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High-entropy oxides (HEOs), similar to high-entropy materials (HEMs), have "four-core effects", i.e., high-entropy effect, delayed diffusion effect, lattice distortion effect and cocktail effect, which have attracted more and more attention in the scientific field of renewable energy technology due to their unique structural characteristics, variable chemical composition and corresponding functional properties. HEOs have become potential candidates for electrocatalytic oxygen evolution reaction (OER), which is a key half reaction for electrolytic CO2, nitrogen reduction, and water electrolysis. However, the precise synthesis of HEOs with a wide range of components and structures is challenging, not to mention their active and stable operation for OER. In this paper, we review the recent advancements in the electrocatalytic oxygen evolution facilitated by HEOs in water electrolysis. We analyze these developments from the perspectives of activity and stability in acid and alkaline conditions, respectively. Furthermore, we summarize the design from the aspect of element composition, structure, morphology, and catalyst-support interactions, along with related reaction mechanism of HEOs. Additionally, we discuss the current challenges faced by HEOs in the field of OER and suggest potential directions for the future development of HEOs beyond water electrolysis application., (© 2024 Wiley‐VCH GmbH.)

Neonicotinoids are widely used insecticides that accumulate in various environmental matrixes and potentially harm non-target organisms. However, the mechanism of sorption/desorption of neonicotinoids in different loess soils remains poorly understood. Therefore, this study investigated the sorption/desorption of nitenpyram (NIT), a commonly used neonicotinoid, in three different types of loess soils and examined factors influencing the adsorption process using batch experiments. The findings revealed that NIT reached adsorption equilibrium in 4 h in all three loess soil samples. The R 2 value (> 0.898) obtained from fitting the sorption/desorption kinetics indicated a good match with the pseudo-second-order model, suggesting the involvement of multiple mechanisms, including chemisorption. The linear and Freundlich models also adequately described the sorption of NIT in loess soils. Additionally, a clear hysteresis phenomenon was observed. The adsorption capacity of NIT is significantly related to the adsorption temperature, solution pH and ionic strength. Upon increasing the initial concentration, the equilibrium adsorption capacity of NIT for gray-cinnamon soil, sierozem, and cultivated loessial soil increased from 3.56, 2.51, and 2.64 mg/kg to 8.49, 3.92, and 5.22 mg/kg, respectively. FTIR spectral analysis revealed that the adsorption of NIT in loess soil was primarily governed by mixed mechanism. This study elucidates the behavior and fate of NIT in soil-water systems in the Northwest, while also establishing a foundation for assessing its ecological risks. The findings have significant practical implications for the future development of environmental management and pollution control strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Current therapies against pancreatic ductal adenocarcinoma (PDAC) have limited clinical benefits owing to tumor heterogeneity and their unique immunosuppressive microenvironments. The eukaryotic initiation factor (eIF) 4F complex is involved in regulating translation and various downstream carcinogenic signaling pathways. We report that eIF4G1, one of the subunits of eIF4F, is overexpressed in cancer cells and cancer-associated fibroblasts, and this correlates with poor prognosis in patients with PDAC. In PDAC mice, eIF4G1 inhibition limits tumor progression and prolongs overall survival, especially when combined with PD1/PDL1 antagonists and gemcitabine. Mechanistically, eIF4G1 inhibition hinders the production of cytokines and chemokines that promote fibrosis and inhibit cytotoxic T cell chemotaxis. Moreover, eIF4G1 inhibition impairs integrinβ1 protein translation and exerts tumor suppression effects through the FAK-ERK/AKT signaling pathway. These findings highlight the effects of eIF4G1 on tumor immune dependence and independence and identify eIF4G1 as a promising therapeutic target for PDAC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Postoperative high-activity delirium (PDHA) manifests as a high alertness, restlessness, hallucinations, and delusions. Occurrence of PDHA represents an increased risk of poor prognosis for patients., Objective: To establish and validate a nomogram prediction model for high-activity delirium after non-cardiac surgery in a post-anesthesia care unit (PACU)., Methods: This study retrospectively enrolled adult patients who underwent non-cardiac surgery and were observed in the PACU as training data. Patients were divided into PDHA (199 patients) and non-PDHA (396 patients) groups. Patients' general data, preoperative indicators, intraoperative conditions, and postoperative PACU conditions were collected. The risk factors for PDHA were identified using univariate and multivariate logistic regression analyses. A predictive column chart was created using R language. Adult patients who underwent non-cardiac surgery and entered the PACU for observation were randomly selected as the validation set data (198 cases) for model performance validation., Results: The incidence rate of adult PDHA in the PACU was 0.275%. Sex, age, smoking history, low preoperative albumin level, Society of Anesthesiologists (ASA) classification, anesthesia duration, and postoperative PACU pain score were independent risk factors for hyperactive delirium in PACU adults. In this study, an adult PACU PDHA nomogram prediction model was developed. The training dataset verified that the ROC curve (area under the curve) and 95% confidence interval (95% CI) were 0.936 (0.917-0.955). The ROC curve of the validation data row showed that the area under the curve and 95% CI were 0.926 (0.885-0.967)., Conclusion: The nomogram predictive model for PACU adult high-activity delirium constructed in this study showed good predictive performance. This model could enable the visualization and graphical prediction of adult high-activity delirium occurrence after PACU, which has clinical value., Competing Interests: The authors have no competing interests to declare relevant to the content of this article., (© 2024 Tu et al.)

Fluoroquinolone antibiotics have been extensively used in clinical treatments for human and animal diseases. However, their long-term presence in the environment increases the risk of producing resistance genes and creates a potential threat to ecosystems and the health of humans and animals. Batch equilibrium experiments were utilized to investigate the adsorption and retention behavior and mechanism of the quinolone antibiotic enrofloxacin (ENR) in farmland soil in North China. The adsorption and desorption kinetics of ENR in soil were best fitted by pseudo-second-order model (R 2  > 0.999). Both the adsorption and desorption processes of ENR in soil reached equilibrium in 1 h. The desorption amounts of ENR were significantly lower than the adsorption amounts, with the hysteresis coefficient (HI) being less than 0.7. The adsorption thermodynamic process of ENR followed the Linear and Freundlich models (0.965 < R 2  < 0.985). Hydrophobic distribution and heterogeneous multimolecular layer adsorption were identified as critical factors in the adsorption process. The adsorption amount of ENR gradually decreased with increasing temperature and the initial concentration of ENR. The adsorption rate of ENR was above 80%, while the desorption rate remained below 15%, indicating strong retention ability. The adsorption rate of ENR in soil decreased with increasing pH, the adsorption rate reached 98.3% at pH 3.0 but only 31.5% at pH 11. The influence of coexisting ions on adsorption primarily depended on their properties, such as ion radius, ionic strength, and hydrolysis properties, and the inhibition of adsorption increased with increasing ionic strength. These findings contribute to understanding the fate and risk of veterinary antibiotics in loess soil in North China., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Microscopic cell detection is a challenging task due to significant inter-cell occlusions in dense clusters and diverse cell morphologies. This paper introduces a novel framework designed to enhance automated cell detection. The proposed approach integrates a deep learning model that produces an inverse distance transform-based detection map from the given image, accompanied by a secondary network designed to regress a cell density map from the same input. The inverse distance transform-based map effectively highlights each cell instance in the densely populated areas, while the density map accurately estimates the total cell count in the image. Then, a custom counting-aided cell center extraction strategy leverages the cell count obtained by integrating over the density map to refine the detection process, significantly reducing false responses and thereby boosting overall accuracy. The proposed framework demonstrated superior performance with F-scores of 96.93%, 91.21%, and 92.00% on the VGG, MBM, and ADI datasets, respectively, surpassing existing state-of-the-art methods. It also achieved the lowest distance error, further validating the effectiveness of the proposed approach. These results demonstrate significant potential for automated cell analysis in biomedical applications.

To achieve a selective degradation of pollutants in a water body, 3D/1D magnetic molecularly imprinted fibers Fe 3 O 4 @TiO 2 /TC-TiO 2 /SiO 2 were fabricated by an electrospinning method. The molecularly imprinted layer was successfully prepared by a direct imprinting method using TiO 2 as a functional monomer. Fe 3 O 4 facilitates the catalyst recovery and light utilization. The as-prepared fibrous photocatalyst has a large specific surface area of 132.4 m 2 /g. The successful generation of imprinted sites was proven by various characterizations. The weak interaction between the inorganic functional monomer and tetracycline (TC) was determined to be van der Waals force and hydrogen bonds by the IGMH isosurface theory. The construction of the 3D/1D homojunction of molecularly imprinted materials is beneficial to charge transfer. The as-prepared photocatalyst exhibits a high selectivity coefficient α = 737.38 competing with RhB. The TC removal efficiency reached 100% within only 20 min. In addition, the possible degradation pathway and the degradation mechanism are reasonably proposed. This work not only provides an in-depth mechanism of the weak interaction between the inorganic molecularly imprinted functional monomer and pollutant molecules but also offers new thoughts on the fabrication of photocatalysts for the effective and selective treatment of pollutants in water bodies.

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer. Abbreviation : AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Per- and polyfluoroalkyl substances (PFASs) are known to be linked with dyslipidemia. Between March and June 2022, we collected 575 fasting serum samples from individuals without occupational exposure in Jinan, China. Eighteen PFASs were analyzed using UHPLC-Orbitrap MS. Multiple linear regression (MLR), Bayesian kernel machine regression (BKMR), and Quantile g-computation (QGC) models were utilized to assess the effects of both individual PFAS and PFAS mixtures on serum lipid levels, including triglycerides (TG), cholesterol (CHO), high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The PFAS mixture, composed of perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonic acid (PFHpS), perfluorooctane sulfonate (PFOS), and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA), showed a positive association with CHO and LDL levels, while no distinct trend was noted in HDL and TG levels about changes in PFAS mixtures levels in BKMR and QGC models, adjusted for gender, age, BMI, occupation, and educational level. The effects of individual PFASs on lipid levels were in general consistent across MLR, BKMR and QGC models. PFUnDA and PFTrDA demonstrated greater impacts on blood lipid levels compared to other PFAS, albeit with varied directional effects. Age-stratified analysis revealed PFAS mixture effect was more pronounced in participants aged higher than 40. No obvious trend in lipid levels with changes in PFAS mixture levels in participants with age ranged from 18 to 40, while positive association between PFAS mixture and CHO and LDL was detected in participants aged higher than 40., 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.)

Prenatal exposure to phthalates (PAEs) is ubiquitous among Chinese neonates. PAEs entering the body will be transformed to various hydrolyzed and oxidated PAE metabolites (mPAEs). PAEs and mPAEs exposure may lead to adverse birth outcomes through disruption of multiple hormone signaling pathways, induction of oxidative stress, and alterations in intracellular signaling processes. In this study, the concentrations of 11 mPAEs in 318 umbilical cord serum samples from neonates in Jinan were quantified with HPLC-ESI-MS. Multiple linear regression, Bayesian kernel machine regression, and quantile g-computation models were utilized to investigate the effects of both individual mPAE and mPAE mixture on birth outcomes. Stratified analysis was performed to explore whether these effects were gender-specific. mPAE mixture was negatively associated with birth length (BL) z-score, birth weight (BW) z-score, head circumference (HC) z-score, and ponderal index (PI). Mono(2-ethylhexyl) phthalate (MEHP) manifested negative associations with BL(z-score), BW(z-score), HC(z-score), and PI, whereas mono(2-carboxymethylhexyl) phthalate (MCMHP) was negatively associated with BW(z-score) and PI within the mPAE mixture. Stratified analysis revealed that the negative associations between mPAE mixture and four birth outcomes were attenuated in female infants, while the positive impact of mono(2-ethyl-5carboxypentyl) phthalate (MECPP) on BL(z-score) and BW(z-score) could be detected only in females. In summary, our findings suggest that prenatal exposure to phthalates may be associated with intrauterine growth restriction, and these effects vary according to the gender of the infant., 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.)

Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME 2 ) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs 3 ) and adoptive cell transfer (ACT 4 ), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xueli Bai reports financial support was provided by National Natural Science Foundation of China. Xueli Bai reports financial support was provided by Key Research and Development Program of Zhejiang Province. Xueli Bai reports financial support was provided by Fundamental Research Funds for the Zhejiang Provincial Universities., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most prevalent subtypes of primary liver cancer, with high mortality and poor prognosis. Immunotherapy has revolutionized treatment strategies for many cancers. However, only a subset of patients with HCC achieve satisfactory benefits from immunotherapy. Therefore, a reliable biomarker that could predict the prognosis and immunotherapy response in patients with HCC is urgently needed. Taurine plays an important role in many physiological processes. However, its participation in the occurrence and progression of liver cancer and regulation of the composition and function of various components of the immune microenvironment remains elusive. In this study, we identified and validated two heterogeneous subtypes of HCC with different taurine metabolic profiles, presenting distinct genomic features, clinicopathological characteristics, and immune landscapes, using multiple bulk transcriptome datasets. Subsequently, we constructed a risk model based on genes related to taurine metabolism to assess the prognosis, immune cell infiltration, immunotherapy response, and drug sensitivity of patients with HCC. The risk model was validated using several independent external cohorts and showed a robust predictive performance. In addition, we evaluated the expression patterns of taurine metabolism-related genes in the tumor microenvironment and the heterogeneity of taurine metabolism among cancer cells using a single-cell transcriptome. In conclusion, our study provides insights into the important role played by taurine metabolism in tumor progression and immune regulation. Furthermore, the risk model can serve as a biomarker to assess patient prognosis and immunotherapy response, potentially helping clinicians make more precise and personalized clinical decisions., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 The Authors.)

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Protective immunity following vaccination is sustained by long-lived antibody-secreting cells and resting memory B cells (MBCs). Responses to two-dose SARS-CoV-2 mRNA-1273 vaccination are evaluated longitudinally by multimodal single-cell analysis in three infection-naïve individuals. Integrated surface protein, transcriptomics, and B cell receptor (BCR) repertoire analysis of sorted plasmablasts and spike + (S-2P + ) and S-2P - B cells reveal clonal expansion and accumulating mutations among S-2P + cells. These cells are enriched in a cluster of immunoglobulin G-expressing MBCs and evolve along a bifurcated trajectory rooted in CXCR3 + MBCs. One branch leads to CD11c + atypical MBCs while the other develops from CD71 + activated precursors to resting MBCs, the dominant population at month 6. Among 12 evolving S-2P + clones, several are populated with plasmablasts at early timepoints as well as CD71 + activated and resting MBCs at later timepoints, and display intra- and/or inter-cohort BCR convergence. These relationships suggest a coordinated and predictable evolution of SARS-CoV-2 vaccine-generated MBCs., Competing Interests: Declaration of interests S.H.K. receives consulting fees from Peraton. K.B.H. receives consulting fees from Prellis Biologics., (Published by Elsevier Inc.)

Background: Uterine cervical carcinoma is a severe health threat worldwide, especially in China. The International Federation of Gynecology and Obstetrics (FIGO) has revised the staging system, emphasizing the strength of magnetic resonance imaging (MRI). We aimed to investigate long-term prognostic factors for FIGO 2018 stage II-IIIC2r uterine cervical squamous cell carcinoma following definitive radiotherapy and establish a prognostic model using MRI-derived tumor volume., Methods: Patients were restaged according to the FIGO 2018 staging system and randomly grouped into training and validation cohorts (7:3 ratio). Optimal cutoff values of squamous cell carcinoma antigen (SCC-Ag) and tumor volume derived from MRI were generated for the training cohort. A nomogram was constructed based on overall survival (OS) predictors, which were selected using univariate and multivariate analyses. The performance of the nomogram was validated and compared with the FIGO 2018 staging system. Risk stratification cutoff points were generated, and survival curves of low-risk and high-risk groups were compared., Results: We enrolled 396 patients (training set, 277; validation set, 119). The SCC-Ag and MRI-derived tumor volume cutoff values were 11.5 ng/mL and 28.85 cm 3 , respectively. A nomogram was established based on significant prognostic factors, including SCC-Ag, poor differentiation, tumor volume, chemotherapy, and FIGO 2018 stage. Decision curve analysis indicated that the net benefits of our model were higher. The high-risk group had significantly shorter OS than the low-risk group in both the training (p < 0.0001) and validation sets (p = 0.00055)., Conclusions: Our nomogram predicted long-term outcomes of patients with FIGO 2018 stage II-IIIC2r uterine cervical squamous cell carcinoma. This tool can assist gynecologic oncologists and patients in treatment planning and prognosis., (© 2023. The Author(s).)

Autophagy helps maintain energy homeostasis and protect cells from stress effects by selectively removing misfolded/polyubiquitylated proteins, lipids, and damaged mitochondria. Cancer-associated fibroblasts (CAFs) are cellular components of tumor microenvironment (TME). Autophagy in CAFs inhibits tumor development in the early stages; however, it has a tumor-promoting effect in advanced stages. In this review, we aimed to summarize the modulators responsible for the induction of autophagy in CAFs, such as hypoxia, nutrient deprivation, mitochondrial stress, and endoplasmic reticulum stress. In addition, we aimed to present autophagy-related signaling pathways in CAFs, and role of autophagy in CAF activation, tumor progression, tumor immune microenvironment. Autophagy in CAFs may be an emerging target for tumor therapy. In summary, autophagy in CAFs is regulated by a variety of modulators and can reshape tumor immune microenvironment, affecting tumor progression and treatment., Competing Interests: Conflict of interest statement No potential conflict of interest was reported by the authors., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cork spot disorder has affected the fruit of Asian pear since the 1990s and has become serious in recent years with increasingly affected cultivars and areas. The commodity value of affected fruit is greatly decreased, resulting in severe economic losses. Cork spot disorder of pear fruit is a physiological disorder, and the factors responsible are relatively complex. Research on the cause of cork spot disorder is still at an early stage and, thus, further investigations are needed to elucidate the underlying mechanism of the disorder. In this review, current knowledge of the factors associated with the incidence of cork spot disorder in Asian pear fruit is summarized, including fruit growth and development, fruit nutrient status, and environmental factors. Potential preventive measures and priorities for future research are outlined., 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 Zhang and Cui.)

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5 high CAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5 high CAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment., (© 2023. The Author(s).)

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future., (© 2022. The Author(s).)

Background: The study aimed to evaluate the effect of a galectin-9 and PD-L1 combined blockade in pancreatic ductal adenocarcinoma (PDAC). Methods: The expression of galectin-9 and PD-L1 was analyzed in PDAC. Furthermore, we explored the therapeutic effect of combined anti-galectin-9 and anti-PD-L1 therapy on pancreatic cancer in vivo . Results: Higher expression of galectin-9 and PD-L1 was observed in human PDAC compared with the normal pancreas. Furthermore, in a murine model of PDAC, combined anti-galectin-9 and anti-PD-L1 treatment was associated with a greater decrease in tumor growth compared with treatment with either antibody therapy alone. Conclusion: Anti-PD-L1 antibody treatment for PDAC patients may be enhanced by inhibiting galectin-9.

The VG161 represents the first recombinant oncolytic herpes simplex virus type 1 carrying multiple synergistic antitumor immuno-modulating factors. Here, we report its antitumor mechanisms and thus provide firm theoretical foundation for the upcoming clinical application in pancreatic cancer. Generally, the VG161-mediated antitumor outcomes were analyzed by a collaboration of techniques, namely the single-cell sequencing, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADSI-MSI) and nanostring techniques. In vitro, the efficacy of VG161 together with immune checkpoint inhibitors (ICIs) has been successfully shown to grant a long-term antitumor effect by altering tumor immunity and remodeling tumor microenvironment (TME) metabolisms. Cellular functional pathways and cell subtypes detected from patient samples before and after the treatment had undergone distinctive changes including upregulated CD8+ T and natural killer cells. More importantly, significant antitumor signals have emerged since the administration of VG161 injection. In conclusion, VG161 can systematically activate acquired and innate immunity in pancreatic models, as well as improve the tumor immune microenvironment, indicative of strong antitumor potential. The more robusting antitumor outcome for VG161 monotherapy or in combination with other therapies on pancreatic cancer is worth of being explored in further clinical trials., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri , which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27 lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

This research on porphyrin-based photosensitizer system has a very important theoretical and practical significance in the photodynamic therapy (PDT) treatment of cancer. Based on this, in this article, a series of porphyrin derivatives were first designed and synthesized, and a "push-pull" porphyrin photosensitizer with two symmetrical ethanethioate groups was finally constructed. Based on the characterization of their chemical structures ( 1 H and 13 C NMR, MS, IR, and UV-Vis spectroscopy) and the use of the density functional theory (DFT) and time-dependent DFT (TDDFT) to address the nature of the excited states as well as the dark/phototoxicity, the results have indicated the relationship between the porphyrin structure and properties. The experimental and theoretical UV-Vis absorption properties of porphyrins were discussed. The four porphyrin compounds synthesized all demonstrated a high capacity to generate singlet oxygen under long-wavelength (590 nm) light and low dark toxicity. Compared with the conventional porphyrin photosensitizers, P4 with a CT band (from 580 to 750 nm) is beneficial to the penetration of the light, presenting the potential for applications in PDT., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a pathogenic splicing mutation in CEP78 in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype. We further created Cep78 knockout mice, which showed an extremely low sperm count, completely aberrant sperm morphology, and approximately null sperm motility. The infertility of the patients and knockout mice could not be rescued by an intracytoplasmic sperm injection treatment. Mechanistically, CEP78 might regulate USP16 expression, which further stabilizes Tektin levels via the ubiquitination pathway. Cep78 knockout mice also exhibited impairments in retina and outer hair cells of the cochlea. Collectively, our findings identified nonfunctional CEP78 as an indispensable factor contributing to male infertility and revealed a role for this gene in regulating retinal and outer hair cell function in mice.

Constructing the strong interaction between the matrix and the active centers dominates the design of high-performance electromagnetic wave (EMW) absorption materials. However, the interaction-relevant absorption mechanism is still unclear, and the design of ultrahigh reflection loss ( R L < -80 dB) absorbers remains a great challenge. Herein, CoFe-based Prussian blue (PB) nanocubes are coprecipitated on the surface of ultrathin CoAl-LDH nanoplates with the assistance of unsaturated coordination sites. During the subsequent pyrolysis process, CoAl-LDH serves as a "ligand" providing a Co source and reacts with Fe or C in the CoFe-PB "host" to form stable CoFe alloys or CoC x species. As a result, strong reactions emerged between the CoAl-LDH matrix and the active CoFe-CoC x @NC centers. Based on the experimental results, the CoAl/CoFe-CoC x @NC hierarchical heterostructure delivers good dielectric losses (dipolar polarization, interface polarization, and conductive loss), magnetic losses (eddy current loss, natural resonance, and exchange resonance), and impedance matching, resulting in a remarkable EMW absorption performance with a reflection loss ( R L ) value of -82.1 dB at a matching thickness of 3.8 mm. Theoretical results (commercial CST) identify that the strong interaction between the 2D CoAl-LDH "ligand" and 2D CoFe-CoC x "host" promotes a robust heterointerface among the nanoparticles, nanosheets, and nanoplates, which extremely contribute to the dielectric loss. Meanwhile, the coupling effect of nanosheets and nanoplates greatly contributes to the matching performance. This work provides an aggressive strategy for the effect of ligands and hosts on high-performance EMW absorption.

O-linked β-D-N-acetylglucosamine (O-GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process. O-GlcNAc transferase is responsible for adding O-GlcNAc to proteins, while O-GlcNAcase is responsible for removing it. Aberrant O-GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that O-GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of O-GlcNAcylation and the structure and function of O-GlcNAc cycling enzymes. In addition, we detail the occurrence of O-GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of O-GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis., (© 2022. The Author(s).)

Nickel-rich (Ni-rich) cathode materials, LiNi x Co y Mn z O 2 (NCM, x ≥ 0.9, x + y + z = 1) hold great promise for developing high energy density lithium ion batteries especially for vehicle electrification. However, the practical application of Ni-rich cathode materials is still suffered from fast structural and interfacial degradation, and the resulted capacity decay. In this study, a diazacyclo type electrolyte additive, 2-fluoropyrazine (2-FP), was explored for the first time to boost the interfacial stabilization of single crystal LiNi 0.90 Co 0.05 Mn 0.05 O 2 (NCM90) cathode. The capacity retention of the NCM90 is evidently promoted from 72.3% to 82.1% after 200 cycles at 1C (180 mA g -1 ) when adding 0.2% 2-FP into the electrolyte. The improvement of the electrochemical performance is ascribed to the generation of a compact and homogeneous cathode electrolyte interphase (CEI) film through ring-opening electrochemical polymerization of 2-FP upon the NCM90 electrode particles. This enhanced CEI layer benefits the suppression of the decomposition of LiPF 6 electrolyte and the dissolution of the transition metals (Co and Mn), thus preventing the detrimental side reactions between the NCM90 electrode and the electrolyte., 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 © 2022 Elsevier Inc. All rights reserved.)

LncRNA MNX1-AS1 is known to be involved in progression of several tumor types. However, few studies have investigated the molecular mechanism of MNX1-AS1 in lung adenocarcinoma (LAC). To explore the function of MNX1-AS1 in the pathogenesis of LAC, qRT-PCR was performed to show MNX1-AS1 expression. MNX1-AS1 expression in LAC cells was suppressed by siRNA to detect the biologic behavior. The relationships among miR-34a, MNX1-AS1 and SIRT1 were confirmed by pull-down and dual-luciferase reporter assay. Whether MNX1-AS1 was involved in LAC by targeting miR-34a/SIRT1 axis was verified. MNX1-AS1 was up-regulated in LAC, and over-expression of MNX1-AS1 was significantly associated with lymph node metastasis and poor prognosis. In A549 and H1299 cells, cell proliferation, migration, and invasion were suppressed, the cell cycle was regulated, as well as apoptosis was increased after silencing MNX1-AS1. Mechanistically, MNX1-AS1 served as a ceRNA of miR-34a to down-regulate miR-34a expression. SIRT1 is targeted by miR-34a and its expression is regulated by MNX1-AS1 and miR-34a. Up-regulation of SIRT1 salvaged the effect of silencing MNX1-AS1 on A549 and H1299 cells, to some extent. These results showed that MNX1-AS1 contributes to LAC progression by targeting the miR-34a/SIRT1 axis., Competing Interests: None., (AJTR Copyright © 2022.)

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Cancer is the leading cause of mortality worldwide. Regulator of calcineurin 1 (RCAN1), as a patent endogenous inhibitor of calcineurin, plays crucial roles in the pathogenesis of cancers. Except for hypopharyngeal and laryngopharynx cancer, high expression of RCAN1 inhibits tumor progression. Molecular antitumor functions of RCAN1 are largely dependent on calcineurin. In this review, we highlight current research on RCAN1 characteristics, and the interaction between RCAN1 and calcineurin. Moreover, the dysregulation of RCAN1 in various cancers is reviewed, and the potential of targeting RCAN1 as a new therapeutic approach is discussed., (© 2022. The Author(s).)

Human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2) is a newly emerging immune checkpoint that belongs to B7 family. HHLA2 has a co-stimulatory receptor transmembrane and immunoglobulin domain containing 2 (TMIGD2) and a newly discovered co-inhibitory receptor killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3), which endows it with both immunostimulant and immunosuppression functions in cancer development. In this review, we summarize the HHLA2 expression profile in human cancers, its association with cancer prognosis and clinical features, and its dual roles in regulating cancer immune response through up-to-date literatures. Furthermore, we highlight that precision cancer immunotherapy through manipulating HHLA2-KIR3DL3/TMIGD2 interaction is a promising antitumour strategy., Competing Interests: Declaration of interests All authors report grants from National Natural Science Foundation of China, grants from Fundamental Research Funds for the Zhejiang Provincial Universities, grants from Key Research and Development Program of Zhejiang Province, grants from Key Program of Medical Scientific Research Foundation of Zhejiang Province, during the conduct of the study., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Tumor necrosis factor (TNF) receptor type II (TNFR2) is expressed in various tumor cells and some immune cells, such as regulatory T cells and myeloid-derived suppressing cells. TNFR2 contributes a lot to the tumor microenvironment. For example, it directly promotes the occurrence and growth of some tumor cells, activates immunosuppressive cells, and supports immune escape. Existing studies have proved the importance of TNFR2 in cancer treatment. Here, we reviewed the activation mechanism of TNFR2 and its role in signal transduction in the tumor microenvironment. We summarized the expression and function of TNFR2 within different immune cells and the potential opportunities and challenges of targeting TNFR2 in immunotherapy. Finally, the advantages and limitations of TNFR2 to treat tumor-related diseases are discussed, and the problems that may be encountered in the clinical development and application of targeted anti-TNFR2 agonists and inhibitors are analyzed., 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 © 2022 Li, Zhang, Bai and Liang.)

Rutile TiO 2 pigments codoped with chromophore ion Cr 3+ and various charge-balancing ions (i.e., counterions species of Sb, Nb, W and Mo) were prepared by a solid-phase reaction method. The effects of the counterions and calcination temperatures on the phase structure, color-rendering and spectroscopic properties, microstructure, and stability of the synthesized pigments were investigated in detail. The results showed that the introduction of 5-10% counterions improved the solubility of Cr 3+ in the TiO 2 lattice to form the single-phase rutile pigments calcined at 1100 °C for 2 h. The 10% Cr-doped pigment showed a dark brown color. Depending on the content and type of counterions, the color of the codoped pigments was tailored from yellow to reddish or yellowish-orange to black with different brightness and hue. The influence mechanism of counterions was ascribed to the lattice distortion and variation in the charge balance condition. It was found that the addition of Sb, Nb, or Mo resulted in a remarkable improvement in the NIR reflectance of pigments. The grain growth was inhibited with the codoping of Cr/Sb and Cr/Nb to achieve the nano-sized pigments. In addition, the prepared pigments exhibited good acid and alkali corrosion resistance as well as excellent stability and coloring performance in transparent ceramic glazes.

Backgrounds: In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy., Methods: Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype., Results: TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells., Conclusions: Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Stimulus-responsive polymers with luminescence properties have a wide range of applications in the fields of controlled drug release, fluorescent probes, and biological stents. In this paper, carbon dioxide (CO 2 )/oxygen (O 2 ) dual-responsive fluorescent diblock copolymers were synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization method with two fluorescent monomers synthesized as its luminescence source, DEAEMA (CO 2 responsive monomer) and tFMA (O 2 responsive monomer). An experimental study demonstrated that the synthesized stimulus-responsive fluorescent polymer had a high sensitivity to CO 2 ; the double-responsive fluorescent diblock copolymer could form and achieve the reversal of polymer micelles in the aqueous solution when it was sequentially subjected to the introduction of CO 2 and O 2 ., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To present a nomogram to predict overall survival in patients with FIGO-2018 II to III squamous cell cervical carcinoma undergoing radical radiotherapy., Patients and Methods: Patients diagnosed with FIGO-2018 II to III squamous cell cervical cancer between December 2013 and December 2014 were analyzed retrospectively. The optimal cutoff point for tumor length and width were determined by R package. We identified prognostic factors by univariate and multivariate Cox proportional-hazard regression, then built a nomogram to visualize the prediction model. Our model was compared to the 2018 FIGO staging prediction model. Harrell's concordance index, receiver operating characteristic curve, calibration plot were used to evaluate the discriminability and accuracy of the predictive models, and decision curve analysis (DCA) was used to show the net benefits., Results: Data from 469 patients were included in the final analyses. The cutoff values of tumor length and width were 5.10 cm and 4.13 cm, respectively. Four independent prognostic variables-tumor length, tumor width, lower one-third vaginal involvement, and lymph node metastases-were used to establish the nomogram. The C-index of the nomogram was 0.71 (95%, CI = 0.66-0.77), which was better than that of the 2018 FIGO stage prediction model (C-index: 0.62, 95% CI = 0.58-0.66, p = 0.009). The calibration plot of the nomogram was a good fit for both 3-year and 5-year overall survival predictions. And DCA curves showed that net benefits for our model were higher than FIGO-2018 staging system., Conclusion: A clinically useful nomogram for calculating overall survival probability in FIGO-2018 II to III squamous cell cervical cancer patients who had received radical radiotherapy was developed. Tumor length, tumor width, lower one-third vaginal involvement, and lymph node metastases were found to be independent prognostic factors. Our model performed better than the 2018 FIGO staging model. The findings could help clinicians in China to predict the survival of these patients in clinical care and research., Competing Interests: The authors declare no conflicts of interest., (© 2021 Zang et al.)

This paper presents an in-depth analysis and study of the diagnostic effectiveness of EUS-RTE in giant cystic tumours of the oesophagus utilizing cluster analysis. A new form of interval data expression was designed based on the cluster analysis algorithm, as well as a new way of updating the cluster radius and cluster centre. Feature triads are defined, eliminating the need to access all historical data at the time of update. It also prevents the case of overfusion of clusters and outputting only one cluster. If there exist a very low number of clusters, the newly merged clusters are reclustered according to the density clustering method for the internal data objects based on the cluster segmentation so that the data objects in the same cluster have a high similarity as possible. All accumulated electronic files of oesophageal cancer cases were collected and comprehensively organized, and all clinical data of 129 eligible cases with a total of 356 consultations were screened in strict accordance with inclusion and exclusion criteria. A database of oesophageal cancer cases was established using Visual FoxPro software, and frequency distribution, cluster analysis, association rule, and chi-square test were used to focus on mining the association between symptoms, disease mechanisms, prescriptions, and medications. The results were analysed and summarized. Overall, the therapeutic efficacy and safety of the three groups of treatment modalities for gastric mesenchymal tumours were positive, and the preoperative endoscopic treatment modalities should be selected based on the EUS-RTE characteristics of the tumour, the site, and the operator's skill level in a comprehensive manner., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Huizhen Yang et al.)

Programmed death ligand 1 (PD-L1) has conventionally been considered as a type I transmembrane protein that can interact with its receptor, programmed cell death 1 (PD-1), thus inducing T cell deactivation and immune escape. However, targeting the PD-1/PD-L1 axis has achieved adequate clinical responses in very few specific malignancies. Recent studies have explored the extracellularly and subcellularly located PD-L1, namely, nuclear PD-L1 (nPD-L1), cytoplasmic PD-L1 (cPD-L1), soluble PD-L1 (sPD-L1), and extracellular vesicle PD-L1 (EV PD-L1), which might shed light on the resistance to anti-PD1/PDL1 therapy. In this review, we summarize the four atypical localizations of PD-L1 with a focus on their novel functions, such as gene transcription regulation, therapeutic efficacy prediction, and resistance to various cancer therapies. Additionally, we highlight that non-cytomembrane PD-L1s are of significant cancer diagnostic value and are promising therapeutic targets to treat cancer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy., (© 2021. The Author(s).)

Background: Fasting changes mitochondrial function, and mTOR acts as a major regulator of mitochondrial energy production ensuring the survival under reduced supply of nutrition. This study assessed the role of protein arginine methyltransferase 1 (PRMT1), which regulates mitochondrial function, in the context of fasting., Methods: The effect of fasting on mTOR signaling and mTOR-regulated mitochondrial mass was assessed in LO2 cells (in vitro) and C57BL/6J mice (in vivo). Biochemical parameters of fasting were determined in blood samples of mice. PRMT1 expression was investigated by transfecting LO2 cells with an expression vector. Gene expression was determined by real-time quantitative PCR, protein interaction by chromatin immunoprecipitation, protein expression by Western blotting and immunofluorescence microscopy, and the mitochondrial mass by MitoTracker staining., Results: After 48 h of fasting, mTOR and PRMT1 expression, as well as mitochondrial mass, were significantly reduced in LO2 cells, and in liver tissue sections. Fasting downregulated the expression of miR-21 and upregulated the expression of its target phosphatase and tensin homolog (PTEN), which was responsible for reduced mTOR expression. Inhibition of mTOR reduced phosphorylation of STAT1, and thereby PRMT1 expression in LO2 cells. Low PRMT1 down-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ and thereby decreased mitochondrial mass. Supplementation of insulin contracted the effect of fasting on all mentioned parameters., Conclusions: Fasting downregulates miR-21 and increases its target PTEN, thereby inhibiting mTOR signaling, p-STAT1, PRMT1, and mitochondrial mass. These findings highlight the role of mTOR and PRMT1 in the regulation of cellular energy availability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ternary LiNi x Co y Mn z O 2 oxides with extremely high nickel (Ni) contents ( x ≥ 0.9) are promising cathode candidates developed for higher-energy-density lithium-ion batteries, with an aim to relieve mileage anxiety. However, the structural and interfacial instability still restrict their application in electric vehicles. In this work, a novel electrolyte additive 1,2,4-1 H -Triazole (HTZ) is introduced to improve the interfacial stability of LiNi 0.9 Co 0.05 Mn 0.05 O 2 (NCM90), promoting cycle life both at 30 °C and a harsh condition of 60 °C, as well as rate capability. The NCM90||Li cells with 0.3% HTZ-added electrolyte retain 86.6% of their original capacity after 150 cycles at 1C and 30 °C, well exceeding 74.8% obtained with the baseline electrolyte. It is revealed that the additive HTZ could inhibit the thermal decomposition of LiPF 6 salt and suppress the generation of HF acidic species. More importantly, additive HTZ is preferentially oxidized to construct a compact and dense cathode electrolyte interphase (CEI) layer, which is beneficial for stabilizing the electrode/electrolyte interface and suppressing unwanted side reactions.

Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

Enhancing the functions of mesenchymal stem cells (MSCs) is considered a potential approach for promoting tissue regeneration. In this study, we investigated the effects of Matrix Metalloproteinase-1 (MMP-1) on bone marrow mesenchymal stem cells (BMSCs) and its mechanism. Our results showed that knockdown of MMP-1 impeded scratch closure, attenuated proliferation, inhibited ALP activity, ALP denser staining and mineralization in vitro, and decreased expression of RUNX2, OSX, OPN and OCN in BMSCs, while 20 ng/mL recombinant human MMP-1 protein (rhMMP-1) significantly accelerated scratch closure, enhanced proliferation, ALP activity, ALP denser staining and mineralization in vitro, and increased expression of RUNX2, OSX, OPN and OCN. In addition, knockdown of MMP-1 inhibited the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated extracellular regulated protein kinases (p-ERK), while 20 ng/mL rhMMP-1 increased the expression of p-JNK and p-ERK in BMSCs. Furthermore, inhibition of c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases (ERK) by their inhibitor SP600125 and PD98059 dramatically blocked MMP-1-enhanced ALP activity and mineralization in BMSCs. Our results revealed that MMP-1 could accelerate the osteogenic differentiation potentials of BMSCs via the JNK and ERK pathway, providing the mechanism underlying MSC biology and identifying a potential target for improving bone tissue regeneration., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Curcumol was presented to unleash antitumor effects in a variety of cancers, including gastric cancer. However, the relevance between curcumol and cisplatin resistance in gastric cancer still remains unclear. Therefore, the current research was performed to survey the role of curcumol in cisplatin sensitivity in gastric cancer., Methods: First, BGC-823 and BGC-823/DDP cells were incubated with cisplatin for 48 hr and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) analysis was applied to determine the inhibition rate of cell proliferation and the half-maximal inhibitory concentration (IC 50 ) of cisplatin. In addition, BGC-823 and BGC-823/DDP cells were treated with curcumol for 48 hr followed with detection of cell viability and apoptosis using MTT and flow cytometry assay, respectively. Moreover, MTT analysis was applied to test the effects of curcumol on cisplatin sensitivity in gastric cancer cells. Lastly, Western blot assay and qRT-PCR analysis were utilized to check the functions of curcumol on PI3K/AKT pathway-related markers., Results: We found that BGC-823/DDP cells exhibited stronger resistance to cisplatin compared with BGC-823 cells. Furthermore, curcumol evidently reduced cell proliferation and facilitated cell apoptosis in BGC-823/DDP and BGC-823 cells. Moreover, results from MTT assay demonstrated that curcumol notably promoted the suppression effect of cisplatin and decreased the IC 50 of cisplatin in BGC-823/DDP and BGC-823 cells. It was also presented that curcumol suppressed the PI3K/AKT pathway dose-dependently in BGC-823/DDP and BGC-823 cells., Conclusion: The findings in the current research demonstrated that curcumol could promote the sensitivity of gastric cancer cells to cisplatin-based chemotherapies via inhibiting the phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT) pathway., (© 2020 Wiley Periodicals, LLC.)

Background: Oncolytic virus therapy has shown benefits for multiple cancers, while limitations remain for traditional treatment. However, few studies have concentrated on comparing whether oncolytic virus combined with traditional treatment is better than traditional treatment alone in patients with cancer. We conducted a meta-analysis of the curative effect and safety of oncolytic virus combination therapy., Methods: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases comprehensively for articles comparing oncolytic virus combined with traditional treatment to traditional treatment alone in patients with cancer. A meta-analysis and trial sequential analysis were performed., Results: A total of 12 studies involving 1494 patients (combination therapy group, 820 patients; traditional treatment group, 674 patients) were included in the study. Compared with traditional treatment alone, combination therapy was significantly associated with high objective response rate [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.01-1.82, p = 0.04]. There were no significant differences for other outcomes such as 1- and 2-year survival rate, and 4- and 12-month progression-free survival rate. Combination therapy was significantly associated with high incidence of grade ≥ 3 adverse effects (OR 1.47, 95% CI 1.06-2.05, p = 0.02) and high incidence of grade ≥ 3 neutropenia (OR 1.65, 95% CI 1.13-2.43, p = 0.01). There were no significant differences for other grade ≥ 3 adverse effects, e.g., gastrointestinal adverse effects, influenza-like illness, fatigue, anemia, and thrombocytopenia., Conclusion: Despite partially increased toxicity, the combination therapy improves the effectiveness of cancer treatment. However, high-quality, large-scale studies are needed to evaluate its effectiveness and safety.

Despite recent progress in hepatitis treatment, there have been no significant advances in the development of liver cancer vaccines in recent years. In this study, we investigated the regulatory effect and potential mechanism of hepatocyte growth factor receptor (MET, also known as HGFR) on tumor vaccinations for liver cancer in mice. Herein, we demonstrate that MET expression is significantly associated with the immunogenicity of liver cancer in mice and humans, and that MET depletion dramatically enhances the protective efficacy of chemotherapy-based anti-liver cancer vaccination. Mechanistically, MET repressed liver cancer immunogenicity independent of the traditional PI3K-AKT cascade, and MET interacted with vacuolar ATP synthase (V-ATPase) and mediated the activation of mammalian target of rapamycin (MTOR), thus suppressing liver cancer immunogenicity. The efficacy of chemotherapy-based liver cancer vaccination was markedly enhanced by targeting the MET-V-ATPase-MTOR axis, highlighting a translational strategy for identifying MET-associated drug candidates for cancer prevention.

The efficacy of cancer immunotherapy depends on the fine interplay between tumoral immune checkpoints and host immune system. However, the up-to-date clinical performance of checkpoint blockers in cancer therapy revealed that higher-level regulation should be further investigated for better therapeutic outcomes. It is becoming increasingly evident that the expression of immune checkpoints is largely associated to the immunotherapeutic response and consequent prognosis. Deubiquitinating enzymes (DUBs) with their role of cleaving ubiquitin from proteins and other molecules, thus reversing ubiquitination-mediated protein degradation, modulate multiple cellular processes, including, but not limited to, transcriptional regulation, cell cycle progression, tissue development, and antiviral response. Accumulating evidence indicates that DUBs also have the critical influence on anticancer immunity, simply by stabilizing pivotal checkpoints or key regulators of T-cell functions. Therefore, this review summarizes the current knowledge about DUBs, highlights the secondary checkpoint-like role of DUBs in cancer immunity, in particular their direct effects on the stability control of pivotal checkpoints and key regulators of T-cell functions, and suggests the therapeutic potential of DUBs-based strategy in targeted immunotherapy for cancer., (Copyright © 2020 Huang, Zhang, Xu, Wang, Zhang, Tang, Shen, Liang and Bai.)