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Xin Xiong,1,&ast; Rong Rong,2,&ast; Li-Ying Tang,3,&ast; Tie Sun,1 Yi-Cong Pan,1 Hui-Ye Shu,1 Li-Juan Zhang,1 Qian-Min Ge,1 Rong-Bin Liang,1 Yi Shao1 1Department of Pathology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Centre of Natural Ocular Disease Clinical Research Center, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Ophthalmology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, 361004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Shao, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Wai Zheng Street, Dong Hu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel/Fax +86 791-88692520, Email freebee99@163.comObjective: To explore the risk factors of ocular metastasis (OM) in patients with hepatocellular carcinoma (HCC) by analyzing the demographic characteristics and serum markers.Methods: From July 2002 to December 2012, 1064 HCC patients were included in our study. The chi-squared test and Student’s t-test were used to assess the difference between OM and any other metastasis (NOM). Receiver operating curve (ROC) was used to analyze the diagnostic value of serum biomarkers in HCC patients with OM.Results: The incidence of OM in HCC patients was 1.88% in our research. There are no significant differences in age, gender, or histopathology in the OM group and the group without any metastasis. Binary logistic regression analysis presented that compared with the patients without cancer metastasis, carbohydrate antigen 125 (CA-125) and hemoglobin (Hb) were risk factors in hepatocellular carcinoma patients with OM (P < 0.05). The ROC curve analysis showed that the areas under the CA-125, Hb, and CA125+Hb curves were 0.877, 0.554, and 0.431, and the cutoff values of CA-125 and Hb each were 115.78 u/mL and 120.50 g/L.Conclusion: Our data suggest that CA-125 and Hb are risk indicators in hepatocellular carcinoma patients with OM, and that CA-125+Hb has potentially greater utility in diagnosing hepatocellular carcinoma.Keywords: hepatocellular carcinoma, ocular metastases, CA-125, Hb, risk factors

Electrospinning is a simple, low-cost, and highly efficient technique to generate desirable nano/microfibers from polymer solutions. Silk fibroin (SF), a biopolymer found in Bombyx mori cocoons, has attracted attention for various biomedical applications. In this study, functionalized CNT was incorporated in SF to generate biocomposite fibers by electrospinning. The electrospun (E-spun) fibers were well aligned with morphology mimicking the locally oriented ECM proteins in connective tissues. While as-spun fibers dissolved in water in just two minutes, ethanol vapor post-treatment promoted β-sheet formation leading to improved fiber stability in an aqueous environment (>14 days). The addition of a minute amount of CNT effectively improved the E-spun fiber alignment and mechanical strength while retained high biocompatibility and biodegradability. The fibers’ electrical conductivity increased by 13.7 folds and 21.8 folds, respectively, in the presence of 0.1 w% and 0.2 w% CNT in SF fibers. With aligned SF-CNT 0.1 % fibers as a cell culture matrix, we found electrical stimulation effectively activated fibroblasts from patients of pelvic organ prolapse (POP), a connective tissue disorder. The stimulation boosted the fibroblasts’ productivity of collagen III (COLIII) and collagen I (COLI) by 74 folds and 58 folds, respectively, and reduced the COLI to COLIII ratio favorable for tissue repair. The developed material and method offer a simple, direct, and effective way to remedy the dysfunctional fibroblasts of patients for personalized cell therapeutic treatment of diseases and health conditions associated with collagen disorder.

Fibrillar collagen is a one-dimensional biopolymer and is the most abundant structural protein in the extracellular matrix (ECM) of connective tissues. Due to the unique properties of carbon nanotubes (CNTs), considerable attention has been given to the application of CNTs in developing biocomposite materials for tissue engineering and drug delivery. When introduced to tissues, CNTs inevitably interact and integrate with collagen and impose a discernible effect on cells in the vicinity. The positive effect of the collagen-CNT (COL-CNT) matrix in tissue regeneration and the cytotoxicity of free CNTs have been investigated extensively. In this study, we aimed to examine the effect of COL-CNT on mediating the interaction between the matrix and SKOV3 ovarian cancer cells. We generated unidirectionally aligned collagen and COL-CNT nanofibrils, mimicking the structure and dimension of collagen fibrils in native tissues. AFM analysis revealed that the one-dimensional structure, high stiffness, and low adhesion of COL-CNT greatly facilitated the polarization of SKOV3 cells by regulating the β-1 integrin-mediated cell–matrix interaction, cytoskeleton rearrangement, and cell migration. Protein and gene level analyses implied that both collagen and COL-CNT matrices induced the epithelial–mesenchymal transition (EMT), and the COL-CNT matrix prompted a higher level of cell transformation. However, the induced cells expressed CD44 at a reduced level and MMP2 at an increased level, and they were responsive to the chemotherapy drug gemcitabine. The results suggested that the COL-CNT matrix induced the transdifferentiation of the epithelial cancer cells to mature, less aggressive, and less potent cells, which are inapt for tumor metastasis and chemoresistance. Thus, the presence of CNT in a collagen matrix is unlikely to cause an adverse effect on cancer patients if a controlled dose of CNT is used for drug delivery or tissue regeneration.

Abstract Background The relationship between thyroid hormone (TH) levels in vivo and osteoarthritis (OA) remains inconclusive. This study aims to investigate the association between TH levels and OA, analyze the effect of triiodothyronine on hypertrophic chondrocyte differentiation and OA progression, and identify potential target genes of triiodothyronine in OA to evaluate its diagnostic value. Methods Two-sample mendelian randomization method was used to probe the causal links between hyperthyroidism and OA. Differentially expressed genes (DEGs) from two RNA-sequencing data in Gene Expression Omnibus (GSE199847 and GSE114007) and enrichment analysis of DEGs (166 commonly upregulated genes and 71 commonly downregulated genes of GSE199847 and GSE114007) was performed to analyze the effect of triiodothyronine (T3) on hypertrophic chondrocyte differentiation and OA. C28/I2 cells treated with T3 and reverse transcription and quantitative real-time polymerase chain reaction were used to validate T3 targeted genes. The diagnostic performance of target genes was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). Results There was a positive causal association between hyperthyroidism and OA (IVW result, OR = 1.330, 95% CI 1.136–1.557, P = 0.0004). Weighted median and Weighted mode analysis also demonstrated that hyperthyroidism had a positive causal association with OA (p 1). Bioinformatics analysis indicated T3 can partially induce the emergence of late hypertrophic chondrocyte and promote OA through extracellular matrix organization, blood vessel development, skeletal system development and ossification. Post-T3 treatment, MAFB, C1QTNF1, COL3A1 and ANGPTL2 were significantly elevated in C28/I2 cells. ROC curves in GSE114007 showed that AUC of all above genes were ≥ 0.7. Conclusions This study identified that hyperthyroidism has a positive causal association with OA by MR analysis. T3 induced hypertrophic chondrocytes promote OA progression by upregulating genes such as MAFB, C1QTNF1, COL3A1 and ANGPTL2, which can also serve as OA diagnosis.

Current cytotoxic T lymphocyte (CTL) activating immunotherapy requires a major histocompatibility complex I (MHC-I)-mediated presentation of tumor-associated antigens, which malfunctions in around half of patients with triple-negative breast cancer (TNBC). Here, we create a LCL161-loaded macrophage membrane decorated nanoparticle (LMN) for immunotherapy of MHC-I-deficient TNBC. SIRPα on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161, which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells. The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds. LMNs also block CD47-mediated phagocytosis suppression. LMNs inhibit the growth of MHC-I-deficient TNBC tumors, as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel, and prolong the survival of animals, during which process CTLs also play important roles. This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.

Abstract Background Peritoneal dialysis (PD) and conventional in‐center hemodialysis (HD) are treatment options for patients with end‐stage kidney disease (ESKD). However, their impact on all‐cause mortality is unclear. Methods We conducted a multicenter, open‐label, randomized, non‐inferiority trial to determine the effect of dialysis modality on mortality in patients with ESKD. Eligible patients were recruited from 30 sites across China and assigned to receive either PD or HD in a ratio of 1:1. The primary outcome was all‐cause mortality. Non‐inferiority was defined as the upper bound of the one‐sided 95% confidence interval (CI) for the hazard ratio (HR) being ≤1.25. Results A total of 414 patients with incident ESKD were randomly assigned to PD (n = 213) or HD (n = 201). During a median follow‐up of 1.7 years, 37 patients in the PD group and 31 in the HD group died, giving respective event rates per patient‐year of 0.061 and 0.071. The HR for mortality on PD in comparison with HD was 0.76 (95% CI 0.47–1.24) after adjustment for age, sex, and diabetes status, achieving the limit for non‐inferiority. There were more adverse events (p = 0.003), serious adverse events (p = 0.009), and adverse events leading to hospitalization (p = 0.003) in the PD group than in the HD group; however, there was no significant between‐group difference in adverse events leading to death or discontinuation of treatment. Conclusions PD was non‐inferior to conventional in‐center HD in terms of survival in patients with ESKD. Our findings underscore the need for shared decision‐making between physicians and patients regarding the selection of dialysis modality. Trial registration Registered at ClinicalTrials.gov (NCT01413074).

To report a case of staged surgical excision of giant porokeratosis. A 54-year-old man had been seeking medical attention for 29 years due to an itchy purplish-red spot on the right upper abdomen. Dermatological examination revealed a well-defined round purplish-red patch, approximately 15 cm×15 cm, with rough keratinization and few attached scales on the surface. Brown color was observed around the lesion without any noticeable elevation, erosion or exudation. Histopathological analysis showed hyperkeratosis and parakeratosis, loss of granular layers, irregular thickening of the stratum spinosum, superficial dermal vasodilation and perivascular infiltration of mononucleated cells along with melanophages. Dermoscopy revealed dark red background with clear boundaries, whitish peripheral rim and linear vessels, focal hypopigmentation, comma-like vessels at center, as well as thickened yellow scales in the surrounding area. Diagnosis was porokeratosis of Mibelli. The skin lesion was surgically removed using a staged excision method over four stages, resulting in successful healing without recurrence during one-year follow-up.

Electrospinning is a simple, low-cost, and highly efficient technique to generate desirable nano/microfibers from polymer solutions. Silk fibroin (SF), a biopolymer found in Bombyx mori cocoons, has attracted attention for various biomedical applications. In this study, functionalized CNT was incorporated in SF to generate biocomposite fibers by electrospinning. The electrospun (E-spun) fibers were well aligned with morphology mimicking the locally oriented ECM proteins in connective tissues. While as-spun fibers dissolved in water in just two minutes, ethanol vapor post-treatment promoted β-sheet formation leading to improved fiber stability in an aqueous environment (>14 days). The addition of a minute amount of CNT effectively improved the E-spun fiber alignment and mechanical strength while retained high biocompatibility and biodegradability. The fibers' electrical conductivity increased by 13.7 folds and 21.8 folds, respectively, in the presence of 0.1 w% and 0.2 w% CNT in SF fibers. With aligned SF-CNT 0.1 % fibers as a cell culture matrix, we found electrical stimulation effectively activated fibroblasts from patients of pelvic organ prolapse (POP), a connective tissue disorder. The stimulation boosted the fibroblasts' productivity of collagen III (COLIII) and collagen I (COLI) by 74 folds and 58 folds, respectively, and reduced the COLI to COLIII ratio favorable for tissue repair. The developed material and method offer a simple, direct, and effective way to remedy the dysfunctional fibroblasts of patients for personalized cell therapeutic treatment of diseases and health conditions associated with collagen disorder. [ABSTRACT FROM AUTHOR]

Notch signaling pathway is activated abnormally in solid and hematological tumors, which perform essential functions in cell differentiation, survival, proliferation, and angiogenesis. The activation of Notch signaling and communication among Notch and other oncogenic pathways heighten malignancy aggressiveness. Thus, targeting Notch signaling offers opportunities for improved survival and reduced disease incidence. Already, most attention has been given to its role in the cancer cells. Recent research shows that natural bioactive compounds can change signaling molecules that are linked to or interact with the Notch pathways. This suggests that there may be a link between Notch activation and the growth of tumors. Here, we sum up the natural bioactive compounds that possess inhibitory effects on human cancers by impeding the Notch pathway and preventing Notch crosstalk with other oncogenic pathways, which provoke further study of these natural products to derive rational therapeutic regimens for the treatment of cancer and develop novel anticancer drugs. This review revealed Notch as a highly challenging but promising target in oncology.

Objective Irrigation is a conventional treatment for acute and chronic periprosthetic joint infections (PJI). However, there has been no unified standard for irrigation during surgery for PJI in the past, and the efficacy is uncertain. The purpose of this study is to create a new irrigation protocol to enhance the infection control rate and reduce the postoperative recurrence rate of PJI patients. Methods We conducted a single‐institution retrospective review with a total of 56 patients who underwent revision total hip or knee arthroplasties due to PJI from January 2011 to January 2022. Conventional irrigation (CI) was used in 32 cases, and standard operating procedure of irrigation (SOPI) was used in 24. The CI protocol carries out an empirical irrigation after debridement, which is quite random. Our SOPI protocol clearly stipulates the soaking concentration and time of hydrogen peroxide and povidone‐iodine. The irrigation is carried out three times, and tissue samples are taken from multiple parts before and after irrigation, which are sent for microbial culture. The important statistical indicators were the rate of positive microbiological culture and postoperative recurrence rate with an average follow‐up of 24 average months. Results The drainage volume was lower in the SOPI group than in the CI group on postoperative day 3 (p

Abstract Environmental regulations are important means to influence manufacturing enterprise green development. However, there are two completely different conclusions both in theoretical and in empirical research, namely the “Follow Cost” theory and the “Porter Hypothesis”. The nonlinear mechanism needs to be considered. Therefore, this study aims to explain the threshold impact of heterogeneous environmental regulations on enterprise green total factor productivity. Environmental regulations are divided into different sub-categories, then based on the panel data of 1220 Chinese manufacturing listed companies from 2011 to 2020, this paper uses threshold regression model to examine the impact of heterogeneous environmental regulations on Chinese manufacturing enterprise Green Total Factor Productivity. The empirical results show that: (1) Command-controlled, market-incentive and voluntary-agreement environmental regulation all have a significant nonlinear impact on enterprise Green Total Factor Productivity. (2) Enterprise R&D investment plays a threshold role in the impact. (3) There are industry and equity type differences in the impact process. This study focuses on the micro level of enterprises and tests the threshold mechanism, which make some theoretical complement to previous researches. The research results are not only beneficial for the government to propose appropriate environmental regulatory policies, but also for enterprises to achieve green growth through heterogeneous R&D investment.

The Burgers-KdV equation as a highly nonlinear model, is commonly used in weakly nonlinear analysis to describe small but finite amplitude ion-acoustic waves. In this study, we demonstrate that by considering viscous dissipation, we can derive the Burgers-KdV limit from a one-dimensional plasma system by using the Gardner-Morikawa transformation. This transformation allows us to obtain both homogeneous and inhomogeneous Burgers-KdV equations, which incorporate dissipative and dispersive terms, for the ionic acoustic system. To analyze the remaining system, we employ the energy method in Sobolev spaces to estimate its behavior. As a result, we are able to capture the Burgers-KdV dynamics over a time interval of order $ O(\varepsilon^{-1}) $, where $ \varepsilon $ represents a small parameter.

AbstractA new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski’s rule of five.

Shrub encroachment in grassland has become an ecological issue of mounting concern. Accordingly, an accurate estimation of aboveground biomass (AGB) of shrub vegetation is the basis for a sound assessment and in-depth understanding of carbon cycling in shrub-encroached grassland ecosystems. Yet the relatively low stature of plants in the shrub community, coupled with the high spatial heterogeneity of their distribution, contributes substantially to greater uncertainty in remote sensing estimation of shrub vegetation’s AGB. This study proposes a space–air-ground integrated approach to accurately estimate the AGB of shrub vegetation in shrub-encroached grassland ecosystems. The results showed that, at the UAV scale, the estimation of AGB for a monoculture shrub was highly dependent on planar geometric features. Based on the orthorectified images obtained from unmanned aerial vehicles (UAVs), four planar geometric features of shrub plants, namely crown area (S), crown perimeter (C), long-to-short crown dimension ratio (A1, A2), were retained as the most crucial predictors for AGB estimation. Among the 102 features related to vertical structure extracted via Light Detection and Ranging (LiDAR), only the crown height variation and the first layer’s density variable were retained. Utilizing the mentioned features and a random forest regression, the AGB prediction model for the shrub Caragana microphylla performed remarkably well, in having an R2 value of 0.84 and an RMSE of 310.14 g/plant. At the satellite scale, there was significant nonlinear relationship between the AGB of the shrubs and the band, texture, and index features extracted from GF-6 imagery. The derived AGB estimation model based on the Random Forest method demonstrates higher accuracy (R2 = 0.81, RMSE = 14.61 g/m2, MAE = 11.26 g/m2) than the linear stepwise regression (SR) and partial least squares regression (PLSR) models. Notably, the green band reflectance was retained in all three modeling approaches despite pronounced differences in their selected features uses. Yet both NDVIre1 and NDREI indices with red-edge bands were more important, suggesting the red-edge bands of GF-6 can serve as an ideal tool for remote sensing investigations of the AGB of shrub in shrub-encroached grasslands. This study provides technical and scientific support for quantitative assessments of shrub AGB in arid and semi-arid grassland regions.

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

BackgroundAlthough there is solid epidemiological evidence supporting the connection between hypertension and gout, little has been said about the relationship between diastolic and systolic blood pressure and gout, the causal relationship and direction associated are uncertain, so we aim to research the causal relationship between diastolic and systolic blood pressure and gout.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect between 2 blood pressure phenotypes (including diastolic blood pressure and systolic blood pressure) and 5 gout phenotypes (including gout, drug-induced gout, idiopathic gout, unspecified gout, and strictly defined gout) using genome-wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR-Egger, weighted median, Cochran’s Q test, Egger intercept test, and leave-one-out analysis, were performed to assess the stability and reliability of the results.ResultsAfter the screening, we found a causal relationship between diastolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout, and a causal relationship between systolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout.ConclusionFrom a genetic predisposition, controlling blood pressure may reduce the risk of gout.

BackgroundNowadays, e-learning significantly affects college students’ academic life. This study aims to examine the factors that influence college students’ satisfaction with online learning outcomes.MethodThe study population consisted of undergraduate students from Dalian Medical University, with a total of 715 college students participating in the study. Out of these participants, 602 valid questionnaires were obtained. Demographic data was analyzed using SPSS.22, and the data was cleaned and prepared for testing the research hypotheses. The proposed research framework was examined using structural equation modeling (SEM) through Smart-PLS 3.0.ResultsThe results of the study showed that student satisfaction with learning outcomes was positively correlated with several factors: quality of teacher instruction (β = 0.100, p