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Chaenomeles plants belong to the Rosaceae family and include five species, Chaenomeles speciosa (Sweet) Nakai, Chaenomeles sinensis (Thouin) Koehne, Chaenomeles japonica (Thunb.) Lindl, Chaenomeles cathayensis (Hemsl.) Schneid and Chaenomeles thibetica Yu. Chaenomeles plants are found and cultivated in nearly every country worldwide. China serves as both the origin and distribution hub for the plants in the Chaenomeles genus, and all Chaenomeles species except for C. japonica are indigenous to China. Chaenomeles spp. is a type of edible medicinal plant that has been traditionally used in China to treat various ailments, such as rheumatism, cholera, dysentery, enteritis, beriberi, and scurvy. A variety of chemical constituents have been extracted from this genus, including terpenoids, phenolics, flavonoids, phenylpropanoids and their derivatives, benzoic acid derivatives, biphenyls, oxylipins, and alkaloids. The biological activity of some of these constituents has already been evaluated. Pharmacological investigations have demonstrated that the plants in the genus Chaenomeles exhibit anti-inflammatory, analgesic, antioxidant, antihyperglycemic, antihyperlipidemic, gastrointestinal protective, antitumor, immunomodulatory, antibacterial, antiviral, hepatoprotective, neuroprotective and other pharmacological activities. The objective of this review is to provide a comprehensive and up-to-date summary of the available information on the genus Chaenomeles to serve as a valuable reference for further investigations., (© 2023. The Pharmaceutical Society of Korea.)

In recent years, China has achieved numerous economic miracles but it has also been plagued by severe air pollution. The frequent hazy weather has severely restricted China's sustainable development. To investigate the nonlinear threshold effect of socio-economic factors on urban haze in China, this study constructs a spatial econometric Smooth Transition Autoregressive Regression (STAR) model based on the STIRPAT theory by using the remote sensing inversion PM 2.5 data of 223 prefecture-level and above cities in China mainland during 2004-2016. In this study, the ARAR-STAR model is estimated by quasi-maximum likelihood estimation, and the accuracy of parameter estimation is verified by Monte Carlo simulation, which proves that the ARAR-STAR model constructed in this study is robust. It is concluded that: there is a complex spatial nonlinear relationship between socio-economic factors such as economic development level, population density, advanced industrial structure, energy consumption, opening-up, and haze pollution. The effect of socio-economic factors on haze emission reduction under the spatial influence has complex heterogeneity with the smooth transition between high and low regimes with economic development. The ARAR-STAR model constructed in this paper, which has both individual fixed effects and time fixed effects, expands the form of existing spatial panel nonlinear models and enriches and implements the application of spatial panel smooth transfer threshold models in the environmental field. Not only can it provide policy recommendations for China to achieve "coordinated efficiency in pollution reduction and carbon reduction" as soon as possible, but it also contributes to China's plan to address global climate change and promote global sustainable development., 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. Published by Elsevier Ltd.)

Objectives: To investigate the performance of US LI-RADS in surveillance for recurrent hepatocellular carcinoma (RHCC) after curative treatment., Materials and Methods: This study enrolled 644 patients between January 2018 and August 2018 as a derivation cohort, and 397 patients from September 2018 to December 2018 as a validation cohort. The US surveillance after HCC curative treatment was performed. The US LI-RADS observation categories and visualization scores were analyzed. Four criteria using US LI-RADS or Alpha-fetoprotein (AFP) as the surveillance algorithm were evaluated. The sensitivity, specificity, and negative predictive value (NPV) were calculated., Results: A total of 212 (32.9%) patients in derivation cohort and 158 (39.8%) patients in validation cohort were detected to have RHCCs. The criterion of US-2/3 or AFP ≥ 20 µg/L had higher sensitivity (derivation, 96.7% vs 92.9% vs 81.1% vs 90.6%; validation, 96.2% vs 90.5% vs 80.4% vs 89.9%) and NPV (derivation, 95.7% vs 93.3% vs 88.0% vs 91.8%; validation, 94.6% vs 89.4% vs 83.6% vs 89.0%), but lower specificity (derivation, 35.9% vs 48.2% vs 67.6% vs 51.9%; validation, 43.5% vs 52.7% vs 66.1% vs 54.0%) than criterion of US-2/3, US-3, and US-3 or AFP ≥ 20 µg/L. Analysis of the visualization score subgroups confirmed that the sensitivity (89.2-97.6% vs 81.0-83.3%) and NPV(88.4-98.0% vs 80.0-83.3%) of score A and score B groups were higher than score C group in criterion of US-2/3 in both two cohorts., Conclusions: In the surveillance for RHCC, US LI-RADS with AFP had a high sensitivity and NPV when US-2/3 or AFP ≥ 20 µg/L was considered a criterion., Clinical Relevance Statement: The criterion of US-2/3 or AFP ≥ 20 µg/L improves sensitivity and NPV for RHCC surveillance, which provides a valuable reference for patients in RHCC surveillance after curative treatment., Key Points: • US LI-RADS with AFP had high sensitivity and NPV in surveillance for RHCC when considering US-2/3 or AFP ≥ 20 µg/L as a criterion. • After US with AFP surveillance, patients with US-2/3 or AFP ≥ 20 µg/L should perform enhanced imaging for confirmative diagnosis. Patients with US-1 or AFP < 20 µg/L continue to repeat US with AFP surveillance. • Patients with risk factors for poor visualization scores limited the sensitivity of US surveillance in RHCC., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Globally, the prevalence of hypertension and the accompanying burden of cardiovascular disease are increasing. Through drug utilization research, we can understand the prescription status of hypertension patients and promote rational drug use. The purpose of this retrospective study was to describe the current prescription pattern of antihypertensive drugs in Chinese patients and determine the compliance level of treatment guidelines., Materials and Methods: Around 11.1 million patients who received a prescription for antihypertensive therapy between January 2021 to December 2021 were obtained from a database of Hangzhou Kang Sheng Health Consulting CO., Ltd., Results: The mean age of hypertensive patients was 54.75 ± 12.98 years. About 6.7 million (60.30%) were males. About 46.07% of patients had comorbidities. The most common classes of antihypertensive medications used were calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). Around 78.33% of participants were on monotherapy. Diuretics + ARBs and Diuretics + CCBs + ARBs were the most commonly prescribed pattern in two-drug combination therapy and three-drug combination therapy, respectively., Conclusions: CCBs and ARBs were the two most frequently prescribed for patients with hypertension. The prescription pattern of antihypertensive medications in the study largely complied with recommended Chinese hypertension guidelines.Key messagesCardiovascular disease is the most common complication of hypertension.Calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) are the two most commonly used drugs for hypertension patients in China.The proportion of combination prescription pattern in Chinese hypertensive patients is low.

Objectives: To identify the risk factors for predicting the malignant progression of LR-3/4 observations on the baseline and contrast-enhanced ultrasound (CEUS)., Methods: In total, 245 liver nodules assigned to LR-3/4 in 192 patients from January 2010 to December 2016 were followed up by baseline US and CEUS. The differences in the rate and time of progression to hepatocellular carcinoma (HCC) among subcategories (defined as P1-P7) of LR-3/4 in CEUS Liver Imaging Reporting and Data System (LI-RADS) were analyzed. The risk factors to predict progression to HCC were analyzed by univariate and multivariate Cox proportional hazard model analysis., Results: A total of 40.3% of LR-3 nodules and 78.9% of LR-4 nodules eventually progressed to HCC. The cumulative incidence of progression was significantly higher for LR-4 than LR-3 (p < 0.001). The rate of progression was 81.2% in nodules with arterial phase hyperenhancement (APHE), 64.7% in nodules with late and mild washout, and 100% in nodules with both characteristics. The overall progression rate and median progression time of subcategory P1 nodules (LR-3a) were lower (38.0% vs. 47.6-100.0%) and later (25.1 months vs. 2.0-16.3 months) than those of other subcategories. The cumulative incidence of progression of LR-3a (P1), LR-3b (P2/3/4), and LR-4 (P5/6/7) categories were 38.0%, 52.9%, and 78.9%. The risk factors of HCC progression were Visualization score B/C, CEUS characteristics (APHE, washout), LR-4 classification, echo changes, and definite growth., Conclusion: CEUS is a useful surveillance tool for nodules at risk of HCC. CEUS characteristics, LI-RADS classification, and changes in nodules provide useful information for the progress of LR-3/4 nodules., Clinical Relevance Statement: CEUS characteristics, LI-RADS classification, and nodule changes provide important predictions for LR-3/4 nodule progression to HCC, which may stratify the risk of malignant progression to provide a more optimized and refined, more cost-effective, and time-efficient management strategy for patients., Key Points: • CEUS is a useful surveillance tool for nodules at risk of HCC, CEUS LI-RADS successfully stratified the risks that progress to HCC. • CEUS characteristics, LI-RADS classification, and changes in nodules can provide important information on the progression of LR-3/4 nodules, which may be helpful for a more optimized and refined management strategy., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: Both alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDL-C) are closely related to glucose homeostasis in the body, and the main objective of this study was to investigate the association between ALT to HDL-C ratio (ALT/HDL-C ratio) and the risk of diabetes in a Chinese population., Methods: The current study included 116,251 participants who underwent a healthy physical examination, and the study endpoint was defined as a diagnosis of new-onset diabetes. Multivariate Cox regression models and receiver operator characteristic curves were used to assess the association of the ALT/HDL-C ratio with diabetes onset., Results: During the average observation period of 3.10 years, a total of 2,674 (2.3%) participants were diagnosed with new-onset diabetes, including 1,883 (1.62%) males and 791 (0.68%) females. After fully adjusting for confounding factors, we found a significant positive association between the ALT/HDL-C ratio and the risk of diabetes [Hazard ratios 1.06, 95% confidence intervals: 1.05, 1.06], and this association was significantly higher in males, obese individuals [body mass index ≥ 28 kg/m 2 ] and individuals aged < 60 years (All P interaction < 0.05). In addition, the ALT/HDL-C ratio was significantly better than its components ALT and HDL-C in predicting diabetes in the Chinese population., Conclusion: There was a positive relationship between ALT/HDL-C ratio and diabetes risk in the Chinese population, and this relationship was significantly stronger in males, obese individuals, and individuals younger than 60 years old., 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 He, Yu, Kuang, Qiu, Yang, Zhang, Sheng and Zou.)

Objective: The newly proposed Metabolic Visceral Fat Score (METS-VF) is considered a more effective measure for visceral adipose tissue (VAT) than other obesity indicators. This study aimed to reveal the association between METS-VF and non-alcoholic fatty liver disease (NAFLD), and its variations across age groups within both sexes., Methods: Data from 14,251 medical examiners in the NAGALA project were employed in this study. 3D fitted surface plots were constructed based on multivariate logistic regression models to visualize the isolated and combined effects of aging and METS-VF on NAFLD. Receiver operating characteristic curve (ROC) analysis was conducted to compare the diagnostic performance of METS-VF with other VAT surrogate markers in predicting NAFLD., Results: The results of multivariate logistic regression analysis showed that each unit increase in METS-VF was independently associated with a 333% and 312% increase in the odds of NAFLD in males and females, respectively. Additionally, the 3D fitted surface plot showed that age significantly influenced the association between METS-VF and the odds of NAFLD in both sexes, as follows: (i) In males, when METS-VF was less than 6.2, the METS-VF-related odds of NAFLD increased gradually with age in the 20-45 age group, reached a plateau in the 45-65 age group, and then decreased in the group above 65 years old; however, when male METS-VF exceeded 6.2, aging and METS-VF combined to further increase the odds of NAFLD in all age groups, particularly in the 45-65 age group. (ii) In females, aging seemed to reduce METS-VF-related odds of NAFLD in the 18-40 age group, but significantly increased it in the 40-60 age group, particularly for those with higher METS-VF levels. Further ROC analysis revealed that compared to other VAT surrogate markers, METS-VF showed the highest diagnostic accuracy for NAFLD in females, especially in those under 45 years of age [area under the curve (AUC) = 0.9256]., Conclusions: This study firstly revealed a significant positive correlation between METS-VF and the odds of NAFLD, with METS-VF surpassing other VAT surrogate markers in NAFLD diagnosis. Moreover, age significantly influenced the METS-VF-related odds of NAFLD and METS-VF's diagnostic efficacy for NAFLD in both sexes., 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 Kuang, Qiu, Li, Hu, Zhang, Sheng and Zou.)

Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated 61 BTC patient-derived organoids (PDOs) from 82 tumors (74.4%) that show similar histological and genetic characteristics to the corresponding primary BTC tissues. BTC tumor tissues with enhanced stemness- and proliferation-related gene expression by RNA sequencing can more easily form organoids. As expected, BTC PDOs show different responses to the chemotherapies of gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, etc. The drug screening results in PDOs are further validated in PDO-based xenografts and confirmed in 92.3% (12/13) of BTC patients with actual clinical response. Moreover, we have identified gene expression signatures of BTC PDOs with different drug responses and established gene expression panels to predict chemotherapy response in BTC patients. In conclusion, BTC PDO is a promising precision medicine tool for anti-cancer therapy in BTC patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

A mild and general protocol involving amnio- and oxyselenation of diverse alkenes for the efficient synthesis of organo-Se compounds is achieved via an environmentally benign calcium-catalyzed three-component reaction. This selenofunctionalization reaction exhibits excellent substrate/functional group tolerance and high levels of chemo- and regioselectivity. Its utility was exemplified in the late-stage functionalization and even aggregation-induced emission luminogen labeling of organo-Se compounds.

Background: The intestinal microbiota (IM) has been found to contribute to metabolic disorders that lead to excessive fat accumulation, systemic and chronic low-grade inflammation, and insulin resistance in the host. Current research highlights a pivotal interaction between IM and traditional Chinese medicine (TCM) in mitigating obesity-related diseases. Undeniably, IM stands as a central focus in TCM research aimed at preventing and treating obesity. Therefore, tracing the progress and trends in this field can offer valuable references and insights for future studies., Methods: On June 17, 2023, we conducted a literature search on the topic of "IM and obesity in TCM" spanning the period from 2009 to 2023. We extracted the primary information of the publications, which includes complete records and reference citations, from the Science Citation Index Expanded (SCI-E) within the Web of Science Core Collection (WoSCC). To visualize and analyze the literature, we utilized CiteSpace and VOSviewer for bibliometric analysis., Results: During the past fifteen years, a rapid increase in the number of publications has been observed. The cooperative networks demonstrate China, Beijing University of Chinese Medicine, and Food & Function as the most active countries, organizations, and journals in this field, respectively. Liu Bin has contributed the most publications. A paper by Xu Jia, published in 2014, holds the highest Local Citation Score (LCS). Analyses of keyword co-occurrence and reference co-citation indicate that the research hotspots of IM and obesity in TCM are primarily focused on the metabolic benefits driven by endogenous functional metabolic molecules generated by TCM regulation of IM. Other focal points include the mechanism by which TCM regulates IM to restore the intestinal mucosal barrier This is a provisional file, not the final typeset article, and manages the gut-organ axis, the metabolic advantages of acupuncture's regulation of IM, and the process by which Chinese medicine small molecules transform IM., Conclusion: This research offers a comprehensive understanding of the current status, hotspots, and trends in global TCM research. Additionally, it provides a comprehensive summary and exploration of the latest advancements in this field, thereby emphasizing the essence of TCM more effectively., 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 Huang, Wang, Kuang, Xiao, Fan, Sun and Tan.)

Objective: The increasing prevalence of diabetes is strongly associated with visceral adipose tissue (VAT), and gender differences in VAT remarkably affect the risk of developing diabetes. This study aimed to assess the predictive significance of lipid accumulation products (LAP) for the future onset of diabetes from a gender perspective., Methods: A total of 8,430 male and 7,034 female non-diabetic participants in the NAGALA (NAfld in the Gifu Area, Longitudinal Analysis) program were included. The ability of LAP to assess the risk of future new-onset diabetes in both genders was analyzed using multivariate Cox regression. Subgroup analysis was conducted to explore the impact of potential modifiers on the association between LAP and diabetes. Additionally, time-dependent receiver operator characteristics (ROC) curves were used to assess the predictive power of LAP in both genders for new-onset diabetes over the next 2-12 years., Results: Over an average follow-up of 6.13 years (maximum 13.14 years), 373 participants developed diabetes. Multivariate Cox regression analysis showed a significant gender difference in the association between LAP and future diabetes risk ( P -interaction<0.05): the risk of diabetes associated with LAP was greater in females than males [hazard ratios (HRs) per standard deviation (SD) increase: male 1.20 (1.10, 1.30) vs female 1.35 (1.11, 1.64)]. Subgroup analysis revealed no significant modifying effect of factors such as age, body mass index (BMI), smoking history, drinking history, exercise habits, and fatty liver on the risk of diabetes associated with LAP (All P -interaction <0.05). Time-dependent ROC analysis showed that LAP had greater accuracy in predicting diabetes events occurring within the next 2-12 years in females than males with more consistent predictive thresholds in females., Conclusions: This study highlighted a significant gender difference in the association between LAP and future diabetes risk. The risk of diabetes associated with LAP was greater in females than in males. Furthermore, LAP showed superior predictive ability for diabetes at different time points in the future in females and had more consistent and stable predictive thresholds in females, particularly in the medium and long term., 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 Qiu, Kuang, Zou, Yang, Shangguan, Liu, Sheng and Wang.)

Skin Cancer (SC) is one of the most dangerous types of cancer and if not treated in time, it can threaten the patient's life. With early diagnosis of this disease, treatment methods can be used more effectively and the progression of the disease can be prevented. Machine Learning (ML) techniques can be utilized as a useful and efficient tool for SCD. So far, various methods for automatic SCD based on ML techniques have been presented; However, this research field still requires the application of optimal and efficient models to increase the accuracy of SCD. Therefore, in this article, a new method for SCD using a combination of optimization techniques and Artificial Neural Networks (ANNs) is presented. The proposed method includes four steps: pre-processing, segmentation, feature extraction, and classification. Image segmentation for identifying the lesion region is performed using a Kohonen neural network, where the identified region of interest (ROI) is enhanced using the Greedy Search Algorithm (GSA). The proposed method, uses a Convolutional Neural Network (CNN) for extracting features from ROIs. Also, to classify features, an ANN is used, and by the Improved Gray Wolf Optimization (IGWO) algorithm, the number of neurons and weight vector are adjusted. In this method, a probabilistic model is used to improve the convergence speed of the GWO algorithm. Based on the evaluation results, using the IGWO model to optimize the structure and weight vector of the ANN can be effective in increasing the diagnosis accuracy by at least 5%. The results of implementing the proposed method and comparing its performance with previous methods also show that this method can diagnose SC in the ISIC-2016 and ISIC-2017 databases with an average accuracy of 97.09 and 95.17%, respectively; which improves accuracy by at least 0.5% compared to other methods., (© 2023. The Author(s).)

The magneto-optical Kerr effect (MOKE) is a powerful probe of magnetism and has recently gained new attention in antiferromagnetic (AFM) materials. Through extensive first-principles calculations and group theory analysis, we have identified Fe 2 CX 2 (X = F, Cl) and Janus Fe 2 CFCl monolayers as ideal A-type collinear AFM materials with high magnetic anisotropy and Néel temperatures. By applying a vertical external electrical field ( E f ) of 0.2 V/Å, the MOKE is activated for Fe 2 CF 2 and Fe 2 CCl 2 monolayers without changing their magnetic ground state, and the maximum Kerr rotation angles are 0.13 and 0.08°, respectively. Due to the out-of-plane spontaneous polarization, the intrinsic and nonvolatile MOKE is found in the Janus Fe 2 CFCl monolayer and the maximal Kerr rotation angle without external electronic field is 0.25°. Moreover, the intrinsic built-in electronic field also gives origin to more robust A-type AFM ordering and reversible Kerr angle against external E f . Our study suggests that E f is an effective tool for controlling MOKE in two-dimensional (2D) AFM materials. This research opens the possibility of related studies and applications in AFM spintronics.

Objective: To develop and validate a nomogram based on liver stiffness (LS) for predicting symptomatic post-hepatectomy (PHLF) in patients with hepatocellular carcinoma (HCC)., Methods: A total of 266 patients with HCC were enrolled prospectively from three tertiary referral hospitals from August 2018 to April 2021. All patients underwent preoperative laboratory examination to obtain parameters of liver function. Two-dimensional shear wave elastography (2D-SWE) was performed to measure LS. Three-dimensional virtual resection obtained the different volumes including future liver remnant (FLR). A nomogram was developed by using logistic regression and determined by receiver operating characteristic (ROC) curve analysis and calibration curve analysis, which was validated internally and externally., Results: A nomogram was constructed with the following variables: FLR ratio (FLR of total liver volume), LS greater than 9.5 kPa, Child-Pugh grade, and the presence of clinically significant portal hypertension (CSPH). This nomogram enabled differentiation of symptomatic PHLF in the derivation cohort (area under curve [AUC], 0.915), internal fivefold cross-validation (mean AUC, 0.918), internal validation cohort (AUC, 0.876) and external validation cohort (AUC, 0.845). The nomogram also showed good calibration in the derivation, internal validation, and external validation cohorts (Hosmer-Lemeshow goodness-of-fit test, p = 0.641, p = 0.06, and p = 0.127, respectively). Accordingly, the safe limit of the FLR ratio was stratified using the nomogram., Conclusion: An elevated level of LS was associated with the occurrence of symptomatic PHLF in HCC. A preoperative nomogram integrating LS, clinical and volumetric features was useful in predicting postoperative outcomes in patients with HCC, which might help surgeons in the management of HCC resection., Clinical Relevance Statement: A serial of the safe limit of the future liver remnant was proposed by a preoperative nomogram for hepatocellular carcinoma, which might help surgeons in 'how much remnant is enough in liver resection'., Key Points: • An elevated liver stiffness with the best cutoff value of 9.5 kPa was associated with the occurrence of symptomatic post-hepatectomy liver failure in hepatocellular carcinoma. • A nomogram based on both quality (Child-Pugh grade, liver stiffness, and portal hypertension) and quantity of future liver remnant was developed to predict symptomatic post-hepatectomy liver failure for HCC, which enabled good discrimination and calibration in both derivation and validation cohorts. • The safe limit of future liver remnant volume was stratified using the proposed nomogram, which might help surgeons in the management of HCC resection., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m 6 A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (log rank test, p < 0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m 6 A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m 6 A modification that hampers ribosome synthesis and inhibits translation of G-quadruplex-containing mRNAs that are enriched in the transforming growth factor (TGF)-β pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m 6 A modification in ICC and unravels the mechanism of rRNA m 6 A modification-mediated oncogenic mRNA translation control., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background & Aims: RNA N 6 -methyladenosine (m 6 A) reader protein YTHDF1 has been implicated in cancer; however, its role in hepatocellular carcinoma (HCC), especially in non-alcoholic steatohepatitis-associated HCC (NASH-HCC), remains unknown. Here, we investigated the functional role of YTHDF1 in NASH-HCC and its interplay with the tumor immune microenvironment., Methods: Hepatocyte-specific Ythdf1-overexpressing mice were subjected to a NASH-HCC-inducing diet. Tumor-infiltrating immune cells were profiled with single-cell RNA-sequencing, flow cytometry, and immunostaining. The molecular target of YTHDF1 was elucidated with RNA-sequencing, m 6 A-sequencing, YTHDF1 RNA immunoprecipitation-sequencing, proteomics, and ribosome-profiling. Ythdf1 in NASH-HCC models was targeted by lipid nanoparticle (LNP)-encapsulated small-interfering Ythdf1., Results: YTHDF1 is overexpressed in tumor tissues compared to adjacent peri-tumor tissues from patients with NASH-HCC. Liver-specific Ythdf1 overexpression drives tumorigenesis in dietary models of spontaneous NASH-HCC. Single-cell RNA-sequencing and flow cytometry revealed that Ythdf1 induced accumulation of myeloid-derived suppressor cells (MDSCs) and suppressed cytotoxic CD8 + T-cell function. Mechanistically, Ythdf1 expression in NASH-HCC cells induced the secretion of IL-6, which mediated MDSC recruitment and activation, leading to CD8 + T-cell dysfunction. EZH2 mRNA was identified as a key YTHDF1 target. YTHDF1 binds to m 6 A-modified EZH2 mRNA and promotes EZH2 translation. EZH2 in turn increased expression and secretion of IL-6. Ythdf1 knockout synergized with anti-PD-1 treatment to suppress tumor growth in NASH-HCC allografts. Furthermore, therapeutic targeting of Ythdf1 using LNP-encapsulated small-interfering RNA significantly increased the efficacy of anti-PD-1 blockade in NASH-HCC allografts., Conclusions: We identified that YTHDF1 promotes NASH-HCC tumorigenesis via EZH2-IL-6 signaling, which recruits and activates MDSCs to cause cytotoxic CD8 + T-cell dysfunction. YTHDF1 may be a novel therapeutic target to improve responses to anti-PD-1 immunotherapy in NASH-HCC., Impact and Implications: YTHDF1, a N 6 -methyladenosine reader, is upregulated in patients with non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC); however, its role in modulating the tumor immune microenvironment in NASH-HCC remains unclear. Here, we show that Ythdf1 mediates immunosuppression in NASH-HCC and that targeting YTHDF1 in combination with immune checkpoint blockade elicits robust antitumor immune responses. Our findings suggest novel therapeutic targets for potentiating the efficacy of immune checkpoint blockade in NASH-HCC and provide the rationale for developing YTHDF1 inhibitors for the treatment of NASH-HCC., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC, whereas IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer., Significance: The immunomodulatory patterns of tumor-infiltrating B cells are distinct in primary and secondary liver cancer, with plasma cells mediating important physiologic processes that drive cancer progression., (©2023 American Association for Cancer Research.)

Electrochemical reduction of CO 2 into high-value hydrocarbons and alcohols by using Cu-based catalysts is a promising and attractive technology for CO 2 capture and utilization, resulting from their high catalytic activity and selectivity. The mobility and accessibility of active sites in Cu-based catalysts significantly hinder the development of efficient Cu-based catalysts for CO 2 electrochemical reduction reaction (CO 2 RR). Herein, a facile and effective strategy is developed to engineer accessible and structural stable Cu sites by incorporating single atomic Cu into the nitrogen cavities of the host graphitic carbon nitride (g-C 3 N 4 ) as the active sites for CO 2 -to-CH 4 conversion in CO 2 RR. By regulating the coordination and density of Cu sites in g-C 3 N 4 , an optimal catalyst corresponding to a one Cu atom in one nitrogen cavity reaches the highest CH 4 Faraday efficiency of 49.04% and produces the products with a high CH 4 /C 2 H 4 ratio over 9. This work provides the first experimental study on g-C 3 N 4 -supported single Cu atom catalyst for efficient CH 4 production from CO 2 RR and suggests a principle in designing highly stable and selective high-efficiency Cu-based catalysts for CO 2 RR by engineering Cu active sites in 2D materials with porous crystal structures., (© 2023. The Author(s).)

Objective: Several recent reports have suggested the use of mean arterial blood pressure (MAP) to assess/predict the risk of developing atherosclerosis, chronic kidney disease, diabetes, metabolic syndrome, and poor prognosis in a variety of cardiovascular and cerebrovascular diseases. The current study aimed to investigate the association of MAP with non-alcoholic fatty liver disease (NAFLD) and to explore the differences in this association across populations., Methods: This study used data from the NAGALA study from 1994 to 2016. MAP was calculated as 1/3 systolic blood pressure (SBP) + 2/3 diastolic blood pressure (DBP). Restricted cubic spline (RCS) and logistic regression models were used to examine the correlation of MAP with NAFLD., Results: The study population was 14,251 general people undergoing health screening, with a median (interquartile range) age of 42 (36-50) years; among them, 48% were women, and 2,507 (17.59%) were diagnosed with NAFLD. After fully controlling for confounders in the current dataset, MAP was positively and non-linearly associated with NAFLD [(odds ratios (ORs): 1.39, 95% confidence intervals (CIs): 1.15, 1.68); P for non-linearity = 0.024]; the dose-response curve showed that there was a transient saturation effect interval when MAP was between 85 and 95 mmHg, where the risk of NAFLD was neither increased nor decreased. The results of the stratified analysis showed that the risk of NAFLD associated with MAP appeared to be influenced only by age ( P -interaction = 0.002), but not by sex, body mass index (BMI), habits of exercise, drinking status, or smoking status ( P -interaction > 0.05); further age-stratified RCS analysis showed that the non-linear association between MAP and NAFLD in the young and middle-aged and the middle-aged and elderly populations was consistent with the results of the whole population, whereas, in the elderly population, a U-shaped curve association between MAP and NAFLD was observed, with both low and high MAP increasing the risk of NAFLD., Conclusion: In the general population, MAP was positively and non-linearly associated with NAFLD, and this association only differed significantly by age, but not by sex, BMI, habits of exercise, drinking status, and smoking status., 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., (© 2023 Li, Yang, Xie, Kuang, Sheng and Zou.)

Background: Insufficient post-operative future liver remnant (FLR) limits the feasibility of hepatectomy for patients. Staged hepatectomy is an effective surgical approach that can improve the resection rate of hepatocellular carcinoma (HCC). This study aimed to compare the safety and efficacy of laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS) and classical associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in the treatment of hepatitis B virus (HBV)-related HCC., Methods: Clinical data of patients with HBV-related HCC who underwent LAPS or ALPPS in our institute between January 2017 and May 2022 were retrospectively analysed., Results: A total of 18 patients with HBV-related HCC were retrospectively analysed and divided into the LAPS group ( n  =   9) and ALPPS group ( n  =   9). Eight patients in the LAPS group and eight patients in the ALPPS group proceeded to a similar resection rate (88.9% vs 88.9%, P  =   1.000). The patients undergoing LAPS had a lower total comprehensive complication index than those undergoing ALPPS but there was not a significant different between the two groups (8.66 vs 35.87, P  =   0.054). The hypertrophy rate of FLR induced by ALPPS tended to be more rapid than that induced by LAPS (24.29 vs 13.17 mL/d, P  =   0.095). The 2-year recurrence-free survival (RFS) was 0% for ALPPS and 35.7% for LAPS ( P  =   0.009), whereas the 2-year overall survival for ALPPS and LAPS was 33.3% and 100.0% ( P  =   0.052), respectively., Conclusions: LAPS tended to induce lower morbidity and FLR hypertrophy more slowly than ALPPS, with a comparable resection rate and better long-term RFS in HBV-related HCC patients., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Background: Liver resection is the mainstay of curative treatment for intrahepatic cholangiocarcinoma (ICC) while the postoperative prognosis varies greatly, with no recognized biomarker. We aimed to identify the plasma metabolomic biomarkers that could be used for preoperative risk stratification of ICC patients., Methods: 108 eligible ICC patients who underwent radical surgical resection between August 2012 and October 2020 were enrolled. Patients were randomly divided into a discovery cohort (n = 76) and a validation cohort (n = 32) by 7:3. Metabolomics profiling of preoperative plasma was performed and clinical data were collected. The least absolute shrinkage and selection operator (LASSO) regression, Cox regression, and receiver operating characteristic (ROC) analyses were used to screen and validate the survival-related metabolic biomarker panel and construct a LASSO-Cox prediction model., Results: 10 survival-related metabolic biomarkers were used for construction of a LASSO-Cox prediction model. In the discovery and validation cohorts, the LASSO-Cox prediction model achieved an AUC of 0.876 (95%CI: 0.777-0.974) and 0.860 (95%CI: 0.711-1.000) in evaluating 1-year OS of ICC patients, respectively. The OS of ICC patients in the high-risk group was significantly worse than that in the low-risk group (discovery cohort, p < 0.0001; validation cohort: p = 0.041). Also, the LASSO-Cox risk score (HR 2.43, 95%CI: 1.81-3.26, p < 0.0001) was a significant independent risk factor associated with OS., Conclusions: The LASSO-Cox prediction model has potential as an important tool in evaluating the OS of ICC patients after surgical resection and can be used as prediction tools to implement the best treatment options that could result in better outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Posthepatectomy liver failure is one of the main causes of death in patients after hepatectomy. This study intends to establish a prediction model to predict the risk of posthepatectomy liver failure and provide a scientific basis for further reducing the incidence of posthepatectomy liver failure., Methods: This was a retrospective analysis of 1,172 patients with hepatocellular carcinoma undergoing partial hepatectomy. Using univariate and multivariate logistic regression analyses and stepwise regression, a prediction model for posthepatectomy liver failure was established based on the independent risk factors for posthepatectomy liver failure and validated by bootstrapping with 100 resamples, and the receiver operating characteristic curve was used to evaluate the predictive value of the prediction model., Results: The incidence rate of posthepatectomy liver failure was 22.7% (266/1172). The results showed that the indocyanine green retention rate at 15 minutes (odds ratio = 1.05, P = .002), alanine transaminase (odds ratio = 1.02, P < .001), albumin rate (odds ratio = 0.92, P < .001), total bilirubin (odds ratio = 1.04, P < .001), prothrombin time (odds ratio = 2.44, P < .001), aspartate aminotransferase-neutrophil ratio (odds ratio = 0.95, P < .001), and liver fibrosis index (odds ratio = 1.35, P < .001) were associated with posthepatectomy liver failure. These 7 independent risk factors for posthepatectomy liver failure were integrated into a nomogram prediction model, the predictive efficiency for posthepatectomy liver failure (area under the curve = 0.818, 95% confidence interval 0.789-0.848) was significantly higher than in other predictive models with a liver fibrosis index (area under the curve = 0.651), indocyanine green R15 (area under the curve = 0.669), albumin-bilirubin score (area under the curve = 0.709), albumin-indocyanine green evaluation score (area under the curve = 0.706), model for end-stage liver disease score (area under the curve = 0.636), and Child‒Pugh (area under the curve = 0.551) (all P < .001). The risk of posthepatectomy liver failure in the high-risk posthepatectomy liver failure group (score ≥152) was higher than that in the posthepatectomy liver failure low-risk group (score <152)., Conclusion: This study developed and validated a nomogram model to predict the risk of posthepatectomy liver failure before surgery that can effectively predict the risk of posthepatectomy liver failure in patients with hepatocellular carcinoma., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDL-C) are important predictive factors for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyze the association between the ALT/HDL-C ratio and NAFLD., Methods: We conducted a retrospective analysis of data from 14,251 individuals participating in the NAGALA project's health screening program. The presence of NAFLD was diagnosed based on the participants' alcohol consumption status and liver ultrasonography images. Multivariable logistic regression models were used to assess the association between the ALT/HDL-C ratio and NAFLD. Receiver operating characteristic (ROC) analysis was performed to determine and compare the effectiveness of ALT, HDL-C, the aspartate aminotransferase to HDL-C (AST/HDL-C) ratio, the gamma-glutamyl transferase to HDL-C (GGT/HDL-C) ratio and the ALT/HDL-C ratio in identifying NAFLD., Results: We observed a significant positive association between the ALT/HDL-C ratio and the prevalence of NAFLD. For each standard deviation (SD) increase in the ALT/HDL-C ratio, the adjusted odds ratio (OR) for NAFLD among the participants was 3.05 [95% confidence interval (CI): 2.63, 3.53], with the highest quartile of ALT/HDL-C ratio having a 9.96-fold increased risk compared to the lowest quartile. In further subgroup analyses stratified by gender, age, and waist circumference (WC), we observed a significantly higher risk of NAFLD associated with the ALT/HDL-C ratio among individuals aged ≥45 years, males, and those who were abdominal obesity. Furthermore, based on the results of ROC analysis, we found that the ALT/HDL-C ratio [area under the curves (AUC): 0.8553] was significantly superior to ALT, HDL-C, AST/HDL-C ratio and GGT/HDL-C ratio in identifying NAFLD (All Delong P <0.05); the threshold of suggested ALT/HDL-C ratio for identifying NAFLD was 15.97., Conclusion: This population-based study demonstrates a positive association between the ALT/HDL-C ratio and NAFLD. The ALT/HDL-C ratio can effectively identify individuals with NAFLD., 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 Qiu, Kuang, Yang, Yu, He, Sheng and Zou.)

By-product cottonseed proteins are excellent options for numerous applications due to their superior properties and lower cost. However, its complex folded structure and large molecular weight lead to lower reactivity and insufficient amphiphilicity. Cottonseed protein isolate (CPI) is less-soluble in water. Therefore, we improved the amphiphilicity of CPI with associated hydrolysis, molecular structure unfolding, and activation by alkaline-induced deamidation (at 24, 36, and 72 h) and produced three cottonseed protein hydrolysates CPH 24, 36, and 72. FTIR/UV-CD measurements confirmed the conformational changes and conversion of the structural content. Particle size decreased 2503.4-771.8 nm, while surface hydrophobicity (133.5-326.7), carboxyl content (1.13 × 10־ 3 -2.09 × 10־ 3 ), and flexibility increased, signifying hydrolysis, unfolding, and amphiphilicity improvement. Longer deamidation (CPH 72) exhibited the best properties, its prepared emulsions were long-term stable under all the environmental stresses without visible phase separation after at least 40 days of storage except at pH 4. Compared to CPI, it had smaller droplets (939.3-264.9 nm) and larger absolute ζ-potential (-26.5 to -58.0 mV). From the in-vitro cytotoxicity test, deamidated CPI is extremely safer than commonly used synthetic surfactants. This research provides a new method for producing multifunctional emulsifiers from CPI, which could be utilized in the development of functional foods/non-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 © 2023. Published by Elsevier B.V.)

A rapid induction of antiviral genes is critical for eliminating viruses, which requires activated transcription factors and opened chromatins to initiate transcription. However, it remains elusive how the accessibility of specific chromatin is regulated during infection. Here, we found that XAF1 functioned as an epigenetic regulator that liberated repressed chromatin after infection. Upon RNA virus infection, MAVS recruited XAF1 and TBK1. TBK1 phosphorylated XAF1 at serine-252 and promoted its nuclear translocation. XAF1 then interacted with TRIM28 with the guidance of IRF1 to the specific locus of antiviral genes. XAF1 de-SUMOylated TRIM28 through its PHD domain, which led to increased accessibility of the chromatin and robust induction of antiviral genes. XAF1-deficient mice were susceptible to RNA virus due to impaired induction of antiviral genes. Together, XAF1 acts as an epigenetic regulator that promotes the opening of chromatin and activation of antiviral immunity by targeting TRIM28 during infection.

Right heart failure is the leading cause of death in pulmonary hypertension (PH), and echocardiography is a commonly used tool for evaluating the risk hierarchy of PH. However, few studies have explored the dynamic changes in the structural and functional changes of the right heart during the process of PH. Previous studies have found that pulmonary circulation coupling right ventricular adaptation depends on the degree of pressure overload and other factors. In this study, we performed a time-dependent evaluation of right heart functional changes using transthoracic echocardiography in a SU5416 plus hypoxia (SuHx)-induced PH rat model. Rats were examined in 1-, 2-, 4-, and 6-week using right-heart catheterization, cardiac echocardiography, and harvested heart tissue. Our study found that echocardiographic measures of the right ventricle (RV) gradually worsened with the increase of right ventricular systolic pressure, and right heart hypofunction occurred at an earlier stage than pulmonary artery thickening during the development of PH. Furthermore, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), a marker of myocardial damage, was highly expressed in week 2 of SuHx-induced PH and had higher levels of expression of γ-H2AX at all timepoints, as well as higher levels of DDR-related proteins p-ATM and p53/p-p53 and p21 in week 4 and week 6. Our study demonstrates that the structure and function of the RV begin to deteriorate with DNA damage and cellular senescence during the early stages of PH development., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The surge in kitchen waste production is causing food-borne disease epidemics and is a public health threat worldwide. Additionally, the effectiveness of conventional treatment approaches may be hampered by KW's high moisture, salt, and oil content. Hydrothermal carbonization (HTC) is a promising new technology to convert waste biomass into environmentally beneficial derivatives. This study used simulated KW to determine the efficacy of hydrothermal derivatives (hydrochar) with different salt and oil content, pH value, and solid-liquid ratio for the removal of cadmium (Cd) from water and identify their high heating value (HHV). The findings revealed that the kitchen waste hydrochar (KWHC) yield decreased with increasing oil content. When the water content in the hydrothermal system increased by 90%, the yield of KWHC decreased by 65.85%. The adsorption capacity of KWHC remained stable at different salinities. The KWHC produced in the acidic environment increases the removal efficiency of KWHC for Cd. The raw material was effectively transformed into a maximum HHV (30.01 MJ/kg). HTC is an effective and secure method for the resource utilization of KW based on the adsorption capacity and combustion characteristic indices of KWHC.

Objective: Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy., Design: Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo., Results: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N 7 -methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models., Conclusions: Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Acute hyperglycemia has been identified as a risk factor for acute kidney injury occurrence and mortality in various diseases. The aim of the current study was to investigate the relationship between stress-induced hyperglycemia and adverse outcomes in critically ill patients with AKI., Methods: We extracted clinical data from Multiparameter Intelligent Monitoring in Intensive Care III version 1.4. Blood glucose and glycosylated hemoglobin during the first 24 h of ICU admission were used to calculate glycemic gap and stress hyperglycemia ratio (SHR). The outcomes included ICU mortality and need for renal replacement therapy. The association of the glycemic gap and SHR with outcomes were determined via logistic regression model and receiver-operating curves. The subgroup analysis of patients with and without diabetes was performed separately., Results: Higher glycemic gap and SHR were observed in patients who had increased need of RRT, higher mortality rates and longer ICU stay. Multivariate analysis demonstrated that higher glycemic gap (OR 1.01, 95%CI 1.00-1.02, P = 0.015), as well as SHR (OR 1.32; 95%CI 1.07-1.64, P = 0.009), were independently associated with ICU mortality after adjusting for potential covariates. In subgroup analysis, the association of glycemic gap and SHR were only significant in the non-diabetic population as for the outcome of ICU mortality (OR 2.25, 95%CI 1.64-3.08, P < 0.001 and OR 1.99; 95%CI 1.46-2.72, P < 0.001, respectively)., Conclusions: The glycemic gap and SHR might serve as a potential prognostic indicator of ICU mortality in critically ill patients with AKI, especially in the non-diabetic population., (© 2023. The Author(s).)

Objective: Visceral adipose tissue assessment holds significant importance in diabetes prevention. This study aimed to explore the association between the newly proposed Metabolic Score for Visceral Fat (METS-VF) and diabetes risk and to further assess the predictive power of the baseline METS-VF for the occurrence of diabetes in different future periods., Methods: This longitudinal cohort study included 15,464 subjects who underwent health screenings. The METS-VF, calculated using the formula developed by Bello-Chavolla et al., served as a surrogate marker for visceral fat obesity. The primary outcome of interest was the occurrence of diabetes during the follow-up period. Established multivariate Cox regression models and restricted cubic spline (RCS) regression models to assess the association between METS-VF and diabetes risk and its shape. Receiver operating characteristic (ROC) curves were used to compare the predictive power of METS-VF with body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and visceral adiposity index (VAI) for diabetes, and time-dependent ROC analysis was conducted to assess the predictive capability of METS-VF for the occurrence of diabetes in various future periods., Results: During a maximum follow-up period of 13 years, with a mean of 6.13 years, we observed that the cumulative risk of developing diabetes increased with increasing METS-VF quintiles. Multivariable-adjusted Cox regression analysis showed that each unit increase in METS-VF would increase the risk of diabetes by 68% (HR 1.68, 95% CI 1.13, 2.50), and further RCS regression analysis revealed a possible non-linear association between METS-VF and diabetes risk ( P for non-linearity=0.002). In addition, after comparison by ROC analysis, we found that METS-VF had significantly higher predictive power for diabetes than other general/visceral adiposity indicators, and in time-dependent ROC analysis, we further considered the time-dependence of diabetes status and METS-VF and found that METS-VF had the highest predictive value for predicting medium- and long-term (6-10 years) diabetes risk., Conclusion: METS-VF, a novel indicator for assessing visceral adiposity, showed a significantly positive correlation with diabetes risk. It proved to be a superior risk marker in predicting the future onset of diabetes compared to other general/visceral adiposity indicators, particularly in forecasting medium- and long-term diabetes risk., 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 Yang, Kuang, Qiu, Yu, Sheng and Zou.)

Background & Aims: The immune landscape of hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE) remains to be clarified. This study aimed to characterise the immune landscape following TACE and the underlying mechanism of HCC progression., Methods: Tumour samples from five patients with treatment-naive HCC and five patients who received TACE therapy were collected and subjected to single-cell RNA sequencing. Another 22 paired samples were validated using immunofluorescence staining and flow cytometry. To clarify the underlying mechanisms, in vitro co-culture experiments and two types of TREM2-KO/WT mouse models, namely, an HCC cell orthotopic injection model and a spontaneous HCC model, were used., Results: A reduced number of CD8 + T cells and an increased number of tumour-associated macrophages (TAMs) were observed in the post-TACE microenvironment. TACE therapy reduced the cluster CD8&#95;C4, which was highly enriched with tumour-specific CD8 + T cells of pre-exhausted phenotype. TREM2 was found to be highly expressed in TAMs following TACE, which was associated with a poor prognosis. TREM2 + TAMs secreted less CXCL9 but more galectin-1 than did TREM2 - TAMs. Galectin-1 promoted PD-L1 overexpression in vessel endothelial cells, impeding CD8 + T cell recruitment. TREM2 deficiency also increased CD8 + T cell infiltration, which inhibited tumour growth in both in vivo HCC models. More importantly, TREM2 deficiency enhanced the therapeutic effect of anti-PD-L1 blockade., Conclusions: This study shows that TREM2 + TAMs play an important role in suppressing CD8 + T cells. TREM2 deficiency increased the therapeutic effect of anti-PD-L1 blockade by enhancing antitumour activity of CD8 + T cells. These findings explain the reasons for recurrence and progression after TACE and provide a new target for HCC immunotherapy after TACE., Impact and Implications: Studying the immune landscape in post-TACE HCC is important to uncover the mechanisms of HCC progression. By using scRNA sequencing and functional assays, we discovered that both the number and function of CD8 + T cells are compromised, whereas the number of TREM2 + TAMs is increased in post-TACE HCC, correlating with worse prognosis. Moreover, TREM2 deficiency dramatically increases CD8 + T cell infiltration and augments the therapeutic efficacy of anti-PD-L1 blockade. Mechanistically, TREM2 + TAMs display lower CXCL9 and increased Gal-1 secretion than do TREM2 - TAMs, with Gal-1 mediating the overexpression of PD-L1 in vessel endothelial cells. These results suggest that TREM2 could be a novel immunotherapeutic target for patients treated with TACE in HCC. This provides an opportunity to break the plateau of limited therapeutic effect. This study has the value of understanding the tumour microenvironment of post-TACE HCC and thinking a new strategy of immunotherapy in the field of HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Radiofrequency heat ablation is an ideal radical treatment for hepatocellular carcinoma (HCC). However, insufficient radiofrequency ablation (IRFA) could lead to high recurrence of HCC. N 7 -methylguanosine (m 7 G) on tRNAs, an evolutionally conservative modification in mammals and yeast, modulates heat stress responses and tumor progression, while its function in HCC recurrence after IRFA remains unknown. Here, we found that IRFA significantly upregulates the level of m 7 G tRNA modification and its methyltransferase complex components METTL1/WDR4 in multiple systems including HCC patient-derived xenograft (PDX) mouse, patients' HCC tissues, sublethal-heat-treated models of HCC cell lines, and organoids. Functionally, gain-/loss-of-function assays showed that METTL1-mediated m 7 G tRNA modification promotes HCC metastasis under sublethal heat exposure both in vitro and in vivo. Mechanistically, we found that METTL1 and m 7 G tRNA modification enhance the translation of SLUG/SNAIL in a codon frequency-dependent manner under sublethal heat stress. Overexpression of SLUG/SNAIL rescued the malignant potency of METTL1 knockdown HCC cells after sublethal heat exposure. Our study uncovers the key functions of m 7 G tRNA modification in heat stress responses and HCC recurrence after IRFA, providing molecular basis for targeting METTL1-m 7 G-SLUG/SNAIL axis to prevent HCC metastasis after radiofrequency heat ablation treatment., Competing Interests: Declaration of interests The authors have no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background and Aims: Radiotherapy is an increasingly essential therapeutic strategy in the management of hepatocellular carcinoma (HCC). Nevertheless, resistance to radiotherapy is one of the primary obstacles to successful treatment outcomes. Hence, we aim to elucidate the mechanisms underlying radioresistance and identify reliable biotargets that would be inhibited to enhance the efficacy of radiotherapy in HCC., Approach and Results: From a label-free quantitative proteome screening, we identified transfer RNA (tRNA; guanine- N [7]-) methyltransferase 1 (METTL1), a key enzyme for N7-methylguanosine (m 7 G) tRNA modification, as an essential driver for HCC cells radioresistance. We reveal that METTL1 promotes DNA double-strand break (DSB) repair and renders HCC cells resistant to ionizing radiation (IR) using loss-of-function and gain-of-function assays in vitro and in vivo. Mechanistically, METTL1-mediated m 7 G tRNA modification selectively regulates the translation of DNA-dependent protein kinase catalytic subunit or DNA ligase IV with higher frequencies of m 7 G-related codons after IR treatment, thereby resulting in the enhancement of nonhomologous end-joining (NHEJ)-mediated DNA DSB repair efficiency. Clinically, high METTL1 expression in tumor tissue is significantly correlated with poor prognosis in radiotherapy-treated patients with HCC., Conclusions: Our findings show that METTL1 is a critical enhancer for HCC cell NHEJ-based DNA repair following IR therapy. These findings give insight into the role of tRNA modification in messenger RNA translation control in HCC radioresistance., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Post-hepatectomy liver failure (PHLF) represents the major source of mortality after liver resection (LR) in hepatocellular carcinoma (HCC) patients. Child-Pugh (CP) score 5 is always considered to indicate a normal liver function but represents a heterogeneous population with a considerable number suffering from PHLF. The present study aimed to access the ability of liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) to predict PHLF in HCC patients with a CP score of 5., Methods: From August 2018 to May 2021, 146 HCC patients with a CP score of 5 who underwent LR were reviewed. The patients were randomly divided into training (n = 97) and validation (n = 49) groups. Logistic analyses were conducted for the risk factors and a linear model was built to predict the development of PHLF. The discrimination and calibration were assessed in the training and validation cohorts by the areas under the receiver operating characteristic curve (AUC)., Results: Analyses revealed that the minimum of LS (Emin) higher than 8.05 (p = 0.006, OR = 4.59) and future liver remnant / estimated total liver volume (FLR/eTLV) (p < 0.001, OR < 0.01) were independent predictors of PHLF in HCC patients with CP score 5, and the AUC calculated by the model based on them for differentiation of PHLF in the training and validation group was 0.78 and 0.76, respectively., Conclusion: LS was associated with the development of PHLF. A model combining Emin and FLR/eTLV showed proper ability in predicting PHLF in HCC patients with a CP score of 5., (© 2023. The Society for Surgery of the Alimentary Tract.)

Objective: Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies., Design: We performed 5'and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts., Results: Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1 + CD8 + T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8 + T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients., Conclusion: True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME., Competing Interests: Competing interests: DGD received consultant fees from Innocoll, and has received research grants from Bayer, Surface Oncology, Exelixis and BMS. No reagents or support from these companies was used for this study. No potential conflicts of interest were disclosed by other authors., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ambroxol is a widely used mucoactive drug in sputum clearance of respiratory diseases taken orally and by injection. However, there is a paucity of evidence for inhaled ambroxol in sputum clearance., Methods: This study performed a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial at 19 centers in China. Hospitalized adult patients with mucopurulent sputum and expectoration difficulty were recruited. Patients were randomized by 1:1 to receive inhalation of either ambroxol hydrochloride solution 3 mL (22.5 mg) + 0.9% sodium chloride 3 mL or 0.9% sodium chloride 6 mL twice daily for 5 days, with an interval of more than 6 h. The primary efficacy endpoint was the absolute change in the sputum property score after treatment compared to the baseline in the intention-to-treat population., Results: Between 10 April 2018 and 23 November 2020, 316 patients were recruited and assessed for eligibility, of whom 138 who received inhaled ambroxol and 134 who received a placebo were included. Patients who received inhaled ambroxol had a significantly greater decrease in the sputum property score compared with patients who received inhalation of placebo (difference: -0.29; 95% CI: -0.53 to -0.05; p  = 0.0215). Compared with the placebo, inhaled ambroxol also significantly reduced more expectoration volume in 24 h (difference: -0.18; 95% CI: -0.34 to -0.03; p   = 0.0166). There was no significant difference in the proportion of adverse events between the two groups, and no deaths were reported., Discussion: In hospitalized adult patients with mucopurulent sputum and expectoration difficulty, inhaled ambroxol was safe and effective for sputum clearance compared with a placebo., Clinical Trial Registration: [https://www.chictr.org.cn/showproj.html?proj=184677], Chinese Clinical Trial Registry [ChiCTR2200066348]., Competing Interests: Author YP was employed by the company Yingu Pharmaceutical Co Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Yingu Pharmaceutical Co Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2023 Zheng, Yang, Liu, Fu, He, Chen, Xu, Wang, Liu, Tang, Zhao, Xu, Yu, Han, Yuan, Jia, Pang, Shi, Kuang, Shao, Xiong, He, Pan and Chen.)

Flexible conductive films based on light-to-heat conversion are promising for the next-generation electronic devices. A flexible waterborne polyurethane composite film (PU/MA) with excellent photothermal conversion performance was obtained by combination of PU and silver nanoparticle decorated MXene (MX/Ag). The silver nanoparticles (AgNPs) uniformly decorated on the MXene surface by γ-ray irradiation induced reduction. Because of the synergistic effect of MXene with outstanding light-to-heat conversion efficiency and the AgNPs with plasmonic effect, the surface temperature of the PU/MA-II (0.4%) composite with lower MXene content increased from room temperature to 60.7 °C at 5 min under 85 mW cm -2 light irradiation. Besides, the tensile strength of PU/MA-II (0.4%) increased from 20.9 MPa (pure PU) to 27.5 MPa. The flexible PU/MA composite film shows great potential in the field of thermal management of flexible wearable electronic devices., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1 + macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The metabolic score for insulin resistance (MetS-IR) is an emerging surrogate marker for insulin resistance (IR). This study aimed to investigate the association and sex differences between MetS-IR and prediabetes risk in a Chinese population., Methods: This cohort study included 100,309 adults with normoglycemia at baseline and had followed longitudinally for 5 years, and with prediabetes, defined according to the 2018 American Diabetes Association (ADA) recommended diagnostic criteria, as the outcome of interest. Multivariate Cox proportional hazards regression and restricted cubic spline (RCS) regression models were used to assess the association between MetS-IR and prediabetes risk., Results: During an observation period of 312,843 person-years, 7,735 (14.84%) men and 4,617 (9.57%) women with pre-diabetes onset were recorded. After fully adjusting for confounders, we found an independent and positive correlation between MetS-IR and the risk of prediabetes in the Chinese population, and the degree of correlation was stronger in women than in men (HR: 1.24 vs 1.16, P -interaction<0.05). Furthermore, using RCS nested in the Cox regression model, we found that there was a nonlinear correlation between MetS-IR and prediabetes risk in both sexes with an obvious saturation effect point, and when the MetS-IR was greater than the value of the saturation effect point, the risk of prediabetes was gradually leveling off. We further calculated the saturation effect points of MetS-IR used to evaluate the risk of prediabetes which in men was 42.82, and in women was 41.78., Conclusion: In this large cohort study, our results supported that MetS-IR was independently and positively associated with the risk of prediabetes in the Chinese population, with the association being stronger in women than in men., 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 Xie, Kuang, Lu, Huang, Wang, Zhang, Sheng and Zou.)

Background: Coronary atherosclerotic heart disease (CAD) remains one of the most serious diseases threatening human health and life. PCI (Percutaneous Coronary Intervention) is the most common treatment for patients with CAD. A rigorous and comprehensive assessment of coronary artery lesions is now needed before PCI, however, there is no consensus on how best evaluate the combination of various intracavitary imaging techniques. By merging the benefits of physiological assessment and high-definition imaging, the optical flow ratio (OFR) has emerged as a novel technology with promising prospects for application., Methods: A systematic review of the literature was conducted. Studies that met the criteria of the meta-analysis were considered to assess OFR and FFR (fractional flow reserve). And the summary values of sensitivity and specificity of diagnostic tests and summary receiver operating curves (SROC) were calculated., Results: A total of 5 studies were included. The sensitivity and specificity of OFR in the diagnosis of coronary artery lesions were 0.83 (95% CI: 0.75-0.88) and 0.94 (95% CI: 0.91-0.96), respectively; the positive likelihood ratio and the negative likelihood ratio were 14 (95% CI: 9.3, 21.3) and 0.18 (95% CI:0.13, 0.27), respectively. OFR showed good correlation and consistency with FFR., Conclusion: The new OFR technique achieve an encouraging diagnostic performance, which also showed good correlation and consistency with FFR., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chen et al. 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: The relationship between body composition fat mass (FM) and lean body mass (LBM) and diabetes risk is currently debated, and the purpose of this study was to examine the association of predicted FM and LBM with diabetes in both sexes., Methods: The current study was a secondary analysis of data from the NAGALA (NAfld in the Gifu Area, Longitudinal Analysis) cohort study of 15,463 baseline normoglycemic participants. Predicted LBM and FM were calculated for each participant using anthropometric prediction equations developed and validated for different sexes based on the National Health and Nutrition Examination Survey (NHANES) database, and the outcome of interest was diabetes (types not distinguished) onset. Multivariate Cox regression analyses were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of predicted FM and LBM with diabetes risk and further visualized their associations using a restricted cubic spline function., Results: The incidence density of diabetes was 3.93/1000 person-years over a mean observation period of 6.13 years. In women, predicted LBM and FM were linearly associated with diabetes risk, with each kilogram increase in predicted LBM reducing the diabetes risk by 65% (HR 0.35, 95%CI 0.17, 0.71; P < 0.05), whereas each kilogram increase in predicted FM increased the diabetes risk by 84% (HR 1.84, 95%CI 1.26, 2.69; P < 0.05). In contrast, predicted LBM and FM were non-linearly associated with diabetes risk in men (all P for non-linearity < 0.05), with an L-shaped association between predicted LBM and diabetes risk and a saturation point that minimized the risk of diabetes was 45.4 kg, while predicted FM was associated with diabetes risk in a U-shape pattern and a threshold point with the lowest predicted FM-related diabetes risk was 13.76 kg., Conclusion: In this Asian population cohort, we found that high LBM and low FM were associated with lower diabetes risk according to anthropometric equations. Based on the results of the non-linear analysis, we believed that it may be appropriate for Asian men to keep their LBM above 45.4 kg and their FM around 13.76 kg., 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 Kuang, Lu, Yang, Chen, Zhang, Sheng and Zou.)

Background: It is known that measuring the triglyceride glucose (TyG) index and TyG-related parameters [triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC), and triglyceride glucose-waist to height ratio (TyG-WHtR)] can predict diabetes; this study aimed to compare the predictive value of the baseline TyG index and TyG-related parameters for the onset of diabetes at different future periods., Methods: We conducted a longitudinal cohort study involving 15,464 Japanese people who had undergone health physical examinations. The subject's TyG index and TyG-related parameters were measured at the first physical examination, and diabetes was defined according to the American Diabetes Association criteria. Multivariate Cox regression models and time-dependent receiver operating characteristic (ROC) curves were constructed to examine and compare the risk assessment/predictive value of the TyG index and TyG-related parameters for the onset of diabetes in different future periods., Results: The mean follow-up period of the current study cohort was 6.13 years, with a maximum of 13 years, and the incidence density of diabetes was 39.88/10,000 person-years. In multivariate Cox regression models with standardized hazard ratios (HRs), we found that both the TyG index and TyG-related parameters were significantly and positively associated with diabetes risk and that the TyG-related parameters were stronger in assessing diabetes risk than the TyG index, with TyG-WC being the best parameter (HR per SD increase: 1.70, 95% CI 1.46, 1.97). In addition, TyG-WC also showed the highest predictive accuracy in time-dependent ROC analysis for diabetes occurring in the short-term (2-6 years), while TyG-WHtR had the highest predictive accuracy and the most stable predictive threshold for predicting the onset of diabetes in the medium- to long-term (6-12 years)., Conclusions: These results suggest that the TyG index combined with BMI, WC, and WHtR can further improve its ability to assess/predict the risk of diabetes in different future periods, where TyG-WC was not only the best parameter for assessing diabetes risk but also the best risk marker for predicting future diabetes in the short-term, while TyG-WHtR may be more suitable for predicting future diabetes in the medium- to long-term., (© 2023. The Author(s).)

Purpose: Reports showed that some of intrahepatic cholangiocarcinoma (ICC) patients with lymph node metastasis (LNM) may also gain survival benefit undergone resection. However, the effect of the extent of LNM on prognosis and surgical indication is barely discussed., Methods: From September 1994 to November 2018, primary ICC patients undergone initial curable surgery were enrolled. Based on the extent of LNM, we divided these patients into 4 groups, including patients with no LNM (group N0), LNM to hepatoduodenal ligament or common hepatic artery (region A, group A), LNM to gastrohepatic lymph nodes for left liver ICC and periduodenal and peripancreatic lymph node for right liver ICC (region B, group B), or LNM beyond these regions (region C, group C). Multivariable Cox regression analysis was performed to identify the prognostic factors for recurrence-free survival (RFS) and overall survival (OS) in all groups., Results: A total of 133 patients were enrolled. There were 56, 21, 17, and 39 patients in groups N0, A, B, and C, respectively. There was significant difference between groups N0 and C in RFS (P < 0.001) and OS (P = 0.002). When we compared group N0 + A + B with group C, we also found that RFS (P < 0.001) and OS (P = 0.007) were significantly different. In multivariable analysis, the extent of LNM was an independent risk factor for RFS (P < 0.050)., Conclusion: ICC patients with the LNM to regions A and B could still achieve good prognosis with resection. Surgery should be carefully considered when LNM to region C., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2023, the Korean Surgical Society.)

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an emerging malignancy due to the rising prevalence of NAFLD. However, no drug is available to target NAFLD-HCC. In this study, we aim to unravel novel therapeutic targets of NAFLD-HCC utilizing a high-throughput CRISPR/Cas9 screening strategy. We utilized the Epi-drug CRISPR/Cas9 library consisting of single-guide RNAs (sgRNAs) targeting over 1,000 genes representing the FDA-approved drug targets and epigenetic regulators to perform loss-of-function screening in two NAFLD-HCC cell lines (HKCI2 and HKCI10). CRISPR/Cas9 library screening unraveled TUBB4B as an essential gene for NAFLD-HCC cell growth. TUBB4B was overexpressed in NAFLD-HCC tumors compared with adjacent normal tissues (N = 17) and was associated with poor survival (p < 0.01). RNA-sequencing and functional assays revealed that TUBB4B knockout in NAFLD-HCC promoted cell apoptosis, cell cycle arrest, and cellular senescence, leading to suppressed NAFLD-HCC growth in vitro and in vivo. We identified that TUBB4B inhibitor mebendazole (MBZ), an FDA-approved drug, inhibited NAFLD-HCC growth by inducing apoptosis and cellular senescence. Since protein expression of pro-survival Bcl-xL was induced in TUBB4B knockout NAFLD-HCC cells, we examined combination of TUBB4B inhibition with navitoclax, a Bcl-xL inhibitor that selectively targets senescent cells. Consistent with our hypothesis, either TUBB4B knockout or MBZ synergized with navitoclax to inhibit NAFLD-HCC cell growth via the induction of intrinsic and extrinsic apoptosis pathways. In summary, TUBB4B is a novel therapeutic target in NAFLD-HCC. Inhibition of TUBB4B with MBZ in combination with navitoclax synergistically inhibited NAFLD-HCC cell growth, representing a promising strategy for the treatment of NAFLD-HCC. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Systemic therapy is the standard care of unresectable hepatocellular carcinoma (uHCC), while transcatheter intra-arterial therapies (TRITs) were also widely applied to uHCC patients in Chinese practice. However, the benefit of additional TRIT in these patients is unclear. This study investigated the survival benefit of concurrent TRIT and systemic therapy used as first-line treatment for patients with uHCC., Methods: This real-world, multi-center retrospective study included consecutive patients treated at 11 centers accross China between September 2018 and April 2022. Eligible patients had uHCC of China liver cancer stages IIb to IIIb (Barcelona clinic liver cancer B or C stage), and received first-line systemic therapy with or without concurrent TRIT. Of 289 patients included, 146 received combination therapy and 143 received systemic therapy alone. The overall survival (OS), as primary outcomes, was compared between patients who received systemic therapy plus TRIT (combination group) or systemic therapy alone (systemic-only group) using survival analysis and Cox regression. Imbalances in baseline clinical features between the two groups were adjusted through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Moreover, subgroup analysis was conducted based on the different tumor characteristics of enrolled uHCC patients., Results: The median OS was significantly longer in the combination group than the systemic-only group before adjustment [not reached vs. 23.9 months; hazard ratio (HR), 0.561; 95% confidence interval (CI), 0.366 to 0.861; P = 0.008], after PSM (HR, 0.612; 95% CI, 0.390 to 0.958; P = 0.031) and after IPTW (HR, 0.539; 95% CI, 0.116 to 0.961; P = 0.008). Subgroup analyses suggested the benefit of combining TRIT with systemic therapy was greatest in patients with liver tumors exceeding the up-to-seven criteria, with an absence of extrahepatic metastasis, or with alfa-fetoprotein ≥ 400 ng/ml., Conclusion: Concurrent TRIT with systemic therapy was associated with improved survival compared with systemic therapy alone as first-line treatment for uHCC, especially for patients with high-intrahepatic tumor load and no extrahepatic metastasis., 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 Pan, Zhu, Liu, Zhong, Zhang, Shen, Jin, Liu, Ye, Hu, Xu, Zhang, Chen, Xing, Zhou, Chen, Zeng, Liang, Kuang, Song, Xiang, Wang, Sun, Xu and China Liver Cancer Study Group Young Investigators (CLEAP).)

Objective: Triglyceride glucose body mass index (TyG-BMI) has been shown to be strongly associated with a variety of chronic diseases. However, little is known about the associations between TyG-BMI and normal-high blood pressure (BP) values and hypertension (HTN)., Method: The current study was cross-sectional in design and included 15,464 non-diabetic participants recruited between 1994 and 2016 in the NAGALA (NAfld in the Gifu Area, Longitudinal Analysis) study. Associations between TyG-BMI and normal-high BP values and HTN were assessed using multivariate logistic regression. The ability of the TyG index, BMI, and their combined index TyG-BMI to identify normal-high BP values and HTN was compared by receiver operating characteristic (ROC) curves., Results: Among the 15,464 eligible non-diabetic participants, 28.56% (4,416/15,464) and 6.23% (964/15,464) had normal-high BP values and HTN, respectively. Multivariate logistic regression analysis showed positive correlations between BMI, TyG index, TyG-BMI and normal-high BP values/HTN; after standardized regression coefficients, TyG-BMI had the strongest association with normal-high BP values and HTN compared to BMI and TyG index. In the fully adjusted model, the odds ratio (OR) value corresponding to the relationship between TyG-BMI and HTN/normal-high BP values was 2.35; when TyG-BMI was used as a categorical variable, compared with the lowest quartile of TyG-BMI the regression coefficient for the association of the highest quartile of TyG-BMI with normal-high BP values increased by 426%, while the regression coefficient for the association with HTN increased by 527%. In further spline regression analysis, we also found that there was a linearly positive correlation between TyG-BMI and systolic BP/diastolic BP (SBP/DBP), which supported the linear trend between TyG-BMI and HTN/normal-high BP values ( P -trend <0.0001). In addition, ROC analysis showed that TyG-BMI had good diagnostic values for both normal-high BP values and HTN, and TyG index combined with BMI can significantly improve the ability of a single index to identify normal-high BP values and HTN., Conclusion: In the non-diabetic population, TyG-BMI showed a significant positive correlation with both normal-high BP values and HTN, and TyG-BMI was of higher value for the identification of both normal-high BP values and HTN compared to BMI and TyG index alone., 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., (© 2023 Peng, Kuang, Peng, Yu, Zhang, Xie, Sheng and Zou.)

Remnant cholesterol (RC) is a highly atherogenic lipid. Previous studies have shown that RC was closely associated with many metabolism-related diseases. However, the relationship of RC with metabolic syndrome (MetS) remains unclear. This study's objective is to investigate the relationship of RC with MetS. A total of 60,799 adults who received health assessments were included in this study. RC was calculated by subtracting the directly measured values for low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) from total cholesterol (TC) and divided into 5 groups according to its quintile. MetS diagnosis according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) definitions. Application of receiver operating characteristic (ROC) curve analysis and multivariate logistic regression to assess the association of RC with MetS. In RC quintile groups, the prevalence of MetS was 0.84, 1.10, 1.92, 3.87 and 37.71%, respectively. Multivariate logical regression analysis showed that RC and MetS maintained a stable independent positive correlation between both sexes. An interaction test further showed that the MetS risk associated with RC was significantly higher in women than in men. Moreover, ROC analysis results showed that RC had high accuracy in identifying MetS, especially among young and middle-aged men [(area under the curve: AUC) < 30 years: 0.9572, 30-39 years: 0.9306, 40-49 years: 0.9067]. The current study provided the first evidence of a positive association between RC and MetS, and that this correlation was stronger in women than in man, which may be due to the relative deficiency of estrogen in women., (© 2023. The Author(s).)

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD). However, low adherence to medication and lifestyle management has limited the benefits of lowering lipid levels. Cognitive behavioral therapy (CBT) has been proposed as a promising solution., Objective: This trial aimed to evaluate the efficacy of mobile-based CBT interventions in lowering LDL-C levels in patients with ASCVD., Methods: This multicenter, prospective, randomized controlled trial enrolled 300 patients with ASCVD, who were randomly assigned to the mobile-based CBT intervention group and the control group in a ratio of 1:1. The intervention group received CBT for ASCVD lifestyle interventions delivered by WeChat MiniApp: "CBT ASCVD." The control group only received routine health education during each follow-up. The linear regression and logistic regression analyses were used to determine the effects of a mobile-based CBT intervention on LDL-C, triglyceride, C-reactive protein, the score of General Self-Efficacy Scale (GSE), quality of life index (QL-index), and LDL-C up-to-standard rate (<1.8 mmol/L) at the first, third, and sixth months., Results: Finally, 296 participants completed the 6-month follow-up (CBT group: n=148; control group: n=148). At baseline, the mean LDL-C level was 2.48 (SD 0.90) mmol/L, and the LDL-C up-to-standard rate (<1.8 mmol/L) was 21.3%. Mobile-based CBT intervention significantly increased the reduction of LDL-C change (%) at the 6-month follow-up (β=-10.026, 95% CI -18.111 to -1.940). In addition, this benefit remained when baseline LDL-C <1.8 mmol/L (β=-24.103, 95% CI -43.110 to -5.095). Logistic regression analysis showed that mobile-based CBT intervention moderately increased the LDL-C up-to-standard rates (<1.8 mmol/L) in the sixth month (odds ratio 1.579, 95% CI 0.994-2.508). For GSE and QL-index, mobile-based CBT intervention significantly increased the change of scores (%) at the 1-, 3-, and 6-month follow-up (all P values <.05)., Conclusions: In patients with ASCVD, mobile-based CBT is effective in reducing LDL-C levels (even for those who already had a standard LDL-C) and can improve self-efficacy and quality of life., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100046775; https://www.chictr.org.cn/showproj.aspx?proj=127140., (©DuanBin Li, Tian Xu, DaQi Xie, MiaoYun Wang, ShuPing Sun, Min Wang, SiSi Zhang, XinRui Yang, ZhongNan Zhang, Shen Wang, Ming Kuang, Jia Tang, HongYing Liu, XuLin Hong, GuoSheng Fu, WenBin Zhang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.04.2023.)