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The continuous aerobic granular sludge (AGS) process is promising for upgrading existing wastewater treatment facilities. However, this approach is still challenging because of its complicated structure and operation. To address this issue, a novel separate aeration self-circulating technology (abbreviated as Zier) was proposed, which is promising for cultivating AGS by its outstanding upflow velocity and circulation multiplier (more than 30 m/h and 200, respectively). This study elaborated on the Zier reactor's feasibility, optimization, and control strategy through computational fluid dynamics simulations, theoretical calculations, and experiments. An appropriate flow regime for efficient removal of pollutant and granulation of sludge was attained at a superficial gas velocity of 1.3 cm/s. Moreover, optimizing the aeration column diameter to half of the reaction column and increasing the height/diameter ratio to 20 dramatically boosted the nitrogen removal capacity over 1.6 kg N/m 3 /d. Utilizing a smaller circulation pipe diameter ensured granulation under a consistent flow regime. By judiciously regulating, multiple CSTRs and PFRs seamlessly integrated within the Zier reactor across a broad spectrum of particle sludge. The validity of these findings was further substantiated through experimental and theoretical validations. Drawing from these findings, a multi-scenario control strategy was proposed as Zier's map. With all the superiorities shown by the Zier reactor, this study could offer new insights into an efficient continuous AGS process., 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 Ltd. All rights reserved.)

Introduction: Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and A. dahurica alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. Methods: HeLa and SiHa cell lines were utilized for in vitro experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the in vivo experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. Results: In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased ( p < 0.001), while the G2/M phase increased notably ( p < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines ( p < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated ( p < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased ( p < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. Discussion: GEB exhibits a robust antitumor effect against cervical cancer, both in vitro and in vivo , in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qin, Peng, Xu, Zhang, Tian, Wan, Pu, Li, Wu, Zheng and Xu.)

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε ( SIKE ) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-β-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

Fufang Xiling Jiedu capsule (FXJC), a traditional Chinese medicine that evolved from "Yinqiao Powder", is widely used for the treatment of cold and influenza. However, due to a lack of in vivo metabolism research, the chemical components responsible for the therapeutic effects still remain unclear. Hence, this study aimed to describe the metabolic profiles of the FXJC in rat plasma, urine, and feces. A combined data mining strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was employed and 201 xenobiotics, including 117 prototype components and 84 metabolites were detected. Phenolic acids, flavonoids, triterpenes, and lignans were prominent ingredients absorbed in vivo, and the major metabolic pathways of the detected metabolites were glucuronidation, sulfation, methylation, and oxidation. This is the first systematic study on the metabolism of the FXJC in vivo, providing valuable information for future studies on the efficacy, toxicity, and mechanism of the FXJC., (© 2024 Wiley-VCH GmbH.)

Background: Kidney renal clear cell carcinoma (KIRC) is an immunogenic tumor, and immune infiltrates are relevant to patients' therapeutic response and prognosis. NDUFS1 , the core subunit of mitochondrial complex I, has been reported to be associated with KIRC patients' prognosis. However, the upstream regulator for NDUFS1 and their correlations with immune infiltration remain unclear. Methods: The expression of NDUFS genes in KIRC and their influences on patients' survival were investigated by UALCAN, ENCORI, Oncomine, TIMER as well as Kaplan-Meier Plotter. miRNAs regulating NDUFS1 were predicted and analyzed by TargetScan and ENCORI. The correlations between NDUFS1 expression and immune cell infiltration or gene marker sets of immune infiltrates were analyzed via TIMER. The overall survival in high/low NDUFS1 or hsa-miR-320b expressed KIRC patients with or without immune infiltrates were analyzed via Kaplan-Meier Plotter. The combined NDUFS1 expression and/or CD4 + T cell infiltration on KIRC patients' overall survival were validated by multiplexed immunofluorescence (mIF) staining in tissue microarray (TMA). Furthermore, the influences of NDUFS1 expression on the chemotaxis of CD4 + T cells to KIRC cells were performed by transwell migration assays. Results: We found that the low expression of NDUFS1 mRNA and protein in KIRC was correlated with unfavorable patients' survival and poor infiltration of CD4 + T cells. In patients with decreased CD4 + T cell infiltration whose pathological grade less than III, TMA mIF staining showed that low expression of NDUFS1 had significantly poor OS than that with high expression of NDUFS1 did. Furthermore, hsa-miR-320b, a possible negative regulator of NDUFS1 , was highly expressed in KIRC. And, low NDUFS1 or high hsa-miR-320b consistently correlated to unfavorable outcomes in KIRC patients with decreased CD4 + T cell infiltration. In vitro , NDUFS1 overexpression significantly increased the chemotaxis of CD4 + T cell to KIRC cells. Conclusion: Together, NDUFS1 , upregulated by decreased hsa-miR-320b expression in KIRC patients, might act as a biomarker for CD4 + T cell infiltration. And, the combination of NDUFS1 with CD4 + T cell infiltration predicts favorable prognosis in KIRC., 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 Wu, He, Xu, Tian, Fan, Fan, Ai, Bian, Qin, Qin and Li.)

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H 2 O 2 -stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While growing evidence indicates the importance of TFF3 in cancer, the molecular mechanism of its action in cancer remains largely unknown. Clonogenic survival is a key ability for tumor cells, which is interpreted as a trait of cancer cells with tumor-initiating capabilities. We investigated the effect and the underlying mechanisms of TFF3 on the clonogenic survival of colorectal cancer (CRC) cells., Methods: Expression of TFF3 in CRC tissues and matched paracancerous tissues was determined by western blotting. Colony formation assays were performed to evaluate the clonogenic survival ability of CRC cells. PTGER4 mRNA expression was detected by quantitative polymerase chain reaction. PTGER4 promoter activity was determined by luciferase reporter assay. STAT3 nuclear localization was investigated using immunofluorescence staining. Expression of TFF3 and EP4 in CRC tissues was determined by immunohistochemistry., Results: TFF3 knockout led to decreased clonogenic survival of CRC cells, while overexpression of TFF3 resulted in the opposite effect. EP4 was found to be upregulated by TFF3 at both the mRNA and protein level. Moreover, EP4 antagonist abrogated TFF3-mediated clonogenic survival of CRC cells. PGE2 and EP4 agonist could restore the effect of TFF3 knockout on the clonogenic survival of CRC cells. Furthermore, TFF3 promoted STAT3 activation and nuclear localization. Activated STAT3 bound to PTGER4 promoter, the gene encoding for EP4, and facilitated PTGER4 transcription., Conclusions: TFF3 promotes clonogenic survival of CRC cells via upregulating EP4 expression., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2552/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Background and Aims: Pancreatic adenocarcinoma (PAAD) is highly aggressive and characterized by a poor prognosis. Oxidative stress has great impacts on the occurrence and development of tumors. However, the predictive role of oxidative stress related genes on PAAD patients' prognosis remains unclear. In this study, we aimed to construct a prognostic model for PAAD based on oxidative stress genes and to evaluate its predictive value., Methods: The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets were used to identify differentially expressed oxidative stress genes. Univariate Cox regression, Kaplan-Meier and multivariate Cox regression analysis were used to select genes and to construct a prognosis model. According to the median value of the model's risk score, patients were divided into high and low risk groups, and gene set enrichment analysis (GSEA), immune infiltration and immunotherapy effect, drug resistance and the expression of immune checkpoint related genes and synthetic driver genes of T cell proliferation were analyzed. Finally, the mRNA and protein levels of four genes in PAAD were verified by the clinical proteomic tumor analysis consortium (CPTAC) database and the immunostaining of patients' tissue., Results: 55 differentially expressed oxidative stress genes were identified, and four genes including MET, FYN, CTTN and CDK1 were selected to construct a prognosis model. GESA indicated that immune related pathways, metabolic pathways and DNA repair pathways were significantly enriched in the high risk group as compared to the low risk group. The frequency of genetic mutations was also significantly higher in high risk groups than that in low risk groups. Moreover, the infiltration level of 23 immune cells as well as the expression of immune checkpoint related and synthetic driver genes of T cell proliferation were significantly altered, with the better immunotherapy effect occurring in low risk group. In patient PAAD tissues, the mRNA and protein levels of these four genes were up-regulated., Conclusion: We have successfully constructed a four oxidative stress gene prognostic model that has important predictive value for PAAD patients, and this model might be a promising guidance for prognostic prediction and efficacy monitoring in clinical individualized therapy., 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 Wang, Tian, Liang, Fan, Duan, Fan, Zhang, Yao, Chen and Li.)

Background: Bibliometric software exists as a platform providing multiple algorithms to process the data to suffice diverse goals. Interpretation of the result must be based on insight into the meaning of the original data and the algorithm used. Medical Subject Headings (MeSH) terms represent the macro-level meaning of topics, keywords that commonly reflect the micro-level aspects., Objective: This study attempts to investigate the landscape of photoaging in the recent two decades by using bibliometric analysis., Methods: Published studies of photoaging were obtained from PubMed and Web of Science Core Collection (WoSCC) from 2000 to 2020. Basic bibliometric information was generated by WoSCC. Major MeSH terms were performed in cluster analysis and displayed as a hierarchical form to induce knowledge structure, detection algorithm on keywords was presented as a timeline form to obtain hotspots, and institutional clusters were labeled with keywords to achieve institutional characteristics., Results: A total of 2,727 and 2,705 studies were identified in PubMed and WoSCC, respectively. The number of photoaging-related studies at 3-year intervals grew steadily. The studies were performed in about 80 countries/regions. The highly frequent major MeSH terms were distributed in seven clusters, reflecting the etiology, pathophysiology, treatment, and prevention of photoaging. The hotspots changed as time went on, and the hotspots in recent 5 years were mitogen-activated protein kinase (MAPK), nuclear factor erythroid-derived 2-like 2 (Nrf2), and antioxidant activity. The highly productive institutions labeling in the top four clusters were Seoul National University, University of Michigan, China Medical University, and Harvard University, with corresponding keywords of UVB, retinoic acid, Nrf2, and rejuvenation., Conclusions: This study built a knowledge structure of pathophysiology, treatment and prevention of photoaging, and identified recent hotspots of MAPK, Nrf2, and antioxidant activity. We provide a landscape of photoaging, from the bench (pathophysiology) to bedside (treatment, prevention), and pave the way for future research., 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. The reviewer LT declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2022 Sun, Yan, Tian, Sun and Wu.)

Background: The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA-associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target., Methods: Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient-derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target., Results: PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers. Mechanistic studies showed that c-Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR-mitogen-activated protein kinase (MAPK) signaling activation, which resulted in FOS-related antigen 1 (FRA-1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels., Conclusions: PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer. c-Myc-driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR-MAPK-FRA-1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Though the great success of paclitaxel, the variable response of patients to the drug limits its clinical utility and the precise mechanisms underlying the variable response to paclitaxel remain largely unknown. This study aims to verify the role and the underlying mechanisms of CD147 in paclitaxel resistance. Immunostaining was used to analyze human non-small-cell lung cancer (NSCLC) and ovarian cancer tissues. RNA-sequencing was used to identify downstream effectors. Annexin V-FITC/propidium iodide and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect apoptosis. Co-immunoprecipitation (Co-IP), fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were performed to determine protein interactions. Fluorescence recovery after photobleaching (FRAP) was performed to measure the speed of microtubule turnover. Xenograft tumor model was established to evaluate sensitivity of cancer cells to paclitaxel in vivo. In vitro and in vivo assays showed that silencing CD147 sensitized the cancer cells to paclitaxel treatment. CD147 protected cancer cells from paclitaxel-induced caspase-3 mediated apoptosis regardless of p53 status. Truncation analysis showed that the intracellular domain of CD147 (CD147 ICD ) was indispensable for CD147-regulated sensitivity to paclitaxel. Via screening the interacting proteins of CD147 ICD , Ran binding protein 1 (RanBP1) was identified to interact with CD147 ICD via its C-terminal tail. Furthermore, we showed that RanBP1 mediated CD147-regulated microtubule stability and dynamics as well as response to paclitaxel treatment. These results demonstrated that CD147 regulated paclitaxel response by interacting with the C-terminal tail of RanBP1 and targeting CD147 may be a promising strategy for preventing paclitaxel resistant., (© 2021. The Author(s).)

Non-small cell lung cancer (NSCLC) is a highly malignant tumor, with a significant mortality and morbidity. With the development of tumor immunotherapy, chimeric antigen receptor T cells (CART) gets increasingly attention and achieves prominent contributions in the treatment of hematologic malignancies. However, CART therapy for NSCLC proceeds slowly and further researches need to be investigated. In our study, we performed bioinformatics analysis to evaluate the significant role of CD147 in NSCLC. The expression level of CD147 was detected in human NSCLC cell lines and NSCLC tissues. Meanwhile, CD147-CART was constructed and identified. Cell cytotoxicity and cytokine secretion were performed to evaluate the efficacy of CD147-CART. We also constructed cell-derived xenograft (CDX) model and patient-derived xenograft (PDX) model, which was used to further investigate the safety and efficacy of CD147-CART in vivo. Our observations show that CD147 is a specific tumor antigen of NSCLC and plays an essential role in NSCLC progression, which can be used as a target for CART therapy in NSCLC. CD147-CART cells exhibit robust cytotoxicity and cytokine production in vitro, suggesting a strong anti-tumor activity against NSCLC tumor cells. Importantly, CD147-CART cells have strong anti-tumor activity against NSCLC cells in vivo in both CDX and PDX models and no adverse side effects. Our findings show that CD147-CART immunotherapy for NSCLC is safe and effective, which is an ideal and promising medical patch for treating NSCLC., (Copyright © 2021. Published by Elsevier Inc.)

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Major gaps in understanding the molecular mechanisms of colorectal cancer (CRC) progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders. Trefoil factor 3 (TFF3) has been reported to be involved in CRC progression and intestinal mucosal repair; however, how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood. Here, we found that the upregulated TFF3 in CRC predicted a worse overall survival rate. TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis. CD147, a membrane protein, was identified as a binding partner for TFF3. Via binding to CD147, TFF3 enhanced CD147-CD44s interaction, resulting in signal transducer and activator of transcription 3 (STAT3) activation and prostaglandin G/H synthase 2 (PTGS2) expression, which were indispensable for TFF3-induced migration, proliferation, and invasion. PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype (PTGER4) and contributed to TFF3-stimulated CRC progression. Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression. The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor. Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice. Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression, which widens and deepens the understanding of the molecular function of trefoil factors., (© 2021. The Author(s).)

Objective: To compare and rank the efficacy and acceptability of new antiepileptic drugs (AEDs) for patients with focal drug-resistant epilepsy., Methods: PubMed, EMBASE, Cochrane databases and Clinicaltrials.gov were systematically searched from their inception through January 1, 2020, to identify trials evaluating AEDs for focal drug-resistant epilepsy. We included randomized controlled clinical trials (RCTs) comparing new AEDs with placebo or with other AEDs as adjunctive therapy for focal drug-resistant epilepsy. A Bayesian network meta-analysis was performed to determine efficacy and acceptability, as reflected by odds ratios (ORs), 95 % credible intervals (CrIs) with random-effects and consistent models., Results: Sixty-two RCTs were included, involving 12,739 patients with focal drug-resistant epilepsy. Regarding the seizure-free rate (40 RCTs involving 9,136 patients), 8 AEDs were more efficacious than placebo, with lnORs ranging between 1.69 for brivaracetam (95 % CrI, 0.56-2.81) and 0.72 for pregabalin (95 % CrI, 0.12-1.32). Regarding the responder rate, all AEDs except oxcarbazepine were more efficacious than placebo, with lnORs ranging between 1.31 for levetiracetam (95 % CrI, 0.92-1.71) and 0.66 for carisbamate (95 % CrI, 0.17-1.14). Regarding acceptability (60 RCTs comprising 12,139 patients), 9 AEDs were inferior to placebo. Estimated from seizure-free rate, brivaracetam was ranked as the most efficacious AED based on cumulative probability plots and SUCRAs, with fatigue as the main adverse event., Conclusion: The results indicate that, based on seizure-free rate and all-cause discontinuation rate, brivaracetam is the most efficacious and acceptable AED, with mild adverse events and acknowledgement of potential publication bias., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This study explored the effects of phosphofructokinase-1 (PFK1) on the radiosensitivity of colorectal cancer (CRC) in vivo and in vitro and the underlying mechanisms., Methods: Tissue samples from 48 patients with rectal cancer who had received neoadjuvant radiotherapy followed by surgery were analyzed. The expression of PFK1 in tissue samples was semi-quantitated by immunohistochemistry, and its relationship with clinicopathological features was analyzed. The effects of PFK1 knockdown on the survival, apoptosis, migration, and radiosensitivity of CRC cells were evaluated. Glycolysis-related indicators were used to examine glycolytic activity. The effects of PFK1 on the radiosensitivity of CRC in vivo were assessed by measuring tumor formation in nude mice., Results: PFK1 was overexpressed in rectal cancer and was higher in radiation-resistant tumors than in radiation-sensitive tumors. SiRNA-induced PFK1 silencing increased apoptosis and inhibited migration and proliferation of CRC cells. Knockdown of PFK1 made the CRC cells sensitive to ionizing radiation in vivo. Oligomycin partially restored the expression of PFK1, enhanced glycolysis, and reversed the enhanced radiosensitivity of CRC cells induced by siRNA-PFK1. Downregulation of PFK1 combined with irradiation inhibited growth of nude mice xenografts, which was related to an increase in apoptosis., Conclusions: Our study indicates that high expression of PFK1 is negatively correlated with radiosensitivity in CRC and likely accelerates the proliferation and migration of CRC cells. Downregulation of PFK1 may enhance the radiosensitivity of CRC cells in vivo and in vitro by inhibiting glycolysis., Competing Interests: None., (AJTR Copyright © 2020.)

Non-small cell lung cancer (NSCLC) is a profoundly devastating disease that is the leading cause of cancer-related death worldwide. With the rapid development of next-generation sequencing (NGS), which has supplied the ability to decode tumors at the DNA level, so that targeted therapy plays a crucial role in improving NSCLC survival. We first reported a 32-year-old Chinese female patient received the ninth-line treatment, who was initially diagnosed with advanced NSCLC with EGFR 19 deletion. The patient had a satisfactory clinical response to initial gefitinib treatment. Subsequently, an EGFR T790M mutation was detected from plasma-derived circulating tumor DNA (ctDNA) by ddPCR after disease progression, while NGS did not. Osimertinib was still tried but had no therapeutic effect. Then the disease even progressed on the administration of chemotherapy and gefitinib in succession. Rebiopsy for NGS detection was performed, and gefitinib plus anlotinib/vemurafenib were tried. And then, gefitinib plus crizotinib were administrated for MET amplification after the third biopsy. Furthermore, chemotherapy combined with immunotherapy was performed due to the PD-L1 positive expression. Up to now, osimertinib treatment was undertaken to base on an EGFR exon 20 T790M mutation using NGS-based genotyping in cerebrospinal fluid (CSF) ctDNA. Tumor genome dynamic monitoring can identify tumor driving genes and drug resistance mechanisms to guide tumor treatment. This study found that the total survival time of advanced NSCLC patients was more than four years after chemoradiotherapy and targeted therapy, indicating the significance of dynamic monitoring of gene alterations for cancer treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2020.01.21). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

In the early 20th century, the Chinese Society of Medical History was the only specialty society accepting members with traditional Chinese medicine background in the Chinese medical association. Therefore, it is of special significance to study the TCM members of the early Chinese Society of Medical History. By combing the medical journals of this period and referring to the researches today, this paper makes a comprehensive investigation on the life stories and academic works of the early 14 TCM doctors and scholars of the Chinese Society of Medical History, so as to understand their contributions to the development of Chinese medicine and the institute of medical history in this special historical period.

Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury., (© 2019 by the American Association for the Study of Liver Diseases.)

Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD-binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial-mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ-TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ-TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma., (© 2019 Wiley Periodicals, Inc.)

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.

Aims: To compare serum protein expression profiles between lung cancer patients and healthy individuals, and to examine whether there are differences in serum protein expression profiles among patients with lung cancers of different histological types and whether the characteristic expression of serum proteins may assist in differential diagnosis of various subtypes of lung cancers., Methods: Blood samples were collected from 123 lung cancer patients before commencement of treatment who attended Shanxi Cancer Hospital, China, between 2008 and 2013. Blood samples from 60 healthy individuals were also collected in the same period. Serum protein expression profiles were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. The differences in the serum protein spectrums of lung cancer patients with different histological subtypes were analyzed by one-way Analysis of Variance and receiver operating characteristic curves., Results: A cluster of 48 protein mass-to-change ratio (M/Z) peaks was differentially expressed between sera of lung cancer patients and healthy individuals. The M/Z 1205, 4673, 1429 and 4279 peaks were differentially expressed among patients with lung squamous cell carcinomas, adenocarcinomas and small-cell lung carcinomas., Conclusion: These results reinforce the notion that profiling of serum proteins may be of diagnostic value in lung cancer, and suggest that the differences in serum protein profiles may be useful in differential diagnosis of lung cancers of varying histological subtypes., (© 2015 The Authors. Asia-Pacific Journal of Clinical Oncology published by Wiley Publishing Asia Pty Ltd.)

Aim: To determine whether specific clinical and radiographic factors predispose arteriovenous malformations (AVMs) presenting with seizure and to predict the seizure risk for individual AVM patients., Material and Methods: Clinical features and cerebral angiograms of consecutive 45 unruptured AVM patients who were diagnosed in our center in a 2-year period were reviewed. Patient data (analysis cohort) was used to determine risk factors for seizure and to construct epileptogenic AVM groups. These risk groups were tested with the second half of the patient data (test cohort)., Results: Among 45 unruptured AVMs (47.9%), initial seizures occurred in 20 unruptured AVMs (44.4%). Two of these 20 patients had a bleed in 117 patient-years for an annual bleed rate of 1.7%. There was no significant difference in hemorrhagic risk between epileptogenic AVM and asymptomatic AVM (P=0.918). Multivariate analysis revealed 2 factors associated with seizure: frontal and temporal AVM locations (P < 0.001) and a compact AVM morphology (P=0.003)., Conclusion: Analysis of a group of unruptured AVMs demonstrated that epileptogenic AVMs have an annual hemorrhage risk similar to that of the asymptomatic AVMs. Frontal and temporal AVM locations and a compact AVM morphology were significantly associated with epileptogenic AVMs.

14-3-3 proteins comprise a large family of highly conserved, acidic polypeptides, expressed in all eukaryotic organisms, with highest concentration found in the brain. Multiple isoforms of 14-3-3 proteins have been shown to play an essential role in regulating differentiation, proliferation and transformation. In the previous study, the expression levels of all seven 14-3-3 isoforms were examined in astrocytoma. However, the expression of seven 14-3-3 isoforms in meningioma still remains unknown. This study is the first examination of 14-3-3 isoforms in three grades of meningioma by immunohistochemistry. 14-3-3epsilon, zeta and theta were specifically expressed in meningioma, and their expression levels increased with the increase of pathological grade of meningioma. The 14-3-3 eta, beta, gamma and sigma isoforms were negatively expressed in meningioma. In conclusion, The 14-3-3 epsilon, zeta and theta may be involved in tumorigenesis of meningioma and be efficient markers for predicting the degree of malignancy in meningioma., (Copyright 2010 Elsevier B.V. All rights reserved.)

HIF-1alpha plays an indispensable role in tumor formation and histogenesis. Target genes involved in glucose transport are acutely transactivated by HIF-1alpha. GLUT-3 protein is the rate-limiting factor related to glucose transport, which is classified as brain-type glucose transporter. This study was the initial one aiming to probe into the co-expression and clinical significance of HIF-1alpha and GLUT-3 in glioma. One hundred and twenty cases of glioma tissues and ten human normal cerebral tissues decompressed in glioma excision were examined using immunohistochemistry and Western blot. The expression of HIF-1alpha and GLUT-3 increased gradually with the increase of pathological grade of glioma, respectively. There was significant difference in the expression of HIF-1alpha and GLUT-3 in every two groups, respectively. There was a positive correlation between HIF-1alpha and GLUT-3. In conclusion, the expression of HIF-1alpha and GLUT-3 in glioma was correlated significantly with tumors' pathological grade, which can be taken as a pair of useful markers for predicting the biological behavior of glioma.