a directly pasted CFRP board-reinforced beam and an unreinforced beam are compared. The results show that the load-bearing capacity and stiffness of the test beam can be improved by pasting CFRP plates with anti-arch method, but the ductility of the test beam is reduced. Compared with the unreinforced beam, the maximum cracking load and ultimate load are increased by 56% and 63% respectively. The reverse-arch method can produce low prestress, improve the stiffness and bearing capacity of members, and has a good prospect of engineering application.

The 5-year survival rate of laryngeal cancer continues to decline, and the laryngeal particularity of the anatomy adversely affects the patient's quality of life. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are closely correlated to key steps in the malignant progression of cancer cells. In this study, we report the role of lncRNA SBF2-AS1/miR-302b-3p/TGFBR2 interactions in the metastasis of laryngeal squamous cell carcinoma (LSCC). We verified that SBF2-AS1 was significantly downregulated in LSCC tissues and cell lines using qRT-PCR analysis. Its low expression was correlated to lymph node metastasis and an advanced clinical stage. More importantly, LSCC patients with low expression of SBF2-AS1 tended to have a poor prognosis. Based on this, we performed gain-of-function and loss-of-function experiments in LSCC cell lines. The results confirmed that knocking down SBF2-AS1 can promote the metastasis of LSCC cells and enhance epithelial-mesenchymal transition phenotype, while the upregulation of SBF2-AS1 expression resulted in the opposite. Our in vivo model verified that SBF2-AS1 overexpression could inhibit LSCC cell metastasis. Subsequent mechanistic studies revealed that SBF2-AS1 acted as a competing endogenous RNA that upregulated the expression of TGFBR2 by endogenous sponging for miR-302b-3p in LSCC cell lines. Moreover, miR-302b-3p overexpression reversed the inhibitory effects on LSCC metastasis induced by upregulation of SBF2-AS1 expression, and inhibition of TGFBR2 expression reversed the effect of SBF2-AS1 on metastasis. Our study proposes SBF2-AS1 as a biomarker to predict the prognosis of LSCC patients and a novel potential therapeutic target.

Aim: To explore the relationship between the use of aspirin and the incidence of hepatocellular carcinoma (HCC).Methods: MEDLINE, EMBASE, Web of Science and Cochrane CENTRAL databases were searched systematically from the earliest available date to 13 March 2020. The primary outcome was incidence of HCC, and the secondary outcomes were recurrence and mortality of HCC. The results were expressed as the Hazard Ratio (HR) and 95% confidence interval (CI). Based on the heterogeneity evaluated with the I2 statistic, a meta-analysis was performed using either a random- or fixed-effects model.Results: A total of sixteen articles (2781100 participants) were included. There was lower incidence of HCC in aspirin users than those in non-aspirin users (HR, 0.56; 95% CI, 0.46-0.69; p < 0.001). Subgroup analysis further showed that the incidence of liver cancer in patients with alcoholic cirrhosis (HR, 0.14; 95% CI, 0.09-0.22; p < 0.001) and virus hepatitis (HR, 0.68; 95% CI, 0.62-0.74; p < 0.001) who use aspirin was lower than that of patients who do not use aspirin. In addition, aspirin was found to associate with decreased risk of HCC mortality (HR, 0.71; 95% CI, 0.65-0.78; p < 0.001), not HCC recurrence (HR, 0.52; 95% CI, 0.15-1.76; p = 0.291).Conclusions: Aspirin use is significantly associated with the low incidence rate of liver cancer.

Yunpeng Cui,1 Xuedong Shi,1 Chunwei Li,2 Chuan Mi,1 Bing Wang,1 Yuanxing Pan,1 Yunfei Lin1 1Department of Orthopaedics, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Neurosurgery, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xuedong ShiDepartment of Orthopedic, Peking University First Hospital, No. 7 Xishiku Street, Xicheng District, Beijing, 100032, People’s Republic of ChinaTel +86 10-83575660Email pku_ortho@163.comObjective: This study aimed to investigate the effect of timing of surgery on neurological recovery for patients with metastatic spinal cord compression (MSCC).Methods: According to the timing of surgery, 75 patients with incomplete paraplegia caused by MSCC were assigned to 3 groups: within 3 days (group A), between 4 days and 7 days (group B), and after 7 days (group C). T-test, one-way ANOVA, Mann–Whitney U-test, and Chi-square test were used to evaluate the difference in the improvement of American Spinal Injury Association Impairment Scale (AIS) and ambulatory status, the incidence of perioperative complications, surgical site infection, and the length of hospital stay between 3 groups.Results: Patients with incomplete paraplegia treated in our department had an average of 17.4± 1.8 days delayed and most occurred before hospitalization (4.0± 0.4 vs 13.2± 1.8, P< 0.001). There was no significant difference in the AIS improvement between patients with different pre-op AIS. The timing of surgery was significantly correlated with AIS improvement (correlation coefficient=− 0.257, P=0.019). Sub-analysis showed that patients who underwent surgery within 7 days (group A and group B) had significantly better AIS improvement compared with group C (improved at least 1 grade, P=0.043; improved more than 1 grade, P=0.039) and the surgery timing was more important for patients with AIS B and C. The timing of surgery was significantly correlated with the length of hospital stay (correlation coefficient=0.335, P=0.003). Patients of group C had the longest length of hospital stay (P=0.002). The incidence of perioperative complications and surgical site infection did not differ significantly between the 3 groups.Conclusion: Delay surgery was common in incomplete paraplegia patients with MSCC. Patients with AIS B and C who underwent surgery within 7 days had better AIS improvement.Keywords: timing of surgery, metastatic spinal cord compression, incomplete paraplegia, neurologic function

Purpose To investigate the role of elastase in corneal epithelial barrier dysfunction caused by the exoproteins secreted by Pseudomonas aeruginosa. Methods Exoproteins obtained from Pseudomonas aeruginosa culture supernatant were analyzed by shotgun proteomics approach. In vitro multilayered rabbit corneal epithelial barrier model prepared by air-liquid interface technique (CECs-ALI) were treated with 2 µg/ml exoproteins and/or 8 mM elastase inhibitor. Then the epithelial barrier function was evaluated by transepithelial electrical resistance (TEER) assay and tight junction proteins immunofluorescence. Cell viability and the apoptosis rate were examined by CCK8 assay and flow cytometry. TNF-α, IL-6, IL-8, and IL-1β levels were measured by ELISA. Mice cornea treated with exoproteins and/or elastase inhibitor were evaluated in vivo and in vitro. Results Elastase (24.2%) is one of the major components of exoproteins. After 2 µg/ml exoproteins were applied to CECs-ALI for two hours, TEER decreased from 323.2 ± 2.7 to 104 ± 6.8 Ω/cm2 (P < 0.001). The immunofluorescence results showed a distinct separation in tight junction and significant degradation of ZO-1 and occludin (P < 0.05). Elastase inhibitor (8 mM) alleviated the decrease in TEER value (234 ± 6.8 Ω cm2) induced by exoproteins. Inhibition of elastase decreased the apoptosis rate of CECs treated with exoproteins from 30.2 ± 3.8% to 7.26 ± 1.3% and the levels of inflammatory factors (P < 0.05). Mice corneal epithelium defect could be induced by exoproteins and protected by elastase inhibitor. Conclusions Elastase plays a critical role in corneal epithelial barrier dysfunction caused by Pseudomonas aeruginosa exoproteins via damaging tight junctions. The inhibition of elastase could protect the corneal epithelial barrier via reducing virulence and inflammation.

Purpose Long noncoding RNAs (lncRNAs) have been identified as an important class of noncoding RNAs that are deeply involved in multiple biological processes in tumorigenesis. This study is to investigate the critical roles and biological function of lncRNA growth arrest-specific 5 (GAS5) in tumorigenesis of laryngeal squamous cell carcinoma (LSCC). Patients and methods A total of 59 samples of LSCC and paired adjacent tissue, as well as corresponding clinicopathological information were collected. GAS5 expression in both LSCC tissues and human SUN1076 and SNU899 cell lines were analyzed by Real-time quantitative RT-PCR method. Ectopic expression of GAS5 by vector transfection in LSCC cell lines and followed by in vitro experiments was to investigate the critical roles and function of GAS5 in LSCC. Cell Counting Kit 8 (CCK8) assay and PE/7AAD Annexin V Apoptosis analysis was to evaluate cell proliferation ability and cell apoptosis. Co-transfection of GAS5 and miR-21 was to explore the interaction between GAS5 and miR-21 in LSCC. BAX and CDK6 protein level were analyzed by western blot method. Results This study demonstrated that GAS5 was significantly downregulated in LSCC tissue and human LSCC cell lines. GAS5 levels were correlated with the clinicopathological features of LSCC patients. In addition, the ectopic expression of GAS5 significantly inhibited cell proliferation and promoted apoptosis. Co-expression analyses indicated that GAS5 is negatively correlated with miR-21 in LSCC tissues. Overexpression of miR-21 eliminated GAS5-mediated cell apoptosis and proliferation suppression. Furthermore, GAS5, which upregulated BAX mRNA expression and downregulated CDK6 mRNA expression, was reversed by ectopic expression of miR-21. Conclusion GAS5 suppresses LSCC progression through the negative regulation of miR-21 and its targets involved in cell proliferation and apoptosis, indicating that GAS5 may serve as a biomarker and potential target for LSCC therapy.

Background Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing‐related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. Methods A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non‐sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty‐two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre‐intensive and post‐intensive lifestyle interventions, were measured. Results The sarcopenic group was significantly older (72.05 ± 6.54 years; P 11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6‐fold and 14.3‐fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4‐fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF‐α, IL‐18, insulin, and adiponectin (all P

This paper presented a novel method to prepare organohydrogel-based stretchable O 2 sensor with high performance, including good linearity, anti-drying property, low limit of detection (LOD) and long-term stability. A facile solvent replacement approach was devised to partially exchange water with xylitol molecules, generating the stable organohydrogel. Compared with gas sensor based on pristine hydrogel, this organohydrogel-based sensor displayed high water retention, leading to the prolonged life time (>30 days) therefore. In addition, LOD was lowered by 2.45 times to 0.56 ppm. Furthermore, the sensing mechanism was investigated, revealing an electrochemical reaction mechanism occurred at the electrode-hydrogel interface. This work provided a facile method for enhancing the performance of hydrogel-based gas sensor.

Background: This study aims to evaluate the perioperative safety and efficacy of minimally-invasive tubular surgery for spinal metastasis with different blood supply.Methods: 72 patients with spinal metastasis between January 2011 to June 2020 were retrospectively reviewed. 14 patients underwent minimally-invasive tubular surgery (Mini-invasive group), and 58 patients underwent conventional surgery (Conventional group). T-test and Mann–Whitney U test was used to evaluate the difference in demographic and perioperative data between the two groups.Results: Baseline characteristics did not differ significantly between the two groups except for the Tokuhashi score (p=0.036). Overall, conventional group had significantly more blood loss (P=0.001), blood transfused(P=0.027), drainage(PConclusion: In selected cases with spinal metastasis, minimally-invasive tubular surgery is safe and effective for patients with spinal metastasis. Patients with hypo-vascular tumor were more suitable for this technique with less blood loss, less blood transfused, less drainage and shorter postoperative hospitalization.

This article relies on the reinforcement project of the Mulinghe cable-stayed bridge to explore the changes in the mechanical properties of the reinforced concrete cable-stayed bridge before and after reinforcement. The bridge has large cable spacing, large internal force of a single cable, and the main beam is mainly Reinforced Concrete. Therefore, structural calculation, disease analysis, and damage state simulation are carried out. Afterwards, the bridge's commonly used reinforcement methods were compared, and suitable reinforcement schemes were selected. After the reinforcement, the field test was carried out on the cable-stayed bridge, the main beam deflection, the strain of the main beam and the main tower, and the increase in the cable force of the cable- stayed were analyzed. The results show that external prestressed reinforcement is the best way, which can significantly reduce the vertical displacement of the main beam and the horizontal displacement of the main tower, and also improve the stress on the upper and lower edges of the main beam. After the external prestressed reinforcement, the ratio of the observed value to the observed value in the filed load test of the cable-stayed bridge's decreased significantly. It is up to 31% increase in bending capacity of main beams and up to 24% increase in stiffness. This article is instructive for the reinforcement of the early-built sparse-cable reinforced concrete cable-stayed bridge, while also expanding the scope of implementation of external prestressed reinforcement technology.

Background: The ideal treatment for patients who survive from acute vertebrobasilar artery occlusion but develop aggressive ischemic events despite maximal medical therapy in the early non-acute stage is unknown. This paper reports the technical feasibility and outcome of staged endovascular treatment in a series of such patients with symptomatic intracranial vertebral artery occlusion.Methods: Ten consecutive patients who presented with aggressive ischemic events in the early non-acute stage of intracranial vertebral artery occlusion from Jan 2015 to Nov 2020 were retrospectively reviewed. Among them, eight male and two female patients with a mean age of 66.7 years developed aggressive ischemic events, and the NIHSS score was elevated by a median of 7 points despite medical therapy. All patients received staged endovascular treatment 4–21 days from onset, at an average of 11 days. The strategy of staged treatment was as follows: first, a microwire was passed through the portion of the occlusion, which was then dilated with balloon inflation to maintain the perfusion above TICI grade 2b. Then, with the use of antiplatelet drugs, the residual intravascular thrombus was gradually eliminated by the continuous perfusion and an activated fibrinolytic system, leaving the residual stenosis. A second stage of angioplasty with stent implantation was subsequently performed if residual stenosis was ≥50%. The NIHSS scores and mRS scores were compared between pre- and post-endovascular treatment groups and in the follow-up period.Results: Technical success was achieved in 9 patients who received staged endovascular treatment (perforation occurred in one patient during the first stage). The NIHSS scores were significantly improved, with a median score 7 points lower on discharge compared with the scores for the most severe status. Favorable outcomes with mRS score ≤ 2 were achieved in 7 and 9 patients at the 3-month follow-up and the latest follow-up, respectively, which was better than the preoperative status.Conclusion: Staged endovascular treatment might be a safe, efficient, and viable option in carefully selected patients with symptomatic intracranial vertebral artery occlusion in the early non-acute stage. However, this needs to be confirmed by further investigation, preferably in a large, controlled setting.

Objectives Our aim was to investigate the prevalence and predictive variables of sarcopenia. Methods We recruited participants from the Peking Union Medical College Hospital Multicenter Prospective Longitudinal Sarcopenia Study (PPLSS). Muscle mass was quantified using bioimpedance, and muscle function was quantified using grip strength and gait speed. Logistic regression revealed the relationships between sarcopenia and nutritional, lifestyle, disease, psychosocial and physical variables. Results The prevalence of sarcopenia and sarcopenic obesity was 9.2%‐16.2% and 0.26%‐9.1%, respectively. Old age, single status, undernourishment, higher income, smoking, low physical activity, poor appetite and low protein diets were significantly associated with sarcopenia. Multiple logistic regression analysis showed that age was a risk factor for all stages of sarcopenia, and participants above 80 years were greater than fivefold more susceptible to sarcopenia, while lower physical activity was an independent risk factor. The optimal cut‐off value for age was 71 years, which departs from the commonly accepted cut‐off of 60 years. Female participants were greater than twofold less susceptible to sarcopenia than male participants. The sterol derivative 25‐hydroxyvitamin D was associated with fourfold lower odds of sarcopenia in male participants. Several protein intake variables were also correlated with sarcopenia. Based on these parameters, we defined a highly predictive index for sarcopenia. Conclusions Our findings support a predictive index of sarcopenia, which agglomerates the complex influences that sterol metabolism and nutrition exert on male vs female participants., Dysregulated circadian clock genes were associated with glioma grades and the IDH status. Prognostic model suggests circadian clock genes affect glioma progression. The GO and GSEA enrichment analysis suggested dysregulated circadian clock genes can affect glioma through interfering cell cycle and influencing immunocytes infiltration.

BackgroundHemangioblastomas are uncommon, benign neoplasms of the central nervous system (CNS). This study aims to evaluate the incidence, demographics, clinical characteristics, and prognosis of CNS hemangioblastomas using the data from the Surveillance, Epidemiology, and End Results (SEER) Program.MethodsUnivariate and multivariate analyses using the Cox proportional hazards model were employed to identify prognostic factors of overall survival. The Kaplan-Meier method was utilized to evaluate overall survival distribution by treatment modality. A nomogram was further built to predict survival at 3 and 5 years.ResultsThe overall incidence rate of CNS hemangioblastomas was 0.141 per 100,000 person-years. Through univariate analysis and multivariate analyses, age between 60 and 79 years (HR = 3.697, p < 0.001), age greater than 80 years (HR = 12.318, p < 0.001), African American race (HR = 1.857, p = 0.003), multiple tumors (HR = 1.715, p < 0.001), and prior surgery (HR = 0.638, p = 0.013) were significantly associated with overall survival. Patients receiving surgery alone had better overall survival compared with patients receiving no treatment (p = 0.008) and patients receiving both surgery and radiotherapy (p = 0.002). The calibration plots demonstrated an excellent agreement between nomogram-predicted and actual survival.ConclusionIn conclusion, age, race, tumor location, number of tumors, and prior surgery are prognostic factors for survival. Surgery was the most common modality and was suggested as an effective and optimal treatment. The proposed nomogram can predict the prognosis of patients with CNS hemangioblastomas and help clinicians in making decisions.

Background: Central nervous system (CNS) hemangioblastomas (HGBs) are the most frequent cause of mortality in patients with von Hippel-Lindau (VHL) disease. Characteristics of multiple and recurrent disease cause certain difficulties in the treatment of CNS HGBs. Methods: VHL-related HGB cases treated surgically at our hospital from September 2015 to February 2019 were analyzed. Patients meeting the clinical diagnostic criteria underwent genetic testing. Real-time PCR and immunohistochemistry were used in HGBs to verify differential expression of mRNAs and proteins, respectively. Furthermore, correlations between the differentially expressed proteins and the histological grading, genetic mutations, and tumor burden were also analyzed. Results: A total of 21 patients with VHL syndrome confirmed by genetic testing (missense group, 9; partial deletion group, 12) were enrolled, and 30 CNS HGBs from these patients were studied. Clinical data showed that men at first operation were significantly younger than females (p = 0.005). Real-time PCR demonstrated that EGFR (p = 0.017) and TGFα (p = 0.017) mRNA expression in VHL-related HGBs was significantly higher than that in the control group. Immunohistochemistry showed that the mean optical density in VHL-related HGBs was significantly higher than that in controls (EGFR, p = 0.007; TGFα, p = 0.021). Finally, the cyst volume was related to the upregulation of EGFR (r = 0.782, p < 0.01). Conclusion: Overexpression of EGFR and TGFα may contribute to tumor growth in VHL-related CNS HGBs. The cyst volume was associated with EGFR overexpression. These results provide information for the management of VHL-related HGBs in the era of targeted therapeutics.

Accumulating evidence indicates that lncRNAs can interact with miRNAs to regulate target mRNAs through competitive interactions. However, this mechanism remains largely unexplored in laryngeal squamous cell carcinoma (LSCC). In this study, transcriptome-wide RNA sequencing was performed on 3 pairs of LSCC tissues and adjacent normal tissues to investigate the expression profiles of lncRNAs, miRNAs and mRNAs, with differential expression of 171 lncRNAs, 36 miRNAs and 1709 mRNAs detected. Seven lncRNAs, eight mRNAs and three miRNAs were identified to be dysregulated in patients’ tissues by using qRT-PCR. GO and KEGG pathway enrichment analyses were performed to elucidate the potential functions of these differentially expressed genes in LSCC. Subsequently, a ceRNA (lncRNA-miRNA-mRNA) network including 4631 ceRNA pairs was constructed based on predicted miRNAs shared by lncRNAs and mRNAs. Cis- and transregulatory lncRNAs were analysed by bioinformatics-based methods. Importantly, mRNA-related ceRNA networks (mRCNs) were further obtained based on potential cancer-related coding genes. Coexpression between lncRNAs and downstream mRNAs was used as a criterion for the validation of mRCNs, with the ZNF561-AS1-miR217-WNT5A and SATB1-AS1-miR1299-SAV1/CCNG2/SH3 KBP1/JADE1/HIPK2 ceRNA regulatory interactions determined, followed by experimental validation after siRNA transfection. Moreover, ceRNA activity analysis revealed that different activities of ceRNA modules existing in specific pathological environments may contribute to the tumorigenesis of LSCC. Consistently, both downregulated SATB1-AS1 and ZNF561-AS1 significantly promoted laryngeal cancer cell migration and invasion, indicating their important roles in LSCC via a ceRNA regulatory mechanism. Taken together, the results of this investigation uncovered and systemically characterized a lncRNA-related ceRNA regulatory network that may be valuable for the diagnosis and treatment of LSCC.

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

The slippage of cable clamps during the long-term operation of suspension bridges is a common and detrimental phenomenon. From an experimental point of view, the cable clamp slippage of a suspension bridge was investigated to reveal the effect of this sliding on the force acting on the full bridge. The forces acting on the bridge before and after the slippage were analyzed using a finite element model. The calculation results showed that the cable clamp slippage directly affects the cable forces of the hangers. The hanger cable force decreased by 19.2% when the slippage reached 10.2 cm, while the maximum increase in the cable force of adjacent hangers was 147.7 kN, an increase of 7.25%. The variation of forces in the hanger cable disrupted the force balance of the main girder, thereby producing a torque effect at the corresponding position in the girder, i.e., increased torque. Meanwhile, the slippage affected the axial tension in the main cable and the main girder. The impact of the tower internal force was less than 1%. Hence, the study concluded that the effect of cable clamp slippage is better understood, ensuring the safety of the suspension bridge.

The high power impulse magnetron plasmas (HIPIMS) were employed as a novel deposition technique, which had the benefit of providing a high ionization degree. In contrast, due to the ion return effect, the deposition rate was relatively low compared to the conventional direct current. In this paper, the external electric field and external magnetic field enhanced simultaneously the HIPIMS ((E-MF)-HIPIMS) to achieve higher deposition rate of the coatings. The vanadium coatings were deposited by the (E-MF)-HIPIMS at equivalent average target powers. The substrate peak ion current density measured in the (E-MF)-HIPIMS mode was increased by a factor of 4 to the discovered current density for the HIPIMS conditions when the anode voltage was set to 70 V. The enhanced ion flux bombardment from the highly ionized (E-MF)-HIPIMS plasma led to the formation of a smoother surface and a denser structure. At the same average target power for the vanadium coatings depositions, the (E-MF)-HIPIMS exhibited higher deposition rates compared to the conventional HIPIMS by approximately 73%. The (E-MF)-HIPIMS sputtered vanadium coating exhibited significantly higher-sized film and substrate interface bonding strengths than compared to the HIPIMS by the Rockwell adhesion testing. In addition, the (E-MF)-HIPIMS sputtered vanadium coating exhibited an improved friction coefficient and improved corrosion resistance compared to the substrate and the HIPIMS sample. The improvement occurred due to the enhanced particle ionization and intense ion bombardment.

As a newly emerging high ionization physical vapor deposition method, high power impulse magnetron sputtering (HIPIMS) has wide and promising prospects. Besides, the low efficiency of electron utilization and the ionization rate of the metallic particles still require to be further improved when utilized in practical industry applications. In the present work, a novel HIPIMS discharge mode that being enhanced synergistically by both the electric and magnetic fields were proposed. The synergistic enhancement discharge effect was investigated through a current sensor, plasma emission spectrometry, and higher electron utilization efficiency and sputtering particle ionization rates were obtained. The results demonstrated that, the application of external magnetic field significantly constrained the plasma and enhanced the uni-directionality. The target discharge current decreases remarkably under constant target pulse conditions, whereas the ion current collected by the substrates increases remarkably. This means that more ions participated in the film deposition process, and the number of absorbed ions and lost ions reduce significantly with the low electric potential and the scattering, respectively. The introduction of the external auxiliary anode changed the electric field and electric potential distribution in the discharging zone, which enhanced the discharging intensity, whereas the density and charge state of plasma in the system increased substantially. When the electric and magnetic fields are present at the same time, a synergistic enhancement effect occurs and interaction enhancement and the plasma density is significantly increased in all positions, which is approximately 5 times the conventional HIPIMS under charging.

A plasma electron source design for generating beam plasma at low gas pressures is reported. The designed plasma electron source can run stably in the pressure range between 0.1 Pa and 4 Pa. The electron source emission current increases as the working pressure increases. The DC electron beam can reach 11 A at an extraction voltage of 400 V and a gas pressure of 4.0 Pa, which is experimentally verified in this article. This low energy and high current electron beam interacts with gas molecules to generate a beam plasma, which increased the plasma electron source output current. As the working pressure and emission current increased, the beam plasma emission spectrum intensity increased.