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Rong Jin, Xiangyu Li, Heqing Huang Faculty of Preschool Education, Capital Normal University, Beijing, People’s Republic of ChinaCorrespondence: : Heqing Huang, Faculty of Preschool Education, Capital Normal University, No. 5, North Third Street, Fucheng Road, Haidian District, Beijing, People’s Republic of China, Tel +86 13520262816, Email aivita@126.comPurpose: This research, grounded in the self-other oriented empathy theoretical framework, aimed to explore the classification of empathy and its relationship with mental health among preschool teachers.Methods: A total of 4345 preschool teachers participated in the study. Mental health was assessed using the Symptom Checklist 90 (SCL-90), and empathy was measured with the Chinese version of the Interpersonal Reactivity Index (IRI-C). Data were collected through a comprehensive preschool education service platform. Latent profile analysis (LPA) was employed to identify subgroups of preschool teachers by self- and other empathy pattern types. Descriptive statistics, bivariate cross-tabulations, and multinomial logistic regression were used to characterize each profile while quantifying associations with mental health.Results: A four-profile model was identified as the best fit in this latent profile analysis: the largest profile of preschool teachers was characterized by moderate self- and other-oriented empathy (46.5%), a second profile was characterized by high self- and other-oriented empathy (25.2%), a third profile was characterized by high other-oriented and low self-oriented empathy (20.8%), and the smallest profile was characterized by both low self- and other-oriented empathy (7.5%). Significant differences in mental health were observed between the latent profile. The high empathy profile exhibited the highest level of mental health risk, while the other-oriented groups showed the lowest level.Conclusion: There are four latent profiles of empathy in preschool teachers, and the profiles of empathy are related to mental health.Keywords: preschool teachers, empathy, mental health, latent profile analysis

Ran Jin,* Hailuan Pei,* Feng Yue, Xiaodi Zhang, Zhicong Zhang, Yi Xu, Jinsheng Li Beijing Tongrentang Technology Development Co., Ltd. Pharmaceutical Factory, Beijing, 100079, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Xu; Jinsheng Li, Beijing Tongrentang Technology Development Co., Ltd. Pharmaceutical factory, Beijing, 100079, People’s Republic of China, Tel +86-10-87632655, Email xy706@sina.com; yarily@126.comPurpose: This study aims to explore the mechanism of Yangxuerongjin pill (YXRJP) in the treatment of diabetic peripheral neuropathy (DPN) by network pharmacology and metabolomics technology combined with animal experiments, and to provide scientific basis for the treatment of DPN.Methods: In this study, network pharmacology analysis was applied to identify the active compounds, core targets and signal pathways, which might be responsible for the effect of DPN. The DPN model was established by high-fat diet combined with streptozotocin (STZ) injection, and the rats were given administration for 12 weeks. The body weight, thermal withdrawal latency (TWL), sciatic motor nerve conduction velocity (MNCV), biochemical indexes, pathological sections of sciatic nerve, oxidative stress factors and the expression levels of neuroprotection-related proteins were detected. Metabolomics technology was used to analyze the potential biomarkers and potential metabolic pathways in DPN treated with YXRJP.Results: The results of network pharmacology showed that YXRJP could treat DPN through baicalin, β-sitosterol, 7-methoxy-2-methylisoflavone, aloe-emodin and luteolin on insulin resistance, Toll-like receptor (TLR), tumor necrosis factor (TNF) and other signaling pathways. YXRJP can prolong the TWL, increase the MNCV of the sciatic nerve, alleviate the injury of the sciatic nerve, reduce the levels of triglyceride (TG), improve the expression of Insulin-like growth factor 1 (IGF-1) protein in the sciatic nerve, and reduce the expression of protein kinase B (AKT) protein. Metabolomics results showed that the potential metabolic pathways of YXRJP in the treatment of DPN mainly involved amino acid metabolism such as arginine, alanine, aspartic acid, lipid metabolism and nucleotide metabolism.Conclusion: YXRJP can effectively improve the symptoms of DPN rats and reduce nerve damage. The effects are mainly related to reducing oxidative stress injury, promoting the expression of neuroprotection-related proteins, reducing the expression of inflammation-related proteins, and affecting amino acid metabolism, lipid metabolism, and nucleotide metabolism pathways. Our findings revealed that YXRJP has a good therapeutic potential for DPN, which provides a reference for further studies on YXRJP. Keywords: Yangxuerongjin pill, Type 2 Diabetes, Rat, peripheral neuropathy, network pharmacology, metabolomics

Chunyan Weng,1,* Rijuan Jin,1,* Xiaoliang Jin,1,* Zimei Yang,1,* Chenghai He,1,2 Qiuhua Zhang,1 Jingli Xu,1,3 Bin Lv1 1Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, People’s Republic of China; 3Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingli Xu; Bin Lv, Email joinleo03@163.com; lvbin@medmail.com.cnAbstract: Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates. As E3 ubiquitin ligases, proteins of tripartite motif (TRIM) family play a role in cancer signaling, development, apoptosis, and formation. These proteins regulate diverse biological activities and signaling pathways. This study comprehensively outlines the functions of TRIM proteins in gastrointestinal physiology, contributing to our knowledge of the molecular pathways involved in gastrointestinal tumors. Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates.Keywords: tripartite motif, E3 ubiquitin ligase, ubiquitin–proteasome system, GI cancer, molecular pathways

Junnan Li,1– 4,* Wenjuan Peng,1– 4,* Yuting Zhang,1– 4 Shunai Liu,1– 4 Ming Han,1– 4 Rui Song,2,4 Yuanyuan Zhang,1– 4 Ronghua Jin,1– 4 Xi Wang1– 4 1National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Beijing Institute of Infectious Disease, Beijing, 100015, People’s Republic of China; 4National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ronghua Jin; Xi Wang, National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Email ronghuajin@ccmu.edu.cn; xiwang@ccmu.edu.cnBackground: To compare the clinical characteristics of symptoms and laboratory findings across SARS-CoV-2 variants (Wild-type, Alpha, Delta, Omicron) and assess the effectiveness of COVID-19 vaccines in preventing symptoms and laboratory abnormalities.Methods: We conducted a retrospective cohort study of individuals with SARS-CoV-2 infection at Beijing Ditan Hospital, Capital Medical University. Patients were grouped by the SARS-CoV-2 variant (Wild-type, Alpha, Delta, Omicron) based on whole-genome sequencing. Thirteen symptoms and 22 laboratory indices were compared across variants, and Omicron patients were further analyzed by vaccination status with generalized estimating equations (GEE) model.Results: One thousand four hundred and thirteen participants were included for the analysis as following: Wild-type group (N=322), Alpha group (N=67), Delta group (N=98), and Omicron group (N=926). Omicron patients showed the highest proportion (30.1%) of respiratory symptoms across groups. Patients displayed normal laboratory manifestation, except for inflammatory markers, coagulation function index and glucose. Meanwhile, the Omicron variant was featured by higher inflammatory biomarkers (serum amyloid A protein [SAA] and C-reactive protein [CRP]). In addition, Omicron patients with three or more vaccine doses had fewer symptoms and higher values of SAA and CRP compared to those with fewer than three doses. Results of GEE showed, when compared with ≤ 1 vaccine dose, red blood cell count, white blood cell count, neutrophil count, platelet count, haemoglobin, and C-reactive protein in patients with ≥ 3 doses of vaccine significantly increased; while aspartic transaminase, creatine kinase, blood urea nitrogen, activated partial thromboplastin time, prothrombin time and thrombin time dramatically decreased, respectively.Conclusion: Omicron variant resulted in abnormal inflammatory response. Individuals with three or more vaccine doses are more likely to experience fewer symptoms and have stronger protection against the virus. This study highlights key differences in symptom onset and laboratory profiles across SARS-CoV-2 variants, reinforcing the importance of three vaccine doses in providing strong protection against the Omicron variant.Keywords: COVID-19, clinical characteristics, vaccines, variants

Xianjun Xiao,1,&ast; Peiwen Xue,1,&ast; Xiangyun Yan,2,&ast; Yanqiu Li,2,&ast; Yunzhou Shi,2 Haiyan Qin,2 Di Qin,2 Wei Cao,2 Zihao Zou,2 Lu Wang,2 Rongjiang Jin,1 Ying Li,2 Junpeng Yao,2 Juan Li1,3 1School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China; 2Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China; 3Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Chengdu, Sichuan, 611135, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junpeng Yao; Juan Li, Email yjp@cdutcm.edu.cn; 785939016@qq.comBackground: Emerging evidence links gut microbiota and their by-products, notably short-chain fatty acids (SCFAs), to urticaria. This study employs multiple Mendelian Randomization (MR) analyses to unravel the complex interactions among gut microbiota, SCFAs, and different subtypes of urticaria, aiming to elucidate the underlying mechanisms and enhance future clinical research.Methods: We analyzed published genome-wide association study (GWAS) summary statistics to identify associations between gut microbiota and three common subtypes of urticaria: spontaneous, dermatographic, and temperature-triggered. Initial two-sample and reverse MR analyses explored the causality in these relationships. Subsequent multivariate MR analyses investigated the role of SCFAs in modulating these interactions, with multiple sensitivity analyses to ensure robustness.Findings: Specific taxa were differently associated with various urticaria subtypes. From microbiota to urticaria: one taxon was negatively associated with dermatographic urticaria; seven taxa were negatively associated and four positively associated with temperature-triggered urticaria; four taxa were negatively associated and six positively associated with spontaneous urticaria. Conversely, from urticaria to microbiota: five taxa were negatively associated with dermatographic urticaria; four were negatively and two positively associated with temperature-triggered urticaria; and two were negatively associated with spontaneous urticaria. These associations were observed at a nominal significance level (P < 0.05). After applying Bonferroni correction for multiple testing, these associations did not reach statistical significance. The observed trends, however, provide insights into potential microbiota-urticaria interactions. Multivariate MR analyses elucidated the role of SCFAs, particularly acetate, which plays a crucial role in modulating immune response. Adjusting for acetate revealed direct effects of Actinobacteria, Bifidobacteriales, and Bifidobacteriaceae on spontaneous urticaria, with corresponding mediation effects of − 22%, − 24.9%, and − 24.9% respectively. Similarly, adjustments for Alcaligenaceae and Betaproteobacteria indicated significant negative effects of acetate on dermatographic and spontaneous urticaria, with mediation effects of − 21.7% and − 23.7%, respectively.Conclusion: This study confirms the interconnected roles of gut microbiota, SCFAs, and urticaria. It highlights SCFAs’ potential mediating role in influencing urticaria through microbiota, providing insights for future therapeutic strategies.Keywords: urticaria, short-chain fatty acids, gut microbiota, gut-skin axis, Mendelian randomization

Yiqi Xiong,1,&ast; Wenying Qiao,2,3,&ast; Tingting Mei,1,&ast; Kang Li,4 Ronghua Jin,2,3 Yonghong Zhang1 1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Changping Laboratory, Beijing, 102206, People’s Republic of China; 4Research center for biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong Zhang, Interventional therapy center for oncology; Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, Tel +86-13810108505, Email zhangyh@ccmu.edu.cn Ronghua Jin, National center for infectious diseases, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, Tel +86-13811611118, Email ronghuajin@ccmu.edu.cnPurpose: The aim of our study was to investigate the relationship between albumin-bilirubin (ALBI) grade and recurrence in patients who underwent TACE sequential ablation. We developed and validated a nomogram to predict low levels of ALBI patients’ recurrence.Patients and Methods: A total of 880 patients undergoing TACE combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were retrospectively enrolled, including 415 patients with L-ALBI (≤-2.6) and 465 patients with high levels (>-2.6) of ALBI (H-ALBI). L-ALBI patients were randomized in a 7:3 ratio into the training cohort (N=289) and validation cohort (N=126). Multivariate Cox regression followed by random survival forest was carried out to identify independent risk factors for prediction nomogram construction. An examination of nomogram accuracy was performed using the C-index, receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) curves. According to the nomogram, the patients were divided into low-risk, intermediate-risk, and high-risk groups. Kaplan-Meier (KM) curves were applied to compare the difference in recurrence-free survival (RFS) among the three groups.Results: The median RFS in L-ALBI patients was significantly longer than the H-ALBI patients (40.8m vs 20.1m, HR:1.71, 95% CI:1.44– 2.04, P< 0.0001). The nomogram was composed of five variables, such as age, Barcelona Clinic Liver Cancer (BCLC) stage, globulin, gamma-glutamyl transferase to lymphocyte ratio (GLR), and international normalized ratio (INR). The C-index (0.722 and 0.731) and 1-, 3-, and 5-year AUCs (0.725, 0.803, 0.870, and 0.764, 0.816, 0.798) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves demonstrated good consistency and good clinical utility. There were significant differences in RFS between the low-risk, intermediate-risk, and high-risk groups (P< 0.0001).Conclusion: L-ALBI Patients who underwent TACE combined ablation had better recurrence-free survival than patients with H-ALBI. The nomogram developed and validated in our study had good predictive ability in recurrence for L-ALBI patients.Keywords: hepatocellular carcinoma, HCC, ablation, nomogram, recurrence, albumin-bilirubin, ALBI

Wenying Qiao,1– 3,&ast; Yiqi Xiong,1,&ast; Kang Li,4 Ronghua Jin,2,3 Yonghong Zhang1,5 1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Changping Laboratory, Beijing, 102206, People’s Republic of China; 4Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 5Beijing Research Center for Respiratory Infectious Diseases, Beijing, 100006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong Zhang, Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People’s Republic of China, Tel +86-13810108505, Email zhangyh@ccmu.edu.cn Ronghua Jin, National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, People’s Republic of China, Tel +86-13811611118, Email ronghuajin@ccmu.edu.cnPurpose: We explored the role of tumor size and number in the prognosis of HCC patients who underwent ablation and created a nomogram based on machine learning to predict the recurrence.Patients and Methods: A total of 990 HCC patients who underwent transcatheter arterial chemoembolization (TACE) combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were prospectively enrolled, including 478 patients with single small HCC (S-S), 209 patients with single large (≥ 30mm) HCC (S-L), 182 patients with multiple small HCC (M-S), and 121 patients with multiple large HCC (M-L). S-S patients were randomized in a 7:3 ratio into the training cohort (N=334) and the validation cohort (N=144). Lasso-Cox regression analysis was carried out to identify independent risk factors, which were used to construct a nomogram. The performance of the nomogram was evaluated by C-index, receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) curves. Patients in the training and validation cohorts were divided into low-risk, intermediate-risk, and high-risk groups based on the risk scores of the nomogram.Results: The median recurrence-free survival (mRFS) in S-S patients was significantly longer than the S-L, M-S, and S-L patients (P< 0.0001). The content of the nomogram includes age, monocyte-to-lymphocyte (MLR), gamma-glutamyl transferase-to-lymphocyte (GLR), International normalized ratio (INR), and Erythrocyte (RBC). The C-index (0.704 and 0.71) and 1-, 3-, and 5-year AUCs (0.726, 0.800, 0.780, and 0.752, 0.761, 0.760) of the training and validation cohorts proved the excellent predictive performance of the nomogram. Calibration curves the DCA curves showed that the nomogram had good consistency and clinical utility. There were apparent variances in RFS between the low-risk, intermediate-risk, and high-risk groups (P< 0.0001).Conclusion: S-S patients who underwent ablation had the best prognosis. The nomogram developed and validated in the study had good predictive ability for S-S patients.Keywords: hepatocellular carcinoma, HCC, transcatheter arterial chemoembolization, TACE, ablation, nomogram, recurrence

Xiaomeng Tang,1– 4,&ast; Qi Wang,2– 4,&ast; Ronghua Jin,2– 4 Caixia Hu1 1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China; 3National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Caixia Hu, Interventional therapy center for oncology; Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People’s Republic of China, Tel/Fax +86-13811395702, Email hucaixia1217@126.com Ronghua Jin, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People’s Republic of China, Tel/Fax +86-13811611118, Email ronghuajin@ccmu.edu.cnPurpose: Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Early diagnosis is crucial for improving prognosis. Elderly HCC patients often have underlying liver diseases such as chronic hepatitis and cirrhosis, leading to impaired liver function and suboptimal liver reserve. Radiofrequency ablation (RFA) has rapidly become one of the most important methods for treating early-stage hepatocellular carcinoma (EHCC) due to its advantages, including minimal trauma, short operation time, less intraoperative bleeding, quick postoperative recovery, cost-effectiveness, and few postoperative-complications. However, the prognostic model for early recurrence after local ablation in elderly EHCC patients has not been widely evaluated. We have developed a prognostic model for the recurrence of local RFA in elderly EHCC patients. This is expected to provide a new early warning system for preventing early recurrence in elderly EHCC patients, prolonging patient’s life, and improving overall quality of life.Methods: In this study, we included 661 EHCC patients who underwent local ablation, dividing them into a Primary cohort and a Validation cohort in a 7:3 ratio. We characterized the cohorts and utilized the primary cohort to develop a prognostic nomogram model for recurrence after local ablation in elderly EHCC patients. Additionally, the validation cohort was used to assess the potential of the nomogram as a non-invasive biomarker for post-ablation recurrence in EHCC.Results: The user-friendly nomogram incorporates common clinical variables including gender, BCLC stage, tumor number, tumor size, red blood cell (RBC), gamma-glutamyl transferase (GGT), and prothrombin time activity (PTA). The nomogram constructed using the identified seven variables exhibits robust discriminatory capabilities, favorable predictive performance, and noteworthy clinical utility.Conclusion: We developed a user-friendly nomogram based on the BCLC stage classification, which may provide prognostic assessments for elderly EHCC patients at 1, 3, and 5 years post-RFA.Keywords: hepatocellular carcinoma, elderly, radiofrequency ablation, EHCC, relapse, prognostic model

Wenying Qiao,1– 5,&ast; Shugui Sheng,1– 3,&ast; Junnan Li,1– 3,&ast; Ronghua Jin,1– 4 Caixia Hu5 1Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Changping Laboratory, Beijing, People’s Republic of China; 5Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ronghua Jin, Beijing Key Laboratory of Emerging Infectious Diseases, BeijingDitan Hospital, Capital Medical University, Beijing, People’s Republic of China, Email ronghuajin@ccmu.edu.cn Caixia Hu, Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China, Email hucaixia1217@126.comPurpose: The aim of the study is to identify and evaluate multifaceted factors impacting the survival of elderly cirrhotic HCC patients following ablation therapy, with the goal of constructing a nomogram to predict their 3-, 5-, and 8-year overall survival (OS).Patients and Methods: A retrospective analysis was conducted on 736 elderly cirrhotic HCC patients who underwent ablation therapy between 2014 and 2022. LASSO regression, random survival forest (RSF), and multivariate Cox analyses were employed to identify independent prognostic factors for OS, followed by the development and validation of a predictive nomogram. Harrell’s concordance index (C-index), calibration plot and decision curve analysis (DCA) were used to assess the performance of the nomogram. The nomogram was finally utilized to stratify patients into low-, intermediate-, and high-risk groups, aiming to assess its efficacy in precisely discerning individuals with diverse overall survival outcomes.Results: Alcohol drinking, tumor number, globulin (Glob) and prealbumin (Palb) were identified and integrated to establish a novel prognostic nomogram. The nomogram exhibited strong discriminative ability with C-indices of 0.723 (training cohort) and 0.693 (validation cohort), along with significant Area Under the Curve (AUC) values for 3-year, 5-year, and 8-year OS in both cohorts (0.758, 0.770, and 0.811 for training cohort; 0.744, 0.699 and 0.737 for validation cohort). Calibration plots substantiated its consistency, while DCA curves corroborated its clinical utility. The nomogram further demonstrated exceptional effectiveness in discerning distinct risk populations, highlighting its robust applicability for prognostic stratification.Conclusion: Our study successfully developed and validated a robust nomogram model based on four key clinical parameters for predicting 3-, 5- and 8-year OS among elderly cirrhotic HCC patients following ablation therapy. The nomogram exhibited a remarkable capability in identifying high-risk patients, furnishing clinicians with invaluable insights for postoperative surveillance and tailored therapeutic interventions.Keywords: hepatocellular carcinoma, HCC, nomogram, LASSO regression, random survival forest, RSF, overall survival, OS

Wenying Qiao,1– 3,&ast; Jiashuo Li,2,&ast; Qi Wang,2,&ast; Ronghua Jin,2,3 Honghai Zhang1 1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Di’tan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Changping Laboratory, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ronghua Jin, Beijing Di’tan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People’s Republic of China, Tel/Fax +86-13811611118, Email ronghuajin@ccmu.edu.cn Honghai Zhang, Interventional therapy center for oncology, Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People’s Republic of China, Tel/Fax +86-13260398697, Email haiyuer@yeah.netPurpose: Although alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) have a certain predictive ability for the prognosis of hepatocellular carcinoma (HCC), there are still some cases of aggressive recurrence among patients with AFP and DCP double-negative HCC (DNHC) after local ablation. However, prediction models to forecast the prognosis of DNHC patients are still lacking. Thus, this retrospective study aims to explore the prognostic factors in DNHC patients and develop a nomogram to predict recurrence.Patients and methods: 493 DNHC patients who underwent the local ablation at Beijing You’an Hospital between January 1, 2014, and December 31, 2022, were enrolled. A part that was admitted from January 1, 2014, to December 31, 2018, was designated to the training cohort (n = 307); others from January 1, 2019, to December 31, 2022, were allocated to the validation cohort (n = 186). Lasso regression and Cox regression were employed with the aim of screening risk factors and developing the nomogram. The nomogram outcome was assessed by discrimination, calibration, and decision curve analysis (DCA).Results: Independent prognostic factors selected by Lasso-Cox analysis included age, tumor size, tumor number, and gamma-glutamyl transferase. The area under the receiver operating characteristic (ROC) curves (AUCs) of the training and validation groups (0.738, 0.742, 0.836, and 0.758, 0.821) exhibited the excellent predicted outcome of the nomogram. Calibration plots and DCA plots suggest desirable calibration performance and clinical utility. Patients were stratified into three risk groups by means of the nomogram: low-risk, intermediate-risk, and high-risk, respectively. There exists an obvious distinction in recurrence-free survival (RFS) among three groups (p< 0.0001).Conclusion: In conclusion, we established and validated a nomogram for DNHC patients who received local ablation. The nomogram showed excellent predictive power for the recurrence of HCC and could contribute to guiding clinical decisions.Keywords: hepatocellular carcinoma, nomogram, prognosis, local ablation, alpha-fetoprotein, des-gamma-carboxyprothrombin

Wenying Qiao,1– 3,&ast; Zibo Fan,2,&ast; Qi Wang,2,&ast; Ronghua Jin,2,3 Caixia Hu1 1Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Changping Laboratory, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Caixia HuInterventional Therapy Center for Oncology; Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, People’s Republic of China, Tel/Fax +86-13811395702, Email hucaixia1217@126.comRonghua JinBeijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, People’s Republic of China, Tel/Fax +86-13811611118, Email ronghuajin@ccmu.edu.cnPurpose: We first aimed to compare the prognostic difference between the application of Contrast-enhanced computed tomography (CECT) and Non-enhanced computed tomography (NECT) in hepatocellular carcinoma(HCC) patients with early-stage immediately after ablation. We secondly propose to explore the risk factors for recurrence in patients undergoing CECT, and then develop a nomogram.Patients and Methods: Clinical data were collected from 711 patients who received TACE combined with ablation from January 1, 2015, to December 31, 2022, at Beijing Youan Hospital. According to the imaging methods applied after ablation, patients were categorized into the CECT group and the NECT group and then were compared by Kaplan-Meier (KM) curves. Lasso regression is used to screen risk factors for recurrence and the nomogram was plotted. Finally, discrimination, calibration plot, and decision curve analysis (DCA) were used to measure the performance of the nomogram.Results: The KM curve indicates that recurrence-free survival (RFS) was longer in the CECT group than in the NECT group (HR =0.759, 95% CI 0.606– 0.951, P=0.016). Six variables were selected to construct the nomogram. 1-, 3-, and 5-year area under the curves (AUCs) (0.867, 0.731, 0.773 and 0.896, 0.784, 0.773) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves suggested accuracy and net clinical benefit rates. The nomogram enabled to classify of patients into three groups according to the risk of recurrence: low risk, intermediate risk, and high risk. There was a statistically significant difference in RFS between the two groups in the training and validation cohorts (P< 0.001).Conclusion: We demonstrated that HCC patients who underwent CECT evaluation after ablation had a better prognosis, making this evaluation method highly recommended for guiding clinical management.Keywords: hepatocellular carcinoma, transcatheter arterial chemoembolization, contrast-enhanced computed tomography, recurrence-free survival, risk factors

Qiuling Tong,1,2 Yu Yao,3 Yanhuo Xia,4 Zhibo Chen,2 Gangze Ji,2 Liuzhu Chen,2 Rujun Jin,2 Wanli Dong1 1Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Neurology, Ningbo First Hospital, Ningbo, People’s Republic of China; 4Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Wanli Dong, Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Tel +8651265223637, Fax +8657755579318, Email wanlidong23@163.comObjective: To investigate the influence of patent foramen ovale (PFO) on the clinical features of migraine without aura (MoA).Methods: We consecutively enrolled 390 MoA patients and compared the frequency of headache, episode duration, and the Visual Analogue Scale (VAS), Headache Impact Test 6 (HIT-6), and European Health Interview Survey-Quality of Life 8-item index (EUROHIS-QOL8) scores of patients with and without PFO, those with the mild right-to-left shunt (RLS) and moderate to large RLS, and those with permanent RLS and latent RLS using a nonparametric Mann–Whitney U-test. In addition, we analyzed the clinical features of migraine in 39 MoA patients before and after PFO closure treatment using the paired Wilcoxon test.Results: The prevalence of PFO in the 390 MoA patients was 44.4%. Patients with PFO had significantly higher frequency of headaches, VAS scores, HIT-6 scores, and incidence of white matter lesions than those without PFO (all p< 0.05). Patients with moderate to large RLS had significantly higher VAS scores than those with mild RLS (p = 0.002). Additionally, 39 MoA patients underwent PFO closure, which remarkably decreased their frequency of headache, episode duration, VAS scores, and HIT-6 scores, and increased their EUROHIS-QOL8 scores.Conclusion: The migraine features in MoA patients could be influenced by PFO, especially in patients with moderate to large shunt, in whom PFO closure improved the symptoms.Keywords: migraine without aura, patent foramen ovale, clinical features, closure treatment

Qian Feng,1 Liang-Jie Tang,2 Ding-Hai Luo,3 Ying Wang,1 Nan Wu,1 Hao Chen,1 Meng-Xia Chen,1 Lei Jiang,4 Rong Jin1,5 1Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 2NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Taizhou, 317000, People’s Republic of China; 4Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 5Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaCorrespondence: Rong JinDepartment of Gastroenterology, Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaEmail jinrongjrjr@163.comLei JiangCentral Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaTel +86-577-55579127Fax +86-577-55578999Email jiangleistone79@163.comPurpose: Hyperuricemia and metabolic syndrome (MetS) have been shown to correlate with prognosis in patients with malignant tumors. The present study evaluated the relationship between preoperative hyperuricemia and MetS in colorectal cancer (CRC) patients and analyzed the effect of this combination on prognosis within 5 years.Patients and Methods: The study enrolled patients who had undergone radical CRC resection at three independent medical centers from January 2014 to December 2016. Patients were preoperatively categorized into four groups, those with hyperuricemia alone (H), those with MetS alone (MS), those with MetS-related hyperuricemia (MSH), and those with neither condition (control [C] group). The disease-free survival (DFS) and overall survival (OS) rates of these four groups were compared.Results: The study population consisted of 1271 patients, with 114, 201, 101, and 855 patients categorized into the H, MS, MSH and C groups, respectively. Preoperative MetS was found to be significantly associated with hyperuricemia (P < 0.001). Multivariate Cox regression analysis showed that MetS-related hyperuricemia (hazard ratio [HR] = 2.728; P < 0.001) and MetS alone (HR = 1.631; P < 0.001) were independent predictors of death, whereas simple hyperuricemia was not (P > 0.1). Relative to the C group, the MSH group had the highest rate of tumor recurrence or metastasis (HR = 5.103, P < 0.001), followed by the MS (HR = 2.231, P < 0.001) group. In contrast, prognosis did not differ significantly in the H and C groups (P > 0.1). MetS was significantly associated with poor prognosis, with MetS-related hyperuricemia resulting in a significantly poorer prognosis. In contrast, hyperuricemia alone had no effect on the long-term prognosis of CRC patients.Conclusion: This study highlights the prognostic importance of MetS-related hyperuricemia on the survival of patients with CRC.Keywords: colorectal cancer, metabolic syndrome, hyperuricemia, prognosis

Xiushuai Shang,1,2 Liaoran Zhang,2 Rilong Jin,1 Hu Yang,1 Hairong Tao2 1Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Hairong TaoShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People’s Republic of ChinaTel +86-13761221256Email doctorthr@163.comObjective: Pain is the main symptom of osteoarthritis (OA). Nerve growth factor (NGF) plays a crucial role in the generation of OA pain. And estrogen-alone used resulted in a sustained joint pain reduction in postmenopausal women. So we aim to find whether estrogen alters chondrocytes’ NGF level, affecting OA pain.Methods: Primary chondrocytes and cartilage explants isolated from Sprague Dawley rat knees were cultured with physiological concentrations of estrogen (17β-Estradiol ≥ 98%, E2), Estrogen Receptor α (ERα) inhibitor and stimulants. Then, chondrocytes NGF mRNA expression and protein release were analyzed by a quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) respectively. Additionally, cultures were pre-incubated with MEK-ERK inhibitor to identify the signaling pathway that estrogen alters NGF mRNA and protein levels.Results: We found that chondrocytes NGF expression and release were decreased by E2. E2 also reduced chondrocytes IL-1β-stimulated or TGF-β 1-stimulated NGF expression. Phosphorylated extracellular signal-regulated kinasep1/2 (p-ERK1/2) signals were detected stronger than the control group by Western Blotting (WB). When we cultured chondrocytes with PD98059 (MEK-ERK inhibitor, PD), NGF mRNA expression was added to 1.41Ct (2.07± 0.1 fold).Conclusion: We showed that E2 reduces chondrocytes NGF expression significantly, even after stimulation by TGF-β 1 or IL-1β. MEK-ERK signaling is involved in this process.Keywords: osteoarthritis, pain, estrogens, nerve growth factor

Yubo Wang,1,* Rui Han,1,* Qiushi Wang,2 Jie Zheng,1 Caiyu Lin,1 Conghua Lu,1 Li Li,1 Hengyi Chen,1 Rongbing Jin,3 Yong He1 1Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Department of Pathology, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China; 3Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong HeDepartment of Respiratory Medicine, Daping Hospital, Army Medical University, 10# Changjiangzhilu Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel +86-2368757791Fax +86-2368700970Email heyong@tmmu.edu.cnRongbing JinDepartment of Nuclear Medicine, Daping Hospital, Army Medical University, 10# Changjiangzhilu Daping, Yuzhong District, Chongqing, 400042, People’s Republic of ChinaTel +86-2368757641Email jinrb99@126.comPurpose: To investigate the potential of maximum standardized uptake value (SUVmax) in predicting epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) patients.Methods: Clinical data of 311 NSCLC patients who had undergone both EGFR mutation test and 18F-FDG PET/CT scans between January 2013 and December 2017 at our hospital were retrospectively analyzed. Patients were sub-grouped by their origin of SUVmax. Univariate and multivariate analyses were performed to investigate the association between clinical factors and EGFR mutations. Receiver operating characteristic curve (ROC) analysis was performed to confirm the predictive value of clinical factors. In vitro experiments were performed to confirm the correlation between EGFR mutations and glycolysis.Results: EGFR-mutant patients had higher SUVmax than the wild-type patients in both primary tumors and metastases. In the multivariate analysis, SUVmax, gender and histopathologic type were determined as independent predictors of EGFR mutation status for patients whose SUVmax were obtained from the primary tumors; while for patients whose SUVmax were obtained from the metastases, SUVmax, smoking status and histopathologic type were regarded as independent predictors. ROC analysis showed that SUVmax of the primary tumors (cut off > 10.92), not of the metastases, has better predictive value than other clinical factors in predicting EGFR mutation status. The predict performance was improved after combined SUVmax with other independent predictors. In addition, our in vitro experiments demonstrated that lung cancer cells with EGFR mutations have higher aerobic glycolysis level than wild-type cells.Conclusion: SUVmax of the primary tumors has the potential to serve as a biomarker to predict EGFR mutation status in NSCLC patients.Keywords: non-small cell lung cancer, epidermal growth factor receptor, SUVmax, receiver operating characteristic curve

Miaomiao Li,1,* Juntao Hu,2,* Riming Jin,3,* Hongxia Cheng,1 Huaping Chen,4 Limin Li,4 Kun Guo1 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China; 2Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of First Surgery, the Third Affiliated Hospital, NAVY Medical University, Shanghai, People’s Republic of China; 4Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun GuoLiver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Building 19, No. 180, Fenglin Road, Shanghai 20032, People’s Republic of ChinaTel +86-21-54237962Fax +86-21-54237959Email guo.kun@zs-hospital.sh.cnBackground: To date, aberrated lipid metabolism has been recognized as an important feature of hepatocellular carcinoma (HCC); however, it remains poorly defined. As a large member of the low-density lipoprotein receptor family, LRP1B plays a pivotal role in maintaining lipid homeostasis. Here we investigated the expression feature of LRP1B in HCC and elucidated its effects on lipid metabolism of HCC cells.Materials and Methods: LRP1B expression in HCC cells and tumor tissues was respectively examined by quantitative PCR, Western blotting and immunohistochemistry. Crispr-cas9 RNA inference and CRISPRa transcription activation system were used to downregulate and upregulate LRP1B expression, respectively. Oil red O staining, DiD staining combined with flow cytometry and transmission electron microscopy were used to evaluate the lipid content in HCC cells. Overall survival (OS) and time to recurrence (TTR) were calculated; meanwhile, Kaplan–Meier and the Cox proportional hazards model were used to assess the prognosis of HCC patients.Results: In contrast to inactivation expression in a majority of cancers, LRP1B showed predominantly strong expression in HCC. LRP1B knockdown induced the decrease of intracellular lipid content, downregulated expressions of lipid synthesis-related enzymes and upregulated expressions of β-oxidation-related enzymes as well as activated the AMPK signaling. Moreover, HSF1 directly regulated the transcription of LRP1B and was involved in LRP1B-mediated lipid metabolism in HCC; meanwhile, the combination of LRP1B knockdown and HSF1 inhibition suppressed synergistically the proliferation of HCC cells. In addition, simultaneous expression of HSF1 and LRP1B was an independent prognostic factor for HCC patients.Conclusion: Altogether, the study reveals a novel unique role of LRP1B in HCC by serving as a mediator in lipid metabolism, which provides an insight for making explorable therapeutic strategies for HCC.Keywords: hepatocellular carcinoma, lipid metabolism, LRP1B, HSF1, prognosis

Ning Sun,1,2 Chunxia Yang,1 Xiaoting He,1,3 Zhifen Liu,1 Sha Liu,1 Xinrong Li,1 Yanfang Wang,1 Ruihua Jin,2 Kerang Zhang1 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Nursing College of Shanxi Medical University, Taiyuan, People’s Republic of China; 3University-Town Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Ruihua Jin; Kerang Zhang Email jrh_xy@163.com; atomsxmu@vip.163.comBackground: Patients suffering from major depressive disorder (MDD) commonly demonstrate lower performance across multiple cognitive domains. Cognitive impairment is an intrinsic characteristic of MDD status and is often influenced by genetic factors. microRNAs (miRNAs or miRs) have been shown to have important implications in the etiology of MDD. Therefore, we aimed to identify and analyze the impact of expression and genetic variation of miR-34b/c on cognitive dysfunction in MDD.Methods: First, we analyzed miR-34c-5p expression in 48 cases of MDD and 54 healthy controls in a Chinese population using qRT-PCR. We assessed the relationship between the level of miR-34c-5p expression and cognitive performance by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test (TMT). Second, in order to characterize allelic effects of miR-34b/c on cognitive performance in MDD patients, we performed genetic association analysis of single-nucleotide polymorphism (SNP) loci of the MIR34B/C genes with cognitive function in a second group consisting of 531 MDD patients and 267 healthy controls.Results: We found a significant negative correlation between the level of miR-34c-5p expression and both the language and delayed memory index scores in patients with MDD. We also found a significant positive correlation between the level of miR-34c-5p expression and the time required to complete tests A and B of the TMT. The interaction between the rs2187473 genotype and the disease was significant for both immediate memory and delayed memory. In the patient group, the rs2187473 CC genotype was significantly associated with higher performance on immediate memory (F = 6.683, p < 0.05) and delayed memory tasks (F = 4.221, p < 0.05).Conclusion: Our findings suggest that changes in miR-34c expression level have important impacts on cognitive function in patients with MDD. In particular, the polymorphism rs2187473 is a potential genetic risk factor for cognitive function in MDD, which may be of clinical use.Keywords: major depressive disorder, MDD, microRNA-34c, single-nucleotide polymorphism, cognitive function

Lu Zhou,1 Yanqing Le,1 Jieyu Tian,2 Xia Yang,2 Rong Jin,3 Xiaoyan Gai,1 Yongchang Sun1 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China; 2Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China; 3Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China Background and purpose: Cigarette smoke (CS) induces alveolar destruction through overproduction of proteinases including matrix metalloproteinase (MMP)-9 by alveolar macrophages (AMs). Receptor activator of nuclear factor-κB ligand (RANKL) functions in immune regulation and cytokine secretion; whether it is involved in CS-induced MMP-9 expression is unknown. The purpose of our study was to investigate the expression and functional role of RANKL pathway in MMP-9 production pertaining to the pathogenesis of COPD. Materials and methods: We first localized RANKL and its receptor RANK in the lungs of mice exposed to long-term CS exposure. Next, we studied RANKL and RANK expression under CS extract (CSE) stimulation in vitro. Lastly, we studied the in vitro biological function of RANKL in CS-induced production of MMP-9. Results: Both RANKL and RANK were highly expressed in AMs in CS-exposed mice, but not in the control mice. In vitro, CSE increased the expressions of RANKL and RANK in macrophages. AMs responded to CSE and RANKL stimulation by overexpressing MMP-9, and CSE-induced MMP-9 expression was partly blocked by using monoclonal anti-RANKL antibody. Conclusion: RANKL/RANK pathway mediates CS-induced MMP-9 expression in AMs, suggesting a novel mechanism for CS-associated emphysema. Keywords: COPD, receptor activator of nuclear factor-κB ligand, RANK, alveolar macrophages, MMP-9

Rongbing Jin,1,* Jingjie Ge,2,* Ping Wu,2 Jiaying Lu,2 Huiwei Zhang,2 Jian Wang,3 Jianjun Wu,3 Xianhua Han,2 Weishan Zhang,2 Chuantao Zuo2,4 1Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing 400042, China; 2PET Center, Huashan Hospital, Fudan University, Shanghai 200235, China; 3Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; 4Institute of Functional and Molecular Medical Imaging, Fudan University, Shanghai 200433, China *These authors contributed equally to this work Purpose: We previously identified disease-related cerebral metabolic characteristics associated with Parkinson’s disease (PD) in the Chinese population using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging. The present study aims to assess data reproducibility and robustness of the metabolic activity characteristics across independent cohorts. Patients and methods: Forty-eight patients with PD and 48 healthy controls from Chongqing district, in addition to 33 patients with PD and 33 healthy controls from Shanghai district were recruited. Each subject underwent brain 18F-FDG PET/CT imaging in a resting state. Based on the brain images, differences between the groups and PD-related cerebral metabolic activities were graphically and quantitatively evaluated. Results: Both PD patient cohorts exhibited analogous cerebral patterns characterized by metabolic increase in the putamen, globus pallidus, thalamus, pons, sensorimotor cortex and cerebellum, along with metabolic decrease in parieto-occipital areas. Additionally, the metabolic pattern was highly indicative of the disease, with a significant elevation in PD patients compared with healthy controls (p

Encheng Bai,1,2,* Lehe Yang,1,* Youqun Xiang,2,* Wanle Hu,3 Caleb Li,4 Jiayuh Lin,5 Xuanxuan Dai,2 Guang Liang,1 Rong Jin,2 Chengguang Zhao1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Epidemiology, First Affiliated Hospital, 3Department of Coloproctology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Dublin Coffman High School, Dublin, OH, 5Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA *These authors contributed equally to this work Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values in the range between 0.86 and 2.83 µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer. Keywords: L61H46, STAT3, cancer therapy, interleukin-6, pancreatic cancer

Xiaoyan Wu,1 Lin Wang,1 Yining Qiu,1 Bingyu Zhang,1 Zhenhua Hu,2 Runming Jin1 1Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Pharmacy, Shanghai Jiao Tong University, Shanghai, China Abstract: T cell acute lymphoblastic leukemia (T-ALL) is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid) nanoparticles (IRAK/ABT-NP) to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC50 of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution. Keywords: T cell acute lymphoblastic leukemia, IRAK1/4 inhibitor, ABT-737, Box-Behnken design and response surface methodology, PEG-PLGA

QiHong Wu,1 RongRong Jin,2 Ting Feng,1 Li Liu,2 Li Yang,2 YuHong Tao,3 James M Anderson,4,5 Hua Ai,2,6 Hong Li1,3 1Key Laboratory of Obstetrics, Gynecology, Pediatric Disease, and Birth Defects, Ministry of Education, West China Second University Hospital, 2National Engineering Research Center for Biomaterials, 3Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China; 4Department of Biomedical Engineering, 5Department of Pathology, Case Western Reserve University, Cleveland, OH, US; 6Department of Radiology, West China Hospital, Sichuan University, Chengdu, China Abstract: Superparamagnetic iron oxide nanoparticles have been widely used in biomedical applications, but understanding of their interactions with the biological immune system is relatively limited. This work is focused on dextran-coated iron oxide nanoparticles and their induced autophagy in human monocytes. We found that these nanoparticles can be taken up by human monocytes, followed by localization within vesicles or free in cytoplasm. Autophagosome formation was observed with increased expression of LC3II protein, the specific marker of autophagy. The autophagy substrate p62 was degraded in a dose-dependent manner, and autophagy was blocked by autophagy (or lysosome) inhibitors alone or along with iron oxide nanoparticles, indicating that autophagosome accumulation was mainly due to autophagy induction, rather than blockade of autophagy flux. Interestingly, iron oxide nanoparticles increased the viability of human monocytes, but the mechanism was not clear. We further found that inhibition of autophagy mostly attenuated the survival of cells, with acceleration of the inflammation induced by these nanoparticles. Taken together, autophagic activation in human monocytes may play a protective role against the cytotoxicity of iron oxide nanoparticles. Keywords: autophagy, cytotoxicity, human monocytes, inflammation, iron oxide nanoparticles

Rong Jin,1,3,* Yiqun Xia,1,2,* Qiuxiang Chen,1,2 Wulan Li,2,4 Dahui Chen,2 Hui Ye,2,5 Chengguang Zhao,2 Xiaojing Du,1,2 Dengjian Shi,2 Jianzhang Wu,2 Guang Liang2 1Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 3Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, 4College of Information Science and Computer Engineering, Wenzhou Medical College, 5School of Basic Medical Sciences, Wenzhou Medical College, Wenzhou, People’s Republic of China *These authors contributed equally to this work Background: The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in a variety of human cancers, including gastric cancer. NF-κB inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-κB activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-κB inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-κB in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells. Methods: The expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-κB were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-κB activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay. Results: High levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-κB activation. In addition, Da0324 significantly inhibited tumor proliferation and invasion, arrested the cell cycle, and induced apoptosis in vitro. Conclusion: The asymmetric mono-carbonyl analog of curcumin Da0324 exhibited significantly improved antigastric cancer activity. Da0324 may be a promising NF-κB inhibitor for the selective targeting of cancer cells. However, further studies are needed in animals to validate these findings for the therapeutic use of Da0324. Keywords: gastric cancer, anticancer drug, NF-κB inhibitor, asymmetric MACs, apoptosis, curcumin

Bai E, Yang L, Xiang Y, et al. Cancer Manag Res. 2018;10:565–581. During the publication process there was an operator error that resulted in the Western blot images of Figures 5A and 5B on page 575 appearing spliced. Read the original article

Wu X, Wang L, Qiu Y, Zhang B, Hu Z, Jin R. Int J Nanomedicine. 2017;12:8025–8034.On page 8025, the first affiliation was listed as “Department of Pediatrics, Union Hospital, Tongji Medical College, University of Science and Technology, Wuhan” however it should have been “Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China”.Read the original article

Objective: To improve the water solubility and stability of apigenin and promote its antioxidant biological activity, apigenin liposomes (AP-L) were developed and subsequently surface-modified with chitosan (CS). Methods: The appropriateness of two methods, low-speed centrifugation and membrane filtration, for measuring encapsulation efficiency was evaluated. Encapsulation efficiency served as the evaluation criterion to compare the AP-L preparation methods employing the film dispersion-ultrasound and ethanol injection-ultrasound techniques. Additionally, the preparation process underwent optimization via both single-factor experiments and response surface tests. Chitosan was adsorbed onto the surface of liposomes through electrostatic adsorption to produce chitosan apigenin liposomes (CS-AP-L). The appearance, microstructure, particle size and distribution, potential, encapsulation efficiency and stability of the liposomes were observed before and after chitosan modification. The antioxidant capacity of apigenin dispersion (AP-D), AP-L and CS-AP-L was investigated by DPPH and ABTS+ free radical scavenging assays. Results: The low-speed centrifugation method was found to be more precise in determining the entrapment efficiency of liposomes, while the membrane dispersion-ultrasonic method demonstrated higher encapsulation efficiency. The optimal preparation process for AP-L included 6 mg of apigenin, an apigenin to phospholipid ratio of 1:24, a phospholipid to cholesterol ratio of 6:1, 6.3 mL of ethanol, 20 mL of phosphate buffer solution (PBS), hydration temperature 50 ℃ and ultrasonic time 20 min. The particle size of AP-L was 157.34±1.87 nm, the polydispersity index (PDI) was 0.240±0.025, and the encapsulation efficiency was 66.50%±1.00%. The particle size of CS-AP-L increased to 564.22±39.7 nm, the PDI was 0.292±0.022, and the encapsulation efficiency decreased to 60.17%±1.97%. After being stored at room temperature for 30 days, the leakage rate of AP-L was 21.92%±4.84%, compared to 10.64%±0.28% for CS-AP-L. This indicated that CS-AP-L demonstrated superior stability. Furthermore, the DPPH and ABTS+ free radical scavenging experiment demonstrated that both AP-L and CS-AP-L could enhance the free radical scavenging capacity of apigenin, with CS-AP-L showing even greater scavenging capability. Conclusion: The CS-AP-L prepared in this study exhibits appropriate particle size, uniform distribution, high encapsulation efficiency, good stability, and the capability to enhance the antioxidant activities of apigenin, thereby offering valuable insights for the development of apigenin derivative products.

With the continuous development of power demand side management （DSM） in China， enhancing the participation of key stakeholders， such as power grid enterprises and electricity users， has become an urgent issue to address. By constructing a dynamic evolutionary game model involving the government， power grid enterprises， and electricity users， the paper analyzes the interaction mechanisms， cost-benefit relationships， and the external effects among the three parties under different game strategies， as well as the stability of the system’s equilibrium points. Based on this analysis， the scientific rigor of the dynamic evolutionary game model is validated through simulation. The results indicate that when the government increases incentive while balancing its own costs and benefits， and when the positive external effects for grid enterprises or electricity users increase， the participation levels of all parties significantly rise. Consequently， the time required to achieve a steady-state equilibrium in power demand side management is also reduced.

C13H14N2O7U, monoclinic, P21/n (no. 14), a = 8.6855(14) Å, b = 11.982(2) Å, c = 14.953(2) Å, β = 94.557(5)°, V = 1,551.3(4) Å3, Z = 4, R gt(F) = 0.0559, wR ref (F 2) = 0.1081, T = 150(2) K

Primary biliary cholangitis (PBC) is an autoimmune liver disease. During the diagnostic process, the patient’s autoimmune antibodies are routinely examined. Approximately 20% of PBC patients have positive anti-centromere antibody (ACA). We evaluated the clinical characteristics of ACA-positive and ACA-negative PBC patients to explain the differences in disease progression between these two groups. Retrospective data from 961 PBC patients at Beijing Youan Hospital from 2010 to 2019 were gathered and separated into two groups based on ACA positivity. We collected and evaluated clinical laboratory indices, gastroscopy findings, and liver function assessments. In addition, 60 liver biopsies were available for comparison between the 2 groups. Pathologists staged the histological findings using the Ludwig staging criteria and Nakanuma staging and grading. Immunohistochemical staining was also performed on liver biopsies to examine the expression of cytokeratin 7 (CK7) in the tissue. A synthesis of clinical indicators in the large cohort showed that alanine transaminase, aspartate aminotransferase, total bilirubin, IgG, white blood cell, and platelet were significantly lower in the ACA-positive group, indicating that the overall status of liver injury was more moderate in the ACA-positive group. Additionally, ACA-positive patients in the non-cirrhotic group were more likely to present with gastroesophageal varices related to portal hypertension. Finally, analysis of pathologic findings showed that parameters were mostly comparable in the two groups, but CK7 differed and was more significantly lower in the ACA-positive group in albumin–bilirubin grade 2 and 3 patients. In summary, we characterized and compared the clinical features of ACA-positive and ACA-negative PBC patients, corroborating previous studies on the relationship between ACA positivity and portal hypertension cross-sectionally. It suggested that gastroesophageal varices might happen in the earlier course of PBC natural progression in the ACA-positive group.

Abstract This study investigates the impact of long-term water immersion on the mechanical and hydrochemical properties of cemented calcareous soil, emphasizing the critical role of carbonate content in mechanical performance. Utilizing hydrochemical analysis and triaxial testing, the research revealed that prolonged immersion disrupts the acid-base balance of the solution, resulting in an increased concentration of ions and chemicals. Significant dissolution of carbonates and soluble minerals occurs, which reacts with carbon dioxide to generate bicarbonate ions, thereby elevating the alkalinity of the soaking solution. Additionally, the gradual dissolution of clay minerals compromises the cementitious structure, leading to particle reorientation and interlocking. The study quantitatively assesses the changes in soil properties, demonstrating a substantial reduction in soil cohesion by up to 86.1% and an increase in the internal friction angle by 37.5%. Furthermore, the gradual dissolution of clay minerals compromises the cementitious structure, resulting in particle reorientation and interlocking that contribute to the observed mechanical changes. The findings underscore the importance of understanding the effects of extended immersion on the stability and engineering applicability of cemented calcareous soils.

Under hydrothermal conditions, two novel Zn(ii)/Cd(ii) complexes [Cd2(L)4(Cl)2]·(SO4) (1) and {[Zn2(L)2(Sip)(OH)]·H2O}n (2) (L = 2-(2,6-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline, NaH2Sip = 5-sulfoisophthalic acid monosodium salt) were successfully synthesized and characterized by elemental analysis, single-crystal X-ray diffraction, and Hirshfeld surface analysis. The study reveals that complex 1 is constructed from the binuclear [Cd2L4Cl2] unit, and the [Cd2L4Cl2] units are linked via C–H⋯π and C–Cl⋯π interactions into 2D supramolecular layers. These 2D layers are further connected to generate 3D structures by N–H⋯O and N–H⋯S hydrogen bonds. Complex 2 exhibits a 1D double-chain structure consisting of a binuclear [Zn2L2(OH)] unit, which is further connected by π–π interaction to shape a 2D supramolecular structure.

Background and purposeThe incidence of autonomic dysfunction is frequently underestimated and often overlooked in patients with autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A). This study comprehensively analyzes the clinical manifestations, laboratory and imaging findings, and treatment modalities for patients demonstrating GFAP-A involvement in the autonomic nervous system. The present article primarily elucidates the prevalence and prognosis of diverse autonomic system symptoms while examining the associated laboratory and imaging indicators. These findings aim to establish a foundation for personalized diagnosis and treatment strategies in such patients.MethodWe performed a retrospective data analysis from three cases of GFAP-A involvement in autonomic nerves from the Ninth People’s Hospital of Suzhou and the Second Affiliated Hospital of Soochow University from 2020 to 2023. After an extensive literature review, we identified 39 cases involving GFAP-A and autonomic nervous system dysfunction. We also comprehensively analyzed the patient’s clinical manifestations, laboratory biomarkers, and imaging findings.ResultThe study included a total of 42 patients, consisting of 15 females and 27 males. The primary manifestations of autonomic dysfunction included bladder dysfunction (41/42 cases), gastrointestinal dysfunction (18 /42 cases), heart rate variability (4/42 cases), unusual sweating (2/42 cases), and blood pressure fluctuations (1/42 cases). Other neurological symptoms comprised headache (12 /42 cases), limb weakness presentation (30/42 cases). Blood pressure variability is related to cerebrospinal fluid pressure and convulsive seizures. Heart rate variability is related to disorders of consciousness. unusual sweating was associated to age, gender, cerebrospinal fluid protein content and convulsive seizures. Gastrointestinal disorders have associations with gender, sleep disturbances, protein content in the cerebrospinal fluid, and brain MRI lesions. The prognosis of autonomic nerve dysfunction is associated to sleep disorder and cerebrospinal fluid protein content. The higher the cerebrospinal fluid protein level, the worse the prognosis of autonomic nervous system.ConclusionBladder dysfunction and gastrointestinal dysfunction are the primary manifestations of autonomic dysfunction in GFAP-A patients, with a subset also experiencing abnormalities in heart rate, blood pressure, and sweating. These additional symptoms have implications for prognosis, necessitating heightened attention from clinicians toward GFAP-A patients.

[This corrects the article DOI: 10.1371/journal.pone.0288788.].

Background Burnout negatively impacts healthcare professionals’ well-being, leading to an increased risk of human errors and patient harm. There are limited assessments of burnout and associated stressors among acute care and trauma surgery teams.Methods Acute care and trauma surgery team members at a US academic medical center were administered a survey that included a 2-item Maslach Burnout Inventory and 21 workplace stressors based on the National Academy of Medicine’s systems model of clinician burnout and professional well-being. Stressors were summarized and presented to participants in focus groups. Contextual inquiries (CIs) were conducted to gather additional information about key stressors. Qualitative data were used to generate an affinity model, which participants then validated and used to prioritize top stressors. Participants rated stressors by level of impact and level of effort, and improvement recommendations were made based on these results.Results 74% (n=14/19) acute care and trauma surgery team members reported high burnout. Key stressors included inadequate staffing, organizational culture, excessive workload, and inefficient workflows. Attending faculty (surgeons) classified the following key priorities for improvement: (i) improve throughput and patient flow, (ii) provide better information technology support, and (iii) improve rewards and support. Non-faculty (advanced practice providers (APPs), nurses, staff) classified the following for improvement: (i) align APP job responsibilities, (ii) improve lack of recognition from leadership, and (iii) robust and consistent APP training.Conclusions A contextual design approach to studying burnout using surveys, focus groups, CIs, modeling, and validation and prioritization is a feasible method for identifying key stressors and improvements that may enable more impactful and appropriately targeted interventions. Results indicate high levels of burnout among acute care and trauma surgery team members, requiring prioritized attention to operational and relationship issues necessary to care for patients. Efforts to improve surgery teams’ workflows, auxiliary support, compensation, and relationships with leadership may address burnout.Level of evidence Level V.

Chyloperitoneum (CP) is a rare complication after bariatric surgery. We present a 37-year-old female with CP caused by a bowel volvulus following a gastric clipping with proximal jejunal bypass for morbid obesity. An abdominal CT image of a mesenteric swirl sign and abnormal triglyceride level of ascites fluid can confirm the diagnosis. In this patient, laparoscopy demonstrated dilated lymphatic ducts caused by a bowel volvulus resulting in the exudation of chylous fluid into the peritoneal cavity. After the reduction of bowel volvulus, she made an uneventful recovery with complete resolution of the chylous ascites. The presence of CP could indicate a situation of small bowel obstruction in patients with a history of bariatric surgery.

Ectopic transplantation of the hand remains a rare, innovative yet valuable operation in select cases of trauma and amputation. We aim to describe a novel technique of complex hand reconstruction using a two‐stage ectopic implantation of the contralateral upper limb. A male patient with a near complete avulsion amputation of the right upper limb at the level of the mid‐forearm and a crushing injury to his left hand was admitted after a farming accident. The right palm was ectopically transplanted to the left lower limb and both upper limbs underwent debridement with vacuum assisted dressings (VACs). There was eventual dieback of the left thumb, ring and little finger with a large palmar soft tissue defect that was eventually reconstructed using segments of the ectopically transplanted limb in two separate operations. The patient made an uneventful postoperative recovery and managed to regain protective sensation and gross motor function of his reconstructed hand.

Introduction and Objectives: In the modern context, where fertility is crucial for couples, male factors contribute 40–50% to subfertility. Testicular cancer survivors facing subfertility due to treatments like orchidectomy and chemotherapy can benefit from sperm banking. However, awareness is lacking, especially in culturally sensitive Asian populations where sex and fertility discussions are taboo. This study aims to assess attitudes and utilization of sperm banking, evaluate its impact on pregnancy outcomes, and identify implementation obstacles. Materials and Methods: A phone interview survey targeted testicular cancer patients treated at Hospital Sultanah Aminah Johor Bahru and Sarawak General Hospital in Malaysia (2019–2023). Of the 102 identified patients, 62 participated. Investigators, using contact details from medical records, conducted interviews with a blend of quantitative and qualitative inquiries. Bivariate analysis identified factors linked to the decision to pursue sperm banking. Results: Out of 62 participants, 58.1% were aware of sperm banking, yet 90.3% chose not to utilize it. Reasons for declining included physician non-offer (41.1%), cost concerns (21.4%), a desire for prompt treatment (16.1%), lack of interest (14.3%), and other factors (7.1%). Among six patients opting for sperm banking, 50% utilized banked sperm, resulting in successful progeny for two-thirds. Notably, one case led to multiple pregnancies. Ethnicity (p = 0.046) and religion (p = 0.026) significantly influenced decisions, with Muslim Malays being the least likely to utilize sperm banking. Conclusion: Sperm banking emerges as a cost-effective strategy for safeguarding fertility in testicular cancer patients. Healthcare providers should proactively offer this option before treatment, ensuring patients are well-informed and addressing concerns to foster informed decisions.

Abstract Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Abstract Under the condition that the working face was directly covered with hard roof, the abrupt breaking of hard roof release significant amount of energy, thus prone to triggering dynamic disasters such as roadway instability or rockburst. This paper based on the engineering background of the Xieqiao Coal Mine's 11,618 working face, a numerical simulation method was put forward to study the dynamic response of roadway under the disturbance of hard roof breaking and proposed an evaluation index I C for roadway stability. Research indicates that the elastic energy released during the periodic weighting of the hard roof is higher than that released during the first weighting. Under the dynamic disturbance caused by hard roof breaking, the peak stresses of the roadway was slight decreased, accompanied by a significant increase in the range of stress concentration and plastic zone expansion. Roadway deformation patterns are significantly influenced by hard roof breaking, with noticeable increases in deformation on the roof and right side. During the period of hard roof breaking, the possibility of instability of the roadway increase significantly due to the disturbance caused by the dynamic load. The research results reveal the instability mechanism of roadway under the condition of hard roof, and provide a more reliable basis for evaluating the stability of roadway.

【Objective】 The Grand Canal is a complex hydraulic project in the eastern China. This paper studies the flooding and its detrimental impacts in the lowland areas of the canal. 【Method】 The research was conducted in the Pichang-Tanxin Plain, using multi-source remote sensing data and ground surveys to analyze flooding events. We calculated the normalized difference water body index (NDWI) and the normalized difference vegetation index (NDVI) before and after flooding to assess flood severity, impact on crop growth, as well as the efficacy of hydraulic facilities in mitigating flooding effects. 【Result】 The NDVI difference between 2004 and 2005 for crops in flooded and non-flooded areas was 0.5 and 0.25, respectively, indicating floodings detrimentally affected crop growth and development. NDWI analysis from 2003 to 2017 demonstrated that the Taierzhuang Control Gate project mitigated flooding impacts on nearby farmlands. Flooding also affected crops in non-inundated regions, with lowland crops more adversely impacted than those outside lowlands. The hydraulic facilities significantly reduced economic losses caused by flooding. 【Conclusion】 Remote sensing is an effective tool for monitoring inundated areas and assessing the consequences of flooding on crops. The construction of hydraulic facilities plays a crucial role in reducing the detrimental effects of flooding in lowland regions of the Grand Canal.

Currently, beach nourishment projects are undergoing rapid development. Nourished beaches are distributed from northern temperate zone to southern tropical zone along China’s sandy coastline. Nourished beaches can strengthen the coastal protection, provide entertainment areas and restore the ecological habitats. The macrobenthic fauna and recovery level play an important role in assessing nourishment benefits. The paper introduces the state and gap of nourished beaches monitoring and assessment, and the methodology and results of international research. Furthermore, the paper presents the hypothesis and research area of the effects of nourished beaches on the macrobenthic fauna for Chinese researchers. The paper aims to provide theoretical guidance and technical support for scientific sand nourishment and beach protection, and promote the development of the interdisciplinary fields of marine geology and marine biology.

Chemical optimization of ribose has significantly advanced nucleic acid therapeutics (NATs) by improving the stability, specificity, and safety of therapies like small interfering RNAs, CRISPR-Cas9 guide RNAs, and GAPmers. Recent research has extended this approach to splice-switching oligonucleotides (SSOs), which target splicing events. Our study identifies a set of mixed-modification patterns—combining 2′-O-Methyl, 2′-MethOxyEthyl, 2′-Locked Nucleic Acid, and 2′-Constrained Ethyl ribose moieties (2′OMe, 2′MOE, LNA, and cET)—that enhance SSO potency. We term this strategy lateral mixed positional configuration, which improves SSO efficacy across various sequences and could reduce the trial-and-error process in SSO development. This advancement is supported by NAT Unlabeled Reporter Assay (NATURA), a novel platform for high-throughput quantification of NATs' functional delivery and potency. NATURA uses a reporter gene system and a comprehensive sequence library to test modifications and delivery methods, validated in a transgenic mouse model. This approach aims to accelerate NAT development and address challenges in delivering these therapies to patients.

Abstract EGFR mutations are a major prognostic factor in lung adenocarcinoma. However, current detection methods require sufficient samples and are costly. Deep learning is promising for mutation prediction in histopathological image analysis but has limitations in that it does not sufficiently reflect tumor heterogeneity and lacks interpretability. In this study, we developed a deep learning model to predict the presence of EGFR mutations by analyzing histopathological patterns in whole slide images (WSIs). We also introduced the EGFR mutation prevalence (EMP) score, which quantifies EGFR prevalence in WSIs based on patch‐level predictions, and evaluated its interpretability and utility. Our model estimates the probability of EGFR prevalence in each patch by partitioning the WSI based on multiple‐instance learning and predicts the presence of EGFR mutations at the slide level. We utilized a patch‐masking scheduler training strategy to enable the model to learn various histopathological patterns of EGFR. This study included 868 WSI samples from lung adenocarcinoma patients collected from three medical institutions: Hallym University Medical Center, Inha University Hospital, and Chungnam National University Hospital. For the test dataset, 197 WSIs were collected from Ajou University Medical Center to evaluate the presence of EGFR mutations. Our model demonstrated prediction performance with an area under the receiver operating characteristic curve of 0.7680 (0.7607–0.7720) and an area under the precision‐recall curve of 0.8391 (0.8326–0.8430). The EMP score showed Spearman correlation coefficients of 0.4705 (p = 0.0087) for p.L858R and 0.5918 (p = 0.0037) for exon 19 deletions in 64 samples subjected to next‐generation sequencing analysis. Additionally, high EMP scores were associated with papillary and acinar patterns (p = 0.0038 and p = 0.0255, respectively), whereas low EMP scores were associated with solid patterns (p = 0.0001). These results validate the reliability of our model and suggest that it can provide crucial information for rapid screening and treatment plans.

ObjectiveTo assess the feasibility and safety of conducting robot-mediated impairment training (RMIT) and robot-mediated task-specific training (RMTT). The device deployed is the Optimo Regen (OR®), capable of delivering both impairment-oriented training and task-specific training.MethodsThis was a single-centre, randomized, single-blinded, two-arm, parallel group, controlled trial. Patients fulfilling criteria were randomized into either the RMIT or RMIT + RMTT group and provided with 20 h of robotic therapy on top of standard care.ResultsA total of 4 patients were recruited, with 2 patients receiving treatment in each arm. The study was feasible, with a 66.7% enrolment rate, 75% completion rate, and 100% attendance for each intervention session. We achieved a 90% satisfaction rate with no serious adverse effects. All patients had improvement of motor power, Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Functional Independence Measure (FIM), Hospital Anxiety and Depression Scale (HADS), and quality of life scores at 1 month. FIM continued to improve at 3 months post-commencement of intervention. There was relative ease of use of the device.ConclusionThis trial is feasible. A full-scale study is warranted, to compare RMIT against RMTT, which is a novel application.

Reservoir computing (RC) possesses a simple architecture and high energy efficiency for time‐series data analysis through machine learning algorithms. To date, RC has evolved into several innovative variants. The next generation reservoir computing (NGRC) variant, founded on nonlinear vector autoregression (NVAR) distinguishes itself due to its fewer hyperparameters and independence from physical random connection matrices, while yielding comparable results. However, NGRC networks struggle with massive Kronecker product calculations and matrix‐vector multiplications within the read out layer, leading to substantial efficiency challenges for traditional von Neumann architectures. In this work, a hybrid digital‐analog hardware system tailored for NGRC is developed. The digital part is a Kronecker product calculation unit with data filtering, which realizes transformation of nonlinear vector of the input linear vector. For matrix‐vector multiplication, a computing‐in‐memory architecture based on resistive random access memory array offers an energy‐efficient hardware solution, which markedly reduces data transfer and greatly improve computational parallelism and energy efficiency. The predictive capabilities of this hybrid NGRC system are validated through the Lorenz63 model, achieving a normalized root mean square error (NRMSE) of 0.00098 and an energy efficiency of 19.42TOPS W−1.

ObjectiveTo explore the value of dual-accelerated simultaneous multi-slice (SMS) imaging in diffusion tensor imaging (DTI) of glioma.MethodsThirty-four patients with glioma who underwent magnetic resonance imaging (MRI) in our hospital from January 2022 to March 2023 were randomly selected. The results of dual-accelerated SMS-DTI and conventional DTI were retrospectively analyzed. All patients were scanned using a uMR790 3.0T MRI scanner, and the scanning technicians followed a predefined sequence to ensure consistency in scan parameters. The images were subjectively evaluated using a Likert 5-point scoring system. Objective evaluation was performed by measuring the required values of the images with b-value = 1000 s/mm2, primarily measuring the signal intensity in the tumor region and the contralateral normal brain white matter region. The standard deviation values were used to calculate the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the same encoding direction as the background noise. The number of generated fiber pathways, fractional anisotropy (FA), and mean diffusivity (MD) were measured and analyzed using post-processing software. The relative FA (rFA) and relative MD (rMD) were calculated.ResultsThe results of conventional DTI and SMS-accelerated DTI were compared. In terms of subjective evaluation, including overall image quality, tumor edge clarity, and magnetic sensitivity artifacts, both techniques showed no significant differences, indicating comparable diagnostic performance in anatomical visualization. In terms of objective evaluation and quantitative parameter measurement, there were statistically significant differences in SNR and CNR values, with slightly lower values in the dual-accelerated SMS-DTI compared with conventional DTI, a significant reduction in scanning time can be achieved through a slight loss in image quality. The number of fiber pathways and the rFA and rMD values did not show typical differences between the two techniques. The correlation between these measures was highly similar, with no significant differences observed.ConclusionThe application of dual-accelerated simultaneous multi-slice imaging in DTI of glioma is feasible.

Invasive weed species exhibit both advantages, such as the potential for allelochemicals in bioherbicide development, and risks, including their threat to crop production. Therefore, this study aims to identify an allelochemical from Solidago altissima, an invasive weed species. The dose-dependent effects of S. altissima shoot and root extracts (SSE, SRE) on the signaling in the forage crop Trifolium repens and germination in various weed species (Echinochloa oryzicola, Cyperus microiria, Alopecurus aequalis, Portulaca oleracea, and Amaranthus retroflexus) were evaluated. The results showed that the T. repens seedlings treated with root extracts exhibited a significant decrease in plant height, dry weight, and chlorophyll content, along with an increase in H2O2 levels. Additionally, antioxidant activities, such as superoxide dismutase, catalase, and peroxidase enzyme activities, were significantly elevated in T. repens treated with SRE. Moreover, SRE treatment significantly inhibited the seed germination of all tested weed species in a concentration-dependent manner. Gas chromatography-mass spectrometry analysis of S. altissima root extract identified a high concentration of methyl kolavenate, a clerodane diterpene predicted to act as a phytotoxic agent. These findings highlight the potential of S. altissima for the development of crop-protective agents while emphasizing its potential risks in agriculture.

Abstract Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.

Abstract This study focused on a novel strategy that combines deep learning and radiomics to predict epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer (NSCLC) using computed tomography (CT). A total of 1280 patients with NSCLC who underwent contrast-enhanced CT scans and EGFR mutation testing before treatment were selected for the final study. Regions of interest were segmented from the CT images to extract radiomics features and obtain tumor images. These tumor images were input into a convolutional neural network model to extract 512 image features, which were combined with radiographic features and clinical data to predict the EGFR mutation. The generalization performance of the model was evaluated using external institutional data. The internal and external datasets contained 324 and 130 EGFR mutants, respectively. Sex, height, weight, smoking history, and clinical stage were significantly different between the EGFR-mutant patient groups. The EGFR mutations were predicted by combining the radiomics and clinical features, and an external validation dataset yielded an area under the curve (AUC) value of 0.7038. The model utilized 1280 tumor images, radiomics features, and clinical characteristics as input data and exhibited an AUC of approximately 0.81 and 0.78 during the primary cohort and external validation, respectively. These results indicate the feasibility of integrating radiomics analysis with deep learning for predicting EGFR mutations. CT-image-based genetic testing is a simple EGFR mutation prediction method, which can improve the prognosis of NSCLC patients and help establish personalized treatment strategies.