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Yueyuan Wang,* Bo Lv,* Kai Fan, Cunjin Su, Delai Xu, Jie Pan Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Pan; Delai Xu, Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China, Email panzy1122@163.com; xdlsuzhou@163.comPurpose: Parkinson’s disease (PD) is a common neurodegenerative disease that severely affects patients’ daily lives and places a significant burden on the global economy. There are currently no specific biomarkers for distinguishing between the different stages of PD.Methods: We divided 78 mice into six equal groups, including five model PD groups (W1–W5; based on the PD stage induced by length of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/propofol induction time) and a control group. Then, we used metabolomics technology to detect the serum small-molecule metabolites present in each group. Ultimately, we screened for potential biomarkers using the variable importance in the projection of the orthogonal partial least squares discriminant analysis and the coefficient value of LASSO ordinal logistic regression.Results: We identified 12 potential biomarkers, including dehydroepiandrosterone sulfate, pipecolic acid, N-acetylleucine, 2-aminoadipic acid, L-tyrosine, uric acid, and 5-hydroxyindoleacetaldehyde. Pathway analysis revealed their involvement in amino acid metabolism, caffeine metabolism, steroid hormone biosynthesis, and purine metabolism. Additionally, the receiver operating characteristic curve indicated that a biomarker panel comprising the 12 biomarkers could differentiate between the different PD stages.Conclusion: Different PD stages are characterized by different metabolites. The biomarkers identified in this study are helpful to understand the PD process.Keywords: Parkinson’s disease, metabolomics, biomarkers, metabolic disturbances, LC–MS

Tongfei Feng,1– 3,* Yanlin Zhou,1,3,* Bin Lv,1,3 Lijun Cai1,3 1Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310003, People’s Republic of China; 2The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 3Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, 310006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lijun Cai; Bin Lv, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel +86-571-86613545, Fax +86-571-87073763, Email 20051018@zcmu.edu.cn; lvbin@medmail.com.cnPurpose: Through network pharmacology combined with molecular docking and in vivo validation, the study examines the unexplored molecular mechanisms of Tongxieyaofang (TXYF) in the treatment of irritable bowel syndrome (IBS). In particular, the potential pharmacological mechanism of TXYF alleviating IBS by regulating CHRM3 and intestinal barrier has not been studied.Patients and Methods: LC-MS technique and TCMSP database were used in combination to identify the potential effective components and target sites of TXYF. Potential targets for IBS were obtained from Genecards and OMIM databases. PPI and cytoHub analysis for targets. Molecular docking was used to validate the binding energy of effective components with related targets and for visualization. GO and KEGG analysis were employed to identify target functions and signaling pathways. In the in vivo validation, wrap restraint stress-induced IBS model was employed to verify the change for cytoHub genes and CHRM3 expression. Furthermore, inflammatory changes of colon were observed by HE staining. The changes of Ach were verified by ELISA. IHC and WB validated CHRM3 and GNAQ/PLC/MLCK channel variations. AB-PAS test and WB test confirmed the protection of TXYF on gut barrier. The NF-κB/MLCK pathway was also verified.Results: In TXYF decoction, LC-MS identified 559 chemical components, with 23 remaining effective components after screening in TCMSP. KEGG analysis indicated that calcium plays a crucial role in TXYF treated for IBS. Molecular docking validated the binding capacity of the effective components Naringenin and Nobiletin with cytoHub-gene and CHRM3. In vivo validation demonstrated that TXYF inhibits the activation of Ach and CHRM3 in IBS, and inhibits for the GNAQ/PLC/MLCK axis. Additionally, TXYF downregulates TNF-α, MMP9, and NF-κB/MLCK, while modulating goblet cell secretion to protect gut barrier.Conclusion: TXYF inhibits Ach and CHRM3 expression, regulating the relaxation of intestinal smooth muscle via GNAQ/PLC/MLCK. Additionally, TXYF inhibits NF-κB/MLCK activated and goblet cell secretion to protect gut barrier. Keywords: irritable bowel syndrome, tongxieyaofang decoction, Ach, CHRM3, GNAQ/PCL/MLCK, gut barrier

Jia-Ying Pan,1,* Yuan Chen,1,* Zhi-He Lin,1 Bo Lv,1 Lei Chen,2 Shao-Yan Feng1 1Department of Otorhinolaryngology, Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shao-Yan Feng, Department of Otorhinolaryngology, Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No. 52, Meihua East Road, Xiangzhou District, Zhuhai, 519000, People’s Republic of China, Tel +86-13626927889, Email fshaoy@mail.sysu.edu.cn Lei Chen, Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China, Tel +86-13902878497, Email clzzzz@126.com; chenlei63@mail.sysu.edu.cnObjective: Sensorineural Hearing Loss (SNHL) is a representative human sensory impairment, few studies have paid attention to the correlation between the Triglyceride-Glucose (TyG) index and SNHL to date. We conducted this analysis to elucidate the correlation between the TyG index and pure tone hearing thresholds among US adults.Methods: Our analysis included 1226 adults (age range: 20 to 69 years old) from the 2015– 2016 National Health and Nutrition Examination Survey (NHANES) data. TyG index was scored into three quartiles. Weighted univariate analysis, weighted multivariate linear regression analyses as well as smooth curve fittings evaluated the associations between TyG index and pure tone hearing thresholds.Results: In the multiple regression analysis, the second tertile of TyG index was negatively associated with high-frequency hearing thresholds shifts. Furthermore, the non-linear relationships between TyG index and speech-frequency and high-frequency hearing thresholds were identified by smooth curve fittings. After adjusting for potential confounders, the fitted smooth curves were approximately U-shaped, and the two-segment linear regression models were constructed to calculate their inflection points.Conclusion: Our findings suggested that the TyG index was nearly U-shaped association with speech-frequency and high-frequency hearing thresholds. These results may imply the importance of maintaining a balanced TyG index in health management.Keywords: Sensorineural Hearing Loss, triglyceride glucose index, cross-sectional study, National Health and Nutrition Examination Survey

Zheng Xiang,&ast; Yueyuan Wang,&ast; Yuchen Qu, Bo Lv, Junping Han, Delai Xu, Kai Fan, Cunjin Su, Zhu Shen Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cunjin Su; Zhu Shen, Email sucjgh@vip.163.com; jsdxsz@163.comObjective: To assess the key factors influencing the effectiveness of nirmatrelvir/ritonavir in treating elderly patients with COVID-19.Methods: This study was conducted on patients aged ≥ 60 who were admitted to the Second Affiliated Hospital of Soochow University for COVID-19 infection and were treated with nirmatrelvir/ritonavir. Clinical information was collected from patients and steady-state blood concentrations of nirmatrelvir and ritonavir were measured. Factors associated with treatment effects were searched by univariate and multivariate analysis.Results: A total of 68 (51 males and 17 females) patients had a median age of 80 (73.0– 84.8) years were enrolled in this study. The blood concentration measurements (trough concentrations) of nirmatrelvir and ritonavir were 5.1 (2.6– 7.1) and 0.4 (0.2– 0.9) μg/mL, respectively. Adverse drug reaction was reported in 4 (5.9%) patients. Univariate analysis showed that age, clinical classification, APACHE II score, total bilirubin (TBil), aspartate transaminase (AST), lactate dehydrogenase (LDH), and total cholesterol (TC) were significantly associated with the effectiveness of treatment (P value < 0.05). Concentration of nirmatrelvir was also associated with treatment outcome (P value < 0.1). Based on the results of univariate analysis, the above factors were introduced into the multiple linear regression equation as independent variables, and the results showed that clinical classification was included in the regression equation model and was the most important factor affecting the treatment outcome. By receiver operating characteristic curve analysis, the area under curve of age + biochemical indicators + APACHE II score + clinical classification was 0.968 (95% CI = 0.919– 1.000; P < 0.0001). Among the 68 patients included in the study, 4 cases experienced adverse drug reactions.Conclusion: Age, clinical classification, APACHE II score, TBil, AST, LDH, and TC were significantly associated with the effectiveness of treatment in elderly patients with COVID-19.Keywords: nirmatrelvir/ritonavir, COVID-19, elderly patients, effectiveness

Hanbing Song,&ast; Hongpeng Liu,&ast; XiaoDong Li, Bing Lv, Zonghan Tang, Qipeng Chen, Danqi Zhang, Fei Wang Department of Orthopedics, Heilongjiang University of Traditional Chinese Medicine, Harbin, 150000, Heilongjiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Danqi Zhang; Fei Wang, Surgery Building, Department of Orthopedics, Heilongjiang University of Traditional Chinese Medicine, No. 26 Heping Road, Xiangfang District, Harbin, Heilongjiang Province, People’s Republic of China, Email hljzymzdq@163.com; wangfei631@126.comBackground: This study aims to identify new therapeutic targets and explore the molecular mechanism of ankylosing spondylitis (AS), a rheumatic immune disease that mainly affects the sacroiliac and spinal joints. Despite extensive research, the exact cause of AS is still unknown. The research team utilized a bioinformatics approach to achieve their objectives.Methods: The GSE73754 dataset was downloaded from GEO database. Autophagy-related genes (ARGs) were collected from the Human Autophagy-dedicated Database. The limma package was used to screen for differentially expressed genes (DEGs), which were then intersected with the autophagy-related genes (ARGs) to identify differentially expressed autophagy-related genes (DEARGs). Subsequently, the DEARGs associated with AS were subjected to GO-BP and KEGG enrichment analyses using the clusterProfiler package. Core genes were identified using the cytoHubba plug-in of Cytoscape and were validated by clinical blood samples. Additionally, the Cell algorithm was utilized to evaluate the proportion of immune cell infiltration.Results: A total of 29 DEARGs were identified, which were found to be mainly enriched in autophagy, apoptosis, and necroptosis through functional enrichment analysis. Two core genes, HSPA5 and SQSTM1, were confirmed to have diagnostic value in AS. Immune cell infiltration analysis revealed CD8+ T cells, CD8+ T effector memory (Tem), natural killer (NK) cells, T gamma delta (Tgd) cells, and T-helper 1 (Th1) cells as major participants in AS development. Furthermore, HSPA5 expression was significantly correlated with Th1 cells, CD8+ T cells, CD4+ memory cells, and macrophages.Conclusion: This study suggested that HSPA5 and SQSTM1 can serve as useful diagnostic biomarkers for AS. These findings lay the foundation for identifying crucial mRNAs in the whole blood of AS patients, which may aid in the development of novel markers for AS.Keywords: diagnostic biomarkers, autophagy, immune cell, ankylosing spondylitis

Chengsen Cui,1,2,&ast; Bo Lv,1,&ast; Kai Meng1,3 1School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 2China Center for Health Development Studies, Peking University, Beijing, People’s Republic of China; 3High Quality Development Research Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai Meng, School of Public Health, Capital Medical University, No. 10 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83911577, Email mengkai@ccmu.edu.cnPurpose: Community health centers (CHCs) are an important part of the healthcare system worldwide. Based on the dual process model of organizational capabilities, this study explores the relationship between organizational capabilities and the organizational performance of CHCs, as well as the role played by the medical alliance implementation effect.Methods: In this study, whole-group sampling was used to extract CHCs. All 135 CHCs in 8 of 16 districts of Beijing were selected as subjects. The organizational capabilities of the CHCs and the medical alliance implementation effect were evaluated using a questionnaire survey of 1957 managers and 3622 medical staff, respectively. A pathway analysis of the mediating role of the organizational capabilities of CHCs and the moderating role of the medical alliance implementation effect was conducted using Mplus 8.0.Results: The development capabilities had a positive impact on basic capabilities (β = 0.878, P < 0.001), and core capabilities (β = 0.952, P < 0.001), but had no direct impact on organizational performance. Basic capabilities positively affected organizational performance (β = 1.163, P < 0.001), and core capabilities negatively affected organizational performance (β =- 0.886, P = 0.004). Both basic capabilities (β =1.022, P < 0.001) and core capabilities (β =- 0.843, P = 0.005) played a mediating role in the relationship between development capabilities and organizational performance. The moderating role of the medical alliance implementation effect was not significant.Conclusion: This study found that strengthening the organizational capabilities of CHCs can effectively improve their performance, with the development of basic capabilities being a primary concern. The medical alliance implementation effect has not had a significant impact on organizational performance, and the cooperation between CHCs and high-level hospitals should be further promoted to give full play to the medical alliance’s role and improve the organizational performance of CHCs.Keywords: community health centers, organizational capabilities, organizational performance, medical alliance implementation effect, China

Yifan Zhao, Bai Lv, Guanghe Xue, Yong Sun, Jie Cao Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, 266071, People’s Republic of ChinaCorrespondence: Jie Cao; Yong Sun, Email caojie0829@hotmail.com; sunyong@qdu.edu.cnIntroduction: Here, based on oxygen-dependent photodynamic therapy (PDT) and oxygen-consumed oxidative phosphorylation of cancer tissues, we designed and developed a nanosystem (named CyI&Met-Liposome, LCM) to co-encapsulate the photosensitizer CyI and mitochondrial respiration inhibitor metformin (Met) as a PDT enhancer.Methods: We synthesized nanoliposomes encapsulating Met and CyI with excellent photodynamic/photothermal and anti-tumor immune properties using a thin film dispersion method. Confocal microscopy and flow cytometry were used to assess the cellular uptake, PDT, photothermal therapy (PTT) and immunogenicity of nanosystem in vitro. Finally, two tumor models in mice were constructed to investigate the tumor suppression and immunity in vivo.Results: The resulting nanosystem relieved hypoxia in tumor tissues, enhanced PDT efficiency, and amplified antitumor immunity induced by phototherapy. As a photosensitizer, CyI effectively killed the tumor by generating toxic singlet reactive oxygen species (ROS), while the addition of Met reduced oxygen consumption in tumor tissues, thereby evoking an immune response via oxygen-boosted PDT. Both in vitro and in vivo results illustrated that LCM effectively restricted the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced CyI-mediated PDT. Furthermore, T cells were recruited and activated at high levels, providing a promising platform to eliminate the primary tumors and synchronously realize effective inhibition of distant tumors.Keywords: photodynamic therapy, immunogenic cell death, oxidative phosphorylation, tumor immunotherapy

Yajie Yu,1– 3,&ast; Bin Lv,1,&ast; Juntao Wu,1 Wei Chen2,3 1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Hubei Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Chen, Email weichen86@hust.edu.cnAbstract: Musculoskeletal disorders are the second leading cause of disability worldwide, posing a huge global burden to the public sanitation system. Currently, tissue engineering-based approaches act as effective strategies, which are, however, challenging in limited application scenarios. Mussel-based biomimetic materials, exhibit numerous unique properties such as intense adhesion, biocompatibility, moisture resistance, and injectability, to name only a few, and have attracted extensive research interest. In particular, featuring state-of-the-art properties, mussel-inspired biomaterials have been widely explored in innumerable musculoskeletal disorder treatments including osteochondral defects, osteosarcoma, osteoarthritis, ligament rupture, and osteoporosis. Nevertheless, a comprehensive and timely discussion of their applications in musculoskeletal disorders is insufficient. In this review, we emphasize on (1) the main categories and characteristics of mussel foot proteins and their fundamental mechanisms for the spectacular adhesion in mussels; (2) the diverse synthetic methods and modification of various polymers; and (3) the emerging applications of mussel-biomimetic materials, the future perspectives, and challenges, especially in the area of musculoskeletal disorder. We envision that this review will provide a unique and insightful perspective to improve the development of a new generation of mussel biomimetic strategies.Keywords: mussel, biomimetic, musculoskeletal disorder, tissue engineering, biomaterials

Nan Liu, Bo Chen, Luchuan Li, Qingdong Zeng, Lei Sheng, Bin Zhang, Weili Liang, Bin Lv Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Bin LvDepartment of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaEmail lvbin@sdu.edu.cnBackground: Recurrent laryngeal nerve injury (RLNI) still occurs in total endoscopic thyroidectomy (TET) by using intraoperative neuromonitoring (IONM). As the region where most injuries occur, more attention should be paid to RLNI near the nerve entry point (NEP) in TET.Materials and Methods: This cohort study collected retrospectively data from 415 patients who underwent TET between February 2012 and December 2019. The functions of the recurrent laryngeal nerve (RLN) in TET were recorded by IONM. The patients with RLNI near the NEP were followed up by laryngoscopies. The demographic and clinical characteristics, the mechanisms of RLNI, and the outcomes of RLNI were recorded and analyzed.Results: There were a total of 444 at-risk nerves in 405 patients were analyzed. The incidence of RLNI near the NEP was 7.9%. RLNs with extralaryngeal branches were more likely to be injured near the NEP (P = 0.037). The incidences of different types of RLNI, in order of frequency, were 68.8% for thermal injury (n = 22), 28.1% for traction/compression injury (n = 9), and 3.1% for transverse injury (n = 1). A total of 93.8% (n = 30) of RLNI patients had complete recovery of vocal cord activity function.Conclusion: The extralaryngeal branch was a risk factor for RLNI near the NEP in TET. Thermal injury caused by an ultrasonic scalpel was the most common cause of RLNI near the NEP. Most RLNIs near the NEP would eventually recover.Keywords: thyroid surgery, total endoscopic thyroidectomy, recurrent laryngeal nerve injury, intraoperative neuromonitoring, recovery time

Nan Liu, Bo Chen, Luchuan Li, Qingdong Zeng, Lei Sheng, Bin Zhang, Bin Lv Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of ChinaCorrespondence: Bin LvDepartment of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of ChinaEmail lvbin@sdu.edu.cnPurpose: Papillary thyroid carcinoma (PTC) has a high incidence of lymph node metastasis (LNM). Our aim was to determine whether tumor location is a useful feature to predict bilateral central lymph node metastasis (CLNM) in unilateral 1– 4 cm PTC.Patients and Methods: Data on unilateral 1– 4 cm PTC patients from 2016 to 2019 were collected retrospectively. The clinical and pathological characteristics of the tumors and lymph nodes were analyzed statistically.Results: The mean patient age was 49.1± 12.3 (23– 73) years, and the majority were women (n=1334, 75.4%). A total of 1767 patients were analyzed, and 256 (14.5%) had bilateral CLNM. Tumor location was an independent risk factor in predicting bilateral CLNM (p< 0.001). The odds of bilateral CLNM were the highest in the near isthmus (OR 6.452, 95% CI: 3.658– 11.379, p< 0.001). In a multivariate regression model adjusting for other risk factors, near-isthmus tumors had the highest risk of bilateral CLNM (OR 7.319, 95% CI: 3.844– 13.933, p< 0.001), followed by lower lobe tumors (OR 2.338, 95% CI: 1.315– 4.155, p=0.004) and middle lobe tumors (OR 1.845, 95% CI: 1.035– 3.291, p=0.038), compared to upper lobe tumors.Conclusion: Tumor location is an independent risk factor in predicting the risk of bilateral CLNM. Near-isthmus tumors carry the highest risk of bilateral CLNM.Keywords: papillary thyroid carcinoma, location, predictive factor, lymph node metastasis

Yuanguo Luo,1,* Bo Lv,2,3,* Shaokang He,4,* Kai Zou,1 Kezhi Hu2,3 1Department of Orthopedics, The 923rd Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Nanning, People’s Republic of China; 2Department of Orthopedics, People’s Hospital of Guilin, Guilin, Guangxi, 541001, People’s Republic of China; 3Department of Orthopedics, Fifth Clinical Medical College, Guilin Medical University, Guilin, Guangxi, 541001, People’s Republic of China; 4Department of Orthopedics, The Tenth People’s Hospital of Nanning, Nanning, Guangxi, 530105, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo LvPeople’s Hospital of Guilin, 12 Wenming Road, Guilin, Guangxi, 541001, People’s Republic of ChinaTel +867738997962Email bolv198012@163.comPurpose: Osteosarcoma is the most common malignant bone cancer affecting adolescents and young adults. This study aimed to screen potential diagnostic and therapeutic markers for osteosarcoma.Methods: Differential expression analysis between osteosarcoma and control was performed in GSE99671, the differentially expressed genes (DEGs) were subjected to co-expression analysis. Enrichment analysis was employed to identify the biological functions and KEGG signaling pathways of module genes. In addition, a differential analysis was also performed between recurrent and non-recurrent osteosarcoma samples in GSE39055, and enrichment analysis was performed for DEGs. Further, Kaplan–Meier curve analysis was performed on the module genes, and receiver operating characteristic (ROC) curve was drawn. Comparison of the module with the highest correlation to osteosarcoma identified key genes. Cox regression model was utilized to identify the predictive ability of key genes for the prognosis of osteosarcoma.Results: A total of 13 co-expression modules were identified from 4871 DEGs of GSE99671, module 1 had the highest positive correlation with osteosarcoma. Module genes were mainly enriched in autophagy and macrophage migration functions. A total of 1126 DEGs were obtained from GSE39055, significantly involved in neutrophil mediated immunity. Screening of genes with area under the ROC curve (AUC) values greater than 0.73 in both GSE99671 and GSE39055 identified 5 key genes when compared with genes from module 1. The nomogram results showed that ATF5, CHCHD8, ENOPH1, and LOC286367 might predict 5-year or 8-year survival time of osteosarcoma patients. The Cox model results confirmed that the signals of ATF5, CHCHD8, and LOC286367 were robust, and it may be used in the diagnosis, treatment, and prognosis of osteosarcoma.Conclusion: We found that ATF5, CHCHD8, and LOC286367 can effectively identify osteosarcoma tumorigenesis and even recurrence status. This is helpful for early diagnosis and treatment, improving the clinical treatment of patients with osteosarcoma.Keywords: osteosarcoma, predictive biomarkers, recurrence, weighted co-expressed network analysis

Nan Liu,1 Yupeng Yang,2 Bo Chen,1 Luchuan Li,1 Qingdong Zeng,1 Lei Sheng,1 Bin Zhang,1 Weili Liang,1 Bin Lv1 1Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People’s Republic of China; 2Department of Thyroid Surgery, Jinan Zhangqiu District Hospital of TCM, Jinan 250200, Shandong, People’s Republic of ChinaCorrespondence: Bin LvDepartment of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People’s Republic of ChinaEmail lvbin@sdu.edu.cnPurpose: Papillary thyroid carcinomas (PTCs) frequently metastasize to the central neck compartment. Therapeutic central compartment neck dissection (CCND) is a well-established treatment for PTC nodal metastases; however, the extent to which therapeutic CCND should be performed remains controversial. In this study, we investigated the predictive risk factors for contralateral paratracheal lymph node metastasis (LNM) in unilateral cT1N1a or cT2N1a PTC.Patients and Methods: In this case–control study, which was conducted at a single center, demographic and pathological data from unilateral cT1N1a or cT2N1a PTC patients were collected from January 2017 to March 2019. All patients were treated with total thyroidectomy and bilateral CCND.Results: Two hundred thirty-seven patients met the inclusion criteria. Forty-nine patients (20.7%) were diagnosed with positive lymph nodes in the contralateral paratracheal region. Male sex (p=0.003), T2 disease (21– 40 mm) (p< 0.001), inferior pole tumor (p=0.011), near isthmus tumor (p< 0.001), aggressive pathology (p< 0.001), intraglandular dissemination (p=0.009), pretracheal LNM (p< 0.001), > 5 metastatic lymph nodes (p< 0.001) and extranodal invasion (p=0.003) were significantly associated with contralateral paratracheal LNM in univariate analysis. Multivariate analysis showed that male sex (p=0.005, OR=17.545), T2 disease (p=0.003, OR=34.317), inferior pole tumor (p=0.022, OR=8.289), near isthmus tumor (p=0.001, OR=40.229), aggressive pathology (p=0.027, OR=48.063), pretracheal LNM (p=0.002, OR=14.235) and > 5 metastatic lymph nodes (p=0.025, OR=23.426) were independent risk factors for contralateral paratracheal LNM.Conclusion: Male sex, T2 disease, a tumor located near the isthmus or inferior pole, aggressive pathology, pretracheal LNM and > 5 metastatic lymph nodes were predictive factors for contralateral paratracheal LNM in unilateral cT1N1a or cT2N1a PTC. These data may be useful to identify targets for surveillance or develop therapeutic interventions for patients with CCND.Keywords: papillary thyroid carcinoma, central compartment neck dissection, predictive factor, lymph node metastasis

Ruihao Zhou, 1, 2,* Xiaofeng Tang, 1,* Liping Li, 3,* Feifei Zhang, 1 Jun Sun, 1 Cheng Ju, 1, 4 Yan Zhou, 5 Renfeng Liu, 1, 4 Yiping Liang, 1 Bin Lv, 1, 4 Zhiping Zhang, 1, 4 Haiyan Hu, 5 Xiao-Bin Lv 1 1Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, Nanchang 30008, People’s Republic of China; 2Department of Pain Management, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 3Department of Clinical Laboratory, The Third Affiliated Hospital of Nanchang University, Nanchang 330008, People’s Republic of China; 4Department of Orthopedics, The Third Affiliated Hospital of Nanchang University,Nanchang 330008, People’s Republic of China; 5Department of Oncology,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital of Shanghai, Shanghai 200233, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Bin LvJiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, The Third Affiliated Hospital of Nanchang University, North 128 Xiangshan Road, Nanchang 30008, Jiangxi, People’s Republic of ChinaEmail nclvxiaobin@sina.cnHaiyan HuDepartment of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Xuhui District, Shanghai City 200233, People’s Republic of ChinaEmail xuri1104@163.comIntroduction: Breast cancer metastasis suppressor 1 like (BRMS1-like)was first reported to be a component of the Sin3-HDAC complex, but the role in the progression of cancers was largely unknown. Our previous study reported that BRMS1L promoted the metastasis of breast cancer through facilitating the recruitment of HDAC complex to the promoter FZD10, and hence suppressing the transcription of FZD10.Methods: In this study, we detected the expression level of BRMS1L in esophageal squamous cell carcinoma (ESCC). The effect of BRMS1L in TE-1D (knockdown) and ECA-109 (overexpression) cell lines was explored by transwell assays, wound healing assays, and cell adhesion assays. Quantitative real‑time PCR, Western blot analysis, and luciferase assays were used to detect the interaction of the CBP/P300-BRMS1L-ITGA7 axis.Results: In the present study, we found that knockdown of BRMS1L promoted the migration, invasion, and epithelial–mesenchymal transition (EMT). Conversely, overexpression of BRMS1L inhibited the migration and invasion of ESCC. Mechanistically, BRMS1L exerted their metastasis-suppressing role via transcriptionally repress ITGA7 expression. Moreover, we revealed that CBP/p 300 regulated the expression of BRMS1L and might be responsible for the down-regulation of BRMS1L in ESCC.Conclusion: Collectively, we identified the role of CBP/p300-BRMS1L-ITGA7 axis in the metastasis of ESCC.Keywords: BRMS1L, ESCC, EMT, ITGA7, CBP/P300, cell invasion and migration

Yanfei Wei,1,* Beibei Lv,1,* Jinling Xie,2,* Yuan Zhang,3 Yuning Lin,1 Shengshan Wang,1 Jing Zhong,1 Yongxin Chen,1 Yue Peng,1 Jing Ma11Department of Physiology, Guangxi University of Chinese Medicine, Nanning, Guangxi 530200, People’s Republic of China; 2Medical Science Experimental Center, Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530200, People’s Republic of China; 3Department of State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 710032, People’s Republic of China*These authors contributed equally to this workBackground/aims: Plumbagin (PL) has been shown to effectively inhibit tumor growth and migration of hepatocellular carcinoma cells in previous studies, but the specific mechanism for this remains unclear. The purpose of this study was to investigate the effects of PL-induced apoptosis in epithelial–mesenchymal transition (EMT) of human hepatocellular carcinoma (HCC) in vivo and in vitro.Methods: SMMC-7721 cells were cultured, an EMT model was induced in vitro by TGF-β1, cell proliferation was detected by the MTT assay, cell invasion was analyzed by the Transwell invasion assay, and the apoptosis rate was measured by flow cytometry. RT-PCR was used to detect vimentin, E-cadherin, N-cadherin and snail mRNA, and Western blotting was used to detect the vimentin, caspase-3, PARP-1, E-cadherin, N-cadherin and snail protein expression levels. HE staining and TUNEL staining, immunohistochemistry and immunofluorescence were used to detect the expression levels of bax and bcl-2 in hepatocarcinoma xenografts and to evaluate their apoptosis in vivo.Results: The in vitro results showed that PL inhibited the proliferation of EMT model cells, increased the apoptosis rate of the EMT model, and significantly decreased the vimentin, PARP-1, N-cadherin and snail protein levels, but significantly increased E-cadherin and caspase-3 protein expression. In addition, the in vivo results indicated that PL can affect the expression of bax/bcl-2 apoptotic marker proteins.Conclusion: PL may induce apoptosis of human hepatocellular carcinoma cells undergoing epithelial–mesenchymal transition by increasing the caspase-3 protein level and cleaving vimentin.Keywords: plumbagin, hepatocellular carcinoma, epithelial-mesenchymal transition, apoptosis, caspase-3

Bin Lv1,*, Tao Xu2,*, Bowen Wan2,*, Hua Ding,1 Xiang Yao,1 Jian Chen,2 Peng Ji,1 Yilei Zhao,1 Yongjun Luo,2 Zhimin Zhou,2 Shengquan Yang,3 Qinyi Jiang,1 Jishan Yuan,1 Guoyong Yin21Department of Orthopedics, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212002, People’s Republic of China; 2Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province 210029, People’s Republic of China; 3Department of Orthopedics, Yancheng No.1 People’s Hospital, Yancheng, Jiangsu Province 224000, People’s Republic of China*These authors contributed equally to this work Background: Several studies have substituted the T1 slope (T1S) with the C7 slope (C7S) because the C7 endplate is clearer on radiographs. Further, abnormal serum lipid levels have been proven to be related with the development of disc degeneration. The aim of this study was to explore the relationship between C7S, serum lipid levels, cervical parameters related to cervical sagittal balance and Modic changes (MCs) in patients with multisegment cervical spondylotic myelopathy (CSM).Methods: Between January 2014 and January 2017, 75 patients with multisegment CSM were enrolled in our retrospective study. Gender, age, history of smoking status and alcohol consumption, and laboratory test data were recorded. The cervical sagittal balance parameters C7S, T1S, cervical lordosis (CL), neck tilt (NT), thoracic inlet angle (TIA), C2–C7 sagittal vertical axis (SVA), and T1S-CL were analyzed with Spearman correlation tests and multiple linear regression analysis. We diagnosed MCs through computed tomography or magnetic resonance imaging of the cervical spine. Patients were divided into four subgroups according to the presence or absence of MCs and their C7S values.Results: 75 patients were included in our study. Age, gender, C7S, and T1S were significantly different between the two groups. However, there was no statistical difference with regard to smoking status, alcohol consumption, lipoprotein(a), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, albumin, globulin, triglycerides, total cholesterol, Ca,2+ CL, T1S, TIA, NT, and T1S−CL. The correlation between HDL-C, LDL-C, ALB, GLB, Ca,2+ C7S, T1S, MCs, NT, TIA, and C2–C7 SVA was statistically significant.Conclusion: Significant correlations were observed between MCs and TG (as well as other preoperative sagittal parameters), which may accelerate the development of degeneration of the cervical spine. Therefore, alcohol consumption, TG, and sagittal parameters, such as C7S, and T1S could be a promising candidate for the assessment of cervical sagittal balance and predicting neck pain.Keywords: C7 slope, Modic change, serum lipid, cervical myelopathy, neck pain, cervical sagittal alignment

We report a layered ternary selenide BaPt4Se6 featuring sesqui-selenide Pt2Se3 layers sandwiched by Ba atoms. The Pt2Se3 layers in this compound can be derived from the Dirac-semimetal PtSe2 phase with Se vacancies that form a honeycomb structure. This structure results in a Pt (VI) and Pt (II) mixed-valence compound with both PtSe6 octahedra and PtSe4 square net coordination configurations. Temperature-dependent electrical transport measurements suggest two distinct anomalies: a resistivity crossover, mimic to the metal-insulator (M-I) transition at ~150 K, and a resistivity plateau at temperatures below 10 K. The resistivity crossover is not associated with any structural, magnetic, or charge order modulated phase transitions. Magnetoresistivity, Hall, and heat capacity measurements concurrently suggest an existing hidden state below 5 K in this system. Angle-resolved photoemission spectroscopy measurements reveal a metallic state and no dramatic reconstruction of the electronic structure up to 200 K.

Quasi-one-dimensional (1D) materials provide a superior platform for characterizing and tuning topological phases for two reasons: (i) existence for multiple cleavable surfaces that enables better experimental identification of topological classification and (ii) stronger response to perturbations such as strain for tuning topological phases compared to higher dimensional crystal structures. In this paper, we present experimental evidence for a room-temperature topological phase transition in the quasi-1D material Bi4I4, mediated via a first-order structural transition between two distinct stacking orders of the weakly coupled chains. Using high-resolution angle-resolved photoemission spectroscopy on the two natural cleavable surfaces, we identify the high-temperature β phase to be the first weak topological insulator with two gapless Dirac cones on the (100) surface and no Dirac crossing on the (001) surface, while in the low-temperature α phase, the topological surface state on the (100) surface opens a gap, consistent with a recent theoretical prediction of a higher-order topological insulator beyond the scope of the established topological materials databases that hosts gapless hinge states. Our results not only identify a rare topological phase transition between first-order and second-order topological insulators but also establish a novel quasi-1D material platform for exploring unprecedented physics.

Undoped CaFe2As2 (Ca122) can be stabilized in two slightly different non-superconducting tetragonal phases, PI and PII, through thermal treatments. Upon proper annealing, superconductivity with a Tc up to 25 K emerges in the samples with an admixture of PI and PII phases. Systematic low-temperature X-ray diffraction studies were conducted on undoped Ca122 samples annealed at 350 °C over different time periods. In addition to the diffraction peaks associated with the single-phase aggregation of PI and PII, a broad intermediate peak that shifts with annealing time was observed in the superconducting samples only. Our simulation of phase distribution suggests that the extra peak is associated with the admixture of PI and PII on the nanometer scale. High-resolution transmission electron microscopy confirms the existence of these nano-scale phase admixtures in the superconducting samples. These experimental results and simulation analyses lend further support for our conclusion that interfacial inducement is the most reasonable explanation for the emergence of superconductivity in undoped Ca122 single crystals.

OBJECTIVE: Ferroptosis of neurons is a significant cause of brain injury following intracerebral hemorrhage (ICH). As an iron-containing compound in hemoglobin, heme contributes to nerve injury post-ICH. Melatonin has been shown to mitigate the effects of ICH, yet its specific functions remain largely elusive. In this study, we aimed to explore the roles and mechanisms of melatonin in heme-induced ferroptosis subsequent to ICH. MATERIALS AND METHODS: C57BL/6 mice were intracranially injected with heme and then treated with melatonin. Behavior tests [modified neurological severity score (mNSS), forelimb placing, and corner turn tests], H&E staining, Nissl staining, and Prussian blue staining were used to evaluate mouse brain tissue injury. In vitro, HT-22 cells were stimulated with heme and cell viability was determined by crystal violet staining. The iron contents were determined in heme-treated brains and cells, and the levels of 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) were assessed by ELISA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate the mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Immunoblotting was used to analyze the protein expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Finally, small interfering RNA (siRNA) was used to knock down Nrf2 in HT-22 cells. RESULTS: Melatonin treatment alleviated heme-induced injuries to neural function, as indicated by improved behavior in the mice. Moreover, melatonin decreased cell death and iron concentrations, increased MDA and 4-HNE levels, and reversed the decreases in GPX4, SLC7A11, Nrf2, and HO-1 induced by heme in vitro and in vivo. These results indicated that melatonin could improve the ferroptosis induced by heme. In addition, we found that Nrf2 knockdown attenuated the therapeutic effect of melatonin on neuronal ferroptosis induced by heme. CONCLUSIONS: In general, melatonin alleviates heme-induced ferroptosis by activating the Nrf2/HO-1 pathway, which implies that melatonin is a promising treatment for ferroptosis in ICH. [ABSTRACT FROM AUTHOR]