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Abstract Vitamin C (VC), due to its chemical properties, can provide more oxygen-containing functional groups such as hydroxyl groups for biochar (BC), which promotes the adsorption of tetracycline on biochar. Therefore, in this study, cow dung biochar (CDBC) was modified with VC and VC-modified CDBC (CDBC-VC) was synthesized. The modified biochar was characterized and related factors, adsorption kinetics, isotherms and adsorption mechanisms were investigated. Adsorption kinetics indicate a fast rate of adsorption. The adsorption isotherms showed that the maximum adsorption capacity was 31.72 mg/g (CDBC) and 50.90 mg/g (CDBC-VC), respectively, and the adsorption process was inhomogeneous with multiple molecular layers and the adsorbent has a higher affinity. Mechanistic studies showed that hydrogen bonding interactions, π-π electron donor-acceptor interactions, hydrophobic interactions, and electrostatic interactions were the key to the adsorption process. The analysis of adsorbent regeneration showed that CDBC-VC had good adsorption performance. CDBC and CDBC-VC showed the best performance in simulated industrial wastewater with removal rates of 78.81% and 93.69%. The adsorption mechanism was comprehensively analyzed using six machine learning models. The extreme gradient boosting model gave the best fit. Analysis of the weights of the input variables for predicting adsorption efficiency showed that the ratio of initial TC concentration to BC dosage (29.8%), specific surface area (23%), isoelectric point (8.8%), and ash content (7.7%) had a significant effect on the predicted results.

Bladder urothelial carcinoma is the most common malignant tumor disease in urinary system, and its incidence rate ranks ninth in the world. In recent years, the continuous development of hyperspectral imaging technology has provided a new tool for the auxiliary diagnosis of bladder cancer. In this study, based on microscopic hyperspectral data, an automatic detection algorithm of bladder tumor cells combining color features and shape features is proposed. Support vector machine (SVM) is used to build classification models and compare the classification performance of spectral feature, spectral and shape fusion feature, and the fusion feature proposed in this paper on the same classifier. The results show that the sensitivity, specificity, and accuracy of our classification algorithm based on shape and color fusion features are 0.952, 0.897, and 0.920, respectively, which are better than the classification algorithm only using spectral features. Therefore, this study can effectively extract the cell features of bladder urothelial carcinoma smear, thus achieving automatic, real-time, and noninvasive detection of bladder tumor cells, and then helping doctors improve the efficiency of pathological diagnosis of bladder urothelial cancer, and providing a reliable basis for doctors to choose treatment plans and judge the prognosis of the disease.

In recent years, the environmental impact of microplastics (MPs) and antibiotics (ATs) as pollutants cannot be ignored. In order to evaluate the carrier effect of MPs in the aqueous environment, three MPs, polyamide (PA), polyethylene (PE) and polyethylene terephthalate (PET), were selected in this study, and their structures were analyzed by means of characterization. A preliminary description of their interactions with sulfamonomethoxine was carried out by adsorption kinetics and isotherm fitting. The dominance of non-bonding capacity (van der Waals and electrostatic interaction forces) in the adsorption process was demonstrated using molecular dynamics (MD) simulations and density functional theory (DFT), with the interaction strengths ranked as PA > PE > PET, respectively. PA is less adsorbent stable at the molecular level but exhibits the largest adsorption capacity influenced by the characterized structure and multiple interaction forces. PET possesses a stronger stability and is not easily replaced by other substances. This will help to further understand the complex effect mechanism between MPs and organic pollutants, and provide an important reference for the prevention and control of environmental pollution.

Carboxypeptidase A(CPA) has a great potential application in the food and pharmaceutical industry due to its capability to hydrolyze ochratoxin A(OTA) and remove the bitterness of peptide. However, CPA is a mesophilic enzyme that cannot adequately exert its catalytic activity at elevated temperatures, which seriously restricts its industrial application. In this study, the rational design of disulfide bonds was introduced to improve the thermostability of CPA. The highly flexible regions of CPA were predicted through the HotSpot Wizard program and molecular dynamics (MD) simulations. Then, DbD and MODIP online servers were conducted to predict potential residue pairs for introducing disulfide bonds in CPA. After the conservativeness analysis of the PSSM matrix and the structural analysis of the MD simulation, two mutants with potentially enhanced thermostability were screened. Results showed that these mutants D93C/F96C and K153C/S251C compared to the wild-type(WT) exhibited increase by 10 and 10 °C in Topt, 3.4 and 2.7 min in t1/2 at 65 °C, in addition to rise of 8.5 and 11.4 °C in T5015, respectively. Furthermore, the molecular mechanism responsible for thermostability was investigated from the perspective of advanced structure and molecular interactions. The enhanced thermostability of both mutants was not only associated with the more stable secondary structure and the introduction of disulfide bonds but also related to the changes in hydrogen bonds and the redistribution of surface charges in mutant regions. This study showed for the first time that the rational design of disulfide bonds is an effective strategy to enhance the thermostability of CPA, providing in this way a broader industrial application.

Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

Abstract Background The concept of gene fusion describes the process of fusing two genes into one, which is closely linked to tumour occurrence and development and may even be the direct cause of some tumours. Due to their tumour‐specific expression and ability to drive tumour occurrence and development, there is great potential for fusion genes to be used as diagnostic markers and targets for specific types of tumours. Main body Although many fusion genes have been detected so far, they mainly focus on a small number of highly recurrent fusion genes detected in patients' tumours. There are few studies on the functional mechanism and clinical relevance of rare gene fusions. Our review discusses the generation mechanisms, detection methods, biological functions, and mechanisms of action of fusion genes. Additionally, we discuss the clinical significance of fusion gene detection in some tumour types. Conclusion The function mechanism research of rare gene fusion is very necessary, and more functions of fusion genes independent of unfused/normal genes can be explored in future studies. There is still a long way to go in implementing precision tumour therapy targeting gene fusion.

Abstract The primary challenge in treating esophageal squamous cell carcinoma (ESCC) is resistance to chemotherapy. Cancer stem cell (CSC) is the root cause of tumor drug resistance. Therefore, targeting CSCs has been considered promising therapeutic strategy for tumor treatment. Here, we report that circMALAT1 was significantly upregulated in ESCC CSC‐like cells and primary tumors from ESCC patients. Clinically, there was a positive correlation between circMALAT1 expression and ESCC stage and lymph node metastasis, as well as poor prognosis for ESCC patients. In vitro and in vivo functional studies revealed that circMALAT1 promoted CSC‐like cells expansion, tumor growth, lung metastasis and drug resistance of ESCC. Mechanistically, circMALAT1 directly interacted with CSC‐functional protein Musashi RNA Binding Protein 2 (MSI2). CircMALAT1 inhibited MSI2 ubiquitination by preventing it from interacting with β‐transducin repeat containing protein (BTRC) E3 ubiquitin ligase. Also, circMALAT1 knockdown inhibited the expression of MSI2‐regulating CSC‐markers c‐Myc in ESCC. Collectively, circMALAT1 modulated the ubiquitination and degradation of the MSI2 protein signaling with ESCC CSCs and accelerated malignant progression of ESCC. CircMALAT1 has the potential to serve as a biomarker for drug resistance and as a target for therapy in CSCs within ESCC.

This study aimed to ascertain the delayed effects of various exposure temperatures on infectious diarrhea. We performed a Bayesian random-effects network meta-analysis to calculate relative risks (RR) with 95 % confidence intervals (95 % CI). The heterogeneity was analyzed by subgroup analysis. There were 25 cross-sectional studies totaling 6858735 patients included in this analysis, with 12 articles each investigating the effects of both hyperthermia and hypothermia. Results revealed that both high temperature (RRsingle = 1.22, 95%CI:1.04–1.44, RRcum = 2.96, 95%CI:1.60–5.48, P 0.05), while the statistical significance of low temperatures in lowering bacterial dysentery had vanished. This investigation examined that high temperature and low temperature were the conditions that posed the greatest risk for infectious diarrhea. This research offers fresh perspectives on preventing infectious diarrhea and will hopefully enlighten future studies on the impact of temperature management on infectious diarrhea.

Rapid and accurate monitoring of the chlorophyll content of ginseng leaves to reflect the growth condition of ginseng is of great significance in guiding the cultivation of ginseng. To address the problem that the existing means of detecting chlorophyll in ginseng leaves are time-consuming and disruptive and cannot meet the demand for rapid detection of chlorophyll in ginseng leaves, this study firstly establishes a variety of prediction models for chlorophyll in ginseng leaves based on the hyperspectral reflectance data and the vegetation index, respectively, and determines the strengths and weaknesses of the models by comparing the RMSE and the MAE of the test sets; Secondly, the analytical model construction process used for ginseng leaf chlorophyll content prediction was obtained through comparison and summary, and a fast and non-destructive ginseng leaf chlorophyll prediction method based on hyperspectral imaging technology and combining vegetation indices with machine learning algorithms was proposed; The experimental results showed that the final VI-SPA-RFR ginseng leaf chlorophyll prediction model had the best prediction performance, which had an RMSE of 1.1568 and an MAE of 0.9936 in the test set. In summary, this study provides a method to achieve rapid and accurate monitoring of the chlorophyll content of ginseng leaves, which is expected to provide a scientific means of monitoring for the cultivation of ginseng and expand the application field of hyperspectral imagers in the field of agriculture.

Abstract Background Glioblastoma (GBM) is the most aggressive malignant central nervous system tumor with a poor prognosis.The malignant transformation of glioma cells via epithelial-mesenchymal transition (EMT) has been observed as a main obstacle for glioblastoma treatment. Epithelial membrane protein 3 (EMP3) is significantly associated with the malignancy of GBM and the prognosis of patients. Therefore, exploring the possible mechanisms by which EMP3 promotes the growth of GBM has important implications for the treatment of GBM. Methods We performed enrichment and correlation analysis in 5 single-cell RNA sequencing datasets. Differential expression of EMP3 in gliomas, Kaplan–Meier survival curves, diagnostic accuracy and prognostic prediction were analyzed by bioinformatics in the China Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) database. EMP3-silenced U87 and U251 cell lines were obtained by transient transfection with siRNA. The effect of EMP3 on glioblastoma proliferation was examined using the CCK-8 assay. Transwell migration assay and wound healing assay were used to assess the effect of EMP3 on glioblastoma migration. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect the mRNA and protein expression levels of EMT-related transcription factors and mesenchymal markers. Results EMP3 is a EMT associated gene in multiple types of malignant cancer and in high-grade glioblastoma. EMP3 is enriched in high-grade gliomas and isocitrate dehydrogenase (IDH) wild-type gliomas.EMP3 can be used as a specific biomarker for diagnosing glioma patients. It is also an independent prognostic factor for glioma patients' overall survival (OS). In addition, silencing EMP3 reduces the proliferation and migration of glioblastoma cells. Mechanistically, EMP3 enhances the malignant potential of tumor cells by promoting EMT. Conclusion EMP3 promotes the proliferation and migration of GBM cells, and the mechanism may be related to EMP3 promoting the EMT process in GBM; EMP3 may be an independent prognostic factor in GBM.

Objective: To investigate the association between air pollutants and the incidence of tuberculosis (TB) through a systematic review and meta-analysis, and to provide directions for future research and prevention of TB. Methods: A search was conducted for all literature related to the incidence of TB and air pollution in the database. We screened the retrieved articles and proceeded statistical analyses using random effects models to investigate the relationships between five air pollutants (PM2.5, PM10, SO2, NO2 and O3) and the incidence of TB. Results: The initial search identified 100 pieces of literature and 9 studies met the screening criteria after the screening. The single-day lagged risk ratio (RR) and 95% Confidence Intervals (CIs) for the combined effects estimates are as follows: PM2.5: 1.059 (0.966, 1.160); PM10: 1.000 (0.996, 1.004); SO2: 0.980 (0.954, 1.007); NO2: 1.011 (0.994, 1.027); O3: 0.994 (0.980,1.008). The cumulative lagged results for these five pollutants are listed like this: PM2.5: 1.095 (0.983, 1.219); PM10: 1.035 (1.006, 1.066); SO2: 0.964 (0.830, 1.121); NO2: 1.037 (1.010, 1.065); O3: 0.982 (0.954, 1.010). Conclusion: The single-day lag effects of PM2.5, PM10, SO2, NO2, and O3 are not statistically significantly relevant for the occurrence of TB. However, the cumulative lag results show that both PM10 and NO2 contribute to the prevalence of TB, while the statistical relationship between the cumulative lag effects of PM2.5, SO2, and O3 and the onset of TB remains unknown.

Abstract Background Hypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear. Methods RNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo. Results The expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively. Conclusions Collectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.

Abstract. Background:. Metastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer. Autophagy accelerates tumor metastasis. In our work, we aimed to investigate the possibility of microRNAs (miRNAs) which participate in the regulation of autophagy to inhibit tumor metastasis. Methods:. MiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis. The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction. In vivo and in vitro assays were conducted to determine the function of miR-3653. The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot. The relationship between miR-3653 and epithelial-mesenchymal transition (EMT) was assessed by Western blot. Student's t-test was used to analyze the difference between any two groups, and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test. Results:. miR-3653 was downregulated in breast cancer cells with high metastatic ability, and high expression of miR-3653 blocked autophagic flux in breast cancer cells. Clinically, low expression of miR-3653 in breast cancer tissues (0.054 ± 0.013 vs. 0.131 ± 0.028, t = 2.475, P = 0.014) was positively correlated with lymph node metastasis (0.015 ± 0.004 vs. 0.078 ± 0.020, t = 2.319, P = 0.023) and poor prognosis (P

Ultra-soft soil is distributed in coastal areas around the world and has poor engineering properties. There is a significant difference in settlement between semi-rigid pile and surrounding soil under embankment load. Based on existing research results, the settlement calculation formula of ultra-soft soil composite foundation reinforced by semi-rigid pile is derived in this paper. Based on the Alamgir displacement model, assuming a three-zone model of pile skin friction with a negative skin friction plastic zone in the upper part of the pile, an elastic zone in the middle part of the pile, and a skin friction-bearing plastic zone in the lower part of the pile, the upward and downward penetrations of pile, and pile–soil slip deformation characteristics are considered. Analytical expressions for settlement calculations of semi-rigid pile composite foundations under embankments were derived based on differential equations for pile–soil load transfer in the unit cell. The influences of pile diameter and the compression modulus of the underlying layer at the pile end on the settlement characteristics of the semi-rigid pile composite foundation are discussed. The results show that the derived theoretical calculation method is in good agreement with the field measurement and laboratory model test results. Ultra-soft soil composite foundations have long settlement stabilization times and large settlement deformations. Penetration deformation occurs at the semi-rigid pile end. The relationship between pile end resistance and pile end piercing deformation is hyperbolic. The compression modulus of the underlying layer has a great influence on pile end penetration. The lower the compression modulus of the underlying layer, the larger the penetration deformation of pile end. The larger the pile diameter is, the smaller the penetration deformation is.

This study describes a novel method for grading pathological sections of gliomas. Our own integrated hyperspectral imaging system was employed to characterize 270 bands of cancerous tissue samples from microarray slides of gliomas. These samples were then classified according to the guidelines developed by the World Health Organization, which define the subtypes and grades of diffuse gliomas. We explored a hyperspectral feature extraction model called SMLMER-ResNet using microscopic hyperspectral images of brain gliomas of different malignancy grades. The model combines the channel attention mechanism and multi-scale image features to automatically learn the pathological organization of gliomas and obtain hierarchical feature representations, effectively removing the interference of redundant information. It also completes multi-modal, multi-scale spatial–spectral feature extraction to improve the automatic classification of glioma subtypes. The proposed classification method demonstrated high average classification accuracy (>97.3%) and a Kappa coefficient (0.954), indicating its effectiveness in improving the automatic classification of hyperspectral gliomas. The method is readily applicable in a wide range of clinical settings, offering valuable assistance in alleviating the workload of clinical pathologists. Furthermore, the study contributes to the development of more personalized and refined treatment plans, as well as subsequent follow-up and treatment adjustment, by providing physicians with insights into the underlying pathological organization of gliomas.

Deficiency of natural killer (NK) cells shows a significant impact on tumor progression and failure of immunotherapy. It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment. Unfortunately, mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors, thus declining antitumor efficiency. Herein, we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15 (IL-15). The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction, which provides a new methodology to trigger aggregation. It shows self-adaptive size-enlargement upon acidity, thus improving drug retention in tumor to over 120 h. The diameter of agglomerates is increased and drug release is effectively promoted following reduced pH values. The nanoparticles activate both NK cell and CD8+ T cell immunity in vivo. It significantly suppresses CT26 tumor in immune-deficient BALB/c mice, and the efficiency is further improved in immunocompetent mice, indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity. The approach reported here provides an innovative strategy to improve drug retention in tumors, which will enhance cancer immunotherapy by boosting NK cells.

Abstract Among silicon-based solar cells, heterojunction cells hold the world efficiency record. However, their market acceptance is hindered by an initial 0.5% per year degradation of their open circuit voltage which doubles the overall cell degradation rate. Here, we study the performance degradation of crystalline-Si/amorphous-Si:H heterojunction stacks. First, we experimentally measure the interface defect density over a year, the primary driver of the degradation. Second, we develop SolDeg, a multiscale, hierarchical simulator to analyze this degradation by combining Machine Learning, Molecular Dynamics, Density Functional Theory, and Nudged Elastic Band methods with analytical modeling. We discover that the chemical potential for mobile hydrogen develops a gradient, forcing the hydrogen to drift from the interface, leaving behind recombination-active defects. We find quantitative correspondence between the calculated and experimentally determined defect generation dynamics. Finally, we propose a reversed Si-density gradient architecture for the amorphous-Si:H layer that promises to reduce the initial open circuit voltage degradation from 0.5% per year to 0.1% per year.

Ulcerative colitis (UC), as a chronic inflammatory disease, presents a global public health threat. However, the mechanism of Poria cocos (PC) in treating UC remains unclear. Here, LC-MS/MS was carried out to identify the components of PC. The protective effect of PC against UC was evaluated by disease activity index (DAI), colon length and histological analysis in dextran sulfate sodium (DSS)-induced UC mice. ELISA, qPCR, and Western blot tests were conducted to assess the inflammatory state. Western blotting and immunohistochemistry techniques were employed to evaluate the expression of tight junction proteins. The sequencing of 16S rRNA was utilized for the analysis of gut microbiota regulation. The results showed that a total of fifty-two nutrients and active components were identified in PC. After treatment, PC significantly alleviated UC-associated symptoms including body weight loss, shortened colon, an increase in DAI score, histopathologic lesions. PC also reduced the levels of inflammatory cytokines TNF-α, IL-6, and IL-1β, as evidenced by the suppressed NF-κB pathway, restored the tight junction proteins ZO-1 and Claudin-1 in the colon, and promoted the diversity and abundance of beneficial gut microbiota. Collectively, these findings suggest that PC ameliorates colitis symptoms through the reduction in NF-κB signaling activation to mitigate inflammatory damage, thus repairing the intestinal barrier, and regulating the gut microbiota.

Abstract Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery. On the one hand, bioorthogonal reactions improve therapeutic agent delivery to target sites, overcoming off-target distribution. On the other hand, nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions, providing approaches to developing multi-functional drug delivery systems (DDSs). In this review, we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups. We then highlight recent breakthroughs in developing active targeting DDSs to tumors, immune systems, or bacteria by bioorthogonal chemistry, as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs (biomimetic DDSs, cell-based DDSs, bacteria-based and phage-based DDSs) and hydrogels. Finally, we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery. We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

BackgroundDiabetic osteoporosis exhibits heterogeneity at the molecular level. Ferroptosis, a controlled form of cell death brought on by a buildup of lipid peroxidation, contributes to the onset and development of several illnesses. The aim was to explore the molecular subtypes associated with ferroptosis in diabetic osteoporosis at the molecular level and to further elucidate the potential molecular mechanisms.MethodsIntegrating the CTD, GeneCards, FerrDb databases, and the microarray data of GSE35958, we identified ferroptosis-related genes (FRGs) associated with diabetic osteoporosis. We applied unsupervised cluster analysis to divide the 42 osteoporosis samples from the GSE56814 microarray data into different subclusters based on FRGs. Subsequently, FRGs associated with two ferroptosis subclusters were obtained by combining database genes, module-related genes of WGCNA, and differentially expressed genes (DEGs). Eventually, the key genes from FRGs associated with diabetic osteoporosis were identified using the least absolute shrinkage and selection operator (LASSO), Boruta, support vector machine recursive feature elimination (SVM ­ RFE), and extreme gradient boosting (XGBoost) machine learning algorithms. Based on ROC curves of external datasets (GSE56815), the model’s efficiency was examined.ResultsWe identified 15 differentially expressed FRGs associated with diabetic osteoporosis. In osteoporosis, two distinct molecular clusters related to ferroptosis were found. The expression results and GSVA analysis indicated that 15 FRGs exhibited significantly different biological functions and pathway activities in the two ferroptosis subclusters. Therefore, we further identified 17 FRGs associated with diabetic osteoporosis between the two subclusters. The results of the comprehensive analysis of 17 FRGs demonstrated that these genes were heterogeneous and had a specific interaction between the two subclusters. Ultimately, the prediction model had a strong foundation and excellent AUC values (0.84 for LASSO, 0.84 for SVM ­ RFE, 0.82 for Boruta, and 0.81 for XGBoost). IDH1 is a common gene to all four algorithms thus being identified as a key gene with a high AUC value (AUC = 0.698).ConclusionsAs a ferroptosis regulator, IDH1 is able to distinguish between distinct molecular subtypes of diabetic osteoporosis, which may offer fresh perspectives on the pathogenesis of the disease’s clinical symptoms and prognostic heterogeneity.

The design of the front face of a truck can directly affect the user’s sensory evaluation of the vehicle. Therefore, based on Kansei Engineering theory and deep learning technology, this paper proposes an intelligent design method for the rapid generation of truck front face modeling solutions driven by user images. First, through Kansei Engineering’s relevant experimental methods and scientific data analysis process, the emotional image of the truck’s front face is deeply excavated and positioned, and the corresponding relationship between the characteristics of the truck’s front face and the user’s emotional image cognition is explored. Then, we used the generative confrontation network to integrate the user’s emotional image of the front face of the truck into the intelligent and rapid generation process of the new design scheme of the front face of the truck. Finally, the physiological data of the Electroencephalogram (EEG) experiment are used to evaluate the degree of objective matching between the generated modeling design scheme and the expected image. The purpose of this research is to improve the efficiency, reliability, and intelligence level of truck front face design, and to achieve a more personalized, precise, and high-quality design. This helps to improve the conformity of the modeling design scheme under specific image semantics.

Abstract Colorectal cancer is one of the most common cancers worldwide, accounting for an annual estimated 1.8 million incident cases. With the increasing number of colonoscopies being performed, colorectal biopsies make up a large proportion of any histopathology laboratory workload. We trained and validated a unique artificial intelligence (AI) deep learning model as an assistive tool to screen for colonic malignancies in colorectal specimens, in order to improve cancer detection and classification; enabling busy pathologists to focus on higher order decision-making tasks. The study cohort consists of Whole Slide Images (WSI) obtained from 294 colorectal specimens. Qritive’s unique composite algorithm comprises both a deep learning model based on a Faster Region Based Convolutional Neural Network (Faster-RCNN) architecture for instance segmentation with a ResNet-101 feature extraction backbone that provides glandular segmentation, and a classical machine learning classifier. The initial training used pathologists’ annotations on a cohort of 66,191 image tiles extracted from 39 WSIs. A subsequent application of a classical machine learning-based slide classifier sorted the WSIs into ‘low risk’ (benign, inflammation) and ‘high risk’ (dysplasia, malignancy) categories. We further trained the composite AI-model’s performance on a larger cohort of 105 resections WSIs and then validated our findings on a cohort of 150 biopsies WSIs against the classifications of two independently blinded pathologists. We evaluated the area under the receiver-operator characteristic curve (AUC) and other performance metrics. The AI model achieved an AUC of 0.917 in the validation cohort, with excellent sensitivity (97.4%) in detection of high risk features of dysplasia and malignancy. We demonstrate an unique composite AI-model incorporating both a glandular segmentation deep learning model and a classical machine learning classifier, with excellent sensitivity in picking up high risk colorectal features. As such, AI plays a role as a potential screening tool in assisting busy pathologists by outlining the dysplastic and malignant glands.

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC

The most common primary malignant bone sarcoma is Osteogenic sarcoma (OS) which has a bimodal age distribution. Unfortunately, the treatment of OS was less effective for elderly patients than for younger ones. The study aimed to explore a new microRNA (miRNA) which can bind to combining engineered exosomes for treatment of older OS patients. Based on GSE65071 and miRNet 2.0, two up-regulated miRNAs (miR-328, miR-107) and seven down-regulated miRNAs (miR-133b, miR-206, miR-1-3p, miR-133a, miR-449a, miR-181daysay, miR-134) were selected. Next, we used FunRich software to predict the up-stream transcription factors (TFs) of differentially expressed miRNAs (DE-miRNAs). By comparing target genes predicted from DE-miRNAs with differentially expressed genes, we identified 12 down-regulated and 310 up-regulated mRNAs. For KEGG analysis, the most enriched KEGG pathway was Cell cycle, Spliceosome, and Protein digestion and absorption. By using protein-protein interactions network, topological analysis algorithm and GEPIA database, miR-449a /CCNB1 axis was identified. Experiments in vitro were conducted to confirm the results too. MiRNA-449a is down-regulated in osteosarcoma and suppresses cell proliferation by targeting CCNB1. Our findings not only reveal a novel mechanism of miR-449a /CCNB1 in OS but also had laid the groundwork for further investigation and analysis in the field of exosome engineering.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder without a recognized cause. Aquaporins (AQPs) are transmembrane channels that carry water through cell membranes and are critical for cerebrospinal fluid circulation and cerebral water balance. The function of AQPs in developing and maintaining hydrocephalus should be studied in greater detail as a possible diagnostic and therapeutic tool. Recent research indicates that patients with iNPH exhibited high levels of aquaporin 1 and low levels of aquaporin 4 expression, suggesting that these AQPs are essential in iNPH pathogenesis. To determine the source of iNPH and diagnose and treat it, it is necessary to examine and appreciate their function in the genesis and maintenance of hydrocephalus. The expression, function, and regulation of AQPs in iNPH are reviewed in this article, in order to provide fresh targets and suggestions for future research.

BackgroundGlobally, among all women, the most frequently detected and diagnosed and the most lethal type of cancer is breast cancer (BC). In particular, bone is one of the most frequent distant metastases 24in breast cancer patients and bone metastasis arises in approximately 80% of advanced patients. Thus, we need to identify and validate early detection markers that can differentiate metastasis from non-metastasis breast cancers.MethodsGSE55715, GSE103357, and GSE146661 gene expression profiling data were downloaded from the GEO database. There was 14 breast cancer with bone metastasis samples and 8 breast cancer tissue samples. GEO2R was used to screen for differentially expressed genes (DEGs). The volcano plots, Venn diagrams, and annular heatmap were generated by using the ggplot2 package. By using the cluster Profiler R package, KEGG and GO enrichment analyses of DEGs were conducted. Through PPI network construction using the STRING database, key hub genes were identified by cytoHubba. Finally, K-M survival and ROC curves were generated to validate hub gene expression.ResultsBy GO enrichment analysis, 143 DEGs were enriched in the following GO terms: extracellular structure organization, extracellular matrix organization, leukocyte migration class II protein complex, collagen tridermic protein complex, extracellular matrix structural constituent, growth factor binding, and platelet-derived growth factor binding. In the KEGG pathway enrichment analysis, DEGs were enriched in Staphylococcus aureus infection, Complement and coagulation cascades, and Asthma. By PPI network analysis, we selected the top 10 genes, including SLCO2B1, STAB1, SERPING1, HLA-DOA, AIF1, GIMAP4, C1orf162, HLA-DMB, ADAP2, and HAVCR2. By using TCGA and THPA databases, we validated 2 genes, SERPING1 and GIMAP4, that were related to the early detection of bone metastasis in BC.Conclusions2 abnormally expressed hub genes could play a pivotal role in the breast cancer with bone metastasis by affecting bone homeostasis imbalance in the bone microenvironment.

The purpose of this study was to prepare large hollow particles (LHPs) by spray drying for pulmonary delivery of cyclosporine A (CsA), using L-Leucine (LEU) and hydroxypropyl methylcellulose (HPMC) as excipients and ammonium bicarbonate (AB) as a porogen. The prepared LHPs were spherical particles composed of both CsA and LEU on the surface and HPMC on the inner layer. The formulation of CsA-LEU-0.8HPMC-AB as typical LHPs showed excellent in vitro aerodynamic performance with a minimum mass median aerodynamic diameter (MMAD) of 1.15 μm. The solubility of CsA-LEU-0.8HPMC-AB was about 5.5-fold higher than that of raw CsA, and the dissolution of CsA-LEU-0.8HPMC-AB suggested that the drug was released within 1 h. The cell viability of the A549 cell line showed that CsA-LEU-0.8HPMC-AB was safe for delivering CsA to the lungs. In addition, inhalation administration of CsA-LEU-0.8HPMC-AB with the Cmax and AUC0–∞ increasing by about 2-fold and 2.8-fold compared with the oral administration of Neoral® could achieve therapeutic drug concentrations with lower systemic exposure and significantly improve the in vivo bioavailability of CsA. From these findings, the LHPs, with the advantage of avoiding alveolar macrophage clearance, could be a viable choice for delivering CsA by inhalation administration relative to oral administration.

The post-translational modifications of conopeptides are the most complicated modifications to date and are well-known and closely related to the activity of conopeptides. The hydroxylation of proline in conopeptides affects folding, structure, and biological activity, and prolyl 4 hydroxylase has been characterized in Conus literatus. However, the hydroxylation machinery of proline in conopeptides is still unclear. In order to address the hydroxylation mechanism of proline in μ-PIIIA, three recombinant plasmids encoding different hybrid precursors of μ-PIIIA were constructed and crossly combined with protein disulfide isomerase, prolyl 4 hydroxylase, and glutaminyl cyclase in a continuous exchange cell-free protein system. The findings showed that prolyl 4 hydroxylase might recognize the propeptide of μ-PIIIA to achieve the hydroxylation of proline, while the cyclization of glutamate was also formed. Additionally, in Escherichia coli, the co-expression plasmid encoding prolyl 4 hydroxylase and the precursor of μ-PIIIA containing pro and mature regions were used to validate the continuous exchange cell-free protein system. Surprisingly, in addition to the two hydroxyproline residues and one pyroglutamyl residue, three disulfide bridges were formed using Trx as a fusion tag, and the yield of the fusion peptide was approximately 20 mg/L. The results of electrophysiology analysis indicated that the recombinant μ-PIIIA without C-terminal amidate inhibited the current of hNaV1.4 with a 939 nM IC50. Our work solved the issue that it was challenging to quickly generate post-translationally modified conopeptides in vitro. This is the first study to demonstrate that prolyl 4 hydroxylase catalyzes the proline hydroxylation through recognition in the propeptide of μ-PIIIA, and it will provide a new way for synthesizing multi-modified conopeptides with pharmacological activity.

The effects of global warming have warmed the climate of the Qinghai-Tibetan Plateau (QTP) leading to changes in plant growth and soil nutrients in the alpine meadows. However, few studies have addressed the effects of warming on plant allometric growth and soil stoichiometry in these meadows on a long-term scale. Therefore, the effects of soil stoichiometry on plant allometric growth remain unclear under long-term warming in the alpine meadows. This study adopted infrared radiators to conduct an 8-year warming experiment in a permafrost region on the QTP starting in 2010, and surveyed growth indices of the plant community during the growing season. Soil organic carbon (C), total nitrogen (N), and total phosphorus (P) in an alpine meadow were measured. We initially learned that the aboveground part of the alpine meadow vegetation in the warming treatment changed from an isometric to an allometric growth pattern while the allometric growth pattern of the belowground part was further strengthened. Second, the contents of soil C, N, and P decreased at the 0–20 cm depth and increased at the 20–30 cm depth in warming. The ratios of soil C:N, C:P, and N:P showed increasing trends at different soil depths with artificial warming, and their amplitudes increased with soil depths. Warming promoted the migration of soil stoichiometric characteristics of C, N, and P to deep soil. Finally, the correlations of plant growth with soil stoichiometric characteristics were weakened by warming, demonstrating that the downward migration of soil stoichiometric characteristics to deep soil in warming had effects on the growth of vegetation in the alpine meadow. It concludes that the change in soil stoichiometric characteristics with soil depths promotes plant allometric growth in the alpine meadow under climate warming.

Circular RNAs (circRNAs) were recently reported to be involved in the pathogenesis of ovarian cancer (OC); however, the molecular mechanisms of circRNAs in tumor progression and paclitaxel (PTX) resistance of OC remain largely undetermined. Here, we focused on circTNPO3 (hsa_circ_0001741), which is located on chromosome 7 (chr7): 128655032–128658211 and derived from TNPO3 gene, and thus we termed as circTNPO3. By microarray and qRT-PCR we identified circTNPO3 to be dramatically high expressed in OC samples and correlated with PTX resistance. Functionally, knockdown of circTNPO3 enhanced cell sensitivity to PTX via promoting PTX-induced apoptosis in vitro and in vivo. In mechanism, circTNPO3 acted as a sponge for microRNA-1299 (miR-1299), and NEK2 (NIMA-related kinase 2) was revealed to be target gene of miR-1299. Subsequently, functional assays illustrated that the oncogenic effects of circTNPO3 were attributed to the regulation of miR-1299/NEK2 axis. In conclusion, circTNPO3 contributed to PTX resistance of OC cells at least partly through upregulating NEK2 expression by sponging miR-1299. circTNPO3/miR-1299/NEK2 signaling pathway might play vital roles in the tumorigenesis and chemoresistance of OC.

While treating cancer, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) still faces inevitable drug resistance. Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKI, and is a standard-of-care predictive biomarker used in therapeutic stratification. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR-TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs, and envisions future directions in translational and clinical research.

In some complex labor production and human–machine interactions, such as subway driving, to ensure both the efficient and rapid completion of work and the personal safety of staff and the integrity of operating equipment, the level of mental workload (MW) of operators is monitored at all times. In existing machine learning-based MW classification methods, the association information between neurons in different regions is almost not considered. To solve the above problem, a graph convolution network based on the squeeze-and-excitation (SE) block is proposed. For a raw electroencephalogram (EEG) signal, the principal component analysis (PCA) dimensionality reduction operation is carried out. After that, combined with the spatial distribution between brain electrodes, the dimensionality reduction data can be converted to graph structure data, carrying association information between neurons in different regions. In addition, we use graph convolution neural network (GCN) modified by SE residual to obtain final classification results. Here, to adaptively recalibrate channel-wise feature responses by explicitly modelling interdependencies between channels, the SE block is introduced. The residual connection can ease the training of networks. To discuss the performance of the proposed method, we carry out some experiments using the raw EEG signals of 10 healthy subjects, which are collected using the MATB-II platform based on multi-task aerial context manipulation. From the experiment results, the structural reasonableness and the performance superiority of the proposed method are verified. In short, the proposed GCN modified by the SE residual method is a workable plan of mental workload classification.

Gastric cancer (GC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) have been reported to be the important regulators during the occurrence and development of GC. The present study identified a novel and functional lncRNA in GC, named NR038975, which was confirmed to be markedly upregulated in the Gene Expression Profiling Interactive Analysis (GEPIA) dataset and our independent cohort of GC tissues. We firstly characterized the full-length sequence and subcellular location of NR038975 in GC cells. Our data demonstrated that upregulated NR038975 expression was significantly related to lymph node metastasis and TNM stage. In addition, knockdown of NR038975 inhibited GC cell proliferation, migration, invasion, and clonogenicity and vice versa. Mechanistically, RNA pull-down and mass spectrometry assays identified the NR038975-binding proteins and NF90/NF45 complex, and the binding was also confirmed by RNA immunoprecipitation and confocal experiments. We further demonstrated that genetic deficiency of NR038975 abrogated the interaction between NF45 and NF90. Moreover, NF90 increased the stability of NR038975. Thus, NR038975-NF90/NF45 will be an important combinational target of GC. Finally, we detected NR038975 in serum exosomes and serum of GC patients. Our results indicated that NR038975 was a biomarker for gastric tumorigenesis. The current study demonstrated that NR038975 is a novel lncRNA that is clinically and functionally engaged in GC progression and might be a novel diagnostic marker and potential therapeutic target.

Mycotoxins pose significant risks to humans and livestock. In addition, contaminated food- and feedstuffs can only be discarded, leading to increased economic losses and potential ecological pollution. Mycotoxin removal and real-time toxin level monitoring are effective approaches to solve this problem. As a hot research hotspot, small peptides derived from phage display peptide libraries, combinatorial peptide libraries, and rational design approaches can act as coating antigens, competitive antigens, and anti-immune complexes in immunoassays for the detection of mycotoxins. Furthermore, as a potential approach to mycotoxin degradation, small peptides can mimic the natural enzyme catalytic site to construct artificial enzymes containing oxidoreductases, hydrolase, and lyase activities. In summary, with the advantages of mature synthesis protocols, diverse structures, and excellent biocompatibility, also sharing their chemical structure with natural proteins, small peptides are widely used for mycotoxin detection and artificial enzyme construction, which have promising applications in mycotoxin degradation. This paper mainly reviews the advances of small peptides in the detection of mycotoxins, the construction of peptide-based artificial enzymes, and their potential applications in mycotoxin control.

Abstract Background The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear. Methods The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo. Results TRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells. Conclusions TRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer.

Abstract Background Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. Methods Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. Results PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P

Non-alcoholic fatty liver disease (NAFLD) is one of the chronic liver diseases with high incidence in the world. This study aimed to investigate whether total flavonoids from Chimonanthus nitens Oliv. leaves (TFC) can ameliorate NAFLD. Herein, a high-fat diet (HFD)-induced NAFLD mice model was established, and TFC was administered orally. The results showed that TFC reduced the body weight and liver index and decreased the serum and hepatic levels of triglyceride (TG) and total cholesterol (TC). TFC significantly reduced the activity of liver functional transaminase. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased by 34.61% and 39.57% in serum and 22.46% and 40.86% in the liver, respectively. TFC regulated the activities of oxidative-stress-related enzymes and upregulated the protein expression of nuclear factor E2-related factor (Nrf2)/heme oxygenase (HO-1) pathway in NAFLD mice, and the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) in serum were increased by 89.76% and 141.77%, respectively. In addition, TFC reduced the levels of free fatty acids (FFA), endotoxin (ET), and related inflammatory factors in mouse liver tissue and downregulated the expression of proteins associated with inflammatory pathways. After TFC treatment, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in the liver tissues of NAFLD mice were downregulated by 67.10%, 66.56%, and 61.45%, respectively. Finally, TFC reduced liver fat deposition, oxidative stress, and inflammatory response to repair liver damage and alleviate NAFLD. Further studies showed that TFC regulated the expression of intestinal-barrier-related genes and improved the composition of gut microbiota. Therefore, TFC reduced liver inflammation and restored intestinal homeostasis by regulating the gut–liver axis. Overall, our findings revealed a novel function of TFC as a promising prophylactic for the treatment of NAFLD.

[This corrects the article DOI: 10.1371/journal.pgen.1007888.].

In developing countries, cervical cancer is still the major cause of cancer-related death among women. To better understand the correlation between tumor microenvironment (TME) and prognosis of cervical cancer, we screened 1367 differentially expressed genes (DEGs) of cervical cancer samples in The Cancer Genome Atlas (TCGA) database using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm-derived immune scores. Then, we extracted 401 tumor immune microenvironment (TIME)-related DEGs that related to patients’ survival outcomes. Protein-protein interaction (PPI) network and functional enrichment analysis revealed that the prognostic genes mainly participated in myeloid leukocyte activation, adaptive immune response regulation, and receptor signaling pathways. A total of 79 key prognostic DEGs were obtained through PPI network. A TF-lncRNA-miRNA-mRNA regulatory network was constructed to explore the potential regulatory mechanism. 4 genes (CCR7, PD-1, ZAP70, and CD28) were validated in another independent cohort of cervical cancer from the Gene Expression Omnibus (GEO) database. Finally, potential drugs for key prognostics DEGs were predicted using DrugBank. In conclusion, we obtained a list of potential prognostic TIME-related genes and potential predicted drugs by integrative bioinformatics approaches. A comprehensive understanding of prognostic genes within the TIME may provide new strategies for cervical cancer treatment.

Mammary Paget's disease most commonly affects the nipple areolar complex and is frequently associated with an underlying in-situ or invasive breast carcinoma. Pagetoid Bowen's disease of the breast is extremely rare and contains cells which morphologically resemble those of Paget's disease and may also express CK7 on immunohistochemistry. Here, we report two unusual cases of a 42-year-old Chinese woman with a recurrence of high grade ductal carcinoma in-situ presenting as mammary Paget's disease away from the nipple areolar complex, and a 65-year-old Chinese woman with pagetoid Bowen's disease of the breast skin. To our knowledge, there are only two case reports that are similar to the former and one to the latter. Keywords: Mammary Paget's disease, Pagetoid Bowen's disease

Abstract Background The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment. Methods Joint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis. Results In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC. Conclusions Our study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC.

Abstract Background Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share many common features, including similar morphology, gene expression and in vitro differentiation profiles. However, genomic stability is much lower in iPSCs than in ESCs. In the current study, we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis. Methods Mouse iPSCs, ESCs and embryonic fibroblasts were exposed to ionizing radiation (4 Gy) to introduce double-strand DNA breaks. At 4 h later, fidelity of DNA damage repair was assessed using whole-genome re-sequencing. We also analyzed genomic stability in mice derived from iPSCs versus ESCs. Results In comparison to ESCs and embryonic fibroblasts, iPSCs had lower DNA damage repair capacity, more somatic mutations and short indels after irradiation. iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair. Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice. Conclusions The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due, at least in part, to low fidelity of DNA damage repair.

Poly(sialic acid) (PSA) is a natural hydrophilic biodegradable and non-immunogenic biopolymer, receptors for its monomer are expressed on peripheral blood neutrophils (PBNs), which plays important roles in the progression and invasion of tumors. A poly(sialic acid)–octadecylamine conjugate (PSA–ODA) was synthesized and then anchor it on the surface of liposomal pixantrone (Pix-PSL), to achieve an improved anticancer effect. The liposomes were prepared using a remote loading method via a pH gradient, and then assessed for particle size, zeta potential encapsulation efficiency, in vitro release, and in vitro cytotoxicity. Simultaneously, in vitro and in vivo cellular uptake studies confirmed that PSA-decorated liposomes provided an enhanced accumulation of liposomes in PBNs. An in vivo study presented that the anti-tumor activity of Pix-PSL was superior to that of other Pix formulations, probably due to the efficient targeting of PBNs by Pix-PSL, after which PBN containing Pix-PSL (Pix-PSL/PBNs) in the blood circulation are recruited by the tumor microenvironment. These findings suggest that PSA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumors, which represents a promising approach for the tumor targeting of chemotherapeutic treatments.

Abstract Background Heterotopic pancreas most commonly occurs in the upper gastrointestinal tract of adults, usually as an incidental finding. It seldom occurs at the umbilicus, and even rarely in the pediatric age group. Case presentation Here we present a case of heterotopic pancreatic tissue in the omphalomesenteric duct remnant of a 9-month-old baby girl. She presented with redness at the base of the umbilicus associated with occasional mild wetness. A urachal fistula was suspected by ultrasound. Histology from subsequent resection revealed fibrous tissue with heterotopic pancreatic tissue and accompanying small bowel mucosa. The patient’s umbilical redness resolved after the surgery. Conclusions Upon literature search, we found only 17 other cases of heterotopic pancreas reported in the umbilicus. They described a high male to female ratio, frequent association with omphalomesenteric duct remnant and presentation of umbilical discharge. The Heinrich system is frequently used to classify heterotopic pancreas into 3 types, based on the presence of acini, islets and ducts. Several mechanisms have been proposed on the pathogenesis of heterotopic pancreas, including misplacement, metaplasia and totipotent cell theories. Heterotopic pancreas can manifest clinically with diseases of the pancreas, including malignant transformation, reported as high as 12.7% in a series. Awareness of this finding in the biopsy aids the suitable treatment decisions for the patient.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers in China, but the underlying molecular mechanism of ESCC is still unclear. Involvement of microRNAs has been demonstrated in cancer initiation and progression. Despite the reported function of miR-503 in several human cancers, its detailed anti-oncogenic role and clinical significance in ESCC remain undefined. In this study, we examined miR-503 expression by qPCR and found the downregulation of miR-503 expression in ESCC tissue relative to adjacent normal tissues. Further investigation in the effect of miR-503 on ESCC cell proliferation, migration, and invasion showed that enhanced expression of miR-503 inhibited ESCC aggressive phenotype and overexpression of CCND1 reversed the effect of miR-503-mediated ESCC cell aggressive phenotype. Our study further identified CCND1 as the target gene of miR-503. Thus, miR-503 functions as a tumor suppressor and has an important role in ESCC by targeting CCND1.

Brain metastasis (BM) is a major complication of lung adenocarcinoma (LAD). An investigation of the pathogenic mechanisms of BM, as well as the identification of appropriate molecular markers, is necessary. The aim of this study was to determine the expression patterns of microRNAs (miRNAs) in LAD with BM, and to investigate the biological role of these miRNAs during tumorigenesis. miRNA array profiles were used to identify BM-associated miRNAs. These miRNAs were independently validated in 155 LAD patients. Several in vivo and in vitro assays were performed to verify the effects of miRNAs on BM. We identified six miRNAs differentially expressed in patients with BM as compared to patients with BM. Of these, miR-4270 and miR-423-3p were further investigated. miR-4270 and miR-423-3p directly targeted MMP19 and P21, respectively, to influence cell viability, migration, and colony formation in vitro. miR-4270 downregulation and miR-423-3p upregulation was associated with an increased risk of BM in LAD patients. Thus, our results suggested that miR-4270 and miR-423-3p might play an important role in BM pathogenesis in LAD patients, and that these miRNAs might be useful prognostic and clinical treatment targets.