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Xiao-Hong Xie,* Fei Wang,* Xin-Qing Lin, Yin-Yin Qin, Zhan-Hong Xie, Jie-Xia Zhang, Ming Ouyang, Cheng-Zhi Zhou State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of the Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng-Zhi ZhouState Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of the Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaTel +86-20-83062830Email zhouchengzhi@gird.cnObjective: The study aimed to analyze the efficacy and safety of combination regimen of anlotinib and S-1 for Chinese patients with EGFR mutation-negative advanced squamous cell lung cancer (SqCLC) with poor performance status (PS,2– 3) after progression of second-line or later-line chemotherapy.Methods: Clinical data of 70 SqCLC patients with PS scores of 2– 3 treated in the First Affiliated Hospital of Guangzhou Medical University between January 1, 2018 to September 31, 2019 who failed second- or more-line treatment were analysed retrospectively. The patients were divided into two treatment groups: anlotinib (12mg) plus S-1 (25mg) combination group and anlotinib (12mg) monotherapy group. The efficacy and adverse reactions of the two groups were compared.Results: In terms of the short-term efficacy, there were no significant differences in objective response rate (ORR) (20.0% vs 10.0%, p = 0.464) and disease control rate (DCR) (75.0% vs 60.0%, p = 0.181) between the two groups. As for the long-term efficacy, there was no significant difference in progression-free survival (PFS) between the two groups (3.87± 0.29 months vs 3.00± 0.24 months, p=0. 11). The overall survival (OS) of patients in the combination group was longer than S1 group (8.07± 0.56 months vs 6.17± 0.42 months, p=0.022).Conclusion: Advanced SqCLC patients with higher PS scores still benefit from anlotinib and S-1 combination regimen, even after they failed second-line or later-line systemic treatment.Keywords: anlotinib, S-1, advanced squamous cell lung cancer, performance status, efficacy

Xuan Zhang, Yuan-yuan Qin, Min Chen, Yang-yang Wu, Fa-quan Lin Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaCorrespondence: Fa-quan LinDepartment of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuang Yong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86 13877118318Email fqlin1998@163.comPurpose: For the diagnosis of nasopharyngeal carcinoma (NPC), reliable early indicators with sensitivity and specificity should be sought. This study evaluated the effect of the combined use of mean platelet volume/platelet count ratio (MPV/PC ratio) and platelet distribution width (PDW) for differential diagnosis of NPC. In this study, MPV/PC ratio was used for the first time to diagnostically evaluate NPC.Patients and methods: We retrospectively analyzed various hematological indices of three subject groups (208, 185, and 162 patients with NPC, benign tumors of the nasopharynx, and healthy subjects, respectively) and evaluated the value of combined use of MPV/PC ratio and PDW for differential diagnosis of the three groups using the one-way analysis of variance.Results: Comparison of laboratory variables between the three groups showed a significant difference in MPV/PC ratio and PDW (P

Cheng-Cheng Liao,1,* Yun-Ying Qin,2,* Xiao-Hong Tan,1 Jia-Jie Hu,3 Qi Tang,2 Yan Rong,1 Hong Cen,1 Le-Qun Li4,5 1Department of Chemotherapy, 2Department of Radiology, Affiliated Tumor Hospital of Guangxi Medical University, 3Department of the Communist Youth League, Basic Medical College of Guangxi Medical University, 4Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, 5Department of Liver Cancer Treatment, Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, People’s Republic of China *These authors contributed equally to this work Objective: The objective of the study was to evaluate the prognostic value of positron emission tomography (PET)/computed tomography (CT) visual interpretation in patients with aggressive non-Hodgkin’s lymphoma (NHL) using a meta-analysis and systematic review. Methods: Using the PubMed, Embase, and Web of Science databases, we performed a systematic review of the use of visual evaluation mid-chemotherapy to evaluate the prognosis of aggressive NHL in studies published up to May 2017. Prospective and retrospective studies assessing progression-free survival (PFS) and overall survival (OS) were included. We used hazard ratio (HR) to determine the value of Deauville criteria and International Harmonization Project (IHP) criteria for measuring survival. Subgroup analysis was performed based on the number of chemotherapy cycles before the mid-term evaluation as well as the visual evaluation method. Results: A total of 11 studies were included. PFS (HR =2.93, 95% confidence interval [CI]: 2.93–3.90, p

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant., 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 Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD + ) is a crucial coenzyme involved in catalyzing cellular redox reactions and serving as a substrate for NAD + -dependent enzymes. It plays a vital role in maintaining tissue homeostasis and promoting healthy aging. Exercise, a well-established and cost-effective method for enhancing health, can influence various pathways related to NAD + metabolism. Strategies such as supplementing NAD + precursors, modulating NAD + synthesis enzymes, or inhibiting enzymes that consume NAD + can help restore NAD + balance and improve exercise performance. Various overlapping signaling pathways are known to play a crucial role in the beneficial effects of both NAD + and exercise on enhancing health and slowing aging process. Studies indicate that a combined strategy of exercise and NAD + supplementation could synergistically enhance athletic capacity. This review provides an overview of current research on the interactions between exercise and the NAD + network, underscoring the significance of NAD + homeostasis in exercise performance. It also offers insights into enhancing exercise capacity and improving aging-related diseases through the optimal use of exercise interventions and NAD + supplementation methods., Competing Interests: Declaration of Competing Interest: none., (Copyright © 2024. Published by Elsevier Inc.)

Plant-associated streptomycetes play important roles in plant growth and development. However, knowledge of volatile-mediated crosstalk between Streptomyces spp. and plants remains limited. In this study, we investigated the impact of volatiles from nine endophytic Streptomyces strains on the growth and development of plants. One versatile strain, Streptomyces setonii WY228, was found to significantly promote the growth of Arabidopsis thaliana and tomato seedlings, confer salt tolerance, and induce early flowering and increased fruit yield following volatile treatment. Analysis of plant growth-promoting traits revealed that S. setonii WY228 could produce indole-3-acetic acid, siderophores, ACC deaminase, fix nitrogen, and solubilize inorganic phosphate. These capabilities were further confirmed through genome sequencing and analysis. Volatilome analysis indicated that the volatile organic compounds emitted from ISP-2 medium predominantly comprised sesquiterpenes and 2-ethyl-5-methylpyrazine. Further investigations showed that 2-ethyl-5-methylpyrazine and sesquiterpenoid volatiles were the primary regulators promoting growth, as confirmed by experiments using the terpene synthesis inhibitor phosphomycin, pure compounds, and comparisons of volatile components. Transcriptome analysis, combined with mutant and inhibitor studies, demonstrated that WY228 volatiles promoted root growth by activating Arabidopsis auxin signaling and polar transport, and enhanced root hair development through ethylene signaling activation. Additionally, it was confirmed that volatiles can stimulate plant abscisic acid signaling and activate the MYB75 transcription factor, thereby promoting anthocyanin synthesis and enhancing plant salt stress tolerance. Our findings suggest that aerial signaling-mediated plant growth promotion and abiotic stress tolerance represent potentially overlooked mechanisms of Streptomyces-plant interactions. This study also provides an exciting strategy for the regulation of plant growth and the improvement of horticultural crop yields within sustainable agricultural practices., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Defects can introduce atomic structural modulation and tailor performance of materials. Herein, it demonstrates that semiconductor WO 3 with inert electrocatalytic behavior can be activated through defect-induced tensile strains. Structural characterizations reveal that when simply treated in Ar/H 2 atmosphere, oxygen vacancies will generate in WO 3 and cause defective structures. Stacking faults are found in defects, thus modulating electronic structure and transforming electrocatalytic-inert WO 3 into highly active electrocatalysts. Density functional theory (DFT) calculations are performed to calculate * H adsorption energies on various WO x surfaces, revealing the oxygen vacancy composition and strain predicted to optimize the catalytic activity of hydrogen evolution reaction (HER). Such defective tungsten oxides can be integrated into commercial proton exchange membrane (PEM) electrolyser with comparable performance toward Pt-based PEM. This work demonstrates defective metal oxides as promising non-noble metal catalysts for commercial PEM green-hydrogen generation., (© 2024 Wiley‐VCH GmbH.)

Objective: To understand the effect of collagen peptides on the function of mouse lymphocytes under simulated microgravity., Methods: The splenocytes of mice were isolated, and the rotary cell culture system was used to simulate the microgravity. The T lymphocytes were stimulated with mitotic agents, concanavalin A (ConA), and the cells were treated with different concentrations of collagen peptides. The proliferation of lymphocytes and the levels of cytokines in the supernatant were detected., Results: Simulated microgravity could inhibit the proliferation of spleen T lymphocytes and decrease the level of cytokines in the supernatant. Collagen peptides could promote the lymphocyte proliferation and cytokine production in cells cultured under simulated microgravity., Conclusion: Collagen peptides may attenuate the inhibitory effect of simulated microgravity on T lymphocytes by regulating the cell proliferation and the secretion of cytokines.

Objectives: Analyzing and comparing COVID-19 infection and case-fatality rates across different regions can help improve our response to future pandemics., Methods: We used public data from the WHO to calculate and compare the COVID-19 infection and case-fatality rates in different continents and income levels from 2019 to 2023., Results: The Global prevalence of COVID-19 increased from 0.011 to 0.098, while case fatality rates declined from 0.024 to 0.009. Europe reported the highest cumulative infection rate (0.326), with Africa showing the lowest (0.011). Conversely, Africa experienced the highest cumulative case fatality rates (0.020), with Oceania the lowest (0.002). Infection rates in Asia showed a steady increase in contrast to other continents which observed initial rises followed by decreases. A correlation between economic status and infection rates was identified; high-income countries had the highest cumulative infection rate (0.353) and lowest case fatality rate (0.006). Low-income countries showed low cumulative infection rates (0.006) but the highest case fatality rate (0.016). Initially, high and upper-middle-income countries experienced elevated initial infection and case fatality rates, which subsequently underwent significant reductions., Conclusions: COVID-19 rates varied significantly by continent and income level. Europe and the Americas faced surges in infections and low case fatality rates. In contrast, Africa experienced low infection rates and higher case fatality rates, with lower- and middle-income nations exceeding case fatality rates in high-income countries over time., 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 Du, Lang, Ma, Chen, Qin, Zhang and Huang.)

Introduction: A novel indicator of inflammation is the systemic immune-inflammation index (SII), and liver dysfunction is linked to the advancement of inflammation. In light of this, this study aims to look into any potential connections between SII and markers of liver injury., Methods: A cross-sectional study was conducted using the National Health and Nutrition Examination (NHANES) dataset for 2017-2020. The linear relationship between SII and markers of liver injury was examined using multiple linear regression models. Examining threshold effects and fitted smoothed curves were utilized to describe nonlinear connections., Results: A total of 8213 adults aged 18-80 years participated in this population-based study. In the fully adjusted model, SII maintained a negative association with ALT(β = -0.003, 95%CI:-0.005, -0.002, P<0.00001), AST(β = -0.004, 95% CI:-0.005, -0.002, P<0.00001), and GGT(β = -0.004, 95% CI:-0.007, -0.000, P = 0.03791) and a positive association with ALP (β = 0.005, 95% CI:0.003, 0.007, P<0.00001). In subgroup analyses, it was found that SII remained negatively correlated with ALT, AST and GGT in gender, age and body mass index. SII was positively correlated with ALP at BMI≥25(kg/m2)(β = 0.005, 95% CI:0.003, 0.008, P = 0.00001), and was negatively correlated with ALT(β = -0.004, 95% CI:-0.005, -0.002, P<0.00001), AST(β = -0.004, 95% CI:-0.005, -0.003, P<0.00001) and GGT(β = -0.004, 95% CI:-0.008, -0.000, P = 0.02703) at BMI≥25, whereas no significant correlation was observed at BMI<25 (all P-values>0.05). Furthermore, the association between SII and markers of liver injury was nonlinear. By using a two-stage linear regression model for analysis, a U-shaped relationship was found to exist between SII and ALT with a turning point of 818.40(1,000 cells/μl). The inflection points of SII with AST and GGT were 451.20 (1,000 cells/μl) and 443.33 (1,000 cells/μl), respectively, and no significant inflection point with ALP was observed. Interaction tests demonstrated that SII correlation with ALT, AST, ALP, and GGT was not significantly different between strata (all p for interaction>0.05)., Conclusions: The research findings suggested that there was a negative correlation between SII and ALT, AST and GGT, and a positive correlation with ALP. However, larger prospective investigations are still greatly needed to confirm the findings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang, Qin. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics., Methods: Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively., Results: Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on., Conclusion: BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The mitochondrial calcium uniporter (MCU) is a major protein for the uptake of mitochondrial calcium to regulate intracellular energy metabolism, including processes such as mitophagy. The present study investigated the effect of the MCU on mitophagy in pancreatic ductal epithelial cells (PDECs) in acute pancreatitis (AP) in vitro . The normal human PDECs (HPDE6-C7) were treated with caerulein (CAE) to induce AP-like changes, with or without ruthenium red to inhibit the MCU. The mitochondrial membrane potentials (MMPs) and mitochondrial Ca 2+ levels were analyzed by fluorescence. The expression levels of MCU, LC3, p62, and translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), putative kinase 1 (PINK1), and Parkin were measured by western blotting and immunofluorescence. Mitophagy was observed by confocal fluorescence microscopy and transmission electron microscopy. The results showed that CAE increased the MCU protein expression, mitochondrial Ca 2+ levels, MMP depolarization and the protein expression of mitophagy markers including the LC3II/I ratio, PINK1, and Parkin. CAE decreased the protein expression of p62 and TOMM20, and promoted the formation of mitophagosomes in HPDE6-C7 cells. Notably, changes in these markers were reversed by inhibiting the MCU. In conclusion, an activated MCU may promote mitophagy by regulating the PINK1/Parkin pathway in PDECs in AP., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Lei et al.)

Objective: This article aims to investigate the clinical value of hemoglobin/red cell distribution width ratio (Hb/RDW), C-reactive protein/albumin ratio (CAR) and plateletcrit (PCT) combined with carcinoembryonic antigen (CEA) in colorectal cancer (CRC) auxiliary diagnosis., Methods: We retrospectively analyzed in 718 subjects (212 with CRC, 209 with benign colorectal lesions (BCL), 111 with other cancers, and 186 healthy controls)., Results: The CAR, PCT, and CEA in the CRC group were higher than those in the BCL, other cancers, and the healthy control group. However, Hb/RDW in the CRC group was lower than the other three groups. Moreover, there were significant differences in Hb/RDW and CEA among different T-N-M stages (all P< 0.05). Multivariate logistic regression showed that low level of Hb/RDW and high level of CAR, CEA, PCT were risk factors for CRC, and are correlated with CRC stage. Additionally, the area under the receiver operating characteristic curve (AUC) of Hb/RDW+CEA (AUC: 0.735), CAR+CEA (AUC: 0.748), PCT+CEA (AUC: 0.807) was larger than that of Hb/RDW (AUC: 0.503), CAR (AUC: 0.614), or PCT (AUC: 0.713) alone (all P< 0.001) in distinguishing CRC from BCL., Conclusions: Hb/RDW, CAR, PCT, and CEA are independent risk factors for CRC. Hb/RDW, CAR, and PCT combined with CEA have significant value for auxiliary differential diagnosis of CRC and BCL.

Microbial exopolysaccharides (EPSs) can promote plants growth and protect them against various abiotic stresses, but the role of actinobacteria-produced EPSs in plant growth promoting is still less known. Here, we aim to explore the effect of EPSs from an endophyte Glutamicibacter halophytocota KLBMP 5180 on tomato seeds germination and seedlings growth under salt stress. Our study revealed that 2.0 g/L EPSs resulted in increased seed germination rate by 23.5 % and 11.0 %, respectively, under 0 and 200 mM NaCl stress conditions. Further pot experiment demonstrated that EPSs significantly promoted seedlings growth under salt stress, with increased height, root length and fibrous roots number. Plant physiological traits revealed that EPSs increased chlorophyll content, enhanced the activity of antioxidant enzymes, soluble sugar, and K + concentration in seedlings; malondialdehyde and Na + contents were reduced. Additionally, auxin, abscisic acid, jasmonic acid, and salicylic acid were accumulated significantly in seedlings after EPSs treatment. Furthermore, we identified 1233 differentially expressed genes, and they were significantly enriched in phytohormone signal transmission, phenylpropanoid biosynthesis, and protein processing in endogenous reticulum pathways, etc. Our results suggest that KLBMP 5180-produced EPSs effectively ameliorated NaCl stress in tomato plants by triggering complex regulation mechanism, and showed application potentiality in agriculture., Competing Interests: Declaration of competing interest All authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

The mitogen-activated protein kinases family of genes plays a crucial role in a wide range of inflammatory responses in the human body. The MAPK family of genes includes ERK, ERK5, JNK, P-38 mitogen-activated protein kinases. However, the correlation between MAPK family gene expression and pan-cancer prognosis, as well as the tumor microenvironment, has not been extensively studied. This study integrated multiple bioinformatics analysis methods to assess the expression and prognostic value of MAPK family genes, as well as their relationship with tumor microenvironment in patients with pan-cancer. The results showed that ERK, JNK, and P-38 MAPK expression were found to be significantly upregulated in rectum adenocarcinoma (READ), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COADREAD), and kidney renal clear cell carcinoma (KIRC), and significantly downregulated in acute myeloid leukemia. And the results revealed good prognostic results for ERK, JNK, and P-38 MAPK in READ, COADREAD, and KIRC. We observed significant positive correlation between MAPK family gene expression and immune scores especially dendritic cells in READ, COADREAD, and KIRC. And we observed that the expression levels of MAPK family genes were significantly correlated with the expression of immune-related genes, such as CXCL1, CXCL2, CXCL8, CXCR1, CXCR2, CTLA-4, CD80, CD86, and CD28, suggesting their important role in regulating immune infiltrates and tumor progression. Therefore, our study suggested that MAPK family gene plays an important role in regulating immune infiltrates and tumor progression., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Triptolide, a compound isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. Due to its interesting structural features and diverse pharmacological activities, it has attracted great interest by the Society of Organic Chemistry and Pharmaceutical Chemistry. However, its clinical potential is greatly hampered by limited aqueous solubility and oral bioavailability, and multi-organ toxicity. In recent years, various derivatives of Triptolide have made varying degrees of progress in the treatment of inflammatory diseases, autoimmune diseases, and cancer. The most researched and potentially clinically valuable of them were (5R)-5-hydroxytriptolide (LLDT-8), PG490-88Na (F6008), and Minnelide. In this review, we provide an overview of the advancements made in triptolide and several of its derivatives' biological activity, mechanisms of action, and clinical development. We also summarized some prospects for the future development of triptolide and its derivatives. It is hoped to contribute to a better understanding of the progress in this field, make constructive suggestions for further studies of Triptolide, and provide a theoretical reference for the rational development of new drugs.

Highly efficient genetic transformation technology is beneficial for plant gene functional research and molecular improvement breeding. However, the most commonly used Agrobacterium tumefaciens -mediated genetic transformation technology is time-consuming and recalcitrant for some woody plants such as citrus, hampering the high-throughput functional analysis of citrus genes. Thus, we dedicated to develop a rapid, simple, and highly efficient hairy root transformation system induced by Agrobacterium rhizogenes to analyze citrus gene function. In this report, a rapid, universal, and highly efficient hairy root transformation system in citrus seeds was described. Only 15 days were required for the entire workflow and the system was applicable for various citrus genotypes, with a maximum transformation frequency of 96.1%. After optimization, the transformation frequency of Citrus sinensis , which shows the lowest transformation frequency of 52.3% among four citrus genotypes initially, was increased to 71.4% successfully. To test the applicability of the hairy roots transformation system for gene functional analysis of citrus genes, we evaluated the subcellular localization, gene overexpression and gene editing in transformed hairy roots. Compared with the traditional transient transformation system performed in tobacco leaves, the transgenic citrus hairy roots displayed a more clear and specific subcellular fluorescence localization. Transcript levels of genes were significantly increased in overexpressing transgenic citrus hairy roots as compared with wild-type (WT). Additionally, hairy root transformation system in citrus seeds was successful in obtaining transformants with knocked out targets, indicating that the Agrobacterium rhizogenes -mediated transformation enables the CRISPR/Cas9-mediated gene editing. In summary, we established a highly efficient genetic transformation technology with non-tissue-culture in citrus that can be used for functional analysis such as protein subcellular localization, gene overexpression and gene editing. Since the material used for genetic transformation are roots protruding out of citrus seeds, the process of planting seedlings prior to transformation of conventional tissue culture or non-tissue-culture was eliminated, and the experimental time was greatly reduced. We anticipate that this genetic transformation technology will be a valuable tool for routine research of citrus genes in the future., 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, Qin, Wei, Xue and Dai.)

In this study, we present a cobalt-catalyzed C3-glycosylation of indoles using unfunctionalized glycals, yielding 3-indolyl- C -deoxyglycosides. These compounds hold promise as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for treating type 2 diabetes. Control experiments unveiled that cobalt assumes a dual role, facilitating catalytic C -glycosylation while unexpectedly driving the anomerization of α-anomers through endocyclic cleavage of the C1-O5 bond, resulting in the formation of β- C -deoxyglycosides. Furthermore, density functional theory (DFT) calculations shed light on the reaction mechanism, emphasizing the significant role of the pyridine group of indole in stabilizing transition states and intermediates.

The genus Diestramima comprises 41 species from Asia with 31 species distributed in China. In this study, we reconstruct the phylogeny tree of Diestramima species by maximum likelihood and Bayesian inference based on three mitochondrial genes (COI, 12S and 16S). The result indicates that the phylogenetic results are coherent with that based on five molecular markers (COI, 12S, 16S, 18S and 28S). Moreover, two new species, D. pingmengensis sp. nov. He & Zong and D. gulinjingensis. sp. nov. Zong & He are described. Their validities are also supported by morphological features. Furthermore, D. sichuanensis Zhu & Shi, 2022 is treated as a junior synonym of D. guangxiensis Qin, Wang, Liu & Li, 2016 based on both morphological and molecular features.

Background: Thiamine responsive megaloblastic anemia (TRMA) is a genetic disease caused by SLC19A2 gene mutation. This study aimed to preliminarily explore the relationship between endoplasmic reticulum stress (ERS)-PERK signaling pathway and the pathogenesis of hyperglycemia induced by TRMA., Methods: Islet β (INS.1 and β-TC-6) and HEK293T cell line models with stable overexpression of SLC19A2 and SLC19A2 (c.1409insT) were established. The cells were divided into empty virus group (control), wild-type group (overexpressed SLC19A2), and mutation group (overexpressed SLC19A2 (c.1409insT)). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression levels of ERS-PERK signaling pathway-related proteins, including glucose-regulated protein 78 (GRP78), protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2 (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islet β cells. Protein localization was assessed by immunofluorescence staining., Results: Compared with the control group, the mRNA expression levels of SLC19A2 in wild-type and mutant islet β cells (INS.1 and β-TC-6) and HEK293T cells were significantly upregulated (all p < 0.05). Compared with the control group and the wild-type group, the mRNA expression levels of GRP78, PERK, eIF2α, ATF4, and CHOP were increased (all p < 0.05) in the mutant islet β cells; the protein expression levels of PERK, GRP78, and eIF2α were elevated (all p < 0.05). In addition, the results of immunofluorescence staining showed that SLC19A2 (c.1409insT) mutation changed the localization of the proteins in the cells. Thus, they were not located on the cell surface, but in the cytoplasm and nuclei, and protein aggregation occurred in the cytoplasm., Conclusions: 1. Islet β and HEK293Tcell lines, stably overexpressing SLC19A2 and SLC19A2 (c.1409insT) mutations, were successfully constructed. 2. SLC19A2 (c.1409insT) mutation could raise the expression levels of ERS-PERK signaling pathway-related proteins (GRP78, PERK, eIF2α, ATF4, and CHOP), and activate apoptosis pathway. 3. SLC19A2 (c.1409insT) mutation could change the localization of proteins and produce protein aggregation in cells. It could lead to protein misfolding and ERS, which would participate in the pathological mechanism of hyperglycemia induced by TRMA.

Immune-related adverse events (irAEs) pose a significant challenge for the widespread adoption of immuno-oncology therapies, but their symptoms can vary widely. In particular, the relationship between irAEs and pleural effusion (PE) in patients with advanced non-small cell lung cancer (NSCLC) remains unclear. In this report, we present the case of an advanced NSCLC patient who developed persistent PE despite receiving camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) and chemotherapy as first-line treatment. While the patient's tumor biomarkers decreased after multiple cycles of treatment, the PE persisted despite negative findings on cytology and pleural biopsy. Additionally, the use of anti-angiogenic drugs failed to alleviate the PE. Screening for rheumatic connective tissue markers and tuberculosis yielded negative results, but intrathoracic dexamethasone injections in two doses resulted in a significant reduction of the PE. This case suggests that PE may represent a rare type of irAE that should be monitored for during prolonged immuno-oncology therapy.

Autism spectrum disorders (ASD) is a group of heterogeneous neurodevelopmental disorders. Evidence has implied that environmental pollutants are important factors related to ASD. In this study, several environmental endocrine-disrupting chemicals, including parabens, benzophenone-type ultraviolet filters, hydroxyl polycyclic aromatic hydrocarbons, triclosan and tetrabromobisphenol A were analyzed in blood plasma in ASD children (n = 34) and the control children (n = 28). The results showed that parabens were the most concentrated chemicals (2.18 ng/mL, median value), followed by hydroxyl polycyclic aromatic hydrocarbons (0.73 ng/mL), benzophenone-type ultraviolet filters (0.14 ng/mL), triclosan (0.13 ng/mL) and tetrabromobisphenol A (0.03 ng/mL). ASD children accumulated significantly lower 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 4-hydroxybenzophenone and triclosan but higher 2-hydroxyphenanthrene and tetrabromobisphenol A than the control children (0.02/0.09 ng/mL of 2-hydroxy-4-methoxybenzophenone, p < 0.05; 0.04/0.07 ng/mL of 2,4-dihydroxybenzophenone, p < 0.05; 0.03/0.04 ng/mL of 4-hydroxybenzophenone, p < 0.05; 0.13/1.22 ng/mL of triclosan, p < 0.01; 0.03 ng/mL/not detected of 2-hydroxyphenanthrene, p < 0.05; 0.03/0.004 ng/mL of tetrabromobisphenol A, p < 0.05). Gender differences in certain environmental endocrine-disrupting chemicals were evident, and the differences were more inclined toward boys. Positive associations between 2-hydroxy-4-methoxybenzophenone and triclosan, and tetrabromobisphenol A and 2-hydroxyphenanthrene were found in ASD boys. Binary logistic regression analysis showed that the adjusted odds ratio value of 2-hydroxyphenanthrene in ASD boys was 11.0 (1.45-84.0, p < 0.05). This is the first pilot study on multiple environmental endocrine-disrupting chemicals in children with ASD in China., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Convolutional neural networks (CNNs) have received increased attention in endoscopic images due to their outstanding advantages. Clinically, some gastric polyps are related to gastric cancer, and accurate identification and timely removal are critical. CNN-based semantic segmentation can delineate each polyp region precisely, which is beneficial to endoscopists in the diagnosis and treatment of gastric polyps. At present, just a few studies have used CNN to automatically diagnose gastric polyps, and studies on their semantic segmentation are lacking. Therefore, we contribute pioneering research on gastric polyp segmentation in endoscopic images based on CNN. Seven classical semantic segmentation models, including U-Net, UNet++, DeepLabv3, DeepLabv3+, Pyramid Attention Network (PAN), LinkNet, and Muti-scale Attention Net (MA-Net), with the encoders of ResNet50, MobineNetV2, or EfficientNet-B1, are constructed and compared based on the collected dataset. The integrated evaluation approach to ascertaining the optimal CNN model combining both subjective considerations and objective information is proposed since the selection from several CNN models is difficult in a complex problem with conflicting multiple criteria. UNet++ with the MobineNet v2 encoder obtains the best scores in the proposed integrated evaluation method and is selected to build the automated polyp-segmentation system. This study discovered that the semantic segmentation model has a high clinical value in the diagnosis of gastric polyps, and the integrated evaluation approach can provide an impartial and objective tool for the selection of numerous models. Our study can further advance the development of endoscopic gastrointestinal disease identification techniques, and the proposed evaluation technique has implications for mathematical model-based selection methods for clinical technologies.

Evidence from clinical studies and preclinical studies supports that exercise preconditioning can not only reduce the risk of stroke but also improve brain tissue and functional outcome after stroke. It has been demonstrated that autophagy and mitochondrial dynamics are involved in ischemic stroke. However, it is still unclear whether exercise preconditioning-induced neuroprotection against stroke is associated with modulation of autophagy and mitochondrial dynamics. Although age and sex interactively affect ischemic stroke risk, incidence, and outcome, studies based on young male animals are most often used to explore the role of exercise preconditioning in the prevention of ischemic stroke. In the current study, we examined whether exercise preconditioning could modulate autophagy and mitochondrial dynamics in a brain ischemia and reperfusion (I/R) model of female aged mice. The results showed that exercise preconditioning reduced infarct volume and improved neurological deficits. Additionally, increased levels of autophagy-related proteins LC3-II/LC3-I, LC3-II, p62, Atg7, and mitophagy-related proteins Bnip3L and Parkin, as well as increased levels of mitochondrial fusion modulator Mfn2 and mitochondrial fission modulator Drp1 in the ischemic cortex of female aged mice at 12 h after I/R were present. Our results could contribute to a better understanding of exercise preconditioning-induced neuroprotection against ischemic stroke for the elderly., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this article and funding they have received., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To explore the application value of whole exome sequencing (WES) in the diagnosis of prenatal and postnatal neurodevelopmental disorders (NDDs). A total of 70 patients diagnosed with NDDs who underwent WES at the Medical Genetics Center of the Maternal and Child Health Hospital of Hubei Province between June 2020 and July 2021 were retrospectively analyzed. Genomic DNA was extracted from peripheral blood samples and amniotic fluid. WES-based copy number variant (CNV) analysis was integrated into the routine WES data analysis pipeline. The results showed that a molecular diagnosis rate could be made in 21/70 (30%) cases. Of 21 positive cases, 14 (23%) cases were detected by single-nucleotide variant/small insertion/deletion (SNV/Indel) analysis, of which 12 variants were novel, 6 (9.8%) cases were detected by WES-based CNV analysis, and 1 (1.6%) case was detected by a combination of both. The diagnostic yield of WES combined with CNV analysis was higher than that of SNV/Indel analysis alone (30%, 21/70 vs. 20%, 14/70). Of the 28 prenatally diagnosed cases, 6 cases were found to have inherited parental variation for NDDs, 10 cases were found not to have the same pathogenic variation as the proband, and the remaining 12 cases were found to have no pathogenic or likely pathogenic variation that could explain the NDDs phenotype. Clinical follow-up showed that 5 families opted for abortion and the remaining had no current abnormalities. In conclusion, WES may be an effective method to clarify the genetic etiology and prenatal diagnosis of NDDs, which is helpful in assessing the prognosis to aid clinical management and reproductive guidance.

The acid-base properties of supports have an enormous impact on catalytic reactions to regulate the selectivity and activity of supported catalysts. Herein, a train of Pd-X-UiO-66 (X = NO 2 , NH 2 , and CH 3 ) catalysts with different acidity/alkalinity functional groups and encapsulated Pd(II) species is first developed, whose activities in dimethyl carbonate (DMC) catalysis are then investigated in details. Thereinto, the Pd-NO 2 -UiO-66 catalyst with acidity functionalization exhibits the best catalytic behavior: the DMC selectivity stemmed from methyl nitrite (MN) is up to 68%, the conversion of CO is 73.4%. The obtained experimental results demonstrate that the NO 2 group not only affected the interaction between X-UiO-66 and Pd(II) active sites but also play an indispensable role in the adsorption and activation of MN and CO, which remarkably promote the formation of the COOCH 3 * intermediate and DMC product., (© 2023 Wiley-VCH GmbH.)

Objective: The aim of the work described here was to develop a non-invasive tool based on the radiomics and ultrasound features of automated breast volume scanning (ABVS), clinicopathological factors and serological indicators to evaluate axillary lymph node metastasis (ALNM) in patients with early invasive breast cancer (EIBC)., Methods: We retrospectively analyzed 179 ABVS images of patients with EIBC at a single center from January 2016 to April 2022 and divided the patients into training and validation sets (ratio 8:2). Additionally, 97 ABVS images of patients with EIBC from a second center were enrolled as the test set. The radiomics signature was established with the least absolute shrinkage and selection operator. Significant ALNM predictors were screened using univariate logistic regression analysis and further combined to construct a nomogram using the multivariate logistic regression model. The receiver operating characteristic curve assessed the nomogram's predictive performance., Discussion: The constructed radiomics nomogram model, including ABVS radiomics signature, ultrasound assessment of axillary lymph node (ALN) status, convergence sign and erythrocyte distribution width (standard deviation), achieved moderate predictive performance for risk probability evaluation of ALNs in patients with EIBC. Compared with ultrasound, the nomogram model was able to provide a risk probability evaluation tool not only for the ALNs with positive ultrasound features but also for micrometastatic ALNs (generally without positive ultrasound features), which benefited from the radiomics analysis of multi-sourced data of patients with EIBC., Conclusion: This ABVS-based radiomics nomogram model is a pre-operative, non-invasive and visualized tool that can help clinicians choose rational diagnostic and therapeutic protocols for ALNM., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Immunosuppression is associated with long-term mortality during sepsis. However, the underlying mechanism of immunosuppression remains poorly understood. Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis. We sought to determine the role of TLR2 in immunosuppression in the spleen during polymicrobial sepsis. Using an experimental model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we measured the expression of inflammatory cytokines and chemokines in spleen 6 and 24 h after CLP to evaluate the immune response, and compared the expression of inflammatory cytokines and chemokines, apoptosis, and intracellular ATP production in spleen of wild-type (WT) and TLR2-deficient (TLR2 -/- ) mice 24 h after CLP. We found that pro-inflammatory cytokines and chemokines, such as TNF-α and IL-1β peaked 6 h after CLP, while IL-10, an anti-inflammatory cytokine, peaked 24 h after CLP in the spleen. At this later time point, TLR2 -/- mice presented decreased levels of IL-10 and decreased caspase 3 activation but no significant difference in intracellular ATP production in spleen compared to WT mice. Our data imply that TLR2 has a pronounced effect on sepsis-induced immunosuppression in spleen., 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 GmbH. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world. The complex mechanisms of NAFLD formation are still under identification. Carnitine palmitoyltransferase-II (CPT-II) on inner mitochondrial membrane (IMM) regulates long chain fatty acid β-oxidation, and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD. The sequences of its peptide chain and DNA nucleotides have been identified, and the catalytic activity of CPT-II is affected on its gene mutations, deficiency, enzymatic thermal instability, circulating carnitine level and so on. Recently, the CPT-II dysfunction has been discovered in models of liver lipid accumulation. Meanwhile, the malignant transformation of hepatocyte-related CD44 + stem T cell activation, high levels of tumor-related biomarkers (AFP, GPC3) and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology. This review focuses on some of the progress of CPT-II inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Six new limonoids, named hainanxylogranolides A-F (1-6), together with nineteen known ones (7-25) were isolated from the seeds of a Hainan mangrove Xylocarpus granatum. The structures of the new compounds were established by extensive NMR spectroscopic data combined with the DFT and TDDFT calculated electronic circular dichroism spectra. Hainanxylogranolide A (1) is the aromatic B-ring limonoid containing a central pyridine ring and a C-17 substituted γ(21)-hydroxybutenolide moiety. Hainanxylogranolide B (2) belongs to the small group of mexicanolides containing a C 3 -O-C 8 bridge, whereas hainanxylogranolides C and D (3 and 4) are mexicanolides comprising a C 1 -O-C 8 bridge. Compounds 9 and 25 posed obvious inhibition effect on the tube formation of HUVECs. There are only about 25% tube-like structures were observed at the concentration of 40.0 μM of compound 25. The antiviral activities of the isolates against herpes simplex virus-1 (HSV-1) and severe fever with thrombocytopenia syndrome virus (SFTSV) were tested in vitro. Compound 23 exhibited moderate anti-SFTSV activity with the IC 50 value of 29.58 ± 0.73 μM. This is the first report of anti-angiogenic effect and anti-SFTSV activity of limonoids from the genus Xylocarpus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Objective: This study aimed to observe the relationship between education level and outcomes after total knee arthroplasty (TKA)., Methods: One thousand two hundred sixty four patients after TKA in our hospital from April 2016 to April 2020 were reviewed. These patients were divided into 4 groups (A who were illiterate, B who had elementary school degree, C who had junior high school degree, D who had senior high school degree or higher) by the educational level, which was blinded to the observers. The postoperative outcomes of KSS score, pain, joint extension and flexion function were observed 1 year after discharged from hospital., Results: Among 1253 patients met the inclusion criteria, the average age was 68.63 years, the average body mass was 57.73 kg. There are no distinctions among 4 groups one day after the surgery. However, the outcomes of the follow up were that, the KSS score was: 77.84 ± 10.635; 80.70 ± 8.956; 87.92 ± 8.123;91.27 ± 8.262, with significant differences (P < 0.05). The mean VAS scores were: 1.97 ± 1.60; 2.07 ± 1.66; 1.197 ± 1.5265, 1.044 ± 1.4662. Patients in Group C and D had significantly less pain than that in Group A and B (P < 0.05). The knee flexion range of motion (ROM) was: 91.21 ± 11.69°; 91.77 ± 11.95°; 102.12 ± 11.38°; 109.96 ± 10.64°, Group D performed best, with significant differences (P < 0.05). The knee extension ROM were: - 2.41 ± 4.49°; - 0.91 ± 2.82°; - 0.83 ± 2.87°; - 0.35 ± 1.60°, with significant difference between Group D and the others (P < 0.05)., Conclusion: Education level affects the outcomes such as VAS score, KSS score, the extension and flexion ROM of the knee after TKA. The patients with higher education level have better outcomes., (© 2022. The Author(s).)

Resonant integrated optical gyroscopes (RIOGs) can integrate discrete optical components as a promising candidate for high-performance micro-optical gyroscopes. However, the current RIOG still consists of discrete elements due to the difficulty and complexity of heterogeneous integration of resonator and modulators. This paper presents on-chip integration of optical functional components including modulator, resonator, beam splitter, and coupler for the organic-polymer-based RIOG. Simple integrated optical processes such as spin coating, lithography, and etching can realize RIOG chips with low cost, size, weight, and power (CSWaP) features. Thereinto, the electro-optic modulator (EOM) fabricated by self-synthesized electro-optic (EO) polymer (side chain bonded polyurethane imide) exhibits less than 2 V half-wave voltage, which is half of the lithium niobate (LiNbO 3 ) modulator. With respect to the resonator, a quality factor of approximately million was achieved using low-loss fluorinated polymer. In addition, the angular velocity sensing of RIOG was also investigated. By demonstrating the monolithic integration of the resonator and modulators, such an all-polymer RIOG chip prototype builds the technical foundation for the precision fully integrated optical gyroscope.

Background: Ribonucleotide reductase (RR) is a key enzyme in tumor proliferation, especially its subunit-RRM2. Although there are multiple therapeutics for tumors, they all have certain limitations. Given their advantages, traditional Chinese medicine (TCM) monomers have become an important source of anti-tumor drugs. Therefore, screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development., Aim: To screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2., Methods: The Gene Expression Profiling Interactive Analysis database was used to analyze the level of RRM2 gene expression in normal and tumor tissues as well as RRM2's effect on the overall survival rate of tumor patients. TCM monomers that potentially act on RRM2 were screened via literature mining. Using AutoDock software, the screened monomers were docked with the RRM2 protein., Results: The expression of RRM2 mRNA in multiple tumor tissues was significantly higher than that in normal tissues, and it was negatively correlated with the overall survival rate of patients with the majority of tumor types. Through literature mining, we discovered that berberine, ursolic acid, gambogic acid, cinobufagin, quercetin, daphnetin, and osalmide have inhibitory effects on RRM2. The results of molecular docking identified that the above TCM monomers have a strong binding capacity with RRM2 protein, which mainly interacted through hydrogen bonds and hydrophobic force. The main binding sites were Arg330, Tyr323, Ser263, and Met350., Conclusion: RRM2 is an important tumor therapeutic target. The TCM monomers screened have a good binding capacity with the RRM2 protein., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background and Purpose: Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury., Experimental Approach: Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro., Results: Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2., Conclusion: XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway., Competing Interests: Conflict of interest statement We confirm no existence of any known conflict of interest related with this publication and no significant financial support for this work that could have affected its outcome., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: Patients with hepatocellular carcinoma (HCC) bile duct tumor thrombus (BDTT) have a high rate of postoperative recurrence. We aimed to describe the patterns and kinetics of recurrence in BDTT patients and provide management options accordingly., Methods: This retrospective study included 311 HCC patients with BDTT who underwent surgery from 2009 to 2017 at five centers in China. The hazard rate of recurrence was calculated using the hazard function., Results: The hazard rate of intrahepatic recurrence was higher than that of extrahepatic recurrence (0.0588 vs. 0.0301), and both showed a decreasing trend, and the intrahepatic recurrence and extrahepatic recurrence risk decreased to a lower level after 40 and 20 months, respectively. Patients who underwent anatomic resection had a consistently lower hazard rate of recurrence than patients who underwent nonanatomic resection, whereas patients who received postoperative adjuvant transarterial chemoembolization (TACE) mainly had a lower hazard rate of recurrence in the first year than patients who did not., Conclusion: The follow-up of BDTT patients should be at least 40 months because of its high rate of recurrence, in parallel with the need for vigilance for extrahepatic recurrence within 20 months. Anatomic hepatectomy and adjuvant TACE are recommended to improve BDTT patient outcomes., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the dynamic expression pattern of carcinoembryonic Wnt3a and its early monitoring value using a hepatocellular carcinoma model. Methods: Forty-eight Sprague Dawley (SD) rats were fed with pellet feed containing 2-acetylaminofluorene (2-AAF, 0.05%) to induce hepatocarcinogenesis, and control rats were fed a pellet diet. Liver tissue and blood samples were collected every two weeks. Liver tissues were pathologically examined using HE staining and grouped. The gene and Wnt3a mRNA expression were analyzed by genome-wide microarray. The expression and distribution of Wnt3a in liver tissue were analyzed by immunohistochemistry. Wnt3a concentration in liver tissue and serum was quantified by enzyme-linked immunosorbent assay. Statistical methods such as χ 2 test, Mann-Whitney test and analysis of variance were used to analyze the differences between groups. Results: According to the pathological examination results, the rat livers were divided into four groups: control, hepatocyte degeneration, precancerous lesions and hepatocellular carcinoma. Genome-wide expression profiling analysis and comparison with the control group revealed that 268 and 312 genes were up-regulated and 57 and 201 genes were down-regulated in the precancerous and cancerous group when signal logarithm ratio (SLR) was >8 log 2 cy5/cy3 , and these significantly altered genes mainly involved in cell proliferation, signal transduction, tumor metastasis, and apoptosis. The expression of Wnt3a at mRNA level was significantly increased in all stages of cancer induction, including degeneration group (1.15±0.24, q =8.227), precancerous group (1.85±0.18, q =12.361) and cancerous group (2.59±0.55, q =18.082). Compared with the control group (0.25±0.11, F =121.103, P <0.001), the degeneration group, the precancerous group and the liver cancer group were up-regulated by 4.6, 7.4 and 10.4-folds, respectively. Immunohistochemistry showed that compared with the control group, the positive rate of Wnt3a in the degeneration group was 66.7% (12/18, χ 2 =10.701, P =0.001), and both the precancerous and liver cancer groups were positive (9/9, χ 2 =17.115, P <0.001). Wnt3a expression was gradually increased in liver and blood samples during the process of carcinogenesis, and the difference between two groups was statistically significant ( F =176.711, P <0.001). Wnt3a overexpression was secreted into blood stream via cancerous liver tissue, and there was a linear correlation between Wnt3a levels in blood and liver samples ( r =0.732, P <0.001). Conclusions: Wnt3a overexpression is closely related with hepatocellular carcinogenesis, and thus may become a new monitoring marker.

Background: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients., Methods: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks., Results: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started., Conclusions: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 ., (© 2022. The Author(s).)

Background and Purpose: We have previously reported a cardioprotective effect with Xin-Ji-Er-Kang (XJEK) treatment in mice with myocardial infarction (MI)-induced heart failure, but no report about its potential functions in myocardial ischemia-reperfusion (MIR) injury. Here we studied the therapeutic effects of XJEK on MIR injury and investigated the mechanisms involved. Experimental Approach: MIR model of Balb/c mice induced by left anterior descending coronary artery ligation for half an hour, followed by reperfusion, was utilized to study the potential therapeutic effects of XJEK on MIR-induced cardiac injury. Ultra-performance liquid chromatography tandem Orbitrap mass spectrometry platform was used for studying serum lipid metabolic signatures. Key Results: MIR caused cardiac dysfunctions, cardiac injury, myocardial fibrosis, and increased inflammation, and all the observed abnormalities caused by MIR were largely corrected by XJEK treatment. Mechanistically, XJEK exerts its cardioprotective effect in the context of MIR injury by suppressing MIR-induced inflammation and dysregulation of serum lipid metabolism. Conclusion and Implications: We have demonstrated for the first time that XJEK protects heart from MIR injury by restoring dysregulated lipidomics. Our data provide new evidence to support a therapeutic effect for XIEK on MIR-induced cardiac injury, and pave the way for exploring the therapeutic potential of XJEK in large animal study and early clinical trial., 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 Sun, Wang, Xia, Xu, Liao, Qin, Ge, Zhao, Xu, Zhu, Gao, Xiao, Liu and Zhou.)

Aim: Transarterial chemoembolization (TACE) combined with a PD-1 inhibitor and TACE combined with a PD-1 inhibitor and lenvatinib have recently been reported as promising treatments to improve the prognosis of hepatocellular carcinoma (HCC) patients. This study aims to compare the efficacy of these two treatments., Methods: A retrospective study was conducted, and patients were recruited from two centers in China. Progression-free survival (PFS) and overall survival (OS) were compared, and the objective response rate (ORR) and disease control rate (DCR) were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment-related adverse events (AEs) were analyzed to assess safety., Results: The median follow-up for the entire cohort was 11.4 months. Of the 103 patients included in this study, 56 received triple therapy, and 47 received doublet therapy. PFS was significantly higher in the triple therapy group than in the doublet therapy group (mPFS 22.5 vs. 14.0 months, P < 0.001). Similar results were obtained in terms of OS (P = 0.001). The ORR and DCR were also better in the triple therapy group (64.3% vs. 38.3%, P = 0.010; 85.7% vs. 57.4%, P = 0.002). The most common AEs in the triple therapy group were decreased albumin (55.3%), decreased platelet count (51.8%) and hypertension (44.6%)., Conclusions: The combination of TACE with a PD-1 inhibitor and lenvatinib in patients with BCLC stage B HCC might result in significantly improved clinical outcomes with a manageable safety profile compared with TACE with a PD-1 inhibitor., (© 2022 Japan Society of Hepatology.)

1. The objective of this study was to investigate the evolution of SCNN1B and AHCYL1 proteins among 10 domestic avian and mammalian animal species, to uncover the expression patterns of SCNN1B and AHCYL1 genes in ducks, identify the genetic variants of the SCNN1B and AHCYL1 genes and analyse their effects on eggshell quality.2. Expression profiles of the SCNN1B and AHCYL1 genes in Sansui female ducks were determined using real-time fluorescence quantitative PCR to identify SNPs. The duck SCNN1B and AHCYL1 genes were amplified to identify SNPs. A total of 502 Sansui female ducks were genotyped by sequencing, and the associations between the mRNA expression/SNP genotypes and 6 eggshell quality indices were analysed using PASW Statistics 18.0.3. The results showed that the SCNN1B and AHCYL1 proteins are highly conserved in different mammalian or domestic animals, especially the AHCYL1 protein. The SCNN1B and AHCYL1 genes were widely expressed in different tissues of male and female ducks, and expression level in the uterus was greater than in other tissues. The expression of SCNN1B and AHCYL1 during the oviposition cycle indicated that expression levels were related to the eggshell mineralisation stage.4. The mRNA expression levels of the uterine SCNN1B and AHCYL1 genes were positively correlated with eggshell strength (ESS), percentage (ESP) and weight (ESW) ( P < 0.05), respectively. Ten novel SNPs in SCNN1B and AHCYL1 genes from Chinese domestic laying ducks were identified through PCR amplicon sequencing.5. Genetic association analysis indicated g.797509 C > T, g.797573 C > T and g.797834 C > T in SCNN1B gene and g.169244 T > A, g.169265 T > C and g.175311 T > C in AHCYL1 gene had a significant effect on eggshell quality. Correlation analysis between the SNP genotype and SCNN1B and AHCYL1 genes expression in the uterus showed that the genotypes of g.797509 C > T, g.797573 C > T, g.797834 C > T, g.169244 T > A and g.175311 T > C sites affected the expression of SCNN1B and AHCYL1 genes in utero ( P < 0.05).6. The study indicated SCNN1B and AHCYL1 as candidate genes to improve eggshell traits in ducks.

Three new andrastin derivatives, 10-formyl andrastone A ( 1 ), 10-demethylated andrastone A ( 2 ) and andrastin G ( 3 ), together with four known andrastin analogues ( 4 - 7 ) were isolated from an endophytic fungus Penicillium vulpinum . Their structures were determined by 1 D, 2 D NMR, and the absolute configurations were further determined by experimental and calculated ECD spectra. Compound 5 exhibited significant antibacterial activity against Bacillus paratyphosus B with an MIC value of 6.25  µ g·mL -1 . Compounds 2 and 6 showed remarkable inhibitory activities against Bacillus megaterium with the MIC value of 6.25  µ g·mL -1 , respectively.

Background: Microvascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). The current classification of MVI is not refined enough to prognosticate long-term survival of these patients, and a new MVI classification is needed., Methods: Patients with HCC who underwent R0 LR at the Eastern Hepatobiliary Surgery Hospital from January 2013 to December 2013 and with resected specimens showing MVI were included in this study with an aim to establish a novel MVI classification. The classification which was developed using multivariate cox regression analysis was externally validated., Results: There were 180 patients in the derivation cohort and 131 patients in the external validation cohort. The following factors were used for scoring: α-fetoprotein level (AFP), liver cirrhosis, tumor number, tumor diameter, MVI number, and distance between MVI and HCC. Three classes of patients could be distinguished by using the total score: class A, ≤3 points; class B, 3.5-5 points and class C, >5 points with distinct long-term survival outcomes (median recurrence free survival (mRFS), 22.6, 10.2, and 1.9 months, P < 0.001). The predictive accuracy of this classification was more accurate than the other commonly used classifications for HCC patients with MVI. In addition, the mRFS of class C patients was significantly prolonged (1.9 months vs. 6.2 months, P < 0.001) after adjuvant transcatheter arterial chemoembolization (TACE)., Conclusions: A novel MVI classification was established in predicting prognosis of HCC patients with MVI after R0 LR. Adjuvant TACE was useful for class C patients., Competing Interests: Declaration of competing interest 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. Published by Elsevier Ltd.)

Gelsolin (GSN) is a calcium-regulated actin-binding protein that can sever actin filaments. Notably, actin dynamics affect the structure and function of epithelial barriers. The present study investigated the role of GSN in the barrier function of pancreatic ductal epithelial cells (PDECs) in hypertriglyceridemia-induced pancreatitis (HTGP). The human PDEC cell line HPDE6-C7 underwent GSN knockdown and was treated with caerulein (CAE) + triglycerides (TG). Intracellular calcium levels and the actin filament network were analyzed under a fluorescence microscope. The expression levels of GSN, E-cadherin, nectin-2, ZO-1 and occludin were evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting. Ultrastructural changes in tight junctions were observed by transmission electron microscopy. Furthermore, the permeability of PDECs was analyzed by fluorescein isothiocyanate-dextran fluorescence. The results revealed that CAE + TG increased intracellular calcium levels, actin filament depolymerization and GSN expression, and increased PDEC permeability by decreasing the expression levels of E-cadherin, nectin-2, ZO-1 and occludin compared with the control. Moreover, changes in these markers, with the exception of intracellular calcium levels, were reversed by silencing GSN. In conclusion, GSN may disrupt barrier function in PDECs by causing actin filament depolymerization in HTGP in vitro ., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yang et al.)

To evaluate the efficacy and safety of Chinese patent medicines in the treatment of ankylosing spondylitis(AS) by frequency network Meta-analysis. Randomized controlled trials(RCTs)of Chinese patent medicines for AS were retrieved from CNKI, Wanfang, VIP, CBM, PubMed, EMbase and Cochrane Library databases from the time of database establishment to January 2021. The quality of the included RCTs was evaluated according to the Cochrane bias risk standard, and the data was analyzed by RevMan 5.3 and Stata/MP 15.1. A total of 12 kinds of Chinese patent medicines in 55 RCTs were included. According to Meta-analysis, in term of the effectiveness, the top three optimal medication regimens were Biqi Capsules, Yishen Juanbi Pills and Yaobitong Capsules combined with western medicine. The top three interventions to reduce the erythrocyte sedimentation rate(ESR)were Yishen Juanbi Pills, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. The top three interventions to reduce the C-reactive protein(CRP)were Biqi Capsules, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. In terms of the safety, top three optimal medication regimens were Total Glucosides of Paeony Capsules, Yishen Juanbi Pills, and Wangbi Tablets combined with western medicine. This network Meta-analysis suggests that Chinese patent medicines combined with conventional western medicine can effectively improve the joint pain symptoms of AS patients and reduce the acute inflammatory indicators, with high safety. However, the literature included in this study is generally of low methodological quality, and the conclusion needs to be verified by high-quality research.