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Background: As women with low ovarian reserve embark on the challenging journey of in-vitro fertilisation (IVF) treatment, the choice between natural and mildly stimulated cycles becomes a pivotal consideration. It is unclear which of these two regimens is superior for women with low ovarian reserve. Our study aims to assess the impact of natural cycles on embryo quality and pregnancy outcomes in women with low ovarian reserve undergoing IVF treatment compared to mildly stimulated cycles., Methods: This retrospective study enrolled consecutive patients with low ovarian reserve who underwent IVF/intracytoplasmic sperm injection (ICSI) at Guangdong Second Provincial General Hospital between January 2017 and April 2021. The primary outcome for pregnancy rate of 478 natural cycles and 448 mild stimulated cycles was compared. Secondary outcomes included embryo quality and oocyte retrieval time of natural cycles., Results: The pregnancy rate in the natural cycle group was significantly higher than that in the mildly stimulated cycle group (51.8% vs. 40.1%, p  = 0.046). Moreover, natural cycles exhibited higher rates of available embryos (84.1% vs. 78.6%, p  = 0.040), high-quality embryos (61.8% vs. 53.2%, p  = 0.008), and utilisation of oocytes (73% vs. 65%, p  = 0.001) compared to mildly stimulated cycles. Oocyte retrievals in natural cycles were predominantly performed between 7:00 and 19:00, with 94.9% occurring during this time frame. In natural cycles with high-quality embryos, 96.4% of oocyte retrievals were also conducted between 7:00 and 19:00., Conclusion: Natural cycles with appropriately timed oocyte retrieval may present a valuable option for patients with low ovarian reserve.

Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses., (© 2024. The Author(s).)

Hyperlipidemia poses a serious threat to human health, but its medication remains some issues including significant adverse reactions. Polyphenols exhibit great potential in lowering blood lipids and the lipid-lowering effects of quinoa polyphenols are still waiting to be explored. In this study, a deep eutectic solvent-based ultrasonic-assisted extraction method of quinoa polyphenols was developed. Then, the constituents of quinoa polyphenols after purification CQP were analyzed. Besides, their lipid-lowering activities and mechanism were explored. Results suggested that CQP comprised at least 12 kinds of polyphenols. CQP could inhibit lipase, adsorb cholesterol, inhibit oxidative stress and lipid peroxidation. Subsequent network pharmacology, cellular experiments and molecular docking revealed that CQP might influence the expression levels or bind to AKT1 and FOXO1, thereby affecting their content or activity, ultimately regulating their functions and leading to changes of the cellular lipid levels. This study lays foundation for developing novel lipid-lowering drugs and functional foods., 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.)

Background and Aims: Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic., Approach and Results: The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 patients with HCC. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1, and LAMA4 were highly expressed in the disease free survival-poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed cross talk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to protein kinase B-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo., Conclusions: This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC., (Copyright © 2024 American Association for the Study of Liver Diseases.)

This paper is devoted to studying the Bessel beam propagation in cylindrical coordinates using the Hankel transform beam propagation method (HT-BPM) and their behavior in different scenarios in the microscale and meter scale of propagation distances. The study compares the results obtained from the HT-BPM with another fast Fourier transform beam propagation method (FFT-BPM) to validate the accuracy and effectiveness of the HT-BPM in modeling Bessel beam propagation. The axial intensity of Bessel beam propagation is analyzed using the HT-BPM. The simulation results obtained from the HT-BPM are compared with those from the FFT-BPM to evaluate the agreement and consistency between the two methods in predicting the axial intensity of Bessel beam propagation. The results show that the HT-BPM is numerically faster than the FFT-BPM by ten times for different sampling points, furthermore, the FFT-BPM accuracy for evaluating the Bessel beam spot radius is 89.9% of the analytical value, while the HT-BPM is 99% relative to analytical value. The prediction of the axial intensity of the Bessel beam has been tested at different types of phase functions and different propagation distances: micrometer, centimeter, and meter scales. The results of the HT-BPM are matched with the analytical and experimental values. Finally, the HT-BPM is tested when the input light source takes different profiles.

Histone lysine crotonylation, an evolutionarily conserved modification differing from acetylation, exerts pivotal control over diverse biological processes. Among these are gene transcriptional regulation, spermatogenesis, and cell cycle processes. However, the dynamic changes and functions of histone crotonylation in preimplantation embryonic development in mammals remain unclear. Here, we show that the transcription coactivator P300 functions as a writer of histone crotonylation during embryonic development. Depletion of P300 results in significant developmental defects and dysregulation of the transcriptome of embryos. Importantly, we demonstrate that P300 catalyzes the crotonylation of histone, directly stimulating transcription and regulating gene expression, thereby ensuring successful progression of embryo development up to the blastocyst stage. Moreover, the modification of histone H3 lysine 18 crotonylation (H3K18cr) is primarily localized to active promoter regions. This modification serves as a distinctive epigenetic indicator of crucial transcriptional regulators, facilitating the activation of gene transcription. Together, our results propose a model wherein P300-mediated histone crotonylation plays a crucial role in regulating the fate of embryonic development., (© 2024. The Author(s).)

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The present study aims to construct an elderly vitality index evaluation system and develop a comprehensive vitality evaluation scale for the elderly to reasonably evaluate the vitality level of the elderly in China, so as to provide a reference for promoting the realization of "active aging" and "healthy aging". Literature research and in-depth interview were used to collect the senile vitality sensitive indexes. The indexes were screened and corrected by Delphi expert consultation method, item analysis method based on classical test theory, factor analysis method, and reliability and validity analysis method. The analytic hierarchy process was used to calculate the weight of each level of indexes. An elderly vitality evaluation system including 4 first-level indexes and 24 second-level indexes was constructed. The consistency test results of all levels of indicators showed that the consistency index (CI) and consistent ratio (CR) were both less than 0.1, which met the requirements and showed satisfactory consistency. The weights of exercise vitality, nutritional vitality, psychological vitality and social vitality were 0.263, 0.141, 0.455 and 0.141, respectively. In conclusion, the comprehensive vitality scale constructed for the Chinese elderly is reliable and scientific, and can be used to evaluate the vitality of the elderly.

Background: Kirsten rat sarcoma (KRAS) and mutant KRAS G12D have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRAS G12D activity in hepatocellular carcinoma (HCC)., Methods: We constructed transgenic mouse strains LC (LSL-Fbxl6 KI/+ ;Alb-Cre, n = 13), KC (LSL-Kras G12D/+ ;Alb-Cre, n = 10) and KLC (LSL-Kras G12D/+ ;LSL-Fbxl6 KI/+ ;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d. Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation. Co‑immunoprecipitation (Co-IP), Western blotting, ubiquitination assay and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS. The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase (ERK)/mammalian target of rapamycin (mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2 (PRELID2) axis was evaluated in 129 paired samples from HCC patients., Results: FBXL6 is highly expressed in HCC as well as other human cancers (P < 0.001). Interestingly, FBXL6 drives HCC in transgenic mice. Mechanistically, elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRAS G12D at lysine 128, leading to the activation of both KRAS and KRAS G12D and promoting their binding to the serine/threonine-protein kinase RAF, which is followed by the activation of mitogen-activated protein kinase kinase (MEK)/ERK/mTOR signaling. The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2, which induces reactive oxygen species (ROS) generation. Furthermore, hepatic FBXL6 upregulation facilitates KRAS G12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis. Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo. In clinical samples, FBXL6 expression positively correlates with p-ERK (χ 2  = 85.067, P < 0.001), p-mTOR (χ 2  = 66.919, P < 0.001) and PRELID2 (χ 2  = 20.891, P < 0.001). The Kaplan-Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival (log‑rank P < 0.001)., Conclusions: FBXL6 activates KRAS or KRAS G12D via ubiquitination at the site K128, leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis. Dual inhibition of MEK and mTOR effectively protects against FBXL6- and KRAS G12D -induced tumorigenesis, providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer., (© 2023. The Author(s).)

Metastatic hepatocellular carcinoma (HCC) is the most lethal malignancy and lacks effective treatment. FBXL6 is overexpressed in human hepatocellular carcinoma (HCC), but whether this change drives liver tumorigenesis and lung metastasis in vivo remains unknown. In this study, we aimed to identify FBXL6 (F-Box and Leucine Rich Repeat Protein 6) as a key driver of HCC metastasis and to provide a new paradigm for HCC therapy. We found that elevated FBXL6 expression in hepatocytes drove HCC lung metastasis and was a much stronger driver than Kras mutation (Kras G12D/+ ;Alb-Cre), p53 haploinsufficiency (p53 +/- ) or Tsc1 loss (Tsc1 fl/fl ;Alb-Cre). Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation. Activated TKT further increased PD-L1 and VRK2 expression via the ROS-mTOR axis, leading to immune evasion and HCC metastasis. Targeting or knockdown of TKT significantly blocked FBXL6-driven immune evasion and HCC metastasis in vitro and in vivo. Notably, the level of active TKT (p-Thr287 TKT) was increased and was positively correlated with the FBXL6 and VRK2 expression levels in HCC patients. Our work provides novel mechanistic insights into FBXL6-driven HCC metastasis and suggests that targeting the TKT-ROS-mTOR-PD-L1/VRK2 axis is a new paradigm for treating patients with metastatic HCC with high FBXL6 expression., (© 2023. The Author(s).)

In this work, magnetic molecularly imprinted polymers (MMIPs) were prepared by a surface imprinting method using Fe 3 O 4 nanoparticles as a support. The products were characterized by FT-IR spectroscopy, VSM, TGA, SEM, and TEM. Combined with HPLC, hydrocortisone in milk powder and milk were separated and purified, and their contents were monitored. The results showed that MMIPs with a particle size of approximately 1000 nm were successfully prepared. The adsorption mechanism of MMIPs was confirmed by kinetic adsorption and thermodynamic adsorption experiments; the maximum adsorption capacity was found to be 17.2 mg g -1 , and adsorption equilibrium could be reached within 40 min. In the actual sample application, the recovery rates of milk powder and milk were 93.88-99.15% and 95.80-98.10%, respectively. These results showed that MMIPs had good performance in selectively identifying hydrocortisone and were suitable for determining hydrocortisone in milk products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, leading to upregulation of the canonical and noncanonical NF-κB pathways, and increases PD-L1 and AR-VRK2 expression, followed by induction of immune evasion, HCC tumorigenesis, and metastasis. Notably, the GAPDH inhibitor koningic acid (KA) activates immune response and protects against FBXW10-driven HCC in vivo. In HCC clinical samples, the expression of active GAPDH is positively correlated with that of FBXW10 and VRK2. We propose that the FBXW10/AR/VRK2/GAPDH/NF-κB axis is critical for HCC tumorigenesis in males. Targeting this axis with KA is a potential therapeutic strategy for male HCC patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The incidence rate of human hepatocellular carcinoma (HCC) is approximately three times higher in males than in females. A better understanding of the mechanisms underlying HCC development in males could lead to more effective therapies for HCC. Our previous study found that FBXW10 played a critical role in promoting HCC development in male mice and patients, but the mechanism remains unknown. Here, we found that FBXW10 promoted K63-linked ANXA2 polyubiquitination and activation in HCC tissues from males, and this process was required for S6K1-mediated phosphorylation. Activated ANXA2 further translocated from the cytoplasm to the cell membrane to bind KRAS and then activated the MEK/ERK pathway, leading to HCC proliferation and lung metastasis. Interfering with ANXA2 significantly blocked FBXW10-driven HCC growth and lung metastasis in vitro and in vivo. Notably, membrane ANXA2 was upregulated and positively correlated with FBXW10 expression in male HCC patients. These findings offer new insights into the regulation and function of FBXW10 signaling in HCC tumorigenesis and metastasis and suggest that the FBXW10-S6K1-ANXA2-KRAS-ERK axis may serve as a potential biomarker and therapeutic target in male HCC patients with high FBXW10 expression., Competing Interests: Declaration of competing interest No potential conflicts of interest were disclosed., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumour suppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, we observed that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with the survival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR) activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdown-mediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlated with elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCC cell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that the β-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potential therapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis., (© The Author(s) (2023). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Purpose: To investigate abnormalities in cortical and subcortical structures of the brain in preschool children with MRI-negative epilepsy., Methods: Cortical thickness, cortical mean curvature, cortical surface area, cortical volume, and volumes of subcortical structures were measured using Freesurfer software in preschool children with epilepsy and age-matched controls., Results: Findings showed cortical thickening in the left fusiform gyrus, left middle temporal gyrus, right suborbital sulcus, and right gyrus rectus, and cortical thinning mainly in the parietal lobe of preschool children with epilepsy compared to controls. The difference in cortical thickness in the left superior parietal lobule remained after correction for multiple comparisons and was negatively correlated with duration of epilepsy. Cortical mean curvature, surface area, and volume were mainly altered in the frontal and temporal lobes. Changes in mean curvature in the right pericallosal sulcus were positively correlated with age at seizure onset, and changes in mean curvature in the left intraparietal sulcus and transverse parietal sulcus were positively correlated with frequency of seizures. There were no significant differences in the volumes of the subcortical structures., Conclusion: Changes in preschool children with epilepsy occur in the cortical rather than subcortical structures of the brain. These findings further our understanding of the effects of epilepsy in preschool children and will inform management of epilepsy in this patient population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

E3 ubiquitin ligases play a role in protein degradation, cellular localization, and activation, and their dysregulation is associated with human diseases. Here, we present a protocol to detect IGF2BP1 ubiquitination and activation by an E3 ubiquitin ligase FBXO45. We describe steps for preparing cells and transfecting plasmids. We detail the use of western blot to detect IGF2BP1 ubiquitination and a Cell Counting Kit-8 (CCK-8) assay to detect IGF2BP1 activation. This protocol is applicable to other proteins of interest. For complete details on the use and execution of this protocol, please refer to Lin et al. (2021). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

FBXO45, an E3 ubiquitin ligase highly expressed in liver tumors, is positively correlated with poor survival of hepatocellular carcinogenesis (HCC) patients, but whether FBXO45 drives HCC tumorigenesis remains largely unclear. Here, we describe a protocol that shortens the observation period for HCC tumorigenesis to assess the effects of FBXO45 in a DEN/CCl 4 -induced HCC mouse model. We describe steps for chemical induction of HCC in FBXO45-overexpressing mice, followed by tissue collection and pathology assessment via quantitative real-time PCR, histology, and immunohistochemistry. For complete details on the use and execution of this protocol, please refer to Lin et al. (2021). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

1,10-Phenanthroline (Phen) is a typical ligand for metal complexation and various metal/Phen complexes have been applied as a catalyst in several organic transformations. This study reports the synthesis of a Phen-based periodic mesoporous organosilica (Phen-PMO) with the Phen moieties being directly incorporated into the organosilica framework. The Phen-PMO precursor, 3,8-bis[(triisopropoxysilyl)methyl]-1,10-phenanthroline (1a), was prepared via the Kumada-Tamao-Corriu cross-coupling of 3,8-dibromo-1,10-phenanthroline and [(triisopropoxysilyl)methyl]magnesium chloride. The co-condensation of 1a and 1,2-bis(triethoxysilyl)ethane in the presence of P123 as the template surfactant afforded Phen-PMO 3 with an ordered 2-D hexagonal mesoporous structure as confirmed by nitrogen adsorption/desorption measurements, X-ray diffraction, and transition electron microscopy. Co(OAc) 2 was immobilized on Phen-PMO 3, and the obtained complex showed good catalytic activity for the hydrosilylation reaction of phenylacetylene with phenylsilane., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Gastric carcinomas have high morbidity and mortality. It produces no noticeable symptoms in the early stage while causing complex complications in its advanced stage, making treatment difficult. Palliative therapy aims to relieve the symptoms of cancer patients and focuses on improving their quality of life. At present, five palliative therapies for advanced gastric carcinomas are offered: resection, gastrojejunostomy, stenting, chemotherapy, and radiotherapy. In recent years, palliative therapy has been used in the clinical treatment of advanced gastric carcinomas and related complications because of its efficacy in gastric outlet obstruction and gastric bleeding. In the future, multimodal and interdisciplinary palliative therapies can be applied to control general symptoms to improve patients' condition, prolong their lifespan and improve their quality of life., 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 Luo, Luo, Zhao, Lin, Li, Jie, Wu, Fang, Pang and Huang.)

Background: Avian influenza A H7N9 emerged in 2013, threatening public health and causing acute respiratory distress syndrome, and even death, in the human population. However, the underlying mechanism by which H7N9 virus causes human infection remains elusive., Methods: Herein, we infected A549 cells with H7N9 virus for different times and assessed tripartite motif-containing protein 46 (TRIM46) expression. To determine the role of TRIM46 in H7N9 infection, we applied lentivirus-based TRIM46 short hairpin RNA sequences and overexpression plasmids to explore virus replication, and changes in type I interferons and interferon regulatory factor 3 (IRF3) phosphorylation levels in response to silencing and overexpression of TRIM46. Finally, we used Co-immunoprecipitation and ubiquitination assays to examine the mechanism by which TRIM46 mediated the activity of TANK-binding kinase 1 (TBK1)., Results: Type I interferons play an important role in defending virus infection. Here, we found that TRIM46 levels were significantly increased during H7N9 virus infection. Furthermore, TRIM46 knockdown inhibited H7N9 virus replication compared to that in the control group, while the production of type I interferons increased. Meanwhile, overexpression of TRIM46 promoted H7N9 virus replication and decrease the production of type I interferons. In addition, the level of phosphorylated IRF3, an important interferon regulatory factor, was increased in TRIM46-silenced cells, but decreased in TRIM46 overexpressing cells. Mechanistically, we observed that TRIM46 could interact with TBK1 to induce its K48-linked ubiquitination, which promoted H7N9 virus infection., Conclusion: Our results suggest that TRIM46 negatively regulates the human innate immune response against H7N9 virus infection., (© 2022. The Author(s).)

Objective: Using visual bibliometric analysis, the application and development of artificial intelligence in clinical esophageal cancer are summarized, and the research progress, hotspots, and emerging trends of artificial intelligence are elucidated., Methods: On April 7th, 2022, articles and reviews regarding the application of AI in esophageal cancer, published between 2000 and 2022 were chosen from the Web of Science Core Collection. To conduct co-authorship, co-citation, and co-occurrence analysis of countries, institutions, authors, references, and keywords in this field, VOSviewer (version 1.6.18), CiteSpace (version 5.8.R3), Microsoft Excel 2019, R 4.2, an online bibliometric platform (http://bibliometric.com/) and an online browser plugin (https://www.altmetric.com/) were used., Results: A total of 918 papers were included, with 23,490 citations. 5,979 authors, 39,962 co-cited authors, and 42,992 co-cited papers were identified in the study. Most publications were from China (317). In terms of the H-index (45) and citations (9925), the United States topped the list. The journal "New England Journal of Medicine" of Medicine, General & Internal (IF = 91.25) published the most studies on this topic. The University of Amsterdam had the largest number of publications among all institutions. The past 22 years of research can be broadly divided into two periods. The 2000 to 2016 research period focused on the classification, identification and comparison of esophageal cancer. Recently (2017-2022), the application of artificial intelligence lies in endoscopy, diagnosis, and precision therapy, which have become the frontiers of this field. It is expected that closely esophageal cancer clinical measures based on big data analysis and related to precision will become the research hotspot in the future., Conclusions: An increasing number of scholars are devoted to artificial intelligence-related esophageal cancer research. The research field of artificial intelligence in esophageal cancer has entered a new stage. In the future, there is a need to continue to strengthen cooperation between countries and institutions. Improving the diagnostic accuracy of esophageal imaging, big data-based treatment and prognosis prediction through deep learning technology will be the continuing focus of research. The application of AI in esophageal cancer still has many challenges to overcome before it can be utilized., 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 Tu, Lin, Ye, Yang, Deng, Zhu, Wu and Zhang.)

Due to increasingly serious environmental pollution problems and governments' strengthening of environmental impact supervision, manufacturing companies are seeking green production methods, implementing carbon trading systems, and promoting the trend towards green remanufacturing. Thus, this paper introduces green factors to the existing closed-loop supply chain network models and studies the impact of carbon trading, green innovation efforts, and green consumers on the choice between two remanufacturing strategies: an in-house remanufacturing strategy and an authorized remanufacturing strategy. The results concerning the choice of the remanufacturing strategy are as follows: from the perspective of obtaining more profits, when the carbon trading price is low, the companies choose the authorized remanufacturing strategy; when the carbon trading price is high, the companies choose to remanufacture by themselves. For all the green innovation efforts and the proportions of green consumers, when the recovery rate of the used product is low, the companies choose to remanufacture by themselves; when the recovery rate of the used product is high, the companies choose the authorized remanufacturing strategy.

The adjustment process to becoming a mother is affected by culture. However, earlier studies have not clarified the relationship between parenting stress, social support, and maternal confidence in non-Western women. This study examined the associations between different types and sources of social support, maternal confidence, and parenting stress experienced by first-time mothers. The sample consisted of first-time mothers with a child under one year of age in northern Taiwan, and a total of 205 valid questionnaires were collected. The results supported the stress-buffering hypothesis, which suggests that social support reduces the adverse effect of stress on maternal confidence. Although previous studies have suggested that spouses and maternal relatives are critical in supporting first-time mothers' transition into their new roles, each source did not show a mediator effect in our study. The beneficial effect of social support was found only when all social network members collectively participated. Regarding the types of social support, only appraisal support had a significant mediator effect; no effect was found for emotional, instrumental, or informational support. These findings add to our understanding of how different types and sources of social support play a role in helping first-time mothers adapt.

Objective: To explore the diagnostic performance of blood urea nitrogen-to-creatinine (BUN/Cr) ratio in differentiating the site of gastrointestinal bleeding, and to assess the predictive value of early elevated BUN/Cr ratio for clinical outcomes in patients with acute nonvariceal upper gastrointestinal bleeding (ANVUGIB)., Methods: The adult patients diagnosed with gastrointestinal bleeding who were hospitalized in the Department of Gastroenterology, Zhongshan Hospital, Xiamen University between May 2020 and May 2021 were retrospectively enrolled. According to the site of gastrointestinal bleeding, the patients were divided into the upper gastrointestinal tract group, the proximal small intestinal bleeding group, and the distal small intestinal and colonic bleeding group. According to the early dynamic changes of BUN/Cr ratio within 6-48 hours after admission, patients with ANVUGIB were divided into early dynamic elevated BUN/Cr ratio group and non-early dynamic elevated BUN/Cr ratio group. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic performance of BUN/Cr ratio in differentiating the site of gastrointestinal bleeding and examine the predictive efficacy of early dynamic elevated BUN/Cr ratio after admission, Rockall scoring system, and the combined indicator of the two for estimating the primary clinical outcomes in ANVUGIB patients., Results: A total of 266 patients were enrolled. Among them, 204 cases were in the upper gastrointestinal bleeding group, 15 cases were in the proximal small intestinal bleeding group, and 47 cases were in the distal small intestinal and colonic bleeding group. In the ANVUGIB patients, 16 were in the group with early dynamic elevated BUN/Cr ratio after admission, and 146 were in the group with non-early dynamic elevated BUN/Cr ratio after admission. The area under the ROC curve of the BUN/Cr ratio was 0.831 (95% CI : 0.780-0.874), the optimal cut-off value being 34.59 mg/g for differentiation between upper and lower gastrointestinal bleeding. The area under the ROC curve of the BUN/Cr ratio was 0.901 (95% CI : 0.798-0.963) and the optimal cut-off value was 19.27 mg/g for differentiation between proximal small intestinal bleeding and the distal small intestinal and colonic bleeding. The area under the ROC curve of the early dynamic elevated BUN/Cr ratio after admission was 0.806 (95% CI : 0.737-0.864) for predicting the primary clinical outcome in patients with ANVUGIB. The area under the ROC curve of the combined indicator included the early dynamic elevated BUN/Cr ratio after admission and the Rockall scoring system was 0.909 (95% CI : 0.854-0.949) for predicting the primary clinical outcome in patients with ANVUGIB., Conclusion: The BUN/Cr ratio shows rather reliable diagnostic performance for identifying the site of gastrointestinal bleeding, and the early dynamic elevated BUN/Cr ratio after admission is a reliable indicator for predicting clinical outcomes in patients with ANVUGIB., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Background: The occurrence and development of hepatocellular carcinoma (HCC) are closely related to immune function, as is the capacity of hepatoma cells to escape. Immunosurveillance is a key mechanism. Catgut implantation at acupoint (CIAA) is a promising acupuncture improvement method that can regulate immunity and has been widely used in the clinical treatment of a variety of diseases. The aim of this study is to observe the therapeutic effect of CIAA on HCC and to investigate the potential mechanism of immune escape., Materials and Methods: A total of 40 mice were randomly divided into three groups: the HCC model group ( n  = 15), the CIAA treatment group ( n  = 15), and the control group ( n  = 10). HCC was chemically induced in 30 mice by the combination of DEN, carbon tetrachloride, and ethanol for 150 days. Among them, 15 were selected for CIAA treatment to ascertain the therapeutic effect. The mRNA expression levels of AFP, IL-10, PD-1, and CTLA-4 in three groups were examined by using RT-PCR. AFP and AKT expressions were measured by using western blotting. PD1, CTLA-4, IL-10, CD4+, and CD8+ protein expression levels were evaluated by using IHC. The mortality rate, body weight, and psychological conditions of three groups were also compared., Results: The mRNA and protein expression levels of AFP, PD-1, CTLA-4, and IL-10 were significantly downregulated in the CIAA-treated mice in comparison with HCC mice. IHC assay shows that CD4+ and CD8+ expression levels were notably upregulated after CIAA treatment. Western blotting assay shows that AKT pathway was deactivated in CIAA-treated mice. CIAA notably reduced the mortality rate and inhibited weight loss caused by HCC and improved the overall psychological condition of the mice., Conclusions: Taken together, our data corroborate the effective potency of CIAA in the treatment of HCC by and inhibiting immune escape and deactivating the AKT pathway., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Shi-Hua Xu et al.)

Background: Pregnancy with renal colic may cause pyelonephritis, decreased renal function, systemic infection and even shock in pregnant women, and cause premature birth and other adverse pregnancy outcomes. When surgery is necessary, the relationship between timing of the operation and the outcome of the mother and child are not known., Aim: To investigate the association between time to ureteral stent placement and clinical outcomes of patients with renal colic during pregnancy., Methods: In this retrospective study, pregnant women with renal colic who underwent surgery were studied. Maternal preoperative acute pyelonephritis (PANP), pregnancy outcome, and length of hospital stay (LOS) were compared between the two groups., Results: 100 patients were included in the analysis, median age was 30 years. Median time to ureteral stent placement was 48 h (interquartile range, 25-96 h), and 32 patients (32%) were diagnosed with PANP. PANP was closely related to hospitalization costs, re-admission to the hospital due to urinary tract infection after surgery and premature delivery. Multivariate analysis found that stone location and time from pain to admission were related to PANP., Conclusion: Both early and delayed surgery are safe and effective for the treatment of renal colic during pregnancy. Early surgery may be superior to a delayed procedure due to shorter LOS. For pregnant patients with renal colic, delayed surgery within 48 h is not related to the clinical outcome of the mother and child. However, the time from pain to hospital admission was related to PANP., Competing Interests: Conflict-of-interest statement: No other sources of funding or conflicts of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

In this study, UiO-66 was selected as sorbent media packed in the tube to selectively enrich trace levels of benzene homologues such as benzene, toluene, and xylene (BTX) in ambient air prior to thermal desorption (TD)-GC-MS determination. A series of experiments were conducted to obtain the optimal TD conditions. The results indicated that the optimal TD parameters were as follows: desorption temperature of 180°C, desorption flow rate of 50 mL min -1 , and desorption time of 30 min. Furthermore, the method based on UiO-66 enrichment integrated with TD-GC-MS for trace levels of BTX was successfully developed. It exhibited a good linearity ( R 2  > 0.99) in the range of 50-1000 ng, except for p, m-xylene in the range of 100-2000 ng, and achieved the recovery of 69.4-101.3%, and the relative standard deviation of 3.8-6.4%. The detection limits of BTX were 1.6-4.0 ng; according to 10 L of sampling volume, the method detection limits would be in the range of 0.16-0.40  µ g m -3 . Additionally, the method was successfully applied to determine BTX in indoor air and showed good selectivity and sensitivity. In summary, the findings in this work revealed that UiO-66 was an attractive adsorbent for selective enrichment trace levels of BTX compounds in ambient air, which was favorable for the subsequent detection by TD-GC-MS., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Xing-Tao Lin et al.)

Purpose: A certain number of early-stage colorectal cancer (CRC) patients suffer tumor recurrence after initial curative resection. In this context, an effective prognostic biomarker model is constantly in need. Autophagy exhibits a dual role in tumorigenesis. Our study aims to develop an autophagy-related gene (ATG) signature-based on high-throughput data analysis for disease-free survival (DFS) prognosis of patients with stage I/II CRC. Methods: Gene expression profiles and clinical information of CRC patients extracted from four public datasets were distributed to discovery and training cohort (GSE39582), validation cohort (TCGA CRC, n = 624), and meta-validation cohort (GSE37892 and GSE14333, n = 420). Autophagy genes significantly associated with prognosis were identified. Results: Among 655 autophagy-related genes, a 10-gene ATG signature, which was significantly associated with DFS in the training cohort (HR, 2.76[1.56-4.82]; p = 2.06 × 10-4), was constructed. The ATG signature, stratifying patients into high and low autophagy risk groups, was validated in the validation (HR, 2.29[1.15-4.55]; p = 1.5 × 10-2) and meta-validation cohorts (HR, 2.5[1.03-6.06]; p = 3.63 × 10-2) and proved to be prognostic in a multivariate analysis. Functional analysis revealed enrichment of several immune/inflammatory pathways in the high autophagy risk group, where increased infiltration of T regulatory cells (Tregs) and decreased infiltration of M1 macrophages were observed. Conclusion: Our study established a prognostic ATG signature that effectively predicted DFS for early-stage CRC patients. Meanwhile, the study also revealed the possible relationship among autophagy process, immune/inflammatory response, and tumorigenesis., 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 © 2021 Lin, Wu, Qin, Fan, Lv, Chen, Cai, Weng, Zou, Rong and Gao.)

Dysregulation of tumor-relevant proteins may contribute to human hepatocellular carcinoma (HCC) tumorigenesis. FBXO45 is an E3 ubiquitin ligase that is frequently elevated expression in human HCC. However, it remains unknown whether FBXO45 is associated with hepatocarcinogenesis and how to treat HCC patients with high FBXO45 expression. Here, IHC and qPCR analysis revealed that FBXO45 protein and mRNA were highly expressed in 54.3% (57 of 105) and 52.2% (132 of 253) of the HCC tissue samples, respectively. Highly expressed FBXO45 promoted liver tumorigenesis in transgenic mice. Mechanistically, FBXO45 promoted IGF2BP1 ubiquitination at the Lys190 and Lys450 sites and subsequent activation, leading to the upregulation of PLK1 expression and the induction of cell proliferation and liver tumorigenesis in vitro and in vivo. PLK1 inhibition or IGF2BP1 knockdown significantly blocked FBXO45-driven liver tumorigenesis in FBXO45 transgenic mice, primary cells, and HCCs. Furthermore, IHC analysis on HCC tissue samples revealed a positive association between the hyperexpression of FBXO45 and PLK1/IGF2BP1, and both had positive relationship with poor survival in HCC patients. Thus, FBXO45 plays an important role in promoting liver tumorigenesis through IGF2BP1 ubiquitination and activation, and subsequent PLK1 upregulation, suggesting a new strategy for treating HCC by targeting FBXO45/IGF2BP1/PLK1 axis., Competing Interests: XL, HY, LF, YT, ZL, DW, JZ, HX, CX No competing interests declared, (© 2021, Lin et al.)

The sodium pump α3 subunit is associated with colorectal liver metastasis. However, the underlying mechanism involved in this effect is not yet known. In this study, we found that the expression levels of the sodium pump α3 subunit were positively associated with metastasis in colorectal cancer (CRC). Knockdown of the α3 subunit or inhibition of the sodium pump could significantly inhibit the migration of colorectal cancer cells, whereas overexpression of the α3 subunit promoted colorectal cancer cell migration. Mechanistically, the α3 subunit decreased p53 expression, which subsequently downregulated PTEN/IGFBP3 and activated mTOR, leading to the promotion of colorectal cancer cell metastasis. Reciprocally, knockdown of the α3 subunit or inhibition of the sodium pump dramatically blocked this effect in vitro and in vivo via the downregulation of mTOR activity. Furthermore, a positive correlation between α3 subunit expression and mTOR activity was observed in an aggressive CRC subtype. Conclusions: Elevated expression of the sodium pump α3 subunit promotes CRC liver metastasis via the PTEN/IGFBP3-mediated mTOR pathway, suggesting that sodium pump α3 could represent a critical prognostic marker and/or therapeutic target for this disease., 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 © 2021 Wu, Yu, Xiong, Zhang, Lin, Zhang, Wu, Wang, Liu and Xie.)

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions., (© 2021 Wiley-VCH GmbH.)

Objective: Obstructive jaundice (OJ) is a common clinical pathological syndrome in hepatobiliary surgery. High incidence of multiple organ injuries during perioperative period and its associated mortality remains challenging in clinical practice. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) is an important enteral immune nutrition. This study investigated the protective role of ω-3 PUFA in the regulation of inflammatory response in OJ., Materials and Methods: Seventy-two rats were randomly divided into obstructive jaundice (OJ) group, obstructive jaundice + ω-3 PUFA group (OJPUFA) group, and sham group. OJ model was created by ligation of the bile duct. Abdominal thoracic catheter was placed to collect lymph. Body weight, liver function, serum and lymphatic levels of TNF-α, IL-1β, IL-10, HMGB1, and nitric oxide (NO) were measured on day 3, day 7, and day 14 after operation. Hematoxylin staining and Alcian blue-periodic acid-Shiff (AB-PAS) staining were performed on the ileum tissue. Protein and mRNA expression of HMGB1, TLR4, and NF-κB p65 were measured at the aforementioned time points., Results: The general condition, including body weight and liver function, were worse in the OJ and the OJPUFA group compared to that in the sham group. On day 14, the body weight recovery and liver function were significantly better in the OJPUFA group than those in the OJ group were (p<0.05 for all). No marked change in the serum and lymphatic levels of TNF-α, IL-1β, IL-10, HMGB1 and NO was observed in the sham group after operation, while corresponding levels in the OJ and the OJPUFA groups were significantly higher. Compared with the OJPUFA group, serum and lymphatic levels of the above factors were consistently higher in the OJ group and were significantly higher on day 14 (p<0.05 for all). At the same time, ω-3 PUFA lowered the damage of intestinal villi and intestinal mucosal epithelium. It also improved the number and function of goblet cells in intestinal mucosal epithelium. The protein and mRNA expression of HMGB1, TLR4, and NF-κB p65 were significantly higher in the OJ group than those in the OJPUFA group (p<0.05 for all)., Conclusions: ω-3 PUFA has protective effect in the management of obstructive jaundice. It can regulate the inflammatory response and reduce its damage to intestinal structure. Reducing the activation of HMGB1/TLR4/ NF-κB pathway might be a mechanism for its protective effect. We suggested that ω-3 PUFA and drugs targeted HMGB1/TLR4/NF-κB pathway might be potential treatment strategies in obstructive jaundice.

Background: Prognosis varies among patients within the same colon adenocarcinoma (COAD) stage, indicating the need for reliable molecular markers to enable individualized treatment. This study aimed to investigate gene signatures that can be used for better prognostic prediction of COAD., Methods: Gene-expression profiles of COAD patients were obtained from the Gene Expression Omnibus database ( n  =   332) and The Cancer Genome Atlas database ( n  =   431). The relationship between gene signature and relapse-free survival was analysed in the training set ( n  =   93) and validated in the internal validation set ( n  =   94) and external validation sets ( n  =   145 and 431)., Results: Overall, 11 genes (N-myc downstream regulated gene 1 [ NDRG1 ], fms-like tyrosine kinase 1 [ FLT1 ], lipopolysaccharide binding protein [ LBP ], fatty acid binding protein 4 [ FABP4 ], adiponectin gene [ ADIPOQ ], angiotensinogen gene [ AGT ], activin A receptor, type II-like kinase 1 [ ACVRL1 ], CC chemokine ligand 11 [ CCL11 ], cell division cycle 42 [ CDC42 ], T-cell receptor alpha variable 9&#95;2 [ TRAV9&#95;2 ], and proopiomelanocortin [ POMC ]) were identified by univariable and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Based on the risk-score model, the patients were grouped into the high-risk or low-risk groups using the median risk score as the cut-off. The area under the curve (AUC) values for 1-, 3-, and 5-year recurrence were 0.970, 0.849, and 0.859, respectively. Patients in the high-risk group had significantly poorer relapse-free survival than did those in the low-risk group. The predictive accuracy of the 11-gene signature was proven in the validation sets. Our gene signature showed better predictive performance for 1-, 3-, and 5-year recurrence than did the other four models., Conclusions: The 11-gene signature showed good performance in predicting recurrence in COAD. The accuracy of the signature for prognostic classification requires further confirmation., (© The Author(s) 2021. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Objective: To explore the role of chronic disease self-management program (CDSMP) in promoting pulmonary rehabilitation of patients with chronic obstructive pulmonary disease (COPD) . Methods: In June 2017 and December 2018, 380 COPD patients were selected from the health management center of Qilu Hospital of Shandong University during the same period. They were randomly divided into the experimental group and the control group. At the end of the study, 17 cases were lost to follow-up and 5 cases were withdrawn from the study. Finally, 175 and 183 patients in the experimental group and the control group completed the study. The experimental group was treated with CDSMP for 6 months, while the control group was not intervened. Lung function and blood gas analysis results, lung rehabilitation related indicators and SF-36 scores were compared between the two groups before and after intervention. The measurement data were expressed by Mean±SD, and the comparison between the two groups was performed by t test. The count data were expressed by frequency and constituent ratio (%) . Chi square test or rank sum test was used for comparison between groups. Results: After CDSMP intervention, compared with the control group, the 6MWD, weekly moderate intensity exercise time, weekly moderate intensity exercise frequency and self exercise efficacy score of the experimental group were significantly increased, and the single exercise duration was longer, the difference was statistically significant ( P <0.05) . The physiological function score, general health score, physical energy score, mental health score and total score of the experimental group were higher, and the differences were statistically significant ( P <0.05) . Conclusion: CDSMP may have a certain effect in promoting lung rehabilitation in COPD patients.

Background & Aims: p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy., Methods: We generated mouse models in which mTOR was hyperactivated by loss of tuberous sclerosis complex 1 (Tsc1) with or without p53 haplodeficiency. Primary cells were isolated from mouse livers. Oncogenic signalling was assessed in vitro and in vivo, with or without targeted inhibition of a single molecule or multiple molecules. Transcriptional profiling was used to identify biomarkers predictive of HCC. Human HCC materials were used to corroborate the findings from mouse models., Results: p53 haploinsufficiency facilitates mTOR signalling via the PTEN/PI3K/Akt axis, promoting HCC tumorigenesis and lung metastasis. Inhibition of PI3K/Akt reduced mTOR activity, which effectively enhanced the anticancer effort of an mTOR inhibitor. ATP-binding cassette subfamily C member 4 (Abcc4) was found to be responsible for p53 haploinsufficiency- and Tsc1 loss-driven HCC tumorigenesis. Moreover, in clinical HCC samples, Abcc4 was specifically identified an aggressive subtype. The mTOR inhibitor rapamycin significantly reduced hepatocarcinogenesis triggered by Tsc1 loss and p53 haploinsufficiency in vivo, as well as the biomarker Abcc4., Conclusions: Our data advance the current understanding of the activation of the PTEN/PI3K/Akt/mTOR axis and its downstream target Abcc4 in hepatocarcinogenesis driven by p53 reduction and Tsc1 loss. Targeting mTOR, an unexpected vulnerability in p53 (haplo)deficiency HCC, can be exploited therapeutically to treat Abcc4-positive patients with HCC., Lay Summary: Tsc1 loss facilitates the p53 (haplo)insufficiency-mediated activation of the PTEN/Akt/mTOR axis, leading to the elevated expression of Abcc4 to drive HCC tumorigenesis and metastasis in mice. Inhibition of mTOR protects against p53 haploinsufficiency and Tsc1 loss-triggered tumour-promoting activity, providing a new approach for treating an aggressive subtype of HCC exhibiting high Abcc4 expression., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Major histocompatibility complex (MHC) class II regulatory genes play a paramount role in immune response that can exert a predominant influence on clinical outcome of Epstein-Barr virus infection consistently assumed as the main pathogenetic factor for nasopharyngeal carcinoma. To elucidate the relationship between allelic variants of MHC class II regulatory genes and susceptibility to nasopharyngeal carcinoma, a total of 28 polymorphic loci at MHC class II regulatory genes, involving CIITA, CREB1, RFX family genes (RFX5, RFXAP, and RFXANK), and NFY family genes (NFYA, NFYB, and NFYC), were genotyped by multiplex SNaPshot minisequencing in 137 patients with nasopharyngeal carcinoma and 107 healthy controls from the southern Chinese population. Allelic analysis disclosed that rs7404873, rs6498121, rs6498126, and rs56074043 shared correlations with nasopharyngeal carcinoma (Ptrend < 0.05). Further, rs6498126 on CIITA was independently associated with the risk of developing nasopharyngeal carcinoma (CC vs. GG, odds ratio: 7.386, 95% confidence interval: 1.934-28.207, Ptrend < 0.01). Conversely, rs7404873 on CIITA and rs56074043 on NFYB manifested epistatic interaction to decreased susceptibility of nasopharyngeal carcinoma (rs7404873, TT vs. GG, odds ratio: 0.256, 95% confidence interval: 0.088-0.740, Ptrend < 0.05; rs56074043, AA vs. AG, odds ratio: 0.341, 95% confidence interval: 0.129-0.900, Ptrend < 0.05). Additionally, bioinformatics analysis revealed that the three variants were transcriptional regulatory in function and might impact the expression of nearby genes. The findings suggested genetic variants on MHC class II regulatory genes contributed to nasopharyngeal carcinoma susceptibility and might provide new insights for screening high-risk population.

Aberrantly low expression of NF-κB inhibitor α (IκBα) is observed in hepatocellular carcinoma (HCC), yet the underlying mechanism via which IκBα regulates HCC remains largely unknown. Therefore, to determine the potential function of IκBα in hepatocarcinogenesis, the present study used immunohistochemistry (IHC) staining to analyze the associations between IκBα protein expression and clinicopathologic characteristics of 107 patients with HCC. It was found that expression of IκBα was significantly associated with tumor recurrence. Moreover, IκBα protein expression was decreased in 107 HCC tissue samples and was positively associated with overall survival. Mechanistically, it was demonstrated that silencing of IκBα activated NF-κB in both Huh7 and HCCLM3 cells, followed by upregulation of Erbb2 interacting protein (Erbin) at both the mRNA and protein levels, confirmed by reverse transcription-quantitative PCR and western blotting, to promote cell proliferation and migration. Furthermore, knockdown of Erbin significantly attenuated NF-κB-mediated cell proliferation and migration. It was also identified that overexpression of Erbin in HCC tissues promoted both cell proliferation and migration, and was negatively associated with IκBα expression in 107 HCC tissue samples. Thus, these results indicated that downregulation of IκBα promoted HCC tumorigenesis via upregulation of NF-κB-mediated Erbin expression., (Copyright: © Tan et al.)

Objective: To investigate the clinical application of carbon nanoparticles mapping lymph nodes in curative resection for colorectal carcinoma. Methods: Patients diagnosed with colorectal cancer before operation and undergoing radical surgery with intact postoperative pathological data in the Sixth Affiliated Hospital, Sun Yat-sen University from March 2016 to March 2018 were included in this retrospective case-control study. Those who were diagnosed with ileus, recurrent carcinoma or underwent emergency operation were excluded. A total of 1421 cases were included, with 156 cases in the carbon nanoparticles mapping group and 1265 cases in the control group. Using 1∶3 case control matching based on gender, weight, TNM staging and neoadjuvant chemotherapy, 145 and 435 cases were finally recruited in the carbon nanoparticles mapping group and control group, respectively. Patients in the carbon nanoparticles mapping group underwent preoperative colonoscopy with carbon nanoparticles submucosal injection 2.4 (1.0 - 14.0) days before operation. Carbon nanoparticles of 0.25 ml was injected at 4 points (3, 6, 9 and 12 o'clock each) 0.5-1.0 cm around the tumor. The number of eliminated lymph node, number of positive lymph node and positive rate between the two groups were compared, and the number of eliminated lymph node in different subgroups of T stage, N stage, TNM stage and neoadjuvant chemotherapy was analyzed and compared. Results: After case control matching, total number of eliminated lymph nodes in the carbon nanoparticles mapping group was significantly higher than that in the control group (22.2±11.2 vs. 19.0±9.5, t =3.025, P =0.003). However, no statistically significant differences were found in the number of positive lymph node and lymph node positive rate between two groups (all P >0.05). Subgroup analysis showed that as compared to the control group, total number of eliminated lymph nodes in the carbon nanoparticles mapping group was significantly higher in T3 stage subgroup (median: 22 vs. 18, Z =2.435, P =0.015), N0 stage subgroup (median: 20.5 vs. 17.5, Z =2.772, P =0.006), TNM II stage subgroup (median: 23.5 vs. 19.0, Z= 2.654, P =0.008) and neoadjuvant chemotherapy (median: 22.5 vs. 13.0, Z =3.287, P =0.001), while compared to the control group, the number of positive lymph node (median: 4.0 vs. 6.5, Z =-2.530, P =0.011) and the lymph node metastasis degree (median: 16% vs. 31%, Z =-2.862, P =0.004) were lower in the carbon nanoparticles mapping group in N2 subgroup. Conclusion: Carbon nanoparticles mapping lymph nodes can effectively enhance the number of eliminated lymph nodes in curative resection for colorectal cancer.

Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

Background: Huaier extract has been a part of traditional Chinese medicine (TCM) for roughly 1600 years and may serve as a potential anti-cancer drug as it is associated with good efficacy and low toxicity. Individuals with inflammatory bowel disease (IBD) are at a higher chance of being diagnosed with colorectal cancer (CRC) and as Huaier extract may potentially influence tumorigenesis, we set out to determine the effect of Huaier extract on colitis-associated CRC., Methods: The CRC mouse model, established through azoxymethane (AOM) and dextran sulfate sodium (DSS), was administered Huaier extract. Weight loss, colon length, tumor number and tumor size were evaluated macroscopically. Pro-inflammatory cytokine expression and STAT3 phosphorylation were assessed in the colon using ELISA, Western blot and/or immunohistochemistry., Results: Huaier extract improved the severity of colitis-associated tumorigenesis compared with control group, with attenuated weight loss and longer colons. Tumor number, size and load were drastically decreased in mice treated with Huaier. Histological assessment suggested that Huaier could decrease histological injury of the colon tissue. Additionally, Huaier extract treatment led to reduced pro-inflammatory cytokine levels (TNF-α, IL-6, IFN-γ and IL-1β) and a decrease of STAT3 phosphorylation in colon tissue. Additionally, present findings demonstrated that Huaier extract inhibited cell proliferation and induced apoptosis in CRC cells HCT116 and HCT8. The migration and invasion of CRC cells were markedly inhibited upon exposure to Huaier treatment. The apoptosis-associated protein levels (P53, Bax, Bcl-2, pro-caspase-3 and cleavage caspase-3) showed significant differences after the administration of Huaier extract in HCT116 and HCT8 cells. In vivo, the administration of Huaier extract to mice inhibited tumor growth and yielded a similar profile of apoptotic proteins expression p53, Bcl-2, pro-caspase-3 and cleaved caspase-3 while no significant differences in Bax were observed. Moreover, the ratio of TUNEL-positive/apoptotic cells was markedly increased in the Huaier-treated mice., Conclusion: Huaier extract may reduce the IBD-associated tumor development by suppressing pro-inflammatory cytokine levels and STAT3 stimulation., Competing Interests: The authors report no conflicts of interest for this work., (© 2020 Zou et al.)

Deoxynivalenol (DON) or "vomitoxin" is a mycotoxin produced by Fusarium species. Few food poisoning cases caused by DON have been reported since the 1990s in China. However, on May 16, 2019, the Zhuhai Center for Disease Control and Prevention received a case report from primary school "S" that many students began vomiting after eating breakfast. To discern the cause and control the outbreak effectively, an epidemiological investigation was carried out. This retrospective cohort study defined both suspected and probable cases of food poisoning using ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry to detect 16 mycotoxins simultaneously. A total of 101 cases (14 suspected and 87 probable) were identified, with an overall attack rate of 8.1%. All cases were in grades 1-3. The main symptoms of probable cases were vomiting (100%) and nausea (63%). The average incubation time was 25 min after eating. Comparison of students who ate breakfast provided by the school with those who did not revealed the relative risk was 6.0 (95% confidence intervals [CI] = 2.2-16) among students in grades 1-3. The concentration of DON in the leftover raw breakfast noodles ranged from 6856 to 11,982 μg/kg and 878.3 to 1074.2 μg/kg in leftover cooked noodles. DON exposure was 1.3-1.6 μg/kg body weight for grades 1-2 and 1.7-2.1 μg/kg body weight for grade 3. The attack rate of grade 3 was 4.3 times higher than that for grades 1-2 (95% CI = 3.0-6.3). The food poisoning outbreak on May 16, 2019 in primary school "S" in China, was determined to be caused by DON-contaminated commercial raw noodles.

Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide, and is well known for its strong invasiveness, rapid recurrence, and poor prognosis. Long non-coding RNAs (lncRNAs) have been shown to be involved in the development of various types of cancers, including colorectal cancer. Here, through transcriptomic analysis and functional screening, we reported that lncRNA LUCRC (LncRNA Upregulated in Colorectal Cancer) is highly expressed in colorectal tumor samples and is required for colorectal cancer cell proliferation, migration, and invasion in cultured cells and tumorigenesis in xenografts. LUCRC was found to regulate target gene expression of unfolded protein response (UPR) in endoplasmic reticulum (ER), such as BIP. The clinical significance of LUCRC is underscored by the specific presence of LUCRC in blood plasma of patients with colorectal cancers. These findings revealed a critical regulator of colorectal cancer development, which might serve as a therapeutic target in colorectal cancer., (Copyright © 2020 Tang, Chen, Ding, Du, Lin, Xia, Lian, Ye, He and Liu.)

Objective: To analyze morphological changes in central sulcus of the cerebral cortex in children with complete growth hormone deficiency (CGHD). Methods: Patients attending the Shandong Provincial Hospital who were diagnosed with CGHD or idiopathic short stature were recruited from January 2015 to January 2019. Thirty children with CGHD (18 males and 12 females, 5 to 14 years old) and 30 children with idiopathic short stature (22 males and 8 females, 5 to 14 years old) were included. Measurements of the central sulcus, including the average width, maximum depth, average depth, top length, bottom length and depth position-based profiles (DPP), were obtained using Brain VISA software. The significant differences between groups were statistically analyzed. Results: The average width of bilateral central sulci in children with CGHD (left: (2.26±0.41) mm; right: (2.19±0.34) mm) were significantly higher than those in children with idiopathic short stature (left: (2.10±0.27) mm; right: (2.02±0.18) mm) ( P <0.05) ; The maximum depth of the left central sulcus ((19.67±1.29) mm) and the average depth of the right central sulcus ((14.18±1.41) mm) were significantly lower than those in children with idiopathic short stature (left maximum depth: (20.69±1.43) mm; right average depth: (14.92±1.21) mm) ( P <0.05) . Children with CGHD had significantly lower DPP at the middle part of the left central sulcus (sites: 46-54) and the inferior part of the right central sulcus(sites: 91-98). Conclusion: There are significant morphological changes of the central sulcus in children with CGHD, which may represent the structural basis of their relatively slower development in motor, cognitive and linguistic functional performance.

In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Allergic rhinitis is an allergic inflammation of the nasal airways, and chronic rhinosinusitis is an inflammation of the paranasal sinuses. It can be induced by infection, allergy, or autoimmune problems. Diagnosis of these two diseases is made primarily based on clinical symptoms, allergen test, and imaging. The allergen test is invasive and expensive. The imaging test is harmful to children. Measurement of nasal nitric oxide (NNO) was noninvasive, without radiation, and inexpensive. This study was to evaluate the clinical significance of NNO in preschool children with nasal inflammatory diseases., Methods: A total of 55 cases of allergic rhinitis, including 35 mild cases and 20 moderate to severe cases, and 33 cases of chronic rhinosinusitis, including 18 mild cases and 15 moderate to severe cases were selected as the experimental group. Fifty healthy preschool children were chosen as the control group. The levels of NNO in all children were measured. The differences in the levels of NNO among allergic rhinitis, chronic rhinosinusitis, and the control group were compared. The levels of NNO in the control group were also analyzed., Results: The levels of NNO were significantly higher in preschool children with allergic rhinitis than in the control group, and the differences were significant. However, the levels of NNO in preschool children with chronic rhinosinusitis were lower than in the control group. In the control group, the levels of NNO were not significantly different between genders, and no significant correlation between NNO levels and the children's height was found., Conclusion: As a noninvasive method for detecting nasal inflammatory diseases, measuring the levels of NNO had a high clinical significance in preschool children., (© 2019 S. Karger AG, Basel.)