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Jia-Yi Wu,1,2,* Zhen-Yu Yin,3,* Yan-Nan Bai,1,2 Yu-Feng Chen,4 Song-Qiang Zhou,1,2 Shuang-Jia Wang,5 Jian-Yin Zhou,6 Yi-Nan Li,2 Fu-Nan Qiu,1,2 Bin Li,5 Mao-Lin Yan1,2 1Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People’s Republic of China; 2Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 3Department of Hepatobiliary Surgery, Xiamen Traditional Chinese Medical Hospital, Xiamen, Fujian Province, 361000, People’s Republic of China; 4Department of Hepatobiliary Surgery, The Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, 363000, People’s Republic of China; 5Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, 361000, People’s Republic of China; 6Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, 361000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mao-Lin Yan; Bin Li Tel +86 0591-88217130; +86 13606056652Fax +86 0591-87557768; +86 0592-2132222Email yanmaolin74@163.com; wasalee@126.comBackground: Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC.Methods: uHCC patients with an ECOG PS score of 0– 1 and Child–Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events.Results: Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6– 33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55– 372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥ 3, 14.5%; grade ≥ 4, 4.8%).Conclusion: Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.Keywords: unresectable hepatocellular carcinoma, tumor response, adverse events, combination therapy, monotherapy

Five brasilane-type sesquiterpenoids, including four previously undescribed compounds named xylaribrasilaids A-D, along with a known analogue, were isolated from the ethyl acetate extracts of solid fermentation from Xylaria nigripes. X. nigripes, a traditional Chinese medicinal fungus utilized for treating various ailments such as insomnia, trauma, and depression, has garnered attention due to its pharmacological potential. Their structures and absolute configurations were elucidated through comprehensive spectroscopic analysis, including NMR, HRESIMS, and experimental ECD data. In vitro bioassays were conducted to assess the neuroprotective activities of these compounds against glutamate-induced damage in PC12 cells. Remarkably, all isolated compounds demonstrated significant enhancements in cell viability while concurrently inhibiting apoptosis. Moreover, they effectively attenuated oxidative stress markers, as evidenced by increased activities of superoxide dismutase and glutathione. Furthermore, these compounds displayed the capacity to mitigate intracellular reactive oxygen species accumulation, highlighting their potential in combating oxidative stress-related neurodegenerative disorders., Competing Interests: Declaration of Competing Interest ☑The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: High-flow nasal oxygenation has been shown to improve oxygenation during induction of anaesthesia in parturients who are not obese. However, data on the efficacy of high-flow nasal oxygen in parturients living with obesity are lacking. This study investigated the effects of high-flow nasal oxygenation on pre-oxygenation and apnoea oxygenation during tracheal intubation in parturients living with obesity., Methods: This prospective, randomised clinical trial was conducted at two tertiary hospitals and included parturients with BMI > 30 kg.m -2 undergoing scheduled caesarean delivery under general anaesthesia. Parturients were allocated randomly to standard facemask or high-flow nasal oxygen groups (oxygen flow rates 10 l.min -1 and 50 l.min -1 , respectively). The primary outcome measure was arterial partial pressure of oxygen after 3 min of pre-oxygenation., Results: 54 patients completed the study. The arterial partial pressure of oxygen after 3 min of pre-oxygenation was significantly lower in parturients allocated to the standard facemask group compared with those allocated to the high-flow nasal oxygen group (mean (SD) 40.1 (8.9) kPa vs. 53.8 (9.7) kPa, p < 0.001). End-tidal oxygen concentration on commencing ventilation was also lower in parturients allocated to the standard facemask group compared with those allocated to the high flow-nasal oxygen group (mean (SD) 78.3 (5.38)% vs. 86.2 (5.10)%, p < 0.001). The arterial partial pressure of carbon dioxide post tracheal intubation and fetal outcomes were similar in both groups., Discussion: Pre-oxygenation using high-flow nasal oxygenation provided a higher arterial partial pressure of oxygen and end-tidal oxygen concentration during general anaesthesia induction than standard facemask oxygenation in parturients living with obesity; however, the differences were not clinically meaningful. High-flow nasal oxygenation may be considered as an alternative option for pre-oxygenation during rapid sequence induction in parturients living with obesity., (© 2024 Association of Anaesthetists.)

Background: Pneumothorax is a potential complication following computed tomography-guided lung biopsy (CT-LB). However, the relationship between the lung needle path CT attenuation values and risk of post-procedural immediate pneumothorax remains unclear. The study aims to investigate this relationship., Methods: The present single-center retrospective cohort study analyzed the data obtained from 453 patients who underwent CT-LB from 2019 to 2022. The relationship between the lung needle path CT attenuation values and post-procedural immediate pneumothorax was assessed using restricted cubic splines, which were adjusted for potential confounders, and validated using linear and nonlinear binomial logistic models., Results: A total of 453 patients (mean age: 60.2 ± 12.0 years old, 217 male patients) were evaluated. The incidence of post-procedural immediate pneumothorax was 41.06% (186/453). The median needle path CT attenuation was - 831 Hounsfield units (Hu). The linear models indicated an unstable association between lung needle path CT attenuation and post-procedural immediate pneumothorax (odds ratio: 0.99, 95% confidence interval: 0.99-1.00). The nonlinear analysis identified an inflection point at a CT attenuation value of -805 Hu. A stronger negative link was identified for needle path CT attenuation values below - 805 Hu (odds ratio: 0.99, 95% confidence interval: 0.98-0.99) between the needle path CT attenuation value and pneumothorax, while no statistically significant association was identified between these when the CT attenuation value was above - 805 Hu., Conclusion: There is a nonlinear association between the lung needle path CT attenuation values and risk of post-procedural immediate pneumothorax. For CT attenuation values below - 805 Hu, increasing the needle path CT attenuation values might reduce the risk of pneumothorax., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was approved by the hospital institutional review board (Ethics 28 Committee of Chongqing General Hospital, ID: XJS S2022-052-01), and all methods were carried out in accordance to relevant guidelines and regulations. The requirement for informed consent was waived, and this was approved by the Ethics 28 Committee of Chongqing General Hospital due to the retrospective design of the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: An injection method called cranial ceiling elevation is used in Asian countries to reduce facial proportions. Scalp injections carry risks such as arterial embolism or compression, leading to adverse events including scalp necrosis and hair loss., Objective: No arterial studies or injection recommendations exist for the injection of specific scalp regions. We aimed to examine blood vessel types and distributions to identify relatively safe areas for scalp injections., Methods: Computed tomography scans were used to evaluate the blood vessels in the scalp of 50 cadaver heads and anatomical studies were performed. Each scalp was divided into two segments (L1/L2) and six areas (S1/S1'-S3/S3'). The total number of arteries and the probability of each named artery occurring in each section were recorded., Results: The total number of arteries in L1 was higher than that in L2 (L1, 78.76 ± 31.07; L2, 75.28 ± 28.68). The most frequently distributed artery in both L1 and L2 was the parietal branch of the superficial temporal artery. No significant difference was observed between the total number of arteries and the number of each named artery in the S1/S1'-S3/S3' segments. Except for S2' and S3', the number of named arteries in L1 was higher than that in L2., Conclusions: Large-volume scalp injections are not recommended. For injections within 30° above the ear, it is advisable to inject at L2. For other regions, it is also recommended to inject at L2. The periosteal layer should be selected for injection., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder primarily affecting the elderly. Relevant studies suggest a significant connection between the mitochondria and PD. Publications exploring this connection have steadily increased in recent years. This study employs a bibliometric approach to comprehensively analyze the current status and future directions of the research on mitochondria and PD., Method: We retrieved data from the Web of Science database and used CiteSpace, VOSviewer, and "Bibliometrix" software to visually analyze various aspects of the research field. These aspects included the number of published papers, contributing countries and institutions, authors, publishing journals, cited references, and keywords., Results: Our analysis identified a total of 3,291 publications involving 14,670 authors from 2,836 organizations across 78 countries. The publication volume exhibited a continuous upward trend from 1999 to 2023. The United States emerged as the leading force in this research area, contributing the highest number of high-quality publications. Notably, the United States collaborated extensively with Germany and the United Kingdom. The University of Pittsburgh stood out as the most prolific institution. Harvard University had the highest academic influence and closely cooperated with the University of Pittsburgh, Juntendo University, and McGill University. Dr. Hattori Nobutaka was identified as the most prolific author, while Dr. Youle, Richard J emerged as the most influential author based on the highest average citation frequency. The Journal of Neurochemistry was the most published journal. The most co-cited paper was titled " Hereditary early-onset Parkinson's disease caused by mutations in PINK1. " The major keywords included oxidative stress, alpha-synuclein, pink1, mitophagy, and mitochondrial dysfunction. Mitofusin 2, ubiquitin, and mitochondrial quality control have been identified as new research hotspots in recent years., Conclusion: Mitochondria-PD research is experiencing a steady increase in activity, fueled by increasing close collaboration between countries and different institutions. However, there is a need to further strengthen collaboration and communication between developed and developing nations. Current research has focused on the specific mechanisms of mitochondrial dysfunction and their relationship with PD. Mitofusin 2, ubiquitin, and mitochondrial quality control are positioned to be the hotspots and future research directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xie, Zhou and Liu.)

Soil organic carbon (SOC) is essential for maintaining soil fertility and promoting sustainable agricultu-ral development. We investigated the impact of long-term tillage practices on soil organic carbon storage (SOCS) and its components in dryland farming areas of the black soil region, based on a 39-year tillage practice experiment. We compared the effects of different tillage practices (conventional rotary and ridge tillage, CT; no-tillage, NT; subsoiling tillage, ST; moldboard plowing, MP) on SOCS, active organic carbon components, and microbial necromass carbon (MNC) content in the 0-40 cm soil layer. The results showed that, compared to CT, NT significantly increased the contents of SOCS, SOC, dissolved organic carbon (DOC), microbial biomass carbon (MBC), easily oxidizable organic carbon (EOC), and MNC in the 0-20 cm soil layer. Both ST and MP significantly improved the contents of SOCS, SOC, and EOC in 0-20 and 20-40 cm soil layers compared to CT and increased MBC content in the 20-40 cm soil layer. Additionally, MP treatment significantly improved the contents of DOC, particulate organic carbon, and MNC in the 20-40 cm soil layer compared to other treatments. ST and MP significantly reduced the contribution rate of MNC to SOC in both soil layers compared to CT and NT treatments. Results of structural equation modeling showed that enhancing the mean weight diameter of soil aggregates, field capacity, and total phosphorus content, along with increasing the activities of β-glucosidase, amylase, and lignin peroxidase, could promote MNC accumulation. MP treatment facilitated the uniform distribution of SOC, active organic carbon, and MNC in the 0-40 cm soil layer, which was more conducive to the fixation of SOC in farmland in the black soil region.

Two pairs of new isobenzofuranone derivative enantiomers, (±)-penicifurans E ( 1 ) and (±)-penicifurans F ( 2 ), together with four know compounds ( 3 - 6 ) were isolated from the solid fermentation of Penicillium canescens DWS225. The structures of these enantiomers were elucidated by extensive NMR spectroscopic data, and their absolute configurations were assigned by the experimental and calculated ECD data. The neuroprotective effects of all the isolates against oxygen-glucose deprivation/reperfusion injury in pheochromocytoma-12 cells (PC12) were investigated.

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype, which is also characterized by the aggressive phenotype, high recurrence rate, and poor prognosis. Antibody-drug conjugate (ADC) is a monoclonal antibody with a cytotoxic payload connected by a linker. ADC is gaining more and more attention as a targeted anti-cancer agent. Clinical studies of emerging ADC drugs such as sacituzumab govitecan and trastuzumab deruxtecan in patients with metastatic breast cancer (including TNBC) are progressing rapidly. In view of its excellent clinical efficacy and good tolerability, Sacituzumab govitecan gained accelerated approval by the FDA for the treatment of advanced metastatic TNBC in 2020. This review discusses the treatment status and challenges in TNBC, with an emphasis on the current status of ADC development and clinical trials in TNBC and metastatic breast cancer. We also summarize the clinical experience and future exploration directions of ADC development for TNBC patients., Competing Interests: The authors declare that they have no conflict of interest to report regarding the present study., (Copyright 2024, Tang et al.)

Introduction: For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3‑DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population., Methods: This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28 days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28 days apart)., Results: In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6 months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1 months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%., Conclusion: The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit., (© 2024. The Author(s).)

Background: Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC)., Aim: To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC., Methods: Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m 2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m 2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group., Results: Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) ( P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) ( P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group ( P > 0.05)., Conclusion: Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The phytochemical investigation of the fruits of Cornus officinalis yielded a new phenolic acid derivative, neophenolic acid A (1), and a novel flavonoid glycoside, (2R)-naringenin-7-O-β-(6''-galloyl-glucopyranoside) (2 a), along with six known flavonoid glycosides (2 b-7). Their structures were determined by 1D, 2D NMR and HRESIMS data. The absolute configuration of 1 was established by ECD analysis. Compounds 1- 7 were evaluated for their neuroprotective activities against corticosterone (CORT)-induced injury in PC-12 cells. Compounds 1, 2 a, 2 b, 5, and 6 exhibited neuroprotective activities against CORT-induced neurotoxicity in PC-12 cells. The underlying mechanism study suggested that compounds 1, 2 a, 2 b, 5, and 6 were able to attenuate CORT-induced apoptosis and damage, increase the levels of MMP and decrease Ca 2+ inward flow in PC-12 cells., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Two new quinoline alkaloids with an α, β-unsaturated amide side chain, xylarinines A and B (1 and 2), were isolated from the ethyl acetate extracts of Xylaria longipes solid fermentation. The structures of these were primarily determined though NMR and HRESIMS data analysis. The absolute configuration of compound 1 was assigned using experimental and calculated ECD data. The neuroprotective effects of compounds 1 and 2 against glutamate-induced damage in PC12 cells were evaluated in vitro bioassay. The results demonstrated that both compounds significantly improved cell viability, inhibited apoptosis, decreased malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced intracellular reactive oxygen species (ROS) accumulation. These findings suggested that these mechanisms contribute to the neuroprotective effects of the compounds., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Real-world lung cancer data in administrative claims databases often lack staging information and specific diagnostic codes for lung cancer histology subtypes. This study updates and validates Turner's 2017 treatment-based algorithm using more recent claims and electronic health record (EHR) data., Methods: This study used Optum's deidentified Market Clarity Data of linked medical and pharmacy claims with EHR data. Eligible patients had an incident lung cancer diagnosis (January 2014-December 2020) and ≥one valid histology code for lung cancer 30 days before to 60 days after diagnosis. Histology and stage information from the EHR were used to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We evaluated the Turner algorithm using cohort 1 patients diagnosed between June 2014 and October 2015 (step 1) and between November 2015 and December 2020 after approval of immunotherapies (step 2). Next, we evaluated cohort 2 patients diagnosed between November 2015 and December 2020 using an updated algorithm incorporating the latest US treatment guidelines (step 3), and compared the results for cohort 2 (Turner algorithm, step 2 patients). Furthermore, an algorithm to determine early NSCLC (eNSCLC; stage I-III) versus metastatic or advanced/metastatic non-small cell lung cancer (stage IV) was evaluated among patients with available histology and stage information., Results: A total of 5,012 patients were included (cohort 1, step 1: n = 406; cohort 1, step 2: n = 2,573; cohort 2, step 3: n = 2,744). The updated algorithm showed improved performance relative to the previous Turner algorithm for sensitivity (0.920-0.932), specificity (0.865-0.923), PPV (0.976-0.988), and NPV (0.640-0.673). The eNSCLC algorithm showed high specificity (0.874) and relatively low sensitivity (0.539)., Conclusion: An updated treatment-based algorithm identifying patients with incident NSCLC was validated using EHR data and distinguished lung cancer subtypes in claims databases when EHR data were not available.

Background: Huangqi (Radix Astragali) is a natural medicine with a wide range of uses. The research related to Huangqi is getting hotter and the number of publications is gradually increasing. This study aims to explore the current status and emerging trends of Huangqi-related research., Method: Huangqi-related literature was systemically obtained from the Web of Science database. The CiteSpace, VOSviewer, and, R package "Bibliometrix" tools were used to analyze the number of publications, countries, research institutions, journals, authors, keywords, references, and trends., Results: A total of 2255 papers were retrieved for analysis. These papers were written by 11,247 authors from 1927 institutions in 71 countries, published in 570 journals, and cited 73,534 references from 11,553 journals. From 1999 to 2022, the number of publications gradually increased. China was the country with the highest number of publications. The most prolific institution was Shanghai University of Chinese Medicine. Evidence-Based Complementary and Alternative Medicine was the journal publishing the most Huangqi-related literature. Dr Karl Wah Keung Tsim was the authors with the most output publications. The Review, entitle "Review of the Botanical Characteristics, Phytochemistry, and Pharmacology of Astragalus membranaceous (Huangqi)," was the reference being cited most frequently. The major keywords were apoptosis, oxidative stress, and inflammation. Gut microbiota and epithelial-mesenchymal transitions were new research hotspots in recent years., Conclusion: This study used quantitative and visual analysis of Huangqi to provide insights into the research priorities, frontier research hotspots, and future research trends in this field., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The alarming mortality rate of sepsis in ICUs has garnered significant attention. The precise etiology remains elusive. Mitochondria, often referred to as the cellular powerhouses, have been postulated to have a dysfunctional role, correlating with the onset and progression of sepsis. However, the exact causal relationship remains to be defined., Method: Employing the Mendelian randomization approach, this study systematically analyzed data from the IEUOpenGWAS and UKbiobank databases concerning mitochondrial function-related proteins and their association with sepsis, aiming to delineate the causal relationship between the two., Results: The findings underscored a statistically significant association of GrpE1 with sepsis, registering a P value of 0.005 and an OR of 0.499 (95% CI: 0.307-0.810). Likewise, HTRA2, ISCU, and CUP3 each manifested significant associations with sepsis, yielding OR values of 0.585, 0.637, and 0.634, respectively. These results suggest potential implications of the aforementioned proteins in the pathogenesis of sepsis., Conclusion: The present study furnishes novel evidence elucidating the roles of GrpE1, HTRA2, ISCU, and CUP3 in the pathophysiology of sepsis. Such insights pave the way for a deeper understanding of the pathological mechanisms underpinning sepsis and hint at promising therapeutic strategies for the future., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Purpose: What to intake during labor is controversial. The purpose of this study was to compare the gastric emptying of high-energy semifluid solid beverage (HESSB) versus that of carbohydrate (CHO) solution of equal calories and volume by evaluating the gastric antral cross-sectional area (CSA) using ultrasonography in parturients during labor at term., Methods: The study was conducted at a maternity and infant hospital between June and October 2020. Forty parturients scheduled for epidural labor analgesia during labor at term were randomly assigned to receive HESSB (300 mL, n = 20) or CHO (300 mL, n = 20). Gastric antral CSA was measured at baseline and 5, 30, 60, 90, and 120 min after consumption of the drink. The primary outcome was gastric antral CSA at 120 min in the HESSB group and CHO group., Results: The gastric antral CSA between the HESSB group and CHO group at 120 min was not statistically significant (2.73 cm 2  ± 0.55 vs. 2.55 cm 2  ± 0.72, P = 0.061). All patients returned to baseline at 120 min after intake of 300 mL isocaloric HESSB and CHO, confirmed by evaluation of gastric antral CSA. The visual analog scale score for satiety was higher in the HESSB group (P < 0.001), with better taste satisfaction (7[5-8] vs. 5[4-6], P < 0.001)., Conclusion: The change of gastric antral cross-sectional area after HESSB is similar to the corresponding calories and volume of CHO and the gastric emptying of HESSB can be emptied within 2 h with better taste satisfaction and satiety in pregnant women under labor analgesia., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood., Methods: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3., Results: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells., Conclusions: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment., (© 2024. The Author(s).)

Background: Periaortic fat is associated with coronary disease. Thus, it was hypothesized that the inflammation associated with acute aortic dissection (AAD) spreads to pericoronary adipose tissue (PCAT) via thoracic periaortic fat. Pericoronary adipose tissue attenuation (PCATa) serves as a marker for inflammation of perivascular adipose tissue (PVAT). This study sought to examine PCATa in individuals diagnosed with AAD., Methods: Consecutive patients with chest pain from May 2020 to September 2022 were prospectively enrolled in this study and underwent coronary computed tomography angiography (CCTA) and/or aorta computed tomography angiography (CTA). Based on the results of the CTA, the patients were divided into the following two groups: (I) the AAD group; and (II) the non-AAD group. PCATa of the right coronary angiography (RCA), left anterior descending (LAD), and left circumflex (LCx) was quantified for each patient using semi-automated software. The PCATa values were compared between the AAD and non-AAD patients according to the atherosclerosis of the coronary arteries. Similarly, the PCATa values of the AAD patients were compared between the preoperative and postoperative steady states., Results: A total of 136 patients (42 female, 94 male; mean age: 63.3±11.9 years) were divided into the two groups according to the presence of aortic dissection on CTA. The RCA PCATa , LAD PCATa , and LCx PCATa values were significantly higher in the AAD subjects than the non-AAD subjects, regardless of the presence or absence of atherosclerosis in the coronary arteries [-85.1±9.3 vs. -92.9±10.0 Hounsfield unit (HU); -83.2±7.4 vs. -89.9±9.1 HU; -77.5±8.4 vs. -85.6±7.9 HU, all P<0.001). The preoperative RCA PCATa , LAD PCATa , and LCx PCATa values were higher in the AAD patients than the postoperative steady-state patients (-82.9±8.7 vs. -97.6±8.8 HU; -79.8±7.6 vs. -92.8±6.8 HU; -74.6±7.1 vs. -87.7±6.9 HU, all P < 0.001). According to the multivariable logistic regression analysis, high RCA PCATa and LAD PCATa values were associated with AAD regardless of the degree of stenosis [odds ratio (OR) =0.014; 95% confidence interval (CI): 0.001-0.177; P=0.001 and OR =0.010; 95% CI: 0.001-0.189; P=0.002]., Conclusions: PCATa on computed tomography was increased in patients with AAD regardless of the presence or absence of coronary artery disease (CAD). This suggests that vascular inflammation is present in AAD independent of CAD. Further research should be conducted to investigate the potential of this imaging biomarker to predict AAD and monitor patients' responses to therapies for AAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-253/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

A pair of new guaiane-type sesquiterpene tautomers ( 1 ) was isolated from rhizomes of Acorus calamus . Meanwhile, three pairs of known compounds, including a pair of dihydroflavone glycoside tautomers ( 2 ), a pair of 4-hydroxybenzoic acid ester glycoside tautomers ( 3 ), as well as a pair of secoiridoid glycoside tautomers ( 4 ) were isolated from fruits of Cornus officinalis . Their structures were elucidated by extensive spectroscopic and computational methods. Furthermore, the tautomeric mechanisms were discussed.

Introduction: Hepatocellular carcinoma (HCC) has a high mortality rate, with curative resection being the primary treatment. However, HCC patients have a large possibility of recurrence within 5 years after curative resection., Methods: Thus, identifying biomarkers to predict recurrence is crucial. In our study, we analyzed data from CCLE, GEO, and TCGA, identifying eight oncogenes associated with HCC. Subsequently, the expression of 8 genes was tested in 5 cases of tumor tissues and the adjacent non-tumor tissues. Then ATP6AP1 , PSMD14 and HSP90AB1 were selected to verify the expression in 63 cases of tumor tissues and the adjacent non-tumor tissues. The results showed that ATP6AP1 , PSMD14, HSP90AB1 were generally highly expressed in tumor tissues. A five-year follow-up of the 63 clinical cases, combined with Kaplan-Meier Plotter's relapse-free survival (RFS) analysis, found a significant correlation between PSMD14 expression and recurrence in HCC patients. Subsequently, we analyzed the PSMD14 mutations and found that the PSMD14 gene mutations can lead to a shorter disease-free survival time for HCC patients., Results: The results of enrichment analysis indicated that the differentially expressed genes related to PSMD14 are mainly enriched in the signal release pathway., Conclusion: In conclusion, our research showed that PSMD14 might be related to recurrence in HCC patients, and the expression of PSMD14 in tumor tissue might be a potential prognostic biomarker after tumor resection in HCC patients., Competing Interests: The authors declare no conflict of interest, financial or otherwise., (© 2023 Bentham Science Publishers.)

The relationship between Needle Track Bleeding (NTB) and the occurrence of postoperative immediate pneumothorax remains unclear. In our cross-sectional study, we conducted a retrospective collected of data from 674 consecutive patients who underwent CT-guided percutaneous transthoracic lung biopsies between 2019 and 2022. A logistic regression model was employed to explore the association between NTB and postoperative immediate pneumothorax, and restricted cubic spline curves was used to investigate the link and its explicit curve shape. A sensitivity analysis was performed by transforming the continuous NTB into categorical variable and calculated an E-value. A total of 453 participants (47.90% male) were included in our analysis. The postoperative immediate pneumothorax rate was 41.05% (186/453). We found a negative correlation between NTB and postoperative immediate pneumothorax (OR = 0.91, 95%CI 0.88-0.95) after adjusting for confounding factors. This relationship was nonlinear, with a key inflection point at NTB of 8 mm. No significant link was noted for NTB > 8 mm (OR = 0.98, 95%CI 0.95-1.02), while a protective association was observed for NTB ≤ 8 mm (OR = 0.74, 95%CI 0.66-0.81). NTB showed a nonlinear, protective correlation with postoperative immediate pneumothorax. However, when NTB exceeded 8 mm, the protective association was not observed., (© 2023. The Author(s).)

Intelligent control of wastewater treatment plants (WWTPs) has the potential to reduce energy consumption and greenhouse gas emissions significantly. Machine learning (ML) provides a promising solution to handle the increasing amount and complexity of generated data. However, relationships between the features of wastewater datasets are generally inconspicuous, which hinders the application of artificial intelligence (AI) in WWTPs intelligent control. In this study, we develop an automatic framework of feature engineering based on variation sliding layer (VSL) to control the air demand precisely. Results demonstrated that using VSL in classic machine learning, deep learning, and ensemble learning could significantly improve the efficiency of aeration intelligent control in WWTPs. Bayesian regression and ensemble learning achieved the highest accuracy for predicting air demand. The developed models with VSL-ML models were also successfully implemented under the full-scale wastewater treatment plant, showing a 16.12 % reduction in demand compared to conventional aeration control of preset dissolved oxygen (DO) and feedback to the blower. The VSL-ML models showed great potential to be applied for the precision air demand prediction and control. The package as a tripartite library of Python is called wwtpai, which is freely accessible on GitHub and CSDN to remove technical barriers to the application of AI technology in WWTPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In recent years, novel agents have become available to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL); the impact of such agents on treatment costs has not been formally studied. We present results from 2 independent, retrospective, real-world cohort analyses to determine the cost of disease progression after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)., Materials and Methods: Analyses were conducted using the IQVIA PharMetrics Ⓡ Plus claims database and the Surveillance, Epidemiology, and End Results registry-Medicare-linked database (SEER-Medicare) and included patients ≥18 years and ≥66 years, respectively. "No progression" was defined as no second-line therapy for ≥2 years after the end of first-line R-CHOP and "treated progression" as initiating a second-line therapy within 2 years following the end of first-line R-CHOP. Analyses were adjusted for baseline covariates, and per-patient-per-month (PPPM) costs were compared between progressors and nonprogressors., Results: The IQVIA PharMetrics Plus analysis (January 1, 2010-June 30, 2018) included 871 patients (nonprogressors, n = 725; progressors, n = 146), including 10 patients who received chimeric antigen receptor T-cell therapy (CAR-T). Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,554 vs. $1561, P < .001). The SEER-Medicare analysis (January 1, 2010-December 31, 2017) included 4099 patients (nonprogressors, n = 3389; progressors, n = 710), including 12 patients receiving CAR-T. Treated progression was associated with significantly higher adjusted PPPM costs than no progression ($10,928 vs. $2902, P < .001)., Conclusion: Treated progression of DLBCL increases adjusted PPPM costs by over $8000 compared with no progression., Competing Interests: Disclosure John M. Burke reports consultancy or advisory role for AbbVie, Adaptive Biotechnologies, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Constellation, Epizyme, Inc., F. Hoffmann-La Roche Ltd, Genentech, Inc., Genmab, Kura, Kymera Therapeutics, Lilly, MorphoSys, Nurix, Seagen, TG Therapeutics, and X4 Pharmaceuticals; speakers bureau for BeiGene and Seagen. Anthony Masaquel, Rongrong Wang, Farah Hossain, Jia Li, Carmen D. Ng are employees of Genentech, Inc., and receive F. Hoffmann-La Roche Ltd. stocks/stock options. Summera Qiheng Zhou is a paid consultant of Genentech, Inc. Matthew Matasar reports stock or other ownership for Merck Sharp & Dohme; honoraria for Genentech, Inc., F. Hoffmann-La Roche Ltd, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Seattle Genetics, and ImmunoVaccine Technologies; research funding for Genentech, Inc., F. Hoffmann-La Roche Ltd, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Rocket Medical, and ImmunoVaccine Technologies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments., (© 2023. The Author(s).)

Background: Vaccines are urgently required to control Staphylococcus aureus hospital and community infections and reduce the use of antibiotics. Here, we report the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in patients undergoing elective surgery for closed fractures., Methods: A randomized, double-blind, placebo-controlled, multicenter phase 2 clinical trial was carried out in 10 clinical research centers in China. Patients undergoing elective surgery for closed fractures, aged 18-70 years, were randomly allocated at a ratio of 1:1 to receive the rFSAV or placebo at a regimen of two doses on day 0 and another dose on day 7. All participants and investigators remained blinded during the study period. The safety endpoint was the incidence of adverse events within 180 days. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as opsonophagocytic antibodies., Results: A total of 348 eligible participants were randomized to the rFSAV (n = 174) and placebo (n = 174) groups. No grade 3 local adverse events occurred. There was no significant difference in the incidence of overall systemic adverse events between the experimental (40.24 %) and control groups (33.72 %) within 180 days after the first immunization. The antigen-specific binding antibodies started to increase at days 7 and reached their peaks at 10-14 days after the first immunization. The rapid and potent opsonophagocytic antibodies were also substantially above the background levels., Conclusions: rFSAV is safe and well-tolerated in patients undergoing elective surgery for closed fractures. It elicited rapid and robust specific humoral immune responses using the perioperative immunization procedure. These results provide evidence for further clinical trials to confirm the vaccine efficacy. China's Drug Clinical Trials Registration and Information Publicity Platform registration number: CTR20181788. WHO International Clinical Trial Registry Platform identifier: ChiCTR2200066259., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people., Methods: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing., Results: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3-12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors., Conclusions: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The assessment of factors that can promote the transmission of antibiotic resistance genes (ARGs) across bacteria in the gastrointestinal tract is in great demand to understand the occurrence of infections related to antibiotic-resistant bacteria (ARB) in humans. However, whether acid-resistant enteric bacteria can promote ARG transmission in gastric fluid under high-pH conditions remains unknown. This study assessed the effects of simulated gastric fluid (SGF) at different pH levels on the RP4 plasmid-mediated conjugative transfer of ARGs. Moreover, transcriptomic analysis, measurement of reactive oxygen species (ROS) levels, assessment of cell membrane permeability, and real-time quantitative assessment of the expression of key genes were performed to identify the underlying mechanisms. The frequency of conjugative transfer was the highest in SGF at pH 4.5. Antidepressant consumption and certain dietary factors further negatively impacted this situation, with 5.66-fold and 4.26-fold increases in the conjugative transfer frequency being noted upon the addition of sertraline and 10% glucose, respectively, compared with that in the control group without any additives. The induction of ROS generation, the activation of cellular antioxidant systems, increases in cell membrane permeability, and the promotion of adhesive pilus formation were factors potentially contributing to the increased transfer frequency. These findings indicate that conjugative transfer could be enhanced under certain circumstances in SGF at elevated pH levels, thereby facilitating ARG transmission in the gastrointestinal tract. IMPORTANCE The low pH of gastric acid kills unwanted microorganisms, in turn affecting their inhabitation in the intestine. Hence, studies on the factors that influence antibiotic resistance gene (ARG) propagation in the gastrointestinal tract and on the underlying mechanisms are limited. In this study, we constructed a conjugative transfer model in the presence of simulated gastric fluid (SGF) and found that SGF could promote the dissemination of ARGs under high-pH conditions. Furthermore, antidepressant consumption and certain dietary factors could negatively impact this situation. Transcriptomic analysis and a reactive oxygen species assay revealed the overproduction of reactive oxygen species as a potential mechanism by which SGF could promote conjugative transfer. This finding can help provide a comprehensive understanding of the bloom of antibiotic-resistant bacteria in the body and create awareness regarding the risk of ARG transmission due to certain diseases or an improper diet and the subsequent decrease in gastric acid levels., Competing Interests: The authors declare no conflict of interest.

Although bone marrow mesenchymal stem cells (BMSCs) might have therapeutic potency in ischemic stroke, the benefits are limited. The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor (VEGF) on behavioral defects in a rat model of transient cerebral ischemia, which was induced by middle cerebral artery occlusion. VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke. We found that compared with the stroke-only group and the vehicle- and BMSCs-control groups, the VEGF-BMSCs treated animals displayed the largest benefits, as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke. Additionally, VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier, increased the regeneration of blood vessels in the region of ischemic penumbra, and reducedneuronal degeneration surrounding the infarct core. Further mechanistic studies showed that among all transplant groups, VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor. These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available., Competing Interests: None

Background: Human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapy for immune and inflammatory diseases. However, how to maintain the activity and unique properties during cold storage and transportation is one of the key factors affecting the therapeutic efficiency of hUCMSCs. Schisandrin B (SchB) has many functions in cell protection as a natural medicine. In this study, we investigated the protective effects of SchB on the hypothermic preservation of hUCMSCs., Methods: hUCMSCs were isolated from Wharton's jelly. Subsequently, hUCMSCs were exposed to cold storage (4 °C) and 24-h re-warming. After that, cells viability, surface markers, immunomodulatory effects, reactive oxygen species (ROS), mitochondrial integrity, apoptosis-related and antioxidant proteins expression level were evaluated., Results: SchB significantly alleviated the cells injury and maintained unique properties such as differentiation potential, level of surface markers and immunomodulatory effects of hUCMSCs. The protective effects of SchB on hUCMSCs after hypothermic storage seemed associated with its inhibition of apoptosis and the anti-oxidative stress effect mediated by nuclear factor erythroid 2-related factor 2 signaling., Conclusion: These results demonstrate SchB could be used as an agent for hypothermic preservation of hUCMSCs., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Three undescribed methylsuccinic acid derivatives, xylaril acids A-C, and two undescribed enoic acid derivatives, xylaril acids D-E, were isolated from the fungus Xylaria longipes. The structures of the undescribed compounds were deduced by spectroscopic means, including HRESIMS and 1D/2D NMR spectroscopy, as well as ECD calculations. The absolute configuration of xylaril acids A was further determined by single-crystal X-ray diffraction experiments. All the isolated compounds displayed neuroprotective activities against oxygen-glucose deprivation/reperfusion injury in PC12 cells by enhancing cell viability and inhibiting cell apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The impact of sarcopenia on textbook outcome (TO) after hepatectomy in hepatocellular carcinoma (HCC) patients remains unclear. This study aimed to investigate the association between sarcopenia and TO, to clarify its long and short-term prognostic value, and to develop a nomogram model based on sarcopenia and TO for survival prediction., Methods: Patients who underwent HCC resection between January 2012 and March 2017 in three large hospitals in Fujian were retrospectively recruited and divided into sarcopenia and non-sarcopenia groups based on skeletal muscle index (SMI) values. TO was defined as no 30-day morality, no 30-day readmission, negative margins, no prolonged hospital stay, and no major complications. Multivariate regression was used to screen for clinical factors associated with TO. Nomograms of overall survival (OS) and recurrence-free survival (RFS) after hepatectomy for HCC were developed., Results: A total of 1172 patients were included in the study. The TO rates were 28.74% (121/421 patients) in the sarcopenia group and 43.4% (326/751 patients) in the non-sarcopenia group. The results showed that sarcopenia was an independent predictor of TO (p < 0.001), TO was an independent predictor of perioperative treatment-related sarcopenia (PTRS)(p = 0.002), and TO was an independent predictor of OS and RFS (p < 0.001). Nomogram models based on sarcopenia and TO were generated and accurately predicted OS and RFS at 1, 3, and 5 years., Conclusion: Both sarcopenia and TO are independent predictors of OS and RFS after HCC resection. Sarcopenia was an independent predictor of TO. Sarcopenia influenced long-term survival by affecting short-term postoperative outcomes., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

An increasing number of studies have found that long non-coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non-protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras-related protein Rab-1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation-associated 2G4 (PA2G4) and stromal cell-derived factor 4 (SDF4; also known as 45-kDa calcium-binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173-knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173-RAB1B-PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Phosphorus-solubilizing microorganisms release organic acids that can chelate mineral ions or reduce the pH to solubilize insoluble phosphates for use by plants; it is important to study potential phosphorus-solubilizing microorganisms for use in agriculture. In this study, PSF7 was isolated from the soil of the Wengfu Phosphorus Tailings Dump in Fuquan City, Guizhou Province, China. PSF7 was identified as Paecilomyces lilacinus, based on morphological characterization and ITS sequencing analysis. The relationship between the phosphorus-solubilizing capacity and pH variation of PSF7 under liquid fermentation was studied. The results showed that there was a significant negative correlation (-0.784) between the soluble phosphorus content of PSF7 and the pH value. When PSF7 was placed under low phosphorus stress, eight organic acids were determined from fermentation broth using HPLC, of which tartaric acid and formic acid were the main organic acids. Different optimization parameters of medium components were analyzed using response surface methodology. The optimized medium components were 23.50 g/L sucrose, 1.64 g/L ammonium sulfate and soybean residue, 1.07 g/L inorganic salts, and 9.16 g/L tricalcium phosphate, with a predicted soluble phosphorus content of 123.89 mg/L. Under the optimum medium composition, the actual phosphorus-solubilizing content of PSF7 reached 122.17 mg/L. Moreover, scanning electron microscopy analysis of the sample was carried out to characterize the phosphate-solubilizing efficiency of PSF7 on mineral phosphate. The results provide useful information for the future application of PSF7 as a biological fertilizer.

A copper-catalyzed annulation of O -acyl oximes with cyclic 1,3-diones has been developed for the concise synthesis of 7,8-dihydroindolizin-5(6 H )-ones and cyclohexanone-fused furans through the substituent-controlled selective radical coupling process. 2-Alkyl cyclic 1,3-diones undergo C-C radical coupling, while 2-unsubstituted cyclic 1,3-diones undergo C-O radical coupling.

To study the anti-tumor effect of Cistanche deserticola Y. Ma , HepG2 cells were treated with 0, 3.5, 10.5, 21, 31.5, and 42 μg/ml of total glycosides (TG) from Cistanche deserticola . The HepG2 cell survival rate and 50% inhibition concentration (IC 50 ) were detected using the CCK-8 method, and the level of reactive oxygen species (ROS) was detected by using a DCFH-DA fluorescence probe. Finally, a Seahorse XFe24 energy analyzer (Agilent, United States) was used to detect cell mitochondrial pressure and glycolytic pressure. The results showed that TG could reduce the survival rate of HepG2 cells and that the IC 50 level was 35.28 μg/ml. With increasing TG concentration, the level of ROS showed a concentration-dependent upward trend. Energy metabolism showed that each dose group of TG could significantly decline the mitochondrial respiratory and glycolytic functions of HepG2 cells. In conclusion, TG could significantly inhibit the mitochondrial respiration and glycolysis functions of HepG2 cells, increase the level of ROS, and inhibit cell proliferation. Thus, this experiment pointed out that Cistanche deserticola can be used as a source of anti-cancer foods or drugs in the future. However, further studies on its mechanisms and clinical applications are needed., Competing Interests: Y-jJ was employed by Inner Mongolia Sankou Biotechnology 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., (Copyright © 2023 Feng, Zhou, Zhou, Jiang, Sun, Song, Cui, Yan and Wang.)

Fifteen previously undescribed minor iridoid glycosides, including four monomers and eleven dimers, were isolated from the fruits of Cornus officinalis Sieb. et Zucc. Their chemical structures were determined on the basis of spectroscopic data and chemical evidence. All of the isolated compounds were evaluated for their effects of the glucose consumption on the insulin resistant HepG2 cells, and four compounds, named cornuofficinalisides F, H, L, and O, increased the glucose consumption significantly at 10 μM, the EC 50 values of them were determined to be 0.898, 1.625, 0.923, and 8.589 μM, respectively. Moreover, the four compounds could improve the ability of glucose uptake significantly in insulin resistant HepG2 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Choroidal neovascularization (CNV) is a hallmark of wet age-related macular degeneration, which severely impairs central vision. Studies have shown that endothelial-mesenchymal transition (EndMT) is involved in the pathogenesis of CNV. Licochalcone A (lico A), a flavonoid extracted from the root of licorice, shows the inhibition on EndMT, but it remains unclear whether it can suppress the formation of CNV. The aim of this study is to investigate the effects of lico A on laser-induced CNV, and EndMT process in vitro and vivo. We established the model of CNV with a krypton laser in Brown-Norway rats and then intraperitoneally injected lico A. Our experimental results demonstrated that the leakage of CNV was relieved, and the area of CNV was reduced in lico A-treated rats. Cell migration and tube formation in oxidized low-density lipoprotein (Ox-LDL)-stimulated HUVECs were inhibited by lico A and promoted by PI3K activator 740Y-P. The protein expressions of snai1 and α-SMA were increased, and CD31 and VE-cadherin were decreased in the model rats of CNV, but partially reversed after treatment with lico A. The expression of CD31 was decreased and α-SMA was increased in OX-LDL-treated HUVECs, which was further strengthened by 740Y-P, while the expression of CD31 was up-regulated and α-SMA was down-regulated in lico A treated HUVECs. Our data revealed that EndMT process was alleviated by lico A. Meanwhile, PI3K/AKT signaling pathway was activated in model rat of CNV and Ox-LDL-stimulated HUVECs, which can be suppressed with treatment of lico A. Our experimental results confirmed for the first time that lico A has the potential to alleviate CNV by inhibiting the endothelial-mesenchymal transition via PI3K/AKT signaling pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The actual rate of conversion surgery and its prognostic advantages remain unclear. This study aimed to assess the outcomes of salvage surgery after conversion therapy with triple therapy (transcatheter arterial chemoembolization [TACE] combined with lenvatinib plus anti-PD-1 antibodies) in patients with initially unresectable hepatocellular carcinoma (uHCC)., Methods: Patients with initially uHCC who received at least one cycle of first-line triple therapy and salvage surgery at five major cancer centers in China were included. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS) rates after salvage surgery. The secondary endpoints were perioperative complications, 90-day mortality, and pathological tumor response., Results: Between June 2018 and December 2021, 70 patients diagnosed with uHCC who underwent triple therapy and salvage surgery were analyzed: 39 with Barcelona Clinic Liver Cancer (BCLC) stage C, 22 with BCLC stage B, and 9 with BCLC stage A disease. The median interval between the start of triple therapy and salvage surgery was 4.3 months (range, 1.7-14.2 months). Pathological complete response and major pathological response were observed in 29 (41.4%) and 59 (84.3%) patients, respectively. There were 2 cases of perioperative mortality (4.3%) and 5 cases of severe perioperative complications (7.1%). With a median follow-up of 12.9 months after surgery (range, 0.3-36.8 months), the median OS and RFS were not reached. The 1- and 2-year OS rates were 97.1% and 94.4%, respectively, and the corresponding RFS rates were 68.9% and 54.4%, respectively., Conclusion: First-line combination of TACE, lenvatinib, and anti-PD-1 antibodies provides a better chance of conversion therapy in patients with initially uHCC. Furthermore, salvage surgery after conversion therapy is effective and safe and has the potential to provide excellent long-term survival benefits., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Introduction: Clinicians increasingly perform laparoscopic surgery for intrahepatic cholangiocarcinoma (ICC). However, this surgery can be difficult in patients with advanced-stage ICC because of the complicated procedures and difficulty in achieving high-quality results. We compared the effects of a three-step optimized procedure with a traditional procedure for patients with advanced-stage ICC., Methods: Forty-two patients with advanced-stage ICC who received optimized laparoscopic hemihepatectomy with lymph node dissection (LND, optimized group) and 84 propensity score-matched patients who received traditional laparoscopic hemihepatectomy plus LND (traditional group) were analyzed. Surgical quality, disease-free survival (DFS), and overall survival (OS) were compared., Results: The optimized group had a lower surgical bleeding score (P = 0.038) and a higher surgeon satisfaction score (P = 0.001). Blood loss during hepatectomy was less in the optimized group (190 vs. 295 mL, P < 0.001). The optimized group had more harvested LNs (12.0 vs. 8.0, P < 0.001) and more positive LNs (8.0 vs. 5.0, P < 0.001), and a similar rate of adequate LND (88.1% vs. 77.4%, P = 0.149). The optimized group had longer median DFS (9.0 vs. 7.0 months, P = 0.018) and median OS (15.0 vs. 13.0 months, P = 0.046). In addition, the optimized group also had a shorter total operation time (P = 0.001), shorter liver resection time (P = 0.001), shorter LND time (P < 0.001), shorter hospital stay (P < 0.001), and lower incidence of total morbidities (14.3% vs. 36.9%, P = 0.009)., Conclusions: Our optimization of a three-step laparoscopic procedure for advanced ICC was feasible, improved the quality of liver resection and LND, prolonged survival, and led to better intraoperative and postoperative outcomes., (© 2022. The Author(s).)

Background: Early recurrence is common after surgical resection (SR) for hepatocellular carcinoma (HCC) with high risk of recurrence and is associated with poor prognosis. The combinations of lenvatinib (LEN), anti-PD-1 antibodies (PD-1) and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. It is unknown whether triple therapy for neoadjuvant treatment of resectable HCC with high risk of recurrence is effective. This article aimed to compare the outcomes of surgery alone and neoadjuvant combination treatment with triple therapy before SR in patients with HCC with high risk of recurrence., Methods: A retrospective study was conducted on patients diagnosed with HCC with high risk of recurrence who received treatment with or without triple therapy. The records of 24 patients in the triple therapy group and 76 patients in the surgery-alone group were analyzed. Propensity score matching (PSM) was performed to minimize the influence of potential confounders., Results: One hundred patients were enrolled. In the triple therapy group, 8 (33.3%) and 12 (50.0%) patients had complete and partial responses, respectively, as assessed by an investigator. Before PSM, the overall survival (OS) rates for the triple therapy group at 6, 12, 18, and 24 months were 100.0%, 100.0%, 100.0%, and 85.7%, respectively, compared with corresponding 92.1%, 73.7%, 53.9%, and 48.7% for the surgery-alone group (P<0.001). The disease-free survival (DFS) rates were 82.2%, 66.95%, 48.8%, and 48.8% for the triple therapy and 41.92%, 28.34%, 27.05%, and 22.99% for the surgery-alone group (P=0.003). After PSM, DFS and OS were significantly longer in the triple therapy group than in the surgery-alone group (DFS, p=0.019; OS, p=0.003)., Conclusions: Neoadjuvant combination treatment before SR had a high rate of tumor response and provided significantly better postoperative survival outcomes than surgery alone in patients with HCC with high risk of recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Wu, Li, Qiu, Zhou, Yin, Chen, Li, Zhou and Yan.)

Aim: To determine whether the injection of haemocoagulase into the biopsy tract can reduce pneumothorax and pulmonary haemorrhage after computed tomography (CT)-guided percutaneous transthoracic lung biopsy (PTLB)., Materials and Methods: A retrospective study was performed involving patients with undiagnosed pulmonary lesions scheduled for PTLB between January 2020 and March 2021. Patients were assigned to the haemocoagulase group or the non-haemocoagulase group. After CT-guided biopsies were performed with a 17 G coaxial system, patients in the haemocoagulase group received a haemocoagulase injection (0.2-0.5 units) in the biopsy tract as the sheath was withdrawn. Postoperative image studies were performed to evaluate complications, including pneumothorax and pulmonary haemorrhage. Factors, including the patient's position, lesion location, and pathological results, were evaluated to determine their associations with the complications., Results: A total of 100 patients were included, with 44 men and a mean age of 53 years old. The overall incidences of pneumothorax and pulmonary haemorrhage were 15% and 13%, respectively. The incidences of pneumothorax and pulmonary haemorrhage were statistically significantly lower in the haemocoagulase group (8% and 6%, respectively) than in the non-haemocoagulase group (22% and 20%, respectively; p=0.04 and 0.03, respectively). There was no statistically significant difference in haemoptysis between the haemocoagulase (6%) and non-haemocoagulase (2%) groups (p=0.23). There were also no statistically significant associations of pneumothorax or pulmonary haemorrhage with the patients' positions, lesion location, or pathological results., Conclusion: Biopsy tract haemocoagulase injection reduced the incidences of postoperative pneumothorax and pulmonary haemorrhage after PTLB., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Qian, Liu, Zhou, Zhang, Peng, Su and Zhang.)

The electrochemical oxidation method is a promising technology for the degradation of perfluorooctane sulfonate (PFOS). However, the elimination processes of PFOS are still unknown, including the electron transfer pathway, key reactive sites, and degradation mechanism. Here, we fabricated diatomite and cerium (Ce) co-modified Sb 2 O 3 (D-Ce/Sb 2 O 3 ) anode to realize efficient degradation of PFOS via peroxymonosulfate (PMS) activation. The transferred electron and the generated hydroxyl radical (•OH) can high-effectively decompose PFOS. The electron can be rapidly transferred from the highest occupied molecular orbital of the PFOS to the lowest unoccupied molecular orbital of the PMS via the D-Ce/Sb 2 O 3 driven by a potential energy difference under electrochemical process. The active site of Ce-O in the D-Ce/Sb 2 O 3 can greatly reduce the migration distance of the electron and the •OH, and thus improving the catalytic activity for degrading various organic micropollutants with high stability. In addition, the electrochemical process shows strong resistance and tolerance to the changing pH, inorganic ions, and organic matter. This study offers insights into the electron transfer pathway and PMS activation mechanism in PFOS removal via electrochemical oxidation, paving the way for its potential application in water purification., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To establish an ultra-sensitive, ultra-fast, visible detection method for Vibrio parahaemolyticus (VP) ., Methods: We established a new method for detecting the tdh and trh genes of VP using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 12a (CRISPR/Cas12a) combined with recombinase polymerase amplification and visual detection (CRISPR/Cas12a-VD)., Results: CRISPR/Cas12a-VD accurately detected target DNA at concentrations as low as 10 -18 M (single molecule detection) within 30 min without cross-reactivity against other bacteria. When detecting pure cultures of VP, the consistency of results reached 100% compared with real-time PCR. The method accurately analysed pure cultures and spiked shrimp samples at concentrations as low as 10 2 CFU/g., Conclusion: The novel CRISPR/Cas12a-VD method for detecting VP performed better than traditional detection methods, such as real-time PCR, and has great potential for preventing the spread of pathogens., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

A copper-catalyzed annulation of α,β -unsaturated O -acyl ketoximes with isoquinolinium N -ylides has been developed for the concise synthesis of stable N-H imines with a benzo[7,8]indolizine core. When β-(2-bromoaryl)- α,β -unsaturated O -acyl ketoximes are used as the starting materials, a cascade cyclization occurs to afford the benzo[7,8]indolizino[1,2- c ]quinolines.

Polyfluoroalkyl and perfluoroalkyl chemicals (PFCs) widely used in lubricants, surfactant, textiles, paper coatings, cosmetics, and fire-fighting foams can release a large deal of organics contaminants into wastewater and pose great risks to the health of humans and eco-environments. Although advanced oxidation processes can effectively deconstruct various organic contaminants via reactive radicals, the stable structure of PFCs makes it difficult to be degraded. Here, we confirm that electrochemical oxidation process coupled with peroxymonosulfate (PMS) reaction can efficiently destroy stable structure of PFCs via electron transfer and meanwhile completely degrade PFCs via generated active radicals. We further studies via capturing and scavenging radicals, and DFT calculations find that electron hydroxyl radials play a dominant role in degrading PFCs. Based on the calculations of adsorption energy and molecular orbital energy we further demonstrate that many active sites on the surface of Ti 4 O 7 (1 0 4) plane can rapidly take part in electrochemical reaction for generating radials and removing organic contaminants. These results give a promising insight towards high-effective and deep degradation of PFCs via electrochemical reaction coupled with advanced oxidation processes, as well as providing guidance and technical support for the remove of multiple organic contaminants., (Copyright © 2022. Published by Elsevier Ltd.)

Enhancer RNAs (eRNAs) are intergenic long noncoding RNAs (lncRNAs) participating in the development of malignant cancers via targeting cancer-associated genes and immune checkpoints. Immune infiltration of the tumor microenvironment was positively associated with overall survival (OS) in lung adenocarcinoma (LUAD). In this study, we aimed to explore the clinical significance of PCBP1-AS1 in LUAD and developed a novel prognostic signature based on two eRNAs. Our team discovered that the expression of PCBP1-AS1 was distinctly downregulated in LUAD specimens compared with nontumor specimens. Lower PCBP1-AS1 expression was related to advanced clinical stages and poor prognosis. KEGG analysis unveiled that the coexpression genes of PCBP1-AS1 were involved in the regulation of several tumor-related pathways. In addition, remarkable associations were observed between the expression of PCBP1-AS1 and the levels of several immune cells. Then, we used PCBP1-AS1 and TBX5-AS1 to develop a prognostic model. Survival assays unveiled that patients with higher risk scores exhibited a shorter OS in contrast to patients with lower risk scores. In addition, multivariable Cox regressive analysis indicated that the risk score was an independent prediction factor in LUAD sufferers. The anticancer drug sensitivity analysis indicated that risk score had a positive relationship with several anticancer drugs. Taken together, our findings indicated PCBP1-AS1 as a function modulator in LUAD development. In addition, we constructed a robust immune-related eRNA signature which might be a clinical prognosis factor for LUAD patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Li Wang et al.)

Antibiotic resistance genes (ARGs) are receiving increasing concerns due to the antibiotic resistance crisis. Nevertheless, little is known about the spatial behavior and sources of extracellular ARGs (eARGs) in the chlorinated drinking water distribution systems (DWDSs). Here, tap water was continuously collected to reveal the occurrence of both eARGs and intracellular ARGs (iARGs) along a chlorinated DWDS. Afterward, the correlation between eARGs, eDNA-releasing communities, and communities of planktonic bacteria was further analyzed. The eARG concentration decreased significantly, whereas the proportion of vanA and bla NDM-1 increased. Further, the diversity of the eDNA-releasing community increased markedly with increasing distance from the drinking water treatment plant (DWTP). Moreover, the dominant eDNA-releasing bacteria shifted from Acinetobacter, Pseudomonas, and Methylobacterium-Methylorubrum in finished water from the DWTP to Bacteroides, Faecalibacterium, Staphylococcus, and Parabacteroides in the DWDS. In terms of eARG source, thirty genera were significantly correlated with seven types of eARGs that resulted from the lysis of dead planktonic bacteria and detached biofilms. Conversely, the iARGs concentration increased, whereas the biodiversity of the planktonic bacteria community decreased in the sampling points along the DWDSs. Our findings provide critical insights into the spatial behavior and sources of eARGs, highlighting the health risks associated with ARGs in DWDSs., (Copyright © 2021 Elsevier B.V. All rights reserved.)