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Cancer immunotherapy is a groundbreaking medical revolution and a paradigm shift from traditional cancer treatments, harnessing the power of the immune system to target and destroy cancer cells. In recent years, DNA nanostructures have emerged as prominent players in cancer immunotherapy, exhibiting immense potential due to their controllable structure, surface addressability, and biocompatibility. This review provides an overview of the various applications of DNA nanostructures, including scaffolded DNA, DNA hydrogels, tetrahedral DNA nanostructures, DNA origami, spherical nucleic acids, and other DNA-based nanostructures in cancer immunotherapy. These applications explore their roles in vaccine development, immune checkpoint blockade therapies, adoptive cellular therapies, and immune-combination therapies. Through rational design and optimization, DNA nanostructures significantly bolster the immunogenicity of the tumor microenvironment by facilitating antigen presentation, T-cell activation, tumor infiltration, and precise immune-mediated tumor killing. The integration of DNA nanostructures with cancer therapies ushers in a new era of cancer immunotherapy, offering renewed hope and strength in the battle against this formidable foe of human health., (© 2024 Wiley‐VCH GmbH.)

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive and highly lethal cancer with an increasing incidence worldwide that lacks effective treatment regimens. Hypocrellin A (HA), a natural small compound isolated from S. bambusicola, has multiple biomedical activities, including antitumor activity., Purpose: We intended to investigate the therapeutic effects of HA on ICC and its potential mechanisms., Methods: RBE and HuccT1 cell lines were utilized for in vitro experiments. CCK8 assay, colony formation analysis, RTCA, and immunofluorescence staining of ki67 were employed to evaluate the suppression effects of HA on proliferation. The inhibitory effects of HA on cell migration and invasion were evaluate through transwell and wound healing assays, and Hoechst 33,258 staining was performed to evaluate apoptosis. Additionally, we performed transcriptome sequencing and molecular docking for targeting identification, and immunoblotting and immunofluorescence of key molecules for validation. Two in vivo models, HuccT1 xenografts, and the primary ICC model (KRAS/P19/SB) established via hydrodynamic tail-vein injection were implemented. Multiplex immunohistochemistry (mIHC) was used to illustrate the multi-target inhibitory effects of HA., Results: The IC50 values of HA against RBE and HuccT1 cells were 4.612 μM and 10.01 μM for 24 h, as determined through the CCK8 assay. Our results confirmed that HA significantly repressed the proliferation, migration, invasion, and promoted the apoptosis of ICC cells at low concentrations. Moreover, HA exerted its anti-cancer effects through multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. This inhibitory effect was rescued by Recilisib, an activator of the PI3K-AKT-mTOR pathway. Bioinformatics analysis of a multi-center RNA-Seq cohort (n = 90) demonstrated significant associations between these target pathways and the occurrence and poor prognosis of ICC. Animal studies suggested that HA strongly inhibited tumor growth in xenograft ICC models, and repressed the tumor number and size in the liver of primary ICC models by suppressing these three crucial pathways., Conclusion: HA, a novel natural small molecule, demonstrated promising therapeutic efficacy against ICC through its multi-target inhibitory effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in a primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for ICC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Aptamers have been widely researched and applied in nanomedicine due to their programmable, activatable, and switchable properties. However, there are few reviews on aptamer-controlled stimuli-responsive drug delivery. This article highlights the mechanisms and advantages of aptamers in the construction of stimuli-responsive drug delivery systems. We summarize the assembly/reconfiguration mechanisms of aptamers in controlled release systems. The assembly and drug release strategies of drug delivery systems are illustrated. Specifically, we focus on the binding mechanisms to the target and the factors that induce/inhibit the binding to the stimuli, such as strand, pH, light, and temperature. The applications of aptamer-based stimuli-responsive drug release are elaborated. The challenges are discussed, and the future directions are proposed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Dichoptic training has emerged as a promising rehabilitation approach for improving binocular visual function in patients with strabismus. A prospective observational study design was employed to assess the effectiveness of online video game-based dichoptic training in rehabilitating binocular visual function in patients who had undergone an operation for intermittent exotropia., Methods: A total of 64 patients who had undergone an operation for intermittent exotropia were recruited and divided into the training group and the control group based on whether they would receive the dichoptic training. The dichoptic training was conducted for 3 months in the training group and the control group would not accept any form of orthoptic therapy. Assessments of binocular visual functions and deviation were conducted at baseline, 3-month and 6-month follow-up., Results: Twenty-nine participants in the training group (mean 9.69 ± 2.66 years old) and 26 participants in the control group (mean 8.41 ± 2.64 years old) completed follow-up. At both 3- and 6-month follow-ups, the training group showed superior distance stereopsis compared to the control group, with near stereopsis only showing significant difference at the 6-month follow-up. Additionally, the training group exhibited significantly less distance exo-deviation drift than the control group at these times, and no significant difference was observed in near exo-deviation drift between the groups. The control group had a significantly higher rate of suboptimal surgical outcomes at both the 3- and 6-month follow-up. However, no significant differences were observed in simultaneous perception and fusion functions between the two groups., Conclusions: Online video game-based dichoptic training has the potential to become a novel postoperative rehabilitation strategy for patients with intermittent exotropia., (© 2024. The Author(s).)

Background: Mitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied., Methods: RNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses., Results: Two hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817-0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4 + T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry., Conclusion: We found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Lu, Chen, Zou, Bo, Li, Zhao, Zhao, Yu, Chen and Wu.)

Objective: This study examines the C-reactive protein (CRP)/albumin ratio (CAR) as an inflammation-based prognostic score for predicting mortality in patients with Traumatic Brain Injury (TBI)., Methods: We systematically searched the electronic databases PubMed, Embase, and Cochrane up to February 2024. Our inclusion criteria encompassed studies investigating CAR-predicted mortality in patients with TBI. We calculated the Odds Ratio (OR) and associated 95 % confidence intervals (95 % CI) using a random-effects model. Quality assessment of the included studies was appraised using a Newcastle-Ottawa scale., Results: A total of five studies comprising 1040 patients were included in this meta-analysis. The pooled results indicated that CAR was associated with mortality in patients with TBI (OR = 1.88, 95 % CI: 1.05-3.36, P < 0.0001). The findings of subgroup analysis indicated that the relationship between CAR and mortality in patients with TBI did not vary with the severity of the condition., Conclusions: CAR emerges as a valuable prognostic tool for mortality in patients with TBI, underscoring its potential role in early risk stratification and management strategies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The structure of samoquasine A has long been a subject of controversy, which was resolved only upon its successful total synthesis. We examined the structures of the associated compounds using the state-of-the-art SVM-M protocol. The method accurately discriminated all putative structures historically attributed to samoquasine A from a pool of 48 isomeric structures, confirming that samoquasine A is indeed identical to perlolidine. Furthermore, by applying the SVM-M protocol to an additional pool of 67 isomeric structures, we successfully assigned a yet unknown natural product, initially misidentified as perlolidine, as a novel oxime, ( E )-3 H -cyclopenta[ c ]quinolin-3-one oxime, representing the first reported cyclone oxime-quinoline natural product.

Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential., (© 2024. The Author(s).)

In order to reduce the sensitization of walnut protein (WP), the effects of the interaction between WP and (-)-Epigallocatechin gallate (EGCG), quercetin, trans-ferulic acid, and resveratrol were investigated. Covalent and non-covalent conjugations were compared. The results suggested that covalent conjugation reduced the free amino acid content, sulfhydryl content, and surface hydrophobicity. When compared to non-covalent conjugation, covalent modification showed a lower IgE binding capacity, accompanied by changes in protein conformation. Moreover, animal experiments revealed that there were up-regulation of transforming growth factor-β, T-box expressed in t cells, and forkhead transcription factor Foxp3 mRNA expression, and down-regulation of IL-4, IL-17, GATA binding protein 3 and retinoid-related orphan nuclear receptor γt mRNA expression in the conjugate groups. These results suggested that covalent conjugation of polyphenols, especially EGCG, likely ameliorated allergy by promoting Th1/Th2 and Treg/Th17 balance and alleviating allergy-induced intestinal barrier damage, which might be a support in reducing the allergenicity of WP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The next-generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T-ALL and B-ALL. In B-ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co-occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3-year RFS rates for the RAS signaling pathway mutation-positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation-positive. RAS signaling pathway mutation is an important biomarker for poorer relapse-free survival in pediatric B-ALL patients despite good early MRD levels., (© 2024 John Wiley & Sons Ltd.)

Background: Dental caries in young children is a difficult global oral health problem. In the last decade, China has put a great deal of effort into reducing the prevalence of dental caries. This study, which is part of the China Population Chronic Disease and Nutrition Surveillance 2021, aimed to investigate the prevalence of dental caries among children aged 5 in Shanghai, China, and its associated factors., Methods: A total of 1281 children aged 5 years from 6 districts in Shanghai were selected by a stratified sampling method. The survey consisted of an oral health questionnaire and an oral health examination. The questionnaire included questions on oral health knowledge, attitudes, and behaviours. The oral health examination used WHO standards. After screening, the data were input and analysed. Chi-square tests and logistic regression analyses were used to study the relevant factors affecting dental caries., Results: The prevalence of dental caries among 1281 children was 51.0%, the dmft index score was 2.46, the Significant Caries Index (SiC) score was 6.39, and the SiC10 score was 10.35. Dental caries experience was related to the frequency of sweet drink consumption, the age of starting tooth brushing, eating habits after brushing, whether the children had received an oral examination provided by the government (p < 0.05), and the mother's education level but was not related to sex, the use of fluoride toothpaste, the frequency of brushing, whether the parents assisted brushing, or the frequency of flossing (p > 0.05). Logistic regression analysis showed that the region of residence, eating after brushing and the age of starting brushing were associated with dental caries., Conclusions: Dental caries remained prevalent among 5-year-old children in Shanghai, China. Prevention strategies that target the associated factors including region of residence, eating after brushing, and the age of starting brushing should be considered., (© 2024. The Author(s).)

Purpose: To evaluate the short-term (1 week after completion of treatment) effect of office-based vergence and anti-suppression therapy (OBVAT) on the Office Control Score when compared to observation alone in children with small-to-moderate angle intermittent exotropia (IXT)., Methods: In this single-masked (examiner masked), two-arm, single-centre randomised clinical trial, 40 participants, 6 to <18 years of age with untreated IXT, were randomly assigned to OBVAT or observation alone. Participants assigned to therapy received 60 min of OBVAT with home reinforcement once per week for 16 weeks. Therapy included vergence, accommodation and anti-suppression techniques. The primary outcome measure was the comparison of the distance Office Control Score between the two groups at the primary outcome visit (i.e., 17-week follow-up visit)., Results: At the primary outcome visit, the OBVAT group (n = 20) had a significantly better distance Office Control Score (adjusted mean difference: -0.9; 95% CI: -0.2 to -1.5; p = 0.008; partial eta squared: 0.19) than the observation group (n = 16). Participants from the OBVAT group were more likely than those from the observation group to have ≥1 point of improvement at the 17-week visit (OBVAT group: 75%; Observation group: 25%; p = 0.006)., Conclusions: In this randomised clinical trial of participants aged 6 to <18 years with IXT, we found that the OBVAT group had a significantly better distance Office Control Score than the observation group at the 17-week visit. This study provides the first data from a randomised clinical trial demonstrating the effectiveness of OBVAT for improving the control of IXT. Eye care practitioners should consider OBVAT as a viable, non-surgical treatment option for IXT. A full-scale randomised clinical trial investigating the long-term effectiveness of OBVAT in treating IXT is warranted., (© 2023 College of Optometrists.)

Background: How colorectal cancer (CRC) gain the ability to growth and metastasis remains largely unknown. Findings from preceding studies have revealed the participation of long non-coding RNAs (lncRNAs) in CRC progression. However, the role of LINC01977 in CRC remains unexplored. This study aims to explore the function and underlying mechanism of LINC01977 in CRC., Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to analyze the expression of LINC01977 in CRC and its correlation with CRC prognosis. In our research, we explored the influence of LINC01977 on CRC progression such as cell proliferation, migration, invasion, and aerobic glycolysis, and identified its fundamental molecular mechanism using in vitro CRC cell lines and in vivo mouse xenograft models., Results: LINC01977 exhibited significantly elevated expression in CRC tissues and cell lines, and its level was significantly correlated with malignant clinicopathological characteristics and negative prognosis. Furthermore, both in vivo and in vitro tests revealed LINC01977's role in facilitating CRC cell proliferation and metastasis. LINC01977's significant part in CRC aerobic glycolysis was also discovered. With an aim to uncover the underlying mechanism, we investigated LINC01977's effect on c-Myc, a key gene in glycolysis. The results showed that LINC01977 regulated c-Myc stability via extracellular signal-regulated kinase (ERK)-mediated phosphorylation, and LINC01977-mediated c-Myc activated the level of vital glycolysis-related genes such as HK2, PGK1, LDHA , and GLUT1 . Rescue experiments further confirmed that LINC01977 promoted CRC proliferation, metastasis, and aerobic glycolysis via c-Myc., Conclusions: This study is the first to report that LINC01977 facilitates CRC proliferation, metastasis, and aerobic glycolysis through c-Myc, suggesting its potential as a therapeutic target for CRC treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-52/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Excessive accumulation of reactive oxygen species (ROS) can lead to oxidative stress and oxidative damage, which is one of the important factors for aging and age-related diseases. Therefore, real-time monitoring and the moderate elimination of ROS is extremely important. In this study, a ROS-responsive circular dichroic (CD) at 553 nm and magnetic resonance imaging (MRI) dual-signals chiral manganese oxide (MnO 2 ) nanoparticles (NPs) are designed and synthesized. Both the CD and MRI signals show excellent linear ranges for intracellular hydrogen peroxide (H 2 O 2 ) concentrations, with limits of detection (LOD) of 0.0027 nmol/10 6 cells and 0.016 nmol/10 6 cells, respectively. The lower LOD achieved with CD detection may be attributable to its higher anti-interference capability from the intracellular matrix. Importantly, ROS-induced cell aging is intervened by chiral MnO 2 NPs via redox reactions with excessive intracellular ROS. In vivo experiments confirm that chiral MnO 2 NPs effectively eliminate ROS in skin tissue, reduce oxidative stress levels, and alleviate skin aging. This approach provides a new strategy for the diagnosis and treatment of age-related diseases., (© 2023 Wiley-VCH GmbH.)

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening disease without an effective drug at present. Fibroblast growth factor 21 (FGF21) was reported to be protective against inflammation in metabolic disease in recent studies. However, the role of FGF21 in ALI has been rarely investigated. In this study, it was found that the expression of FGF21 was markedly increased in lung tissue under lipopolysaccharide (LPS) stimulation in vivo, whereas it was decreased in lung epithelial cells under LPS stimulation in vitro. Therefore, our research aimed to elucidate the potential role of FGF21 in LPS-induced ALI and to detect possible underlying mechanisms. The results revealed that the deficiency of FGF21 aggravated pathological damage, inflammatory infiltration, and pulmonary function in LPS-induced ALI, while exogenous administration of FGF21 improved these manifestations. Moreover, through RNA sequencing and enrichment analysis, it was unveiled that FGF21 might play a protective role in LPS-induced ALI via JAK2/STAT3 signaling pathway. The therapeutic effect of FGF21 was weakened after additional usage of JAK2 activator in vivo. Further investigation revealed that FGF21 significantly inhibited STAT3 phosphorylation and impaired the nuclear translocation of STAT3 in vitro. In addition, the aggravation of inflammation caused by silencing FGF21 can be alleviated by JAK2 inhibitor in vitro. Collectively, these findings unveil a potent protective effect of FGF21 against LPS-induced ALI by inhibiting the JAK2/STAT3 pathway, implying that FGF21 might be a novel and effective therapy for ALI., (© 2023. The Author(s).)

Backgrounds and Aims: Immunotherapies have formed an entirely new treatment paradigm for hepatocellular carcinoma (HCC). Tertiary lymphoid structure (TLS) has been associated with good response to immunotherapy in most solid tumors. Nonetheless, the role of TLS in human HCC remains controversial, and recent studies suggest that their functional heterogeneity may relate to different locations within the tumor. Exploring factors that influence the formation of TLS in HCC may provide more useful insights. However, factors affecting the presence of TLSs are still unclear. The human gut microbiota can regulate the host immune system and is associated with the efficacy of immunotherapy but, in HCC, whether the gut microbiota is related to the presence of TLS still lacks sufficient evidence., Methods: We performed pathological examinations of tumor and para-tumor tissue sections. Based on the location of TLS in tissues, all patients were divided into intratumoral TLS (It-TLS) group and desertic TLS (De-TLS) group. According to the grouping results, we statistically analyzed the clinical, biological, and pathological features; preoperative gut microbiota data; and postoperative pathological features of patients., Results: In a retrospective study cohort of 60 cases from a single center, differential microbiota analysis showed that compared with the De-TLS group, the abundance of Lachnoclostridium, Hungatella, Blautia, Fusobacterium, and Clostridium was increased in the It-TLS group. Among them, the enrichment of Lachnoclostridium was the most significant and was unrelated to the clinical, biological, and pathological features of the patients. It can be seen that the difference in abundance levels of microbiota is related to the presence of TLS., Conclusion: Our findings prove the enrichment of Lachnoclostridium-dominated gut microbiota is associated with the presence of It-TLS in HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Li, Chen, Zhao, Hu, Huang, Chen, Yao, Lin, Bao, Lu, Wang, Chen and Wu.)

Background: Even after curative resection, the prognosis for patients with intrahepatic cholangiocarcinoma (iCCA) remains disappointing due to the extremely high incidence of postoperative recurrence., Methods: A total of 280 iCCA patients following curative hepatectomy from three independent institutions were recruited to establish the retrospective multicenter cohort study. The very early recurrence (VER) of iCCA was defined as the appearance of recurrence within 6 months. The 3D tumor region of interest (ROI) derived from contrast-enhanced CT (CECT) was used for radiomics analysis. The independent clinical predictors for VER were histological stage, AJCC stage, and CA199 levels. We implemented K-means clustering algorithm to investigate novel radiomics-based subtypes of iCCA. Six types of machine learning (ML) algorithms were performed for VER prediction, including logistic, random forest (RF), neural network, bayes, support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost). Additionally, six clinical ML (CML) models and six radiomics-clinical ML (RCML) models were developed to predict VER. Predictive performance was internally validated by 10-fold cross-validation in the training cohort, and further evaluated in the external validation cohort., Results: Approximately 30 % of patients with iCCA experienced VER with extremely discouraging outcome (Hazard ratio (HR) = 5.77, 95 % Confidence Interval (CI) = 3.73-8.93, P < 0.001). Two distinct iCCA subtypes based on radiomics features were identified, and subtype 2 harbored a higher proportion of VER (47.62 % Vs 25.53 %) and significant shorter survival time than subtype 1. The average AUC values of the CML and RCML models were 0.744 ± 0.018, and 0.900 ± 0.014 in the training cohort, and 0.769 ± 0.065 and 0.929 ± 0.027 in the external validation cohort, respectively., Conclusion: Two radiomics-based iCCA subtypes were identified, and six RCML models were developed to predict VER of iCCA, which can be used as valid tools to guide individualized management in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Barrett's esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC), with approximately 3-5% of patients developing EAC. Cuproptosis is a kind of programmed cell death phenomenon discovered in recent years, which is related to the occurrence and development of many diseases. However, its role in BE and EAC is not fully understood. We used single sample Gene Set Enrichment Analysis (ssGSEA) for differential analysis of BE in the database, followed by enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and GSEA, Protein-Protein Interaction (PPI), Weighted Gene Co-expression Network Analysis (WGCNA), Receiver Operating Characteristic Curve (ROC) and finally Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry (IHC) of clinical tissues. Two hub genes can be obtained by intersection of the results obtained from the cuproptosis signal analysis based on BE. The ROC curves of these two genes predicted EAC, and the Area Under the Curve (AUC) values could reach 0.950 and 0.946, respectively. The mRNA and protein levels of Centrosome associated protein E (CENPE) and Shc SH2 domain binding protein 1 (SHCBP1) were significantly increased in clinical EAC tissues. When they were grouped by protein expression levels, high expression of CENPE or SHCBP1 had a poor prognosis. The CENPE and SHCBP1 associated with cuproptosis may be a factor promoting the development of BE into EAC which associated with the regulation of NK cells and T cells.

Solid-state lithium batteries hold great promise for next-generation energy storage systems. However, the formation of lithium filaments within the solid electrolyte remains a critical challenge. In this study, we investigate the crucial role of morphology in determining the resistance of garnet-type electrolytes to lithium filaments. By proposing a new test method, namely, cyclic linear sweep voltammetry, we can effectively evaluate the electrolyte resistance against lithium filaments. Our findings reveal a strong correlation between the microscopic morphology of the solid electrolyte and its resistance to lithium filaments. Samples with reduced pores and multiple grain boundaries demonstrate remarkable performance, achieving a critical current density of up to 3.2 mA cm -2 and excellent long-term cycling stability. Kelvin probe force microscopy and finite element method simulation results shed light on the impact of grain boundaries and electrolyte pores on lithium-ion transport and filament propagation. To inhibit lithium penetration, minimizing pores and achieving a uniform morphology with small grains and plenty of grain boundaries are essential.

Changes in human lifestyles have led to a dramatic increase in the incidence of Crohn's disease worldwide. Predicting the activity and remission of Crohn's disease has become an urgent research problem. In addition, the influence of each attribute in the test sample on the prediction results and the interpretability of the model still deserves further investigation. Therefore, in this paper, we proposed a wrapper feature selection classification model based on a combination of the improved ant colony optimization algorithm and the kernel extreme learning machine, called bIACOR-KELM-FS. IACOR introduces an evasive strategy and astrophysics strategy to balance the exploration and exploitation phases of the algorithm and enhance its optimization capabilities. The optimization capability of the proposed IACOR was validated on the IEEE CEC2017 benchmark test function. And the prediction was performed on Crohn's disease dataset. The results of the quantitative analysis showed that the prediction accuracy of bIACOR-KELM-FS for predicting the activity and remission of Crohn's disease reached 98.98%. The analysis of important attributes improved the interpretability of the model and provided a reference for the diagnosis of Crohn's disease. Therefore, the proposed model is considered a promising adjunctive diagnostic method for Crohn's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Glutathione (GSH) is an abundant metabolite within eukaryotic cells that can act as a signal, a nutrient source, or serve in a redox capacity for intracellular bacterial pathogens. For Francisella, GSH is thought to be a critical in vivo source of cysteine; however, the cellular pathways permitting GSH utilization by Francisella differ between strains and have remained poorly understood. Using genetic screening, we discovered a unique pathway for GSH utilization in Francisella. Whereas prior work suggested GSH catabolism initiates in the periplasm, the pathway we define consists of a major facilitator superfamily (MFS) member that transports intact GSH and a previously unrecognized bacterial cytoplasmic enzyme that catalyzes the first step of GSH degradation. Interestingly, we find that the transporter gene for this pathway is pseudogenized in pathogenic Francisella, explaining phenotypic discrepancies in GSH utilization among Francisella spp. and revealing a critical role for GSH in the environmental niche of these bacteria., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ubiquitin specific peptidase 2a (USP2a) plays critical roles in protein degradation and other cellular activities. Currently, our understanding on USP2a dysregulation in subjects with hepatocellular carcinoma (HCC) and its roles in HCC pathogenesis is limited. In this study, we found that USP2a mRNA and protein levels were significantly upregulated in HCC tumors from both human and mice. USP2a overexpression in HepG2 and Huh 7 cells significantly increased cell proliferation while inhibition of USP2a activity by chemical inhibitor or stable knockout of USP2 by CRISPR markedly reduced cell proliferation. In addition, USP2a overexpression significantly augmented the resistance while knockout of USP2a markedly increased the susceptibility of HepG2 cells to bile acid-induced apoptosis and necrosis. Consistent with the oncogenic activities detected in vitro , overexpression of USP2a promoted de novo HCC development in mice with significantly increased tumor occurrence rates, tumor sizes and liver/body ratios. Further investigations with unbiased co-immunoprecipitation (Co-IP)-coupled proteomic analysis and Western blot identified novel USP2a target proteins involved in cell proliferation, apoptosis, and tumorigenesis. Analysis of those USP2a target proteins revealed that USP2a's oncogenic activities are mediated through multiple pathways, including modulating protein folding and assembling through regulating protein chaperones/co-chaperones HSPA1A, DNAJA1 and TCP1, promoting DNA replication and transcription through regulating RUVBL1, PCNA and TARDBP, and altering mitochondrial apoptotic pathway through regulating VDAC2. Indeed, those newly identified USP2a target proteins were markedly dysregulated in HCC tumors. In summary, USP2a was upregulated in HCC subjects and acted as an oncogene in the pathogenesis of HCC through multiple downstream pathways. The findings provided molecular and pathogenesis bases for developing interventions to treat HCC by targeting USP2a or its downstream pathways., Competing Interests: None., (AJCR Copyright © 2023.)

Residents' low behavioral willingness to dispose of waste in Centralized Collection Points (CCPs) seriously hinders the operational efficiency in waste collection of CCPs regarded as NIMBY ('not in my backyard') facilities. However, fewer researchers notice NIMBY facilities with low hazards. It has been ignored that the NIMBYism may influence behavioral willingness during the operation period persistently. Meanwhile, there is no consistent conclusions on internal factors of waste behavioral willingness, which deserves further study. Therefore, this study took CCPs as a research object and aimed to investigate how NIMBYism influences residents' behavioral willingness to dispose of waste in CCPs. The extended theory of planned behavior and structural equation modeling approach involving 550 respondents were adopted to conduct the analysis. The results revealed that attitude (β = 0.295, p < 0.001), government trust (β = 0.479, p < 0.001), and perceived behavioral control (β = 0.222, p < 0.001) have statistical positive impacts on behavioral willingness to dispose of waste in CCPs. Perceived risk (β = ‒0.047, p = 0.022 < 0.05) can influence behavioral willingness negatively. Additionally, government trust (β = 0.726, p < 0.001) exerts a positive impact on attitude. Furthermore, relevant strategies were proposed to enhance residents' behavioral willingness to dispose of waste in CCPs. This study is expected to inspire the government to formulate policies from the aspects of standards and regulations, resident participation, construction, and publicity. It will provide the government instructive suggestions for the smooth operation of CCPs, and ultimately building a healthy and environment friendly society.

Purpose: To evaluate the reliability of the step vergence method in measuring fusional vergence in subjects with intermittent exotropia., Methods: Thirty-two Chinese participants aged 7-20 years with intermittent exotropia (excluding the convergence insufficiency type) were enrolled in this prospective study. At the eligibility screening, visual acuity, cover test and the Office Control Score were performed. For eligible participants at study visit 1, negative and positive fusional vergence at distance and near, eye dominance and the fusion maintenance test were performed. All eligible participants returned for study visit 2 on the same day (2-4 h later), and the testing was repeated. The primary outcome measures were the intra-class correlation coefficient, coefficient of repeatability and smallest detectable change in the break and recovery points of negative and positive fusional vergence between the two study visits., Results: The intra-class correlation coefficient for different vergence parameters ranged from 0.64 to 0.87. The coefficient of repeatability and the smallest detectable change for the distance positive fusional vergence break point were ±20.5 and 13.1 ∆, respectively. There was no significant difference in any vergence parameter between the first and second visits. The coefficient of repeatability and the smallest detectable change in all distance vergence parameters were high when compared to the mean value. The association between distance vergence parameters and the Office Control Score was significant only when including subjects who failed to fuse at the beginning of the test., Conclusion: The data demonstrate that measurement of fusional vergence with a prism bar has low repeatability in subjects with intermittent exotropia. In these individuals, convergence ability at distance is compromised, whereas other vergence parameters are not adversely affected. While the step vergence method is a valuable test in daily practice, caution is warranted when using it in clinical research., (© 2022 The Authors Ophthalmic and Physiological Optics © 2022 The College of Optometrists.)

Purpose: We aimed to reveal the underlying genetic defect in a multigenerational Chinese family with autosomal dominant concomitant strabismus complicated by multiple ocular developmental abnormalities., Methods: Comprehensive ophthalmic examinations were performed in 14 patients and 24 healthy family members. Whole exome sequencing was performed, and Sanger sequencing was used to confirm the probable mutation in all the family members., Results: Concomitant strabismus was the predominant phenotype in the affected family members, although the patients also exhibited variable phenotypes, including nystagmus, mild iris abnormalities, myopia, cataract, and coloboma. An R208W mutation in PAX6 was identified as the pathogenic mutation in the affected family members., Conclusions: We recommend considering PAX6 as a candidate gene in the diagnostic screen for familial concomitant strabismus in order to avoid missed diagnosis of the mild ocular abnormalities. Careful examinations of mild ocular phenotypes are necessary for an accurate diagnosis of varied ocular abnormalities in the families with the PAX6 mutation, and proper diagnosis can facilitate genetic and clinical counseling for affected patients.

Hollow prism-like NiCo 2 S 4 materials (NiCo 2 S 4 HNPs) were successfully fabricated by a two-step method. Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and powder X-ray diffraction (XRD) confirmed the morphology and structure of the as-prepared NiCo 2 S 4 nanoprisms. A non-enzymatic sensor based on NiCo 2 S 4 HNPs was constructed with outstanding electrochemical activity towards glucose oxidation in alkaline medium. The sensor showed a rapid response time (∼0.1 s), a high sensitivity of 82.9 μA mM -1 cm -2 , a wide linear range (0.005-20.2 mM) and a detection limit of 0.8 μM (S/N = 3) with a good selectivity and reproducibility. Additionally, the proposed electrode also confirmed the feasibility in practical blood serum. These results indicate that NiCo 2 S 4 /ITO has great potential in the development of non-enzymatic glucose sensor applications.

Ubiquitin specific peptidase-2 (USP2) plays important roles in a myriad of cellular activities through deubiquitinating target proteins and its implications in various diseases, especially cancers, are starting to emerge. Our current understanding on USP2 expression in subjects with hepatocellular carcinoma (HCC) and its roles in the pathogenesis of HCC is limited. In this study, we found that USP2 protein and mRNA levels were significantly dysregulated in HCC tumor (HCC-T) when compared to adjacent non-tumor (HCC-NT) or normal liver tissues from both human and mouse HCC model. Among the USP2 isoforms, USP2b was the predominant isoform in the normal liver and markedly down-regulated in HCC-T tissues in both human and mice. Data from overexpression, chemical inhibition and knockout studies consistently demonstrated that USP2b promoted cell proliferation, colony formation and wound healing in HepG2 and Huh 7 cells. On the other hand, USP2b exhibited proapoptotic and pronecrtotic activities through enhancing bile acid-induced apoptosis and necrosis in both HepG2 and Huh 7 cells. Unbiased proteomic analysis of USP2-knockout (KO) and parental HepG2 cells resulted in identification of USP2-regulated downstream target proteins involved in cell proliferation, apoptosis, and tumorigenesis, including serine/threonine kinase 4 (STK4), epidermal growth factor receptor (EGFR), dipeptidyl peptidase 4 (DPP4) and fatty acid binding protein 1 (FABP1). In conclusion, USP2b expression was dysregulated in subjects with HCC and contributed to the pathogenesis of HCC by promoting cell proliferation and exerting proapoptotic and pronecrotic activities. The findings provide the molecular basis for developing therapies for HCC through modulating USP2b expression or activities., Competing Interests: None., (AJCR Copyright © 2021.)

Background: Lp(a) and LDL-C are both risk factors of atherosclerotic cardiovascular disease (ASCVD). But there was a contradiction point in LDL-C and Lp(a) control. The appropriate level of LDL-C and Lp(a) in the prevention of ASCVD is still pending., Objective: To investigate the correlation of Lp(a) and coronary atherosclerotic lesion, and find out the balance point in LDL-C and Lp(a) control., Method: 3449 patients were divided to coronary atherosclerotic heart disease (CAHD) Group and Non-CAHD Group based on the result of coronary angiography. The clinical characteristics were compared, and Logistic regressions were applied to find the CAHD risk factors in total, High-LDL-C Group (LDL-C ≥ 100 mg/dL) and Low-LDL-C Group (LDL-C < 100 mg/dL) patients. Spearman correlation analysis of Lp(a), LDL-C and Gensini Score was performed in patients with different LDL-C concentration., Results: Except male and diabetes, the traditional CAHD risk factors were well matched between two groups. But triglyceride, LDL-C and Lp(a) were higher, HDL-C and Apo-A1 were lower in CAHD group (2771). In the Logistic regression analysis, diabetes, LDL-C and Lp(a) are risk factors of CAHD in all patients, while in High-LDL-C Group, they were age, LDL-C, non-HDL-C and ApoB, in Low-LDL-C Group, they were age, Lp(a) and ApoB. Lp(a) correlated with Gensini with coefficient r = 0.41 in all patients, 0.67 in Low-LDL-C Group and 0.32 in High-LDL-C Group. The coefficient r for Lp(a) and Gensini decreased, while the r for LDL-C and Gensini increased with LDL-C concentration increasing. The two fitted lines of rs crossed at LDL-C = 2.7 mmol/L (104 mg/dL)., Conclusion: Lp(a) was the risk factor of CAHD in patients with LDL-C < 100 mg/dL. The correlation between Lp(a) and Gensini was influenced by LDL-C concentration, and the correlation was stronger than LDL-C when LDL-C < 104 mg/dl.

Purpose: To evaluate the reliability of the Bagolini filter bar and striated lenses for measuring the fusion maintenance score, which is the ability of participants with intermittent exotropia to maintain normal sensorimotor fusion., Methods: Thirty-two Chinese participants aged 7-20 years with intermittent exotropia (excluding the convergence insufficiency type) were enrolled in this prospective study. At the eligibility screening, visual acuity, cover test and assessment of the office control score were performed. At study visit 1, eligible participants underwent negative and positive fusional vergence tests at far and near, eye dominance test and the fusion maintenance test. All eligible participants returned for study visit 2 on the same day (2-4 h later) and the testing was repeated. The primary outcome measure was the intra-class correlation coefficient of the fusion maintenance score between the two study visits., Results: The intra-class correlation coefficient of the fusion maintenance score was 0.84, indicating good reliability. There was no significant difference (mean difference = 0.05, p = 0.95) between the fusion maintenance scores for the first (5.62) and second study visits (5.57). The coefficient of repeatability and the smallest detectable change for the fusion maintenance scores were 7.6 and 6.3, respectively. The fusion maintenance score was significantly associated with the distance (Spearman correlation -0.57, p < 0.001) and near (Spearman correlation -0.4, p = 0.02) office control scores., Conclusion: These data demonstrate that the fusion maintenance score is a reliable tool to evaluate sensorimotor fusion in intermittent exotropia. These results suggest that the fusion maintenance score may be a useful outcome measure in future clinical trials to evaluate the effectiveness of treatments for intermittent exotropia., (© 2020 The Authors Ophthalmic and Physiological Optics © 2020 The College of Optometrists.)

Bending and folding are important stereoscopic geometry parameters of one-dimensional (1D) nanomaterials, yet the precise control of them has remained a great challenge. Herein, a surface-confined winding assembly strategy is demonstrated to regulate the stereoscopic architecture of uniform 1D mesoporous SiO 2 (mSiO 2 ) nanorods. Based on this brand-new strategy, the 1D mSiO 2 nanorods can wind on the surface of 3D premade nanoparticles (sphere, cube, hexagon disk, spindle, rod, etc.) and inherit their surface topological structures. Therefore, the mSiO 2 nanorods with a diameter of ∼50 nm and a variable length can be bent into arc shapes with variable radii and radians, as well as folded into 60, 90, 120, and 180° angular convex corners with controllable folding times. Additionally, in contrast to conventional core@shell structures, this winding structure induces partial exposure and accessibility of the premade nanoparticles. The functional nanoparticles can exhibit large accessible surface and efficient energy exchanges with the surroundings. As a proof of concept, winding-structured CuS&mSiO 2 nanocomposites are fabricated, which are made up of a 100 nm CuS nanosphere and the 1D mSiO 2 nanorods with a diameter of ∼50 nm winding the nanosphere in the perimeter. The winding structured nanocomposites are demonstrated to have fourfold photoacoustic imaging intensity compared with the conventional core@shell nanostructure with an inaccessible core because of the greatly enhanced photothermal conversion efficiency (increased by ∼30%). Overall, our work paves the way to the design and synthesis of 1D nanomaterials with controllable bending and folding, as well as the formation of high-performance complex nanocomposites.

Background: Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors., Objective: The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes., Methods and Results: Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91-1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85-0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37-0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12-4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms., Conclusion: Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.

Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications. Bile acids are recognized as signaling molecules regulating a myriad of cellular and metabolic activities but have not been etiologically linked to PTB. In this study, a hospital-based cohort study with 36,755 pregnant women is conducted. We find that serum total bile acid levels directly correlate with the PTB rates regardless of the characteristics of the subjects and etiologies of liver disorders. Consistent with the findings from pregnant women, PTB is successfully reproduced in mice with liver injuries and dysregulated bile acids. More importantly, bile acids dose-dependently induce PTB with minimal hepatotoxicity. Furthermore, restoring bile acid homeostasis by farnesoid X receptor activation markedly reduces PTB and dramatically improves newborn survival rates. The findings thus establish an etiologic link between bile acids and PTB, and open an avenue for developing etiology-based therapies to prevent or delay PTB.

Ethnopharmacological Relevance: Nelumbo nucifera Gaertn (lotus) leaves were empirically carbonized to enhance the hemostatic effect in traditional Chinese medicines. The mechanism of this application remains unclear., Aim of the Study: The present study aims at exploring the transformation of phytochemical compounds in lotus leaves after heating and figuring out the phytochemical mechanism of the application of charcoal hemostatic styptics., Methods and Results: Raw lotus leaves were heated at 150 °C and 220 °C, respectively, and the transformation of the phytochemicals was studied. Flavonol glycosides in raw lotus leaves were found to be degraded to their corresponding aglycons in 150 °C lotus leaf charcoals (LLC) and the subsequent degradation products of aglycons in 220 °C LLC. 150 °C LLC exhibited the most desirable hemostatic effect in mice on reducing both bleeding time (BT) and clotting time (CT) by more than 30% as compared to the untreated group (P < 0.05). The extracts of 150 °C LLC were further separated by using different solvents. Ethyl acetate fraction which contained much flavonol aglycons displayed the most desirable hemostatic effect. On the contrary, petroleum ether fraction contains poor flavonoid and much alkaloid thus prolonged BT and CT. N-butanol extracts which contained only flavonol glycoside failed to shorten CT. In rats, quercetin (aglycon) standard promoted blood coagulation by shortening APTT (activated partial thromboplastin time) and increasing fibrinogen (P < 0.05). Hyperoside (glycoside) increased fibrinogen and platelet count (P < 0.05). Nuciferine was shown to prolong APTT and TT (thrombin time) and decrease fibrinogen (P > 0.05)., Conclusion: Degradation of flavonoids and alkaloids in lotus leaves was suggested to enhance the hemostatic effect of LLC. Flavonol aglycons were found to be more effective on blood clotting compared with their corresponding glycosides. Nuciferine, a typical alkaloid in lotus leaves which was degraded in LLC showed anticoagulation effect in rats. The content of flavonoid aglycon can be regarded as a criterion to qualify LLC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Spermatogonial stem cells (SSCs) are the cornerstone of sperm production and thus perpetual male fertility. In clinics, transplantation of patient's own SSCs into testes is a promising technique to restore fertility when male germ cells have been depleted by gonadotoxic therapies. Auto-transplantation of genetically modified SSCs even has the potential to treat male infertility caused by genetic mutations. However, SSCs are refractory to transfection approaches. Poly(amidoamine) (PAMAM) dendrimers have the unique three-dimensional architecture, surface charge, and high density of surface groups that are suitable for ligand attachment, thereby facilitating target delivery. The goal of this study was to elucidate whether PAMAM dendrimers can efficiently deliver short interfering RNAs (siRNAs) to SSCs., Methods and Results: We introduced cyclic arginine-glycine-aspartic acid (cRGD) peptides to the fifth generation of PAMAM dendrimers (G5) to generate PAMAM-cRGD dendrimers (G5-cRGD). The characterization of G5-cRGD was detected by Fourier transform infrared spectroscope (FTIR), transmission electron microscope (TEM), and the Cell Counting Kit-8 (CCK-8) assay. Confocal microscopy and flow cytometry were used to evaluate the delivery efficiency of siRNA by G5-cRGD to SSCs. The results showed that G5-cRGD encompassing siRNA could self-assemble into spherical structures with nanoscale size and possess high transfection efficiency, excellent endosomal escape ability, and low cytotoxicity, superior to a commercial transfection reagent Lipofectamine® 2000. Moreover, we demonstrated that G5-cRGD efficiently delivered siRNAs and triggered gene silencing., Conclusions: This study thus provides a promising nanovector for siRNA delivery in SSCs, facilitating the future clinical application of SSC auto-transplantation with genetically modified cells with a hope to cure male infertility that is caused by genetic disorders.

Overexpressed genes in tumors usually contributed to aggressiveness in pancreatic ductal adenocarcinoma (PDAC). Using Gene Expression Omnibus (GEO) profiles including GSE46234, GSE71989, and GSE107610, we detected overexpressed genes in tumors with R program, which were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO), and Reactome pathway databases. Then, we performed a survival analysis of enriched genes based on TCGA profile. Our results revealed that high BUB1B, CCNA2, CDC20, and CDK1 expression in tumors was significantly associated with worse overall survival (OS) (Log rank P =0.00338, P =0.0447, P =0.00965, and P =0.00479, respectively), which was validated using a Kaplan-Meier plotter with a median cutoff (Log rank P =0.028, P =0.0035, P =0.039, and P =0.0033, respectively). Moreover, overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues was significantly associated with disease-free survival (DFS) in PDAC patients (Log rank P =0.00565, P =0.0357, P =0.00104, and P =0.00121, respectively). BUB1B, CCNA2, CDC20, and CDK1 were significantly overexpressed in deceased PDAC patients (all P <0.01) and in patients with recurrence/disease progression (all P <0.05). In addition, PDAC patients with neoplasms of histologic grade G3-4 had significantly higher BUB1B, CCNA2 and CDC20 levels (all P <0.05). In conclusion, the up-regulation of BUB1B, CCNA2, CDC20, CDK1, and WEE1 in tumor tissues are associated with worse OS and DFS in PDAC and is correlated with advanced tumor stage and tumor development., (© 2019 The Author(s).)

Purpose: This study aimed to evaluate the clinical value of high-intensity focused ultrasound (HIFU) combined with gemcitabine (GEM) in treating unresectable pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: A total of 523 unresectable PDAC patients were recruited from December 30, 2007 to January 30, 2015 at Fudan University Shanghai Cancer Center. Among them, 347 received HIFU combined with GEM (with regional intra-arterial chemotherapy [RIAC] or with systemic chemotherapy) and the remaining patients received GEM only. Postoperative complications were observed, and overall survival was recorded., Results: The median overall survival of patients who received HIFU combined with GEM vs GEM alone was 7.4 vs 6.0 months ( P =0.002); the 6-month, 10-month, 1-year, and 2-year survival rates for patients in these two groups were 66.3% vs 47.5% ( P <0.0001), 31.12% vs 15.9% ( P <0.0001), 21.32% vs 13.64% ( P =0.033), and 2.89% vs 2.27% ( P =0.78), respectively. In the combined therapy group, the most obvious survival benefits were obtained among patients who received HIFU plus RIAC and systemic chemotherapy (used in the intervals between RIAC treatments). There were no severe complications in patients undergoing HIFU treatment., Conclusion: We demonstrated the survival benefit of HIFU among PDAC patients treated with GEM. The benefit was most obvious in PDAC patients treated with HIFU plus RIAC and systemic chemotherapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To identify prognostic biomarkers and drugs that target them in colon adenocarcinoma (COAD) based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Methods: The TCGA dataset was used to identify the top 50 upregulated differentially expressed genes (DEGs), and Gene Expression Omnibus profiles were used for validation. Survival analyses were conducted with the TCGA dataset using the RTCGAToolbox package in the R software environment. Drugs targeting the candidate prognostic biomarkers were searched in the DrugBank and herbal databases. Results: Among the top 50 upregulated DEGs in patients with COAD in the TCGA dataset, the Wnt signaling pathway and cytokine-cytokine receptor interactions and pathways in cancer Kyoto Encyclopedia of Genes and Genomes pathway analysis were enriched in DEGs. Tissue development and regulation of cell proliferation were the main Gene Ontology biological processes associated with upregulated DEGs. MYC and KLK6 were overexpressed in tumors validated in the TCGA, GSE41328, and GSE113513 databases (all P < .001) and were significantly associated with overall survival in patients with COAD ( P = .021 and P = .047). Nadroparin and benzamidine were identified as inhibitors of MYC and KLK6 in DrugBank, and 8 herbs targeting MYC, including Da Huang ( Radix Rhei Et Rhizome ), Hu Zhang ( Polygoni Cuspidati Rhizoma Et Radix ), Huang Lian ( Coptidis Rhizoma ), Ban Xia ( Arum Ternatum Thunb ), Tu Fu Ling ( Smilacis Glabrae Rhixoma ), Lei Gong Teng ( Tripterygii Radix ), Er Cha ( Catechu ), and Guang Zao ( Choerospondiatis Fructus ), were identified. Conclusion: MYC and KLK6 may serve as candidate prognostic predictors and therapeutic targets in patients with COAD.

Objective: We conducted a multicenter cohort study to investigate the prognostic value of some commonly-used laboratory indices in advanced pancreatic ductal adenocarcinoma (PDAC)., Methods: A multicenter cohort study was conducted from 2004 to 2013. The associations between laboratory indices and prognosis of advanced PDAC were examined., Results: This cohort consisted of 553 females (36.2%) and 973 males (63.8%). Patients at cancer stage III and IV were 595 (39.0%) and 931 (61.0%), respectively. The median survival of stage III patients was 9.0 months, with 3-, 6-, and 12-month survival rates of 94.5%, 73.4%, and 28.5%, respectively. The median survival of stage IV patients was 5.4 months, with 3-, 6-, and 12-month survival rates of 79.3%, 42.9%, and 15.0%, respectively. In multivariate analyses, primary tumor diameter, low albumin, and elevated CA19-9 were associated with decreased survival for stage III patients. Age, smoking, primary tumor diameter, elevated ALT or AST, low albumin, and elevated CA19-9 were associated with decreased survival for stage IV patients., Conclusion: Elevated CA19-9 level, decreased albumin level, and tumor size were associated with worse survival in stage III patients. Meanwhile, advanced age, smoking, and ALT or AST level were negatively correlated to prognosis in stage IV patients.

Objective: A key step in managing non-alcoholic fatty liver disease (NAFLD) is to differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis (SS)., Method: Serum samples were collected from three groups: NASH patients (N=21), SS patients (N=38) and healthy controls (N=31). High performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyse the metabolic profile of the serum samples. The acquired data were processed by multivariate principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA) to identify novel metabolites. The potential biomarkers were quantitatively determined and their diagnostic power was further validated., Results: A total of 56 metabolites were capable of distinguishing NASH from SS samples based on the OPLS-DA model. Pyroglutamate was found to be the most promising factor in distinguishing the NASH from SS groups. With an optimal cut-off value of 4.82mmol/L, the sensitivity and specificity of the diagnosis of NASH were 72% and 85%, respectively. The area under the receiver operating characteristic (AUROC) of the pyroglutamate levels of NASH versus SS patients was more than those of tumor necrosis factor-α, adiponectin and interleukin-8., Conclusion: These data suggest that pyroglutamate may be a new and useful biomarker for the diagnosis of NASH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Whether the progression of advanced pancreatic ductal adenocarcinoma (PDAC) patients could be affected by HBV exposure remains to be determined. Therefore, we conducted this study to assess the effect of HBV infection on PDAC progression among a large cohort in China., Methods: A multicenter cohort study was conducted to explore whether liver metastasis and overall survival in locally advanced and metastatic PDAC could be affected by HBV infection. In this study, we collected 1,526 advanced PDAC patients at three participating hospitals - Shanghai Cancer Center, Changhai Hospital and Ruijin Hospital from 2004 to 2013. The association between HBV status and advanced PDAC progression was then examined., Results: In multivariable Logistic regression model, chronic hepatitis B(CHB) infection was inversely associated with synchronous liver metastasis compared to non HBV infection (OR 0.41, 95% CI 0.19-0.85) for stage IV patients. In a multivariable Cox model, CHB infection (HR=0.11, 95% CI 0.02-0.82) is considered as a protective factor of metachronous liver metastasis compared to Non HBV infection for stage III patients. For stage IV patients, CHB infection was inversely associated with overall survival compared to non HBV infection (HR 0.70, 95% CI 0.51-0.95). Inactive carrier(IC) and resolved HBV infection showed no significant association with survival compared to non HBV infection., Conclusion: This study indicated that CHB infection may serve as an independent factor which decrease synchronous or metachronous liver metastasis, and increase overall survival among advanced PDAC patients.

Photothermal therapy (PTT) has recently attracted considerable attention owing to its controllable treatment process, high tumour eradication efficiency and minimal side effects on non-cancer cells. PTT can melt cancerous cells by localising tissue hyperthermia induced by internalised therapeutic agents with a high photothermal conversion efficiency under external laser irradiation. Numerous in vitro and in vivo studies have shown the significant potential of PTT to treat tumours in future practical applications. Unfortunately, the lack of visualisation towards agent delivery and internalisation, as well as imaging-guided comprehensive evaluation of therapeutic outcome, limits its further application. Developments in combined photothermal therapeutic nanoplatforms guided by different imaging modalities have compensated for the major drawback of PTT alone, proving PTT to be a promising technique in biomedical applications. In this review, we introduce recent developments in different imaging modalities including single-modal, dual-modal, triple-modal and even multi-modal imaging-guided PTT, together with imaging-guided multi-functional theranostic nanoplatforms., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Epidermal electronic systems feature physical properties that approximate those of the skin, to enable intimate, long-lived skin interfaces for physiological measurements, human-machine interfaces and other applications that cannot be addressed by wearable hardware that is commercially available today. A primary challenge is power supply; the physical bulk, large mass and high mechanical modulus associated with conventional battery technologies can hinder efforts to achieve epidermal characteristics, and near-field power transfer schemes offer only a limited operating distance. Here we introduce an epidermal, far-field radio frequency (RF) power harvester built using a modularized collection of ultrathin antennas, rectifiers and voltage doublers. These components, separately fabricated and tested, can be integrated together via methods involving soft contact lamination. Systematic studies of the individual components and the overall performance in various dielectric environments highlight the key operational features of these systems and strategies for their optimization. The results suggest robust capabilities for battery-free RF power, with relevance to many emerging epidermal technologies., Competing Interests: The authors declare no conflict of interest.

Although there were many prior studies about exotropia, few focused on large-angle intermittent exotropia. The goal of this study was to evaluate single-stage surgical outcomes for large-angle intermittent exotropia and analyze risk factors that may affect the success of surgery. Records from intermittent exotropia patients with exodeviations >60 prism diopters(PD) who were surgically treated at the Zhongshan Ophthalmic Center, of Sun Yat-Sen University were reviewed. Included within this review were data on, pre- and post-operative ocular motility, primary alignment, binocular vision and complications. Patients with exodeviations ≤70PD received two-muscle surgery, while those with exodeviations >70PD were subjected to a three-muscle procedure. A total of 40 records were reviewed. The mean exodeviation was 73±9PD at distance and 75±26PD at near. There were 25 patients received two-muscle surgery and 15 the three-muscle procedure. Orthophoria (deviation within 8PD) was obtained in 77.5% of these patients and the ratios of surgical under-correction and over-correction were 15% and 7.5% respectively. However, when combining ocular alignment with binocular vision as the success criteria, success rates decreased to 30%. No statistically significant differences in success rates were obtained between the two- and three-muscle surgery groups. Seven subjects experienced an abduction deficit during the initial postoperative stages, but eventually showed a full recovery. One patient required a second surgery for overcorrection. No statistically significant risk factors for poor outcome were revealed. Our data showed that single-stage two- and three-muscle surgeries for large-angle intermittent exotropia are effective in achieving a favorable outcome.

Filter paper strips were enclosed between two poly(methyl methacrylate) plates to fabricate paper-packed channel microchips under pressure in the presence of far infrared irradiation. After the enclosed paper strip was oxidized by periodate, trypsin was covalently immobilized in them to fabricate microfluidic proteolysis bioreactor. The feasibility and performance of the unique bioreactor were demonstrated by digesting BSA and lysozyme. The results were comparable to those of conventional in-solution proteolysis while the digestion time was significantly reduced to ∼18 s. The suitability of the microfluidic paper-based bioreactors to complex proteins was demonstrated by digesting human serum., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The clinical characteristics and surgical outcomes in a large sample of patients with intermittent exotropia (IXT) as well as an analysis of risk factors associated with surgical failures are presented in this article. Data from IXT patients who received surgical management at the Eye Hospital, in the Zhongshan Ophthalmic Center, of Sun Yat-Sen University, China from January 2009 to December 2013 were reviewed retrospectively. Included within this analysis were data from pre- and postoperative ocular motility, primary alignment, and binocular vision.A total of 1228 patients with IXT were reviewed. Males (50.4%) and females (49.6%) were nearly equally represented in this sample. Thirty-two patients (2.6%) had a family history of strabismus. The mean age at onset was 6.77  ±  6.43 years (range 7 months -48.5 years), mean duration at presentation was 7.35  ±  6.68 years (range 6 months-47 years), and mean age at surgery was 13.7  ±  8.8 years (range 3-49 years). The mean refractive error was -0.84  ±  2.69 diopter in the right eye and -0.72  ±  2.58 diopter in the left eye. Amblyopia (4.2%), oblique muscle dysfunction (7.0%), and dissociated vertical deviation (4.7%) were also present in these patients. The most common subtype of IXT was the basic type (88.1%). Orthophoria was observed in 80.5% of patients and the ratios of surgical undercorrection and overcorrection were 14.7% and 4.8%, respectively, as determined with a mean follow-up time of 7.8  ±  3.7 months. When combining ocular alignment with binocular vision as the success criteria, the success rate decreased to 35.6%. Multivariate risk factor analysis showed that only the loss of stereoacuity (P = 0.002) was associated with a poor outcome. There were no differences in the long-term results between bilateral lateral rectus recession and unilateral lateral rectus recession with medial rectus resection.Most IXT patients displayed normal vision, with few having positive family histories, amblyopia, oblique muscle dysfunction, and dissociated vertical deviation. The most common subtype of IXT was the basic type. Long-term surgical results were less favorable when sensory status was included in the criteria for success. Patients with stereoacuity loss were at an increased risk for poor outcomes.

Acute acquired concomitant esotropia (AACE) is a rare, distinct subtype of esotropia. The purpose of this retrospective study was to describe the clinical characteristics and discuss the classification and etiology of AACE.Charts from 47 patients with AACE referred to our institute between October 2010 and November 2014 were reviewed. All participants underwent a complete medical history, ophthalmologic and orthoptic examinations, and brain and orbital imaging.Mean age at onset was 26.6 ± 12.2 years. Of the 18 cases with deviations ≤ 20 PD, 16 presented with diplopia at distance and fusion at near vision at the onset of deviation; differences between distance and near deviations were < 8 PD; all cases except one were treated with prism and diplopia resolved. Of the 29 cases with deviations > 20 PD, 5 were mild hypermetropic with age at onset between 5 and 19 years, 16 were myopic, and 8 were emmetropic with age at onset > 12 years; 24 were surgically treated and 5 cases remained under observation; all 24 cases achieved normal retinal correspondence or fusion or stereopsis on postoperative day 1 in synoptophore; in 23 cases diplopia or visual confusion resolved postoperatively. Of the 47 cases, brain and orbital imaging in 2 cases revealed a tumor in the cerebellopontine angle and 1 case involved spinocerebellar ataxia as revealed by genetic testing.AACE in this study was characterized by a sudden onset of concomitant nonaccommodative esotropia with diplopia or visual confusion at 5 years of age or older and the potential for normal binocular vision. We suggest that AACE can be divided into 2 subgroups consisting of patients with relatively small versus large angle deviations. Coexisting or underlying neurological diseases were infrequent in AACE.

We performed a comprehensive meta-analysis to determine the association between XPD/ERCC2 Lys751Gln polymorphism and melanoma susceptibility. Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between XPD/ERCC2 Lys751Gln polymorphism and melanoma risk. A total of 5,961 cases and 8,669 controls in studies were included in this meta-analysis. All studies were conducted in Caucasian populations. Allele model (Lys vs. Gln: P = 0.53; OR = 0.98, 95% CI = 0.91-1.05), and homozygous model (Lys/ Lys vs. Gln/Gln: P = 0.32; OR = 0.93, 95% CI = 0.81 to 1.07) did not show increased risk of developing melanoma. Similarly, dominant model (Lys/ Lys+Lys/Gln vs. Gln/Gln: P = 0.18; OR = 0.93, 95% CI = 0.83 to 1.03) and recessive model (Lys/ Lys vs. Lys/Gln+Gln/Gln: P = 0.73; OR = 0.98, 95% CI = 0.88 to 1.09) failed to show increased risk of developing melanoma. Our pooled data suggest that there was no evidence for a major role of XPD/ERCC2 Lys751Gln polymorphism in the pathogenesis of melanoma among Caucasian populations.

Purpose: To analyze the clinical features, imaging findings and surgical management of rare orbital cystic lesions in children., Materials and Methods: Clinical records of 5 Chinese children with rare orbital cystic lesions including cystic teratoma, congenital cystic eye, optic nerve sheath cyst, parasitic cyst, and meningoencephalocele were reviewed. Their clinical history, symptoms and signs, ultrasonography or computed tomography/magnetic resonance imaging (CT/MRI), surgical management were presented in detail., Results: Among the 5 patients, 2 were male and 3 female. The right orbit was involved in 2 patients and the left orbit in 3 patients. Ages ranged from 2 months to 11 years (mean, 4.2 years). Cystic teratoma showed a well-outlined cystic mass with a focal bone-like structure (or calcific densities) in their lumens as revealed with CT scan. Congenital cystic eye was a rare ocular malformation that existed at birth and showed a cystic lesion with no definite ocular structures in the orbit. With MRI examination, the optic nerve sheath cyst demonstrated a clear figure of the central optic nerve and the surrounding sheath cyst. Patients with parasitic cysts usually had frequent animal contact and high levels of blood eosinophils. Meningoencephalocele, the herniation into the orbit of brain tissue, had the typical CT/MRI features, with bone defect and soft tissue mass in the orbit and a homogenous appearance that was isodense with brain., Conclusions: Besides common dermoid/epidermoid cyst, rare orbital cystic lesions such as cystic teratoma, congenital cystic eye, optic nerve sheath cyst, parasitic cyst, and meningoencephalocele should be considered in children., (Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to report an unusual case of severe microphthalmos, together with an orbital cyst and huge ocular surface dermolipoma., Methods: This is a clinical report relating clinical features as well as imaging and histopathologic findings, along with surgical management of the patient., Results: A 5-month-old Chinese male infant was referred, with 2 large masses in the left eye that were present since birth. Ocular examination results revealed a complete absence of any eye structures in the left orbit. In its place were 2 large masses between the left upper and lower palpebral fissure. One was a 3 × 3 × 2.5-cm spherical red tumor with a smooth surface. The other was a large solid spherical tumor, 4 × 4 × 5 cm, covered with normal skin located in the temporal region and attached to the red mass by a pedicle. Orbital magnetic resonance imaging examination findings confirmed that no eye structures were present in the left orbit. However, a cystic lesion was found in the left orbit, with a low signal on T1-weighted imaging and high signal on T2-weighted imaging, and another huge spherical heterogeneous mass was located "outside" the left orbit. Anterior orbitotomy by conjunctival incision was performed under general anesthesia. A spherical cystic mass of 1.5 × 1.5 × 1.6 cm, a small eye of 0.7 × 0.7 × 0.6 cm, and a huge dermolipoma were removed completely. Pathologic examination results confirmed the diagnosis of severe microphthalmos, together with orbital dermoid cyst and dermolipoma., Conclusions: This rare case demonstrates that severe microphthalmos with a cyst may be completely covered by conjunctiva and associated with an unusually huge dermolipoma.

Patients with pancreatic neuroendocrine tumors (PNETs) diagnosed at late stage are not suitable candidates for surgery. So far, only a limited number of cases have been documented in literature about the effectiveness of HIFU, which has been more frequently reported to treat pancreatic adenocarcinoma rather than PNET. We report herein that a patient with a pancreatic neuroendocrine unresectable tumor was effectively treated with serial high-intensity focused ultrasound (HIFU) ablation, with no significant side effects detected. Upon evaluation, treatment results included: the tendency of tumor shrinkage, pain relief, decreased tumor marker levels, and obvious improvements in quality of life. Sustained efficacy was observed during a follow-up at 25 months with no tumor progression., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)