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Yanyan Lu,1,* Qiang Wang,2,* Xuzhen Liu,1 Shuzhan Gao,1 Sulin Ni,1 Jing Sun,1 Xijia Xu1 1Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing Brain Hospital, Nanjing, People’s Republic of China; 2Department of Medical Psychology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xijia Xu, Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing Brain Hospital, Nanjing, People’s Republic of China, Tel +86-13739192705, Email xuxijia@c-nbh.comPurpose: Acute and transient psychotic disorder (ATPD), a psychosis frequently diagnosed, can potentially evolve into chronic conditions like schizophrenia (SCZ) and other mental disorders. This study aimed to develop a predictive model based on clinical data to forecast the transition from ATPD to SCZ and to identify the predictive factors.Methods: According to the diagnostic criteria issued by the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), 396 inpatients diagnosed with ATPD were collected in this study. The Cox proportional-hazards regression model was performed using demographic data, clinical characteristics, and inflammatory markers to identify independent predictors for subsequent diagnostic transition (SDT) to SCZ.Results: During the follow-up period, 43.69% (n = 173) of ATPD patients had their diagnoses revised to SCZ. The multivariate Cox regression analysis identified post-treatment monocyte count, post-treatment monocyte/lymphocyte ratio (MLR), and the presence of schizophreniform symptoms as significant predictors for the diagnostic revision. Time-dependent receiver operating characteristic (TimeROC) analyses were developed. The AUC value at the 5-year follow-up was 0.728 for combined predictors, 0.702 for post-treatment monocyte count, 0.764 for post-treatment MLR, and 0.535 for the presence of schizophreniform symptoms.Conclusion: The combined predictors had good predictive ability for the diagnostic transition from acute and transient psychotic disorder to schizophrenia.Keywords: acute and transient psychotic disorder, Schizophrenia, inflammation, subsequent-diagnostic-transition, monocyte count, monocyte–lymphocyte ratio

Runing Fu,1,* Wenping Lian,1,* Bohao Zhang,2,* Gang Liu,3 Xinyu Feng,1 Yingjie Zhu,1 Jiuan Zhou,1 Xinyu Zhang,4 Shukai Wang,1 Huijuan Huo,1 Daxin Wang,1 Cui Liu,1 Saisai Gao,1 Yajie Ma,4 Mengle Peng1,* 1Department of Clinical Laboratory, The Third People’s Hospital of Henan Province, Zhengzhou, Henan, 450006, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, People’s Republic of China; 3The Center of Meige Syndrome, The Third People’s Hospital of Henan Province, Zhengzhou, Henan, 450006, People’s Republic of China; 4Department of Medical Affair, the Third People’s Hospital of Henan Province, Zhengzhou, Henan, 450006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mengle Peng; Yajie Ma, Email pengmengle1990@126.com; szsyywk@sina.comPurpose: Inflammatory markers are known to be associated with many diseases, but their role in Meige syndrome (MS) remains unclear. This study aimed to develop and validate a nomogram for the risk prediction of MS based on inflammatory markers.Patient Data and Methods: Data from 448 consecutive patients with MS at the Third People’s Hospital of Henan Province between January 2022 and December 2023 were retrospectively reviewed. The MS cohort was randomly divided into separate training and validation sets. A nomogram was constructed using a multivariate logistic regression model based on data from the training set. The model’s performance was validated through cross-validation, receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis (DCA).Results: A total of five predictors, including red blood cell distribution width (RDW), hemoglobin (HGB), high-density lipoprotein cholesterol (HDL-C), the lymphocyte-to-monocyte ratio (LMR), and the systemic immune‐inflammation index (SII), were identified using multivariate logistic regression from a total of 11 variables. The cross-validation results indicated the stability of the model constructed with the above five predictors. The model showed moderate predictive ability, with an area under the ROC curve of 0.767 in the training set and 0.735 in the validation set. The calibration curve and DCA results indicate that the model has strong consistency and significant potential for clinical application.Conclusion: We constructed a nomogram based on five risk predictors, RDW, HGB, HDL-C, the LMR and the SII, to predict MS and enhance the predictive accuracy for identifying MS risk.Keywords: Meige syndrome, inflammatory marker, nomogram, LMR, SII

Shuqi Gao,1,2,* Zhe Sui,3,* Qian Jiang,1,2 Yueyao Jiang1 1Department of Pharmacy, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China; 2School of Pharmacy, Jilin University, Changchun, Jilin Province, 130021, People’s Republic of China; 3Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yueyao Jiang, Department of Pharmacy, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, 130033, People’s Republic of China, Tel +86 13844817007, Email jyy0705@jlu.edu.cnAbstract: Niosomes are key nanocarriers composed of bilayer vesicles formed by non-ionic surfactants and cholesterol, offering advantages such as high physicochemical stability, biodegradability, cost-effectiveness, and low toxicity. This review discusses their significant role in drug delivery, including applications in anticancer therapy and vaccine delivery. It also highlights the impact of non-ionic surfactants on niosome formation, drug delivery pathways, and protein corona formation—a relatively underexplored topic. Furthermore, the application of artificial intelligence in optimizing niosome design and functionality is examined. Future research directions include enhancing formulation techniques, expanding application scopes, and integrating advanced technologies. This review provides comprehensive insights and practical guidance for advancing niosome-based drug delivery systems. Keywords: niosomes, non-ionic surfactant, drug delivery systems, niosome functionalization

Yi Zhou,1 Weina Gao,2 Zhijiao Cao,3 Shumin Gao,2 Xutong Guo,2 Meng Liu,2 Congjie Cao4 1School of Nursing, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Orthopedics, Baoding No.1 Central Hospital, Baoding, Hebei, People’s Republic of China; 3Department of Nursing, Baoding No.1 Central Hospital, Baoding, Hebei, People’s Republic of China; 4Nursing Department, Langfang Health Vocational College, Langfang, Hebei, People’s Republic of ChinaCorrespondence: Weina Gao, Department of Orthopedics, Baoding No.1 Central Hospital, No. 320, Changcheng North Street, Lianchi District, Baoding, Hebei, 071000, People’s Republic of China, Tel +86 0312-5975023, Email gaoweina984926@163.comBackground: Kinesiophobia is common in patients after total knee arthroplasty and is an important risk factor for post-operative recovery outcomes. Little is known about the complex intercorrelations between different components of pain catastrophizing, self-efficacy, and kinesiophobia. This study aimed to identify the central components of kinesiophobia and to explore the interconnectedness between components of pain catastrophizing, self-efficacy, and kinesiophobia.Methods: A total of 216 patients after total knee arthroplasty were recruited in this study. Pain Catastrophizing Scale, Self-efficacy of Rehabilitation Outcome Scale and Tampa Scale for Kinesiophobia were used to assess pain catastrophizing, self-efficacy and kinesiophobia. R software was used to visualize the networks and analyze the centrality of the networks. The index “strength” and “bridge expected influence” were employed to identify the central components and the bridge components of the networks.Results: In the item network of kinesiophobia, three items (“Simply being careful that I do not make any unnecessary movements is the safest thing I can do to prevent my pain from worsening”, “My accident has put my body at risk for the rest of my life”, and “My body is telling me I have something dangerously wrong”) had the highest strength centrality. In the pain catastrophizing/self-efficacy–kinesiophobia network, rumination had the highest positive bridge expected influence, while coping self-efficacy had the highest negative value.Conclusion: The three central components of kinesiophobia identified in this study, as well as two bridge variables (rumination and coping self-efficacy), could be promising and effective targets for prevention and intervention of kinesiophobia.Keywords: pain catastrophizing, self-efficacy, kinesiophobia, total knee arthroplasty, network analysis

Heidi Chwan Ko,1,* RJ Seager,2,* Sarabjot Pabla,2 Maria-Fernanda Senosain,2 Erik Van Roey,2 Shuang Gao,2 Kyle C Strickland,1,3 Rebecca Ann Previs,1,4 Michelle F Green,1 Maureen Cooper,1 Mary K Nesline,1 Stephanie B Hastings,1 Kobina Agyaful Amoah,1 Shengle Zhang,2 Jeffrey M Conroy,2 Taylor J Jensen,1 Marcia Eisenberg,5 Brian Caveney,5 Eric A Severson,1 Shakti Ramkissoon,1,6 Shipra Gandhi7 1Labcorp Oncology, Durham, NC, USA; 2Labcorp Oncology, Buffalo, NY, USA; 3Department of Pathology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 4Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 5Labcorp, Burlington, NC, USA; 6Department of Pathology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA; 7Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA*These authors contributed equally to this workCorrespondence: Heidi Chwan Ko, Email Heidi.ko@labcorp.comBackground: The understanding of molecular characteristics of HER2-low breast cancer is evolving since the establishment of trastuzumab deruxtecan. Here, we explore the differences in expression patterns of immune-related genes in the tumor immune microenvironment (TME) and survival between HER2-low and HER2-zero breast cancers.Methods: Comprehensive genomic and immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on FFPE samples from 129 patients with advanced HER2-negative (immunohistochemistry (IHC) 0, 1+ or 2+ with negative ERBB2 amplification by in-situ hybridization) breast cancer. Both estrogen receptor (ER) and HER2 statuses were obtained from available pathology reports. mRNA expressions of immune biomarkers, except for PD-L1 IHC and TMB, were derived from RNA-seq. Statistical comparisons were performed using the Kruskal–Wallis or Wilcoxon Rank-Sum test or the two-sample test for equality of proportions with continuity correction (p≤ 0.05 for significance). Survival differences were calculated using Kaplan-Meier analysis (p≤ 0.05 for significance).Results: There were no significant differences in mRNA expressions of immune-related genes between HER2-low and HER2-zero breast cancers. However, HER2-low breast cancers were associated with a higher proportion of ER-positivity. When ER was analyzed along with HER2, we observed a significantly higher tumor immunogenic signature (TIGS) expression in HER2-zero/ER-negative tumors than in HER2-low/ER-positive tumors (p=0.0088). Similarly, lower expression of PD-L1 and T cell immunoglobulin and ITIM domain (TIGIT) mRNA was observed in HER2-low/ER-positive tumors when compared to HER2-zero/ER-negative tumors (p=0.014 and 0.012, respectively). Patients with HER2-low tumors had a longer median OS than those with HER2-zero tumors (94 months vs 42 months, p=0.0044).Conclusion: Patients with HER2-low breast cancer have longer survivals yet display no differences in immune-related gene expression when compared to those with HER2-zero cancers. The differences in survival can be attributed to the higher rate of ER-positivity seen in HER2-low breast cancers, compared to HER2-zero tumors.Keywords: HER2-low breast cancer, estrogen receptor, tumor immune microenvironment, immune checkpoint biomarkers, gene expression profiling, immune profiling

Yantao Yu,1– 3,* Chenkai Zhang,2,3,* Qiannan Sun,2– 4 Shantanu Baral,2,3 Jianyue Ding,2,3 Fanyu Zhao,2,3 Qing Yao,2,3 Shuyang Gao,2,3 Bin Liu,2– 4 Daorong Wang1– 4 1The Yangzhou School of Clinical Medicine of Dalian Medical University, Yangzhou, 225001, People’s Republic of China; 2General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 3Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, People’s Republic of China; 4Northern Jiangsu People’s Hospital, Yangzhou, 225001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Daorong Wang; Bin Liu, Email 18051062590@yzu.edu.cn; liubin2006cool@126.comBackground: Gastric cancer (GC) is a highly phenotypically heterogeneous disease and is caused by a combination of factors. Retinol binding protein 4 (RBP4) is a member of a family of lipid transport proteins that are involved in the transport of substances between cells and play a crucial role in a variety of cancers. However, the expression and role of RBP4 in GC remain unknown.Methods: In this study, we explored the expression, prognostic significance, immune microenvironment, drug responsiveness and function of associated signaling pathways of RBP4 in GC using web-based bioinformatics tools. Immunohistochemistry and real-time quantitative PCR were utilized to analyze the tissue and cell expression levels of RBP4. CCK-8, colony formation, EDU incorporation, wound healing and transwell assays were applied to demonstrate the effect of RBP4 on GC cell function. Flow cytometric detection of apoptosis after RBP4 knockdown. Nude mice xenograft model elucidates the role of RBP4 for GC in vivo. Related proteins of the RAS signaling pathway were analyzed by employing Western blot assays.Results: RBP4 is highly expressed in GC. RBP4 is closely associated with patient survival and sensitivity to a wide range of antitumor agents. Knockdown of RBP4 promoted apoptosis and inhibited cell proliferation, invasion and migration. RBP4 promotes GC tumorigenesis in vivo. Finally, RBP4 modulates the RAS/RAF/ERK axis.Conclusion: RBP4 may promote gastric carcinogenesis and development through the RAS/RAF/ERK axis and is expected to be a novel target for GC treatment.Keywords: RBP4, gastric cancer, invasion, migration, RAS/RAF/ERK axis

Juan Li,1,* Ziqing Gao,1,* Ning Li,1 Ling Yao,1 Chao Liu,1 Che Xu,1 Xiaohui Ren,1 Aiqin Wang,1 Siqi Gao,2 Miao Wang,2 Xiang Gao,2 Kun Li,3 Jianfeng Wang1 1Department of Ophthalmology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 2School of Clinical Medicine, Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 3School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, 233100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun Li; Jianfeng Wang, Email liangliang2419@126.com; wangjianfeng1969@163.comBackground: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers.Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections.Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities.Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.Keywords: ophthalmic safety, hollow mesoporous silica nanoparticles, ophthalmic drug delivery, tetrasulfur bond

Rui Zhou,1,2,* Lijuan Fu,2,* Shu Liu,2,* Sanjie Gao,2 Zhifu Zhao,2 Wencai Jiang,2 Li Liu,2 Weiqiao Ren,2 Dongmei Xiang,2 Xing You,2 Chunyong Tang,2 Yukai Zhou,2 Yanqing Song,2 Juan Xie,2 Li Xie,2 Ru Yu,2 Xianjie Zhang,2 Dan Zhou,2 Jia Han,2 Leqiang Xia,2 Lize Xiong1 1Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China; 2Department of Anesthesiology, Deyang People’s Hospital, Deyang, 618000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leqiang Xia, Department of Anesthesiology, Deyang People’s Hospital, No. 173, Section 1, North Taishan Road, Deyang, Sichuan, 618000, People’s Republic of China, Tel +8613547098458, Email xialq123184@163.com Lize Xiong, Shanghai Fourth People’s Hospital, No. 1279, Sanmen Road, Shanghai, 200434, People’s Republic of China, Tel +86-21-55603002, Fax +86-21-56660851, Email mzkxlz@126.com; lizexiong@tongji.edu.cnPurpose: To compare the influences of propofol, ciprofol and remimazolam on dreaming during painless gastrointestinal endoscopy.Methods: This study was a single-center, prospective, parallel-design, double-blind, randomized clinical trial. Between May 2023 and October 2023, patients undergoing elective painless gastrointestinal endoscopy were recruited and randomly allocated into one of the three groups. Demographic data, intraoperative information, incidence of dreaming, insufficient anesthesia and intraoperative awareness, type of dream, patient satisfaction score, adverse events, and improvement of sleep quality were collected.Results: The difference in incidence of dreaming among the three groups was not significant (33.33% vs 48.33% vs 41.67%, p=0.061). The number of patients with intraoperative hypotension in the propofol group was larger than that of the remimazolam group (32 vs 12, p=0.001). However, the cases of intraoperative hypotension between propofol group and ciprofol group or ciprofol group and remimazolam group were comparable (32 vs 22, p=0.122; 22 vs 12, p=0.064). The percentage of insufficient anesthesia between propofol group and remimazolam group was significant (13.33% vs 1.67%, p=0.001), while no statistical difference was detected between propofol group and remimazolam group or ciprofol group and remimazolam group (13.33% vs 5.00%, p=0.025; 5.00% vs 1.67%, p=0.150). The ability of propofol to improve sleep quality at 1st post-examination day was significantly better than that of remimazolam (86.21% vs 72.88%, p=0.015), while it was not significant between propofol group and ciprofol group or ciprofol group and remimazolam group (86.21% vs 80.36%, p=0.236; 72.88% vs. 72.88%, p=0.181). Incidence of intraoperative awareness, intraoperative hypoxia, type of dream, satisfaction score, adverse events during recovery, and sleep improvement on the 7th post-examination day was not significant among the groups.Conclusion: Anesthesia with propofol, ciprofol and remimazolam, respectively, for gastrointestinal endoscopy did not induce statistical difference in the incidence of dreaming, despite that all of them are more likely to induce pleasant dreams.Keywords: propofol, ciprofol, remimazolam, endoscopic sedation, dreaming

Saiyu Gao,1– 3 Nanqi Huang,4 Wenmin Huang,5 Yu Lian,5 Huiming Xiao,5 Shuyu Yao5 1Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Teaching and Research Section of Clinical Nursing, Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Ocular Emergency and Trauma Department, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, People’s Republic of ChinaCorrespondence: Shuyu Yao, Email yaoshuyu@gzzoc.comIntroduction: Position adherence of patients with Pars Plana Vitrectomy with Silicone Oil Tamponade after discharge is of positive significance. However, patients undergoing a day surgery makes the quality of discharge teaching and readiness for hospital discharge is insufficient, which will influence their position adherence at home.Aim: This study aimed to find the correlation of discharge teaching, readiness for hospital discharge, and position adherence in patients who underwent PPV with silicone oil tamponade from the day ward.Methods: This was a cross-sectional survey. One hundred ninety-four patients with day surgery were recruited by convenient sampling from Zhongshan Ophthalmic Center, China. Data were collected using the quality of discharge teaching scale, readiness for hospital discharge scale, and position adherence scale.Results: Patients’ education level, residence, poor postoperative vision, ophthalmic surgery history, and quality of discharge teaching are the main factors of readiness for discharge. Only 41(21%) patients had good position adherence, and education level and readiness for discharge are the main factors of position adherence.Discussion: Discharge teaching improves patients’ knowledge and competence of self-care and helps patients prepare for the transition from hospital to home, and readiness for hospital discharge significantly influences position adherence after discharge and indirectly plays a vital role in postoperative vision recovery and surgical effect.Keywords: discharge teaching, readiness for hospital discharge, position adherence, pars plana vitrectomy with silicone oil tamponade

Huimin Guo,1,&ast; Songkun Gao,2,&ast; Weimin Kong1 1Gynecology Department, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 2Gynecologic Oncology Department, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weimin Kong, Gynecology Department, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100006, People’s Republic of China, Email kwm1967@ccmu.edu.cnObjective: In current most observational studies, the prognosis of cervical adenocarcinoma is worse than that of cervical squamous cell carcinoma. However, most of the current studies are holistic and lack more detailed staging and grouping analysis of the prognosis of the two types of cervical tumors.Patients and Methods: Inclusion from the SEER database of stage IIB-IVA cervical squamous cell carcinoma and cervical adenocarcinoma patients who did not undergo surgery from 2000 to 2019, underwent radiotherapy/chemotherapy/radiotherapy and chemotherapy/no treatment, and then propensity score matching (PSM) was performed to eliminate confounding factors between cervical squamous cell carcinoma and cervical adenocarcinoma patients with the same stage and treatment method. After matching the original data and propensity score, logarithmic rank test and chi square test were used to evaluate the survival benefits of different stages and treatment methods for patients using Kaplan Meier curve. The prognosis of two types of cervical tumors under the same treatment method was compared, and factors that may cause poor prognosis were analyzed, excluding confounding factors.Results: A total of 10,057 patients were included in this study, and survival analysis showed a significant correlation between the treatment method used and patient prognosis (P< 0.05). However, for patients who received radiotherapy or no special treatment, OS and CSS were only related to tumor stage and not to tumor type. In patients undergoing radiotherapy and chemotherapy, the OS and CSS of stage IIIA and IVA patients are not related to tumor pathological characteristics, while the OS of stage IIB patients is not related to tumor properties after PSM.Conclusion: In patients undergoing radiotherapy and chemotherapy, the OS and CSS of stage IIIA and IVA patients were not related to histological type, while the OS of stage IIB patients was not related to histological type after PSM.Keywords: cervical squamous cell carcinoma, cervical adenocarcinoma, staging, prognosis, SEER

Qiaoni Zhang,1 Weidong Yan,2 Sizhe Gao,3 Xiaolin Diao,4 Gang Liu,1 Jing Wang,1 Bingyang Ji1 1Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Cardiovascular Disease, Beijing, People’s Republic of China; 2Department of Anesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Pain, Beijing Jishuitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Information Center, Fuwai Hospital, Chinese Academy of Medical science and Peking Union Medical College, National Clinical Research Center for Cardiovascular Disease, Beijing, People’s Republic of ChinaCorrespondence: Bingyang Ji, Department of Cardiopulmonary Bypass, Fuwai Hospital, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, People’s Republic of China, Email jibingyang@fuwai.comPurpose: There is currently no consensus on the most appropriate blood transfusion strategy for older adults undergoing cardiovascular surgery. We aimed to investigate the potential benefits of the patient blood management (PBM) program specifically for advanced age patients, and to evaluate the relationship of age and PBM in cardiovascular surgery.Patients and Methods: We collected data from patients over 60 years old who underwent on-pump cardiovascular surgery. We compared transfusion and clinical outcomes between the pre-PBM and post-PBM groups using a propensity score matching method. Then, we conducted a subgroup analysis within the original cohort, specifically focusing on patients aged of 75 and above with multivariable adjusted models.Results: Data of 9703 older adults were analyzed. Red blood cell (RBC) transfusion rates during cardiopulmonary bypass (CPB) (31.6% vs 13.1%, P< 0.001), during the operation (50.8% vs 39.0%, P< 0.001) and after the operation (5.6% vs 3.1%, P< 0.001) were significantly reduced, and mortality and the risk of some adverse events were also reduced after the PBM. Subgroup analysis showed that there was no interaction between age and PBM, and advanced age (over age 75) did not modify the effect of PBM program in reducing RBC transfusion (Pinteraction=0.245), on mortality (Pinteration=0.829) and on certain complications.Conclusion: The comprehensive PBM program could reduce RBC transfusion without adverse outcomes in older patients undergoing CPB. Even patients over age 75 may benefit from a more stringent transfusion indication. Comprehensive blood conservation measures should be applied to optimize the blood management for older patients.Keywords: cardiopulmonary bypass, cardiovascular surgery, older adults, patient blood management, red blood cell transfusion

Baojiang Liu,&ast; Song Gao,&ast; Jianhai Guo, Fuxin Kou, Shaoxing Liu, Xin Zhang, Aiwei Feng, Xiaodong Wang, Guang Cao, Hui Chen, Peng Liu, Haifeng Xu, Qinzong Gao, Renjie Yang, Liang Xu, Xu Zhu Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu Zhu, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China, Tel + 86-10-8819-6059, Email drzhuxu@163.comPurpose: Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity for hepatocellular carcinoma (HCC). Several studies have compared HAIC and Transarterial chemoembolization (TACE). However, comparisons between TACE plus HAIC and HAIC are rarely reported. Here, we evaluated the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) compared to HAIC in patients with advanced HCC.Patients and Methods: In this retrospective study, we enrolled 167 patients diagnosed with advanced HCC and treated at Peking University Cancer Hospital from May 2018 to May 2022. The cohort comprised 74 patients who received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients who received HAIC-FOLFOX. Over 60% of patients received prior treatments. To avoid selection bias, propensity score matching was applied to the efficacy and safety analyses. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoints include objective response rate (ORR), disease control rate (DCR), and safety.Results: Propensity-matching yielded 48 pairs, and group baselines were almost equal after matching. Median PFS and median OS were both higher in the matched Hepa-HAIC cohort (median PFS: 8.9 vs 5.8 months, p = 0.035; median OS: 22.4 vs 9.5 months, p = 0.027), which was consistent with pre-matching analysis. The ORR in the Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; the DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Grade 3– 4 ALT elevation was more frequent in the Hepa-HAIC group (33.3% vs 8.3%, p = 0.003), while vomiting was more frequent in the HAIC group (29.2% vs 12.5%, p = 0.084).Conclusion: The Hepa-HAIC group is superior to the HAIC group in metrics of PFS, OS, ORR, and DCR, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with a comparable safety profile in advanced HCC.Keywords: transarterial chemoembolization, advanced hepatocellular carcinoma, hepatic arterial infusion chemotherapy, propensity score matching

Xin Liu,1,&ast; Fangchao Zhao,2,&ast; Xiaodan Wang,2,&ast; Zheng Ma,2 Hongjiang Yan,2 Xuchao Lu,2 Shujun Li,2 Haiyong Zhu,2,&ast; Shaolin Gao2 1Second Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaolin Gao, Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei, People’s Republic of China, Tel/Fax +86-311-66003588, Email gaoshaolinHB2H@163.comBackground: Long non-coding RNAs (lncRNAs) were demonstrated to be key to cancer progression and highly associated with the tumor immune microenvironment. Oxidative stress and immune may modulate the biological behaviors of tumors. Therefore, biomarkers that combined oxidative stress, immune, and lncRNA can be a promising candidate bioindicator in clinical therapy of cancers.Methods: Immune-related genes (IRGs) and oxidative stress-related genes (ORGs) were identified based on a detailed review of published literatures. The transcriptome data and clinical information of lung adenocarcinoma (LUAD) patients were obtained from TCGA database. Lasso and Cox regression analyses were conducted to develop a prognostic model. Additionally, the link between immune checkpoints, immune cells, and the prognostic model was investigated, and predict the sensitivity of immunotherapy.Results: 2498 IRGs and 809 ORGs were extracted from previous studies, and 190 immune- and oxidative stress-related genes (IOGs) were acquired by overlapping the above genes. 658 immune- and oxidative stress-related lncRNAs (IOLs) were screened by Pearson correlation analysis. A total of 25 prognosis-related IOLs were screened by univariate regression analysis. Finally, LASSO Cox regression analysis was adopted for determining a 12-IOLs prognostic risk signature. The signature performance was confirmed in the training cohort and the testing cohort, and cases were classified into low- and high-risk groups by the risk score calculated from the signature. Patients in the high-risk group had poor prognoses and immunosuppression, while the risk score was significantly associated with tumor-infiltrating immune cells, immune checkpoint expression, and immunotherapy responses. In vitro experiments further confirmed the expression of key signature gene.Conclusion: Our new IOLs-related prognostic signature can be reliable prognostic tools and therapeutic targets for LUAD patients.Keywords: immune, oxidative stress, lung adenocarcinoma, prognostic model

Chen Sun,1,&ast; Shuyue Zhang,1,&ast; Nan Xu,1,&ast; Kun Liu,2 Fang Wei,2 Xiaoqian Zhang,1 Jigang Zhang,1 Shen Gao,3 Yuan Yu,4 Xueying Ding1 1Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of China; 2Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200040, People’s Republic of China; 3Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 4Department of Pharmacy, Naval Medical University, Shanghai, 200433, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueying Ding, Clinical Research Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of China, Email dingxueying@126.com Yuan Yu, Department of Pharmacy, Naval Medical University, Shanghai, 200433, People’s Republic of China, Email pharmyuu@163.comIntroduction: Since intrinsic ocular barrier limits the intraocular penetration of therapeutic protein through eye drops, repeated intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents are the standard therapy for neovascular age-related macular degeneration (nAMD), which are highly invasive and may cause particular ocular complications, leading to poor patient compliance.Methods: Using Penetratin (Pen) as the ocular penetration enhancer and hyaluronic acid (HA) as the retina-targeting ligand, a dual-modified ophthalmic liposome (Penetratin hyaluronic acid-liposome/Conbercept, PenHA-Lip/Conb) eye drop was designed to non-invasively penetrate the ocular barrier and deliver anti-VEGF therapeutic agents to the targeted intraocular tissue.Results: PenHA-Lip effectively penetrates the ocular barrier and targets the retinal pigment epithelium via corneal and non-corneal pathways. After a single topical administration of conbercept-loaded PenHA-Lip (PenHA-Lip/Conb), the intraocular concentration of conbercept peaked at 18.74 ± 1.09 ng/mL at 4 h, which is 11.55-fold higher than unmodified conbercept. In a laser-induced choroidal neovascularization (CNV) mouse model, PenHA-Lip/Conb eye drops three times daily for seven days inhibited CNV formation and progression without any significant tissue toxicity and achieved an equivalent effect to a single intravitreal conbercept injection.Conclusion: PenHA-Lip efficiently and safely delivered conbercept to the posterior eye segment and may be a promising noninvasive therapeutic option for nAMD. Keywords: ocular drug delivery, dual-modified liposomes, Penetratin, hyaluronic acid, conbercept

Shang Gao,1 Chenmoji Wang,1 Lijie Qi,2 Songlin Liang,1 Xintian Qu,1 Wei Liu,3,&ast; Nianhu Li4,&ast; 1The First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 2Qilu Hospital of Shandong University, Jinan, Shandong Province, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 4Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nianhu Li; Wei Liu, Email tigerlee073@126.com; weiliu800109@163.comBackground: The method of action of Bushen Formula (BSHXF) in the treatment of intervertebral disc degeneration (IVDD) was uncovered in this work using in vivo and in vitro tests. To clarify the mechanism of action of BSHXF, we validated the rat intervertebral disc degeneration model and the nucleus pulposus cell degeneration model.Methods: In an in vivo model of IVDD the study explores the impact of BSHXF on mitochondrial function, pro-inflammatory cytokines, pro-apoptotic factors, and matrix metalloproteinases. Additionally, it evaluates the induced degeneration of nucleus pulposus (NP) cells in an in vitro model stimulated by interleukin-1 β (IL-1β). The study measures the effects of BSHXF on both the inflammatory response and mitochondrial function.Results: The MRI results showed that BSHXF reduced intervertebral disc volume reduction and degradation of NP tissue. HE, SO-FG and immunofluorescence further confirmed the protective effect of BSHXF on degenerative intervertebral discs. BSHXF reduced the inflammatory levels of IL-6 IL-1β and TNF-α in degenerative intervertebral disc tissue. Meanwhile, JC-1, mPTP and ROS detection revealed that BSHXF can restore mitochondrial function by regulating the expression of antioxidant proteins, playing a protective role in NP cells. Finally, the WB results showed that BSHXF can alleviate IL-1β mediate the degeneration of NP cells. BSHXF can alleviate NP cell apoptosis by inhibiting the expression of bax, cleaved caspase-3, caspase-3, and cyt-c, and increasing the expression of Bcl-2.Conclusion: This study reveals that BSHXF inhibits the development of inflammatory factors, which may play a significant role in intervertebral disc degeneration. This implies that BSHXF is a suitable herbal medication for future research into inflammatory cytokine treatment.Keywords: intervertebral disc degeneration, nucleus pulposus cell, BSHXF, apoptosis, inflammatory

Chuling Hu,1,&ast; Yan Liu,2,&ast; Wei Cao,3,&ast; Na Li,4 Shen Gao,5 Zhuo Wang,5 Fenfen Gu2 1Department of Pharmacy, Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children’s Hospital of Jiaxing University, Jiaxing, People’s Republic of China; 2Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Neurovascular Disease, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 4Department of Pathology, Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children’s Hospital of Jiaxing University, Jiaxing, People’s Republic of China; 5Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhuo Wang; Fenfen Gu, Email wangzhou088@163.com; fenfen09@163.comIntroduction: Chemotherapy is still the treatment of choice for advanced triple-negative breast cancer. Chemotherapy combined with immunotherapy is being tried in patients with triple-negative breast cancer. As a kind of “cold tumor”, triple-negative breast cancer has a bottleneck in immunotherapy. Indoleamine 2, 3-dioxygenase-1 inhibitors can reverse the immunosuppressive state and enhance the immune response.Methods: In this study, mesoporous silica nanoparticles were coated with the chemotherapeutic drug doxorubicin and indoleamine 2, 3-dioxygenase 1 inhibitor 1-Methyl-DL-tryptophan (1-MT), and then encapsulate the surfaces of a triple-negative breast cancer cell membrane to construct the tumor dual-targeted delivery system CDIMSN for chemotherapy and immunotherapy, and to investigate the immunogenic death effect of CDIMSN.Results and discussion: The CDIMSN could target the tumor microenvironment. Doxorubicin induced tumor immunogenic death, while 1-MT reversed immunosuppression. In vivo findings showed that the tumor size in the CDIMSN group was 2.66-fold and 1.56-fold smaller than that in DOX and DIMSN groups, respectively. CDIMSN group was better than naked DIMSN in stimulating CD8+T cells, CD4+T cells and promoting Dendritic Cells(DC) maturation. In addition, blood analysis, biochemical analysis and Hematoxylin staining analysis of mice showed that the bionic nanoparticles had good biological safety. Keywords: immunogenic cell death, doxorubicin, bionic nanoparticle, IDO1 inhibitor, triple-negative breast cancer

Zhipeng Wang,1,&ast; You Yin,2,&ast; Yuhui Mu,1,3,&ast; Lili Cui,1 Xinhua Song,1 Jianhua Zhuang,2 Shouhong Gao,1 Xia Tao,1 Wansheng Chen1 1Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 2Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianhua Zhuang, Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Email jianhuazh11@126.com Xia Tao, Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel/Fax +86– 21– 81886191, Email taoxia@smmu.edu.cnObjective: This study aims to explore the mechanism underlying the induction of phlebitis by aescinate and create an early-warning model of phlebitis based on metabolomics.Methods: Patients with cerebral infarction enrolled had been treated with aescinate. Plasma samples were collected either before administration of aescinate, upon the occurrence of phlebitis, or at the end of treatment. Non-targeted metabolomics and targeted amino acid metabolomics were carried out to analyze metabolic profiles and quantify the metabolites.Results: Untargeted metabolomics revealed six differential metabolites in baseline samples versus post-treatment samples and four differential metabolites in baseline samples from patients with or without phlebitis. Pathways of these differential metabolites were mainly enriched in amino acid metabolism. Ten differential amino acids with a VIP value of > 1 were identified in the baseline samples, enabling us to distinguish between patients with or without phlebitis. A logistic regression model was constructed (AUC 0.825) for early warning of phlebitis of grade 2 or higher.Conclusion: The occurrence of aescinate-induced phlebitis, which can be predicted early during onset, may be associated with perturbations of the endogenous metabolic profile, especially the metabolism of amino acids. Keywords: aescinate, diagnostic model, mechanism, metabolomics, phlebitis

Heng Wang,1,&ast; Tingting Gao,1,&ast; Ruijing Zhang,2,&ast; Jie Hu,1 Siqi Gao,1 Yuwen Wang,1 Xiaotong Qi,1 Yun Zhou,3 Guoping Zheng,1,4 Honglin Dong1 1Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Shanxi Provincial Integrated TCM and WM Hospital, Taiyuan, People’s Republic of China; 4Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia&ast;These authors contributed equally to this workCorrespondence: Honglin Dong, Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan City, Shanxi Province, 030001, People’s Republic of China, Email honglindong@sxmu.edu.cn Guoping Zheng, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia, Email guoping.zheng@sydney.edu.auBackground: Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury.Methods: First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries.Results: We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo.Conclusion: These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.Keywords: contrast-induced acute kidney injury, neutrophils, neutrophil extracellular traps, glomeruli, peritubular capillaries

Yi Zhou,1 Weina Gao,2 Shumin Gao,2 Xutong Guo,2 Meng Liu,2 Congjie Cao1 1School of Nursing, Langfang Health Vocational College, Langfang, Hebei, People’s Republic of China; 2Department of Orthopedics, Baoding No.1 Central Hospital, Baoding, Hebei, People’s Republic of ChinaCorrespondence: Weina Gao, Department of Orthopedics, Baoding No.1 Central Hospital, No. 320, Changcheng North Street, Lianchi District, Baoding, Hebei, 071000, People’s Republic of China, Tel/Fax +86 312-5975023, Email gaoweina984926@163.comPurpose: To examine whether exercise self-efficacy mediates the contributions of pain catastrophizing and kinesiophobia to exercise adherence in patients after total knee arthroplasty.Patients and Methods: A cross-sectional study design was conducted. A total 211 post-total knee arthroplasty patients were recruited from three orthopedics units of a tertiary hospital in China. Participants were invited to complete questionnaires on pain catastrophizing, kinesiophobia, exercise self-efficacy, and exercise adherence. Mplus 8.3 software was used to construct mediation models.Results: Pain catastrophizing and kinesiophobia were negatively correlated with exercise adherence (r = − 0.509, r = − 0.605, p < 0.001 respectively), while exercise self-efficacy were positively associated with exercise adherence (r = 0.799, p < 0.001). The results found exercise self-efficacy mediated the correlations of pain catastrophizing and kinesiophobia with exercise adherence after adjusting for demographic and clinical covariates. Pain catastrophizing indirectly affected patients’ exercise adherence through its effect on exercise efficacy (indirect effect: − 0.412), while Kinesiophobia is directly associated with exercise adherence and also indirectly through exercise self-efficacy (direct effect: − 0.184, indirect effect: − 0.415).Conclusion: Patients after total knee arthroplasty who have high levels of psychological distress (pain catastrophizing and kinesiophobia) are vulnerable to be non-adherent to exercise behaviors. Exercise self-efficacy explains the effects of pain catastrophizing and kinesiophobia on exercise adherence and may be a key target for measures to improve exercise behaviors in patients after total knee arthroplasty.Keywords: pain catastrophizing, kinesiophobia, self-efficacy, exercise, adherence, total knee arthroplasty

Songkun Gao,1,2,&ast; Lei Huang,1– 3,&ast; Tong Wang,1,2 Jiandong Wang1,2 1Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, People’s Republic of China; 2Gynecologic Oncology Department, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, People’s Republic of China; 3Gynecology department, Yanqing Maternal and Child Health Care Hospital, Beijing, 102199, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tong Wang; Jiandong Wang, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Qihelou Street, Dongcheng District, Beijing, 100006, People’s Republic of China, Email fcyywt@ccmu.edu.cn; wangjiandongxy@ccmu.edu.cnPurpose: Investigation of HPV infection treatment in women undergoing cervical cold-knife conization for advanced cervical intraepithelial neoplasia.Patients and Methods: A retrospective analysis was conducted on patients who underwent cervical cold-knife conization for cervical intraepithelial neoplasia grade II–III at Beijing Obstetrics and Gynecology Hospital from January 2017 to December 2018. The HPV infection status of the patients at 6 months, 1 year, and 2 years after surgery was collected. We use chi square analysis and binary logistic regression to evaluate various factors such as age, number of pregnancies, number of cesarean sections, number of vaginal deliveries, HPV type, size of surgical specimens (diameter and height), and the influence of specimen edge on HPV infection.Results: A total of 334 patients were included in the analysis. The patients are mainly infected with HPV 16/58/52. Age is a influencing factor for HPV recovery 12 months after CKC surgery (P=0.002). Based on the diagnosis of HPV one year after CKC, the recovery rate of HPV58 patients is significantly lower than HPV16. Age is a influencing factor for the recovery of HPV infection (P< 0.05).Conclusion: The treatment of HPV infection by CKC is related to the patient’s age and HPV subtype but not to number of pregnancies, number of pregnancies, number of vaginal deliveries, size of surgical specimens, and marginal conditions. The rate of HPV negative conversion is relatively high 24 months after the patient does not undergo surgery, but there is currently a lack of data on cervical lesions that match HPV results.Keywords: cold-knife conization, HPV infection, recovery rate, high-grade cervical intraepithelial neoplasia

Cheng-Xi Sun,1 Li-Yan Han,2,3 Kai Wang,2,3 Shuai Gao2,3 1Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 3Institute of Hepatology, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Shuai Gao, Department of Hepatology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-82169593, Fax +86-531-86927544, Email qilugaoshuai@sdu.edu.cn; gaoshuai361@163.comBackground: Acute-on-chronic hepatitis B liver failure (ACHBLF) is a clinical syndrome with an extremely high mortality. In this study, we aim to evaluate the potential role of serum exosomal long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) in ACHBLF and its predictive value for 3-month mortality.Methods: From December 2017 to June 2022, we enrolled 110 patients with ACHBLF and 42 healthy controls (HCs). Exosomes were isolated from the serum of the participants. Serum exosomal lncRNA GAS5 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The functional role of lncRNA GAS5 on hepatocyte phenotypes was investigated through loss-of-function and gain-of-function assays. Exosomal labeling and cell uptake assay were used to determine the exosomes-mediated transmission of lncRNA GAS5 in hepatocytes in vitro.Results: The serum exosomal lncRNA GAS5 was identified to be an independent predictor for 3-month mortality of ACHBLF. It yielded an area under the receiver operating characteristic curve (AUC) of 0.88, which was significantly higher than MELD score (AUC 0.73; P < 0.01). Further study found that lncRNA GAS5 could inhibit hepatocytes proliferation and increase hepatocytes apoptosis. Exosomes-mediated lncRNA GAS5 transfer promoted hepatocytes injury. The knocked down of lncRNA GAS5 weakened H2O2-induced hepatocytes injury.Conclusion: We revealed that serum exosomal lncRNA GAS5 might promote hepatocytes injury and showed high predictive value for 3-month mortality in ACHBLF.Keywords: acute-on-chronic hepatitis B liver failure, exosomes, long noncoding RNA, growth arrest-specific 5, prognosis

Min Shen,1 Chunjing Li,1 Xiaocen Wei,1 Linlin Zhang,1 Yang Li,1 Hongxue Wu,2 Xiaobin Zhang,1 Zhibin Dong,1 Shuzhong Gao,1 Yuning Ma,1 Yuxia Ma1 1Department of Acupuncture and Massage College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Department of Rehabilitation, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of ChinaCorrespondence: Yuning Ma; Yuxia Ma, Email myning0405@163.com; phdmayuxia@126.comIntroduction: This overview of systematic reviews (SRs) systematically collected, evaluated, and combined the evidence for migraine treatment with transcranial magnetic stimulation (TMS).Methods: We conducted a systematic literature search in various databases, such as PubMed, The Cochrane Library, Web of Science, Embase, the China National Knowledge Infrastructure, Wanfang, VIP, and China Biomedical Literature. Two reviewers independently assessed the methodological quality, risk of bias, reporting quality, and strength of evidence of the included studies using AMSTAR-2, ROBIS, the PRISMA checklist, and the GRADE system.Results: We performed an overview of 7 relevant SRs, of which 4 were of moderate quality and 3 were of low quality according to AMSTAR 2. All SRs had low risk of bias in Phase 1 (Assessing relevance), Domain 1 (Study eligibility criteria), and Domain 4 (Synthesis and findings) as evaluated by ROBIS. In Domain 2 (Identification and selection of studies), 4 SRs (57.1%) had low risk of bias, while in Domain 3 (data collection and study appraisal) and Risk of Bias in the Review Phase 3, 4 SRs (57.1%) had low risk of bias. The PRISMA reporting standards were generally comprehensive, but some limitations were observed in the assessments, pooled results, evidence reliability, registration and protocols, and funding sources. The GRADE levels ranged from moderate to low, with 10 outcomes of moderate quality and 6 outcomes of low quality. The main reason for the low quality of evidence was the small sample size and high heterogeneity of the available studies.Conclusion: TMS may improve migraine severity and frequency, but the evidence is limited due to methodological flaws and heterogeneity. Future studies should standardize use, assess side effects, and compare with other treatments.Keywords: transcranial magnetic stimulation, migraine, evidence, overview, systematic reviews

Baocuo Gong,1,2,&ast; Xuewen Wang,1,3,&ast; Wanting Guo,1 Hongyi Yang,1 Yanhong Shi,1 Yaying Chen,1 Simiao Gao,1 Jialin Chen,1 Lifang Liu,2 Linbin Lu,1 Xiong Chen1 On behalf of Fujian HCC-biomarker Study Group1Department of Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350025, People’s Republic of China; 2Department of Oncology, Oriental Hospital Affiliated to Xiamen University, Fuzhou, Fujian, 350025, People’s Republic of China; 3Department of Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linbin Lu; Xiong Chen, Department of Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, 321 Xihong Road, Fuzhou, Fujian, 350025, People’s Republic of China, Email doctorxiaolin@fjmu.edu.cn; cxiongzpc@fjmu.edu.cnBackground: Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage Hepatocellular carcinoma (HCC) patients. However, predicting the survival of HCC patients receiving TACE remains challenging.Methods: In this retrospective study, we analyzed a total of 1805 HCC patients who received TACE. The patients were randomly divided into a training set (n = 1264) and a validation set (n = 541). We examined various prognostic factors within the training set and developed a simple ALFP (ALBI grade, AFP, and Prothrombin time) score, which was subsequently validated using the independent validation set.Results: Our multivariate analysis revealed that baseline ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s were independent unfavorable prognostic factors for HCC patients receiving TACE (p 13.1 s. The score has a range of 0 to 3, and higher scores are associated with poorer outcomes. The median overall survival (OS) varied significantly among different ALFP score groups, both in the training set and the validation set (p

Chang Huang,1,2,&ast; Zhutian Zhang,1,2,&ast; Jifeng Gu,3,&ast; Dan Li,1,2 Shunxiang Gao,1,2 Rong Zhang,1,2 Rong Shi,4 Jianguo Sun1,2 1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, People’s Republic of China; 2NHC Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, People’s Republic of China; 3Department of Pharmacy, Eye & ENT Hospital, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai, 200031, People’s Republic of China; 4Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianguo Sun, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China, Email jgsun@fudan.edu.cn Rong Shi, Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email rongshi56@126.comPurpose: Autoimmune uveitis is a kind of sight-threatening ocular and systemic disorders. Recent treatments on autoimmune uveitis still remain many limitations due to extreme complexity and undetermined pathogenesis. In this study, a novel dual-drug nanocomposite formulation is developed to treat experimental autoimmune uveitis by a combined and sustained therapy method.Methods: The dual-drug nanocomposite formulation is constructed by integrating berberine (BBR)-loaded mesoporous silica nanoparticles (MSNs) into dexamethasone (DEX)-loaded thermogel (BBR@MSN-DEX@Gel). The BBR@MSN-DEX@Gel is characterized by transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectrometer and rheometer. The in vitro drug release profile, cytotoxicity and anti-inflammation effectiveness of BBR@MSN-DEX@Gel on lipopolysaccharide-stimulated human conjunctival epithelial cells are investigated. After the in vivo drug release profile and biosafety of the dual-drug nanocomposite formulation are confirmed, its treatment effectiveness is fully assessed based on the induced experimental autoimmune uveitis (EAU) Lewis rat’s model.Results: The dual-drug nanocomposite formulation has good injectability and thermosensitivity, suitable for administration by an intravitreal injection. The BBR@MSN-DEX@Gel has been found to sustainably release both drugs for up to 4 weeks. The carrier materials have minimal in vitro cytotoxicity and high in vivo biosafety. BBR@MSN-DEX@Gel presents obviously anti-inflammatory effectiveness in vitro. After administration of BBR@MSN-DEX@Gel into Lewis rat’s eye with EAU by an intravitreal injection, the nanocomposite formulation significantly suppresses inflammatory reaction of autoimmune uveitis via a dual-drug combined and sustained therapy method, compared with the equivalent dose of single-component formulations.Conclusion: BBR@MSN-DEX@Gel serves as a promising dual-drug nanocomposite formulation for future treatment of autoimmune uveitis.Keywords: nanocomposite formulation, combined and sustained therapy, dexamethasone, berberine, experimental autoimmune uveitis

Sangmi Kim,1 Carolyn Martin,2 John White,2 Maureen Carlyle,2 Bonnie Bui,2 Shiyao Gao,1 Claudia A Salinas1 1Global Patient Safety Pharmacoepidemiology, Eli Lilly and Company, Indianapolis, IN, USA; 2Health Economics and Outcomes Research, Optum Life Sciences, Eden Prairie, MN, USACorrespondence: Claudia A Salinas, Global Patient Safety Pharmacoepidemiology, Eli Lilly and Company, Lilly Corporate Center, 893 Delaware St, Indianapolis, IN, 46285, USA, Tel +1 317 433 9188, Email claudia.salinas@lilly.comPurpose: Health insurance claims databases provide an opportunity to study uncommon events, such as venous thromboembolism (VTE), in large patient populations. This study evaluated case definitions for identifying VTE among patients treated for rheumatoid arthritis (RA) using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes in claims data.Patients and Methods: Study participants were insured adults who received treatment for and had a diagnosis of RA between 2016 and 2020. After a 6-month covariate assessment window, patients were observed for ≥ 1 month until health plan disenrollment, occurrence of a presumptive VTE, or end of the study (12/31/2020). Presumptive VTEs were identified using predefined algorithms based on ICD-10-CM diagnosis codes, anticoagulant use, and care setting. Medical charts were abstracted to confirm the VTE diagnosis. Performance of primary and secondary (less stringent) algorithms was assessed by calculating the positive predictive value (PPV; primary and secondary objectives). Additionally, a linked electronic health record (EHR) claims database and abstracted provider notes were used as a novel alternative source to validate claims-based outcome definitions (exploratory objective).Results: A total of 155 charts identified with the primary VTE algorithm were abstracted. The majority of patients were female (73.5%), with mean (standard deviation) age 66.4 (10.7) years and Medicare insurance (80.6%). Obesity (46.8%), ever smoking (55.8%), and prior evidence of VTE (28.4%) were commonly reported in medical charts. The PPV for the primary VTE algorithm was 75.5% (117/155; 95% confidence interval [CI], 68.7%, 82.3%). A less stringent secondary algorithm had a PPV of 52.6% (40/76; 95% CI, 41.4%, 63.9%). Using an alternative EHR-linked claims database, the primary VTE algorithm PPV was lower, potentially due to the unavailability of relevant records for validation.Conclusion: Administrative claims data can be used to identify VTE among patients with RA in observational studies.Keywords: algorithm validation, rheumatoid arthritis, venous thromboembolism, positive predictive value, administrative claims data, ICD-10-CM

Zhihong Zha,1,&ast; Shuang Gao,2,&ast; Shaofeng Liu,3 Guoqin Hu1 1Department of Otolaryngology Head and Neck Surgery, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Anhui Public Health Clinical Center, The First Affiliated Hospital of Anhui Medical University North District, Hefei, Anhui, People’s Republic of China; 3Department of Otolaryngology Head and Neck Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqin Hu, Department of Otolaryngology Head and Neck Surgery, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email huguoqin2010@yeah.netObjective: Chronic pharyngitis (CP) is a common disease, which has a long duration and a wide range of onset. Anxiety is considered to be a common complication in patients with CP. The purpose of this study was to evaluate the anxiety level and potentially influencing factors in patients with CP, to provide insights for the management of anxiety in patients with CP.Methods: A total of 104 adult patients with CP meeting the inclusion/exclusion criteria were enrolled from a single center in Wuhu, China between October 2015 and December 2016. A Self-rating Anxiety Scale (SAS) was used to measure the status of anxiety. The relationship between SAS scores and illness period in patients with CP was analyzed by Pearson correlation test. Univariate analysis and binary logistic regression analysis were performed to analyze the risk factors of anxiety in patients with CP.Results: The average SAS score of 104 patients with CP was (44.17 ± 8.38), including 82 cases (78.85%) without anxiety and 22 cases (21.15%) with anxiety. Moreover, the illness period was found to be positively related to SAS scores in patients with CP (r = 0.378, P = 0.001). Furthermore, the results of univariate analysis showed that there were significant differences in anxiety state among CP patients with different age, illness period, source of treatment payment, and marital status (P < 0.05). Additionally, the results of binary logistic regression analysis showed that age, source of treatment payment, and marital status were the independent risk factors affecting the anxiety status of patients with CP (P < 0.05).Conclusion: These results suggested that CP patients with advanced age, self-pay, and unmarried status had higher risk for anxiety.Keywords: chronic pharyngitis, risk factor, self-rating anxiety scale, anxiety, prevalence

Shuai Gao,1,&ast; Yuanjie Sun,1,&ast; Hangyu Shi,1,2 Jiufei Fang,1 Zhishun Liu1 1Department of Acupuncture, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhishun Liu, Department of Acupuncture, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange Street, Xicheng District, Beijing, People’s Republic of China, Email zhishunjournal@163.comPurpose: Cyclic mastalgia is prevalent among women and negatively impairs their daily life and work. There is still a lack of effective therapies for mastalgia, and acupuncture may be a promising method. We design this multicenter randomized trial to evaluate the efficacy and safety of acupuncture on cyclic mastalgia.Study Design and methods: Sixty participants with moderate-to-severe cyclic breast pain (with a duration of 5– 21 days and the worst pain scoring 5 points or more on Numerical Rating Scale [NRS]) will be recruited at three hospitals in China. They will be randomly assigned to acupuncture group or sham-acupuncture group at 1:1 ratio to receive 16-session treatment during 3 consecutive menstrual cycles, and follow-up for 6 menstrual cycles after treatment. The primary outcome is the change from baseline in the NRS score on the worst breast pain during the third cycle of treatment period. All statistical tests will be two-sided and P value < 0.05 will be considered statistically significant.Keywords: cyclic breast pain, complementary and alternative medicine, RCT, sham acupuncture

Wenli Hui, Wenhua Mu, Cong Zhao, Dan Xue, Zihua Zhong, Yani Fang, Ming Gao, Xiao Li, Shihao Gao, Kaiyue Liu, Kunping Yan College of Life Science, Northwest University, Xi’an City, Shaanxi Province, 710069, People’s Republic of ChinaCorrespondence: Kunping Yan, Email kpyan@nwu.edu.cnIntroduction: A limitation of hemoglobin-based oxygen carriers (HBOCs) as oxygen therapeutics is unpolymerized hemoglobin, which induces vasoconstriction leading to hypertension. The removal of unpolymerized hemoglobin from polymerized hemoglobin (PolyHb) is complex, expensive, and time-consuming.Methods: Herein, we developed a method to completely polymerize hemoglobin almost without unpolymerized hemoglobin. Hemoglobin was adsorbed on the anion-exchange resin Q Sepharose Fast Flow or DEAE Sepharose Fast Flow, and acetal, a crosslinker prepared from glutaraldehyde and ethylene glycol, was employed to polymerize the hemoglobin. The polymerization conditions, including reaction time, pH, resin type, and molar ratios of glutaraldehyde to ethylene glycol and hemoglobin to acetal, were optimized. The blood pressure and blood gas of mice injected with PolyHb were monitored as well.Results: The optimal polymerization condition of PolyHb was when the molar ratio of glutaraldehyde to ethylene glycol was 1:20, and the molar ratio of 10 mg/mL hemoglobin adsorbed on anion-exchange resin to glutaraldehyde was 1:300 for 60 min. Under optimized reactive conditions, hemoglobin was almost completely polymerized, with < 1% hemoglobin remaining unpolymerized, and the molecular weight of PolyHb was more centrally distributed. Furthermore, hypertension was not induced in mice by PolyHb, and there were also no pathological changes observed in arterial oxygen, blood gas, electrolytes, and some metabolic indicators.Conclusion: The findings of this study indicate that the use of solid-phase polymerization and acetal is a highly effective and innovative approach to HBOCs, resulting in the almost completely polymerized hemoglobin. These results offer promising implications for the development of new methods for preparing HBOCs.Graphical Abstract: Keywords: polymerized hemoglobin, glutaraldehyde, acetal, solid-phase adsorption, hemoglobin-based oxygen carriers, HBOCs

Shenghan Gao,1,2 Xinyu Zhang,1,2 Jie Liu,3 Fuqing Ji,2 Zhihao Zhang,2 Qingjie Meng,2 Qi Zhang,1 Xiaogang Han,2 He Wu,2 Yulong Yin,2 Yonggang Lv,2 Wenzhen Shi3 1The College of Life Sciences, Northwest University, Xi’an, 710069 People’s Republic of China; 2Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China; 3Clinical Medical Center, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of ChinaCorrespondence: Yonggang Lv, Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China, Email lvygwytt@163.com Wenzhen Shi, Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, School of Life Sciences and Medicine, Northwest University, Xi’an, People’s Republic of China, Tel +8615037916770, Email shiwenzhen736@163.comBackground: Breast cancer is a common cancer worldwide. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by a poor prognosis. Icariin (ICA) is a flavonoid glycoside purified from the natural product Epimedium, which is reported to exert an inhibitory effect on a variety of cancers. However, molecular mechanisms behind ICA suppressed TNBC remain elusive.Methods: The curative effects of ICA on TNBC cells and potential targets were predicted by network pharmacology and molecular biology methods screening, and the mechanism of inhibition was explained through in vitro experiments such as cell function determination, Western blot analysis, molecular docking verification, etc.Results: This study showed that ICA inhibits TNBC cell functions such as proliferation, migration, and invasion in a dose-dependent manner. ICA could induce redox‐induced apoptosis in TNBC cell, as shown by ROS upregulation. As a result of network pharmacology, ICA was predicted to be able to inhibit the MAPK signaling pathway. ICA treatment inhibited the expression of JNK and c-Jun and downregulated the antiapoptotic gene cIAP-2. Our results suggested that ICA could induce apoptosis by inducing an excessive accumulation of ROS in cells and suppress TNBC cell invasion via the JNK/c-Jun signaling pathway.Conclusion: We demonstrated that ICA can effectively inhibit cell proliferation and induced apoptosis of TNBC cells. In addition, ICA could inhibit TNBC cell invasion through the JNK/c-Jun signaling pathway. The above suggests that ICA may become a potential drug for TNBC.Keywords: triple-negative breast cancer, icariin, JNK/c-Jun, apoptosis, ROS, invasion

Olga Sergeeva,1 Yifan Zhang,1 Songqi Gao,2 E Ricky Chan,3 Maxim Sergeev,4 Renuka Iyer,5 Sandra Sexton,5 Norbert Avril,4 Zheng-Rong Lu,2 Zhenghong Lee1 1Department of Radiology, Case Western Reserve University, Cleveland, OH, USA; 2Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; 3Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; 4Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 5Medical Oncology and Laboratory Animal Shared Resources, Roswell Park Cancer Institute, Buffalo, NY, USACorrespondence: Zhenghong Lee, Nuclear Medicine, Radiology, Case Western Reserve University, Bolwell S107, 11100 Euclid Avenue, Cleveland, OH, 44106, USA, Tel +1216-844-7920, Email zxl11@case.edu Zheng-Rong Lu, Biomedical Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Ave, Cleveland, OH, 44106, USA, Tel +1 216-368-0187, Email zxl125@case.eduPurpose: We tested a recently developed short peptide radioligand for PET imaging of hepatocellular carcinoma (HCC) by targeting an oncoprotein, extra-domain B fibronectin (EDB-FN) in the tumor microenvironment.Methods: The radioligand consists of a small linear peptide ZD2 with 68Ga-NOTA chelator, and specifically binds to EDB-FN. PET images were acquired dynamically for 1 hour after intravenously (i.v.) injecting 37 MBq (1.0 mCi) of the radioligand into the woodchuck model of naturally occurring HCC. Woodchuck HCC originated from chronic viral hepatitis infection, which recapitulates the corresponding human primary liver cancer. The animals were euthanized post-imaging for tissue collection and validation.Results: For ZD2 avid liver tumors, the radioligand accumulation plateaued a few minutes after injection, while the liver background uptake stabilized 20 min post-injection. The status of EDB-FN in woodchuck HCC was confirmed by histology and validated by PCR and western blocking.Conclusion: We have showed the viability of using the ZD2 short peptide radioligand targeting EDB-FN in liver tumor tissue for PET imaging of HCC, which can potentially impact the clinical care for HCC patients.Keywords: peptide ligand, EDB fibronectin, positron emission tomography, woodchuck model

Xiaonan Meng,1,2,&ast; Jie Sun,3,&ast; Qi Liu,4,&ast; Yueping Huang,5 Xianwen Qiu,6 David Jung Seto,7,8 Ying Li,3 Liping Wang,2 Chunying Li,2 Sen Gao,9 Haikuo Yu,10 Jiping Zhao,1 Baixiao Zhao1 1Department of Acupuncture and Moxibustion, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Acupuncture and Moxibustion, Beijing Huguosi TCM Hospital, Affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Integrated Chinese and Western Medicine Rehabilitation, Beijing Xiaotangshan Hospital, Beijing, People’s Republic of China; 4Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 5School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 6Department of Acupuncture and Moxibustion, Beijing Shichahai Community Healthcare Center, Beijing, People’s Republic of China; 7Division of Integrative Medicine, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; 8Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 9Department of Rehabilitation, Beijing Huguosi TCM Hospital, affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 10Rehabilitation Department, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiping Zhao; Baixiao Zhao, Email zjp7883@sina.com; baixiao100@vip.sina.comBackground: Post-stroke shoulder-hand syndrome (PS-SHS), a common neurological comorbidity after stroke episodes, poses a grave threat on patients’ functional recovery. Preliminary trials have demonstrated that the acupuncture and moxibustion treatment, including a dermal acupuncture tapping method known as plum blossom needling (PBN) can improve pain and motor dysfunctions in patients with PS-SHS. However, there are few reports describing simultaneous moxibustion treatment in combination with PBN. Hence, a novel plum blossom needle device with mild moxibustion (PBNMM) was developed to evaluate its potential efficacy and safety in patients with stage 1 PS-SHS.Materials and Methods: This multicenter, sham-controlled, randomized controlled trial (RCT) will recruit 102 eligible patients with stage 1 PS-SHS from three clinical centers, randomly allocated in a ratio of 1:1:1 to the PBNMM group, PBNMM with no moxa smoke (PBNMM-NMS) group and sham control group. Patients in each group will receive a 30-minute treatment once per day for 4 weeks, with 5 consecutive sessions per week, for a total of 20 sessions. The primary outcome measure will be defined as the decreased scores from baseline in the visual analog scale (VAS) assessment at week 4. Secondary outcome measures will include scores on the Fugl-Meyer Assessment of the Upper Extremity Scale (FMA-UE), the Modified Barthel Index (MBI), and the somatosensory evoked potential (SEP) records. All outcomes will be evaluated at baseline and weeks 4, 5, 6 and 10, and the intention-to-treat analysis will be applied.Conclusion: This study aims to provide robust evidence for the efficacy and safety of the PBNMM for PS-SHS treatment, as well as the specific impact of moxibustion smoke itself in dealing with PS-SHS.Clinical Trial Registration: Chinese Clinical Trial Registry No. ChiCTR2200062441. Registered on 7 August 2022.Keywords: plum blossom needling, mild moxibustion, novel device, post-stroke shoulder-hand syndrome, protocol, randomized controlled trial

Introduction: Lobar torsion is a rare, challenging diagnosis that requires a high index of suspicion and prompt investigation and management. Detection and urgent fixation or lung resection are critical to avoid catastrophic sequelae of lung necrosis, bronchopleural fistulae, and death. Report: A case of lobar torsion following open repair of a type B aortic dissection and thoraco-abdominal aortic aneurysm in a patient with Marfan syndrome is presented. After a non-specific constellation of symptoms, the diagnosis was confirmed with computed tomography and bronchoscopic findings and the patient underwent detorsion and plication of a torted, yet viable, left upper lobe on post-operative day 6. The patient is currently being followed with serial imaging to follow a necrotic consolidation of the left upper lobe. Discussion: This was a case of lobar torsion in a patient with Marfan syndrome and the degree of connective tissue disease may have predisposed the patient to this rare surgical complication. The case presents a challenging dilemma due to the risks associated with exposing a synthetic aortic graft to a potentially infected space if lobar resection or a pneumonectomy was performed.

Qian Xie,1,* Shi Gao,1,* Rui Tian,2 Guohao Wang,3,4 Zainen Qin,5 Minglong Chen,1 Wenhui Zhang,1 Qiang Wen,1 Qingjie Ma,1 Lei Zhu1 1Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130033, People’s Republic of China; 2Department of Ophthalmology Second Hospital, Jilin University, Changchun, 130033, People’s Republic of China; 3Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 4Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 5Department of Oral Radiology, Guangxi Medical University College of Stomatology, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingjie Ma; Lei Zhu, Email maqj@jlu.edu.cn; zeh.ray8@gmail.comIntroduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy.Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5β-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy.Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model.Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.Keywords: chemotherapy, photodynamic therapy, hyaluronic acid, responsive nanoparticle, drug delivery

Yan Xiao,1 Xin-Yue Yao,1 Yong-Hui Wang,1 Lan-Wen Han,1 Lian-Xia Li,1 Ming Li,2 Shan Gao3 1Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Shan Gao, Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xuanwu District, Beijing, 100053, People’s Republic of China, Tel +8613910599635, Email gaoshanmw@163.comPurpose: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular disease which increases the risk of heart failure. This study aimed to determine whether clinical characteristics and subclinical cardiovascular disease (CVD) features are correlated with echocardiographic morpho-functional parameters of T2DM patients.Patients and Methods: Two hundred and fifty-five T2DM patients without a history of coronary heart disease were enrolled in this cross-sectional study. The demographic characteristics, glucose and lipid levels were assessed for each patient. Carotid ultrasonography and peripheral artery examination were performed to measure carotid intima-media thickness (cIMT), carotid plaque, ankle-brachial index (ABI), brachial artery pulse wave velocity (baPWV), and carotid-femoral pulse wave velocity (cfPWV). Furthermore, echocardiography was conducted to evaluate cardiac morphology and systolic and diastolic function. The relationship between clinical characteristics, subclinical cardiovascular diseases, and cardiac morpho-functional parameters was explored with the Pearson and stepwise multivariable linear regression analyses.Results: A total of 255 subjects aged 18– 80 years were enrolled in the study. Multiple regression analysis revealed that left ventricular mass index (LVMI) was correlated with age (β=0.463, p = 0.000) and systolic blood pressure (SBP) (β=0.179, p = 0.003). Relative wall thickness (RWT) was related to cfPWV (β=0.006, p = 0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (β=0.000, p = 0.036). In contrast, left ventricular ejection fraction (LVEF) was inversely related to cIMT (β=− 0.925, p = 0.019). The ratio of the peak flow velocity of early diastole to atrial contraction (peak E/A) was correlated with age (β=− 0.014, p = 0.000), diastolic blood pressure (DBP) (β=− 0.006, p = 0.001) and cfPWV (β=− 0.025, p = 0.044).Conclusion: In preclinical stage A/B heart failure adults with T2DM, age, BP, HOMA-IR, cfPWV and cIMT are correlated with cardiac morpho-functional parameters.Keywords: type 2 diabetes mellitus, preclinical stage A/B heart failure, subclinical cardiovascular diseases, echocardiography

Siyu Gao1 &ast;, Lingfeng Li2 &ast;, Xiaolin Zhou,1 Xiangcheng Dai,1 Lu Lu,1 Yandong Chen,1 Jing Han,1 Xiaoli Huang,1 Qian Xiao,1 Huiqing He,3 Qiang Liu1 1Yichang Central People’s Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, People’s Republic of China; 2Department of Critical Care Medicine, Dongguan Institute of Respiratory and Critical Care Medicine, Dongguan People’s Hospital, Dongguan, Guangdong, People’s Republic of China; 3Centers for Disease Control and Prevention, Yichang, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Liu, Email stellarray@126.comBackground: Severe complications may cause a fatal or disabling outcome in patients with Rickettsia japonica infection but are poorly understood.Methods: We identified 11 patients with only Rickettsia japonica infection with metagenomics next generation sequencing (mNGS) during April to November 2021 at Yichang Central People’s Hospital, China. Clinical data were obtained through review of medical records.Results: Most patients realized that they had symptoms about one or two days after being bitten. Fever (91%), pulmonary effusion (91%), rash or erythema (100%), abnormal urine (100%), neutropenia (100%), lymphopenia (100%), and thrombocytopenia (100%) were the most common clinical signs. Six severely ill patients were admitted to the intensive care unit and five had mild symptoms. Systemic manifestations such as vomiting (83%), neurological manifestations (100%), and disseminated intravascular coagulation (100%) were more frequently observed in the severe cases, 33.3% of whom developed purpura fulminans requiring amputation or skin graft, and 16.6% died two days after admission. Some patients experienced sequelae.Conclusion: Our study found that patients with critical Rickettsia japonica infection complicating disseminated intravascular coagulation had high risk of poor outcome.Keywords: Rickettsia japonica, Japanese spotted fever, infection, tick, disseminated intravascular coagulation, purpura fulminans

Siting Gao,1– 3 Qin Feng1– 3 1Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Hepatopathy Building, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Qin Feng, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 1200 Zhangheng Road, Pudong District, Shanghai, People’s Republic of China, Tel +86 13764380682, Fax +86 021-51322043, Email fengqin@shutcm.edu.cnAbstract: Geniposide is a naturally sourced active ingredient that has diverse pharmacological effects and great potential in improving or treating different kinds of diseases. In recent years, more and more studies have confirmed that geniposide can improve glucose and lipid metabolism disorder, which is an increasingly prevalent health problem causing various metabolic diseases globally. Our review aims to summarize basic information on the pharmacological effects of geniposide on glucolipid metabolism. Geniposide increases glucose utilization and insulin production, protects pancreatic islet β cells, inhibits insulin resistance and hepatic glucose production, and suppresses gluconeogenesis. While in the aspect of lipid metabolism, geniposide can promote lipolysis, inhibit lipogenesis, and regulate lipid transport. Geniposide ameliorates lipid and glucose metabolic disorders, improving the entire glycolipid metabolism network in a three-dimensional manner at the level of molecular mechanism. Growing evidence revealed that geniposide may serve as an effective drug to combat metabolic diseases for the time to come.Keywords: geniposide, lipid metabolism, glucose metabolism, Gardenia Jasminoides Ellis, metabolic disease, glucolipid metabolism, naturally sourced active ingredient, pharmacological evidence

Zhuohui Luo,1 Yongcheng Wang,2 Shuo Pang,1 Shan Gao,1 Ning Liu,1 Xiang Gao,1 Li Zhang,1,3 Xiaolong Qi,1,3 Yajun Yang,2 Lianfeng Zhang1,3 1Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, People’s Republic of China; 2Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People’s Republic of China; 3Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yajun Yang, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Nanwei Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email yangyajun@imm.ac.cn Lianfeng Zhang, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel +86 10-87778442, Fax +86 10-67776394, Email zhanglf@cnilas.orgAim: Alzheimer’s disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.Purpose: The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.Materials and Methods: Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H2O2 and Aβ1– 42 oligomers (AβOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AβOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques.Results: wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.Conclusion: wyc-7-20 was potent in AD therapy.Graphical abstract: Keywords: 1,2,4-oxadiazole, Alzheimer’s disease, animal model, neuroprotective effect

Mei Ma,1,&ast; Yijia Liu,1,&ast; Lichun Wang,2,&ast; Rongrong Yang,1 Zhu Li,1 Sheng Gao,3 Lin Li,1 Chunquan Yu1 1Department of Graduate Schools, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2Department of Information Center, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Department of Endocrine Metabolic Diseases, Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Li, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China, Email llbianji@163.com Sheng Gao, Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin, People’s Republic of China, Email gaosheng6747@163.comPurpose: This study explored the relationship between monocyte-to-lymphocyte ratio (MLR) as well as other leukocyte-derived ratios and carotid plaques in patients with coronary heart disease (CHD).Patients and Methods: A total of 12,093 patients with CHD were selected as research participants. Leukocyte-derived ratios assessed in this study included neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), MLR, platelet-to-lymphocyte ratio (PLR), white blood cell-to-mean platelet volume ratio (WMR), lymphocyte×neutrophil/104 ratio (MNM), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI). Leukocyte-derived ratios were divided into four groups according to quarters. Logistic regression analysis was performed to evaluate the relationship between leukocyte-derived ratios and the incidence, number, and echo characteristics of carotid plaques in patients with CHD. Further analysis was performed after adjusting for confounding factors.Results: Among the 12,093 participants, 71.7% had carotid plaques. After adjusting for confounding factors, MLR, NLR, dNLR, PLR, SII, SIRI, and WMR were found to be associated with carotid plaque formation. Among them, MLR had the strongest association with the incidence of carotid plaques (odd ratio[OR]:1.889; 95% confidence interval[CI]:1.406– 2.539) and hyperechoic plaques (OR:2.024; 95% CI:1.481– 2.767). When MLR was viewed as a categorical variable, the risk of carotid plaque formation in Q4 was 1.4 times higher than that in Q1. The relationship between MLR and carotid plaques in females (OR:2.250; 95% CI:1.458– 3.473) was stronger than that in males (OR: 1.638; 95% CI:1.102–-2.436). The relationship between MLR and carotid plaques in patients younger than 65 years (OR:3.597; 95% CI:2.379– 5.439) was stronger than that in those older than 65 years (OR:1.577; 95% CI:1.046– 2.378).Conclusion: Leukocyte-derived ratios were related to the incidence, number, and echo characteristics of carotid plaques. In particular, MLR, an inflammatory biomarker that encompasses innate and adaptive immunity, may be of great value in revealing the incidence and echo characteristics of plaques.Graphical Abstract: Keywords: coronary heart disease, leukocyte-derived ratios, monocyte-to-lymphocyte ratio, carotid plaque

Fenfen Gu,1,&ast; Chuling Hu,2,&ast; Wei Cao,3,&ast; Chao Li,1 Qingming Xia,4 Yuan Gao,4 Yan Liu,1 Shen Gao1,4 1Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Jiaxing Maternity and Child Health Care Hospital, Jiaxing, People’s Republic of China; 3Department of Neurovascular Disease, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 4Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shen Gao; Yan Liu, Tel/Fax +86 21 81873715 ; +86 21 25077156, Email liullk@126.com; liuyan03@xinhuamed.com.cnIntroduction: Currently, the main treatment for advanced breast cancer is still chemotherapy. Immunological and chemical combination therapy has a coordinated therapeutic effect and achieves some efficacy. However, the immunosuppressive tumor microenvironment is a major cause for the failure of immunotherapy in breast cancer. CpG oligodeoxynucleotides can activate the tumor immune microenvironment to reverse the failure of immunotherapy.Methods: In this study, we designed an amphiphilic peptide micelle system (Co-LMs), which can targeted delivery of the immune adjuvant CpG and the chemotherapeutic drug doxorubicin to breast cancer tumors simultaneously. The peptide micelle system achieved tumor microenvironment pH and redox-sensitive drug release.Results and Discussion: Co-LMs showed 2.3 times the antitumor efficacy of chemotherapy alone and 5.1 times the antitumor efficacy of immunotherapy alone in triple-negative breast cancer mice. Co-LMs activated cytotoxic CD8+ T lymphocytes and CD4+ T cells in mice to a greater extent than single treatments. We also found that Co-LMs inhibited the metastasis of circulating tumor cells in the bloodstream to some extent. These results indicate that the Co-LMs offer a promising therapeutic strategy against triple-negative breast cancer.Keywords: chemo-immunotherapy, tumor microenvironment, CpG, nanoparticles, triple-negative breast cancer

Li Li,1 Rongjin Sun,1 Joseph Zenga,2 Heather Himburg,3 Lu Wang,1 Shengnan Duan,1 Jingwen Liu,1 Dinh Bui,1 Zuoxu Xie,1 Ting Du,4 Lijun Xie,1 Taijun Yin,1 Stu Wong,2 Song Gao,4 Ming Hu1 1Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Ming Hu, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA, Email mhu@uh.edu Song Gao, Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA, Email Song.Gao@tsu.eduObjective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11– 17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.Graphical Abstract: Keywords: cyclooxygenase-1, cyclooxygenase-2, turnover number, inflammation, absolute quantification, liquid chromatography with tandem mass spectrometry

Caihua Wu,1 Yongmin Liu,2 Kexing Wan,2 Yuye Lan,2 Min Jia,3 Lixue Lin,4 Shan Gao,1 Ke Chen,1 Jinmei Yang,1 Hui-Lin Pan,5 Man Li,2 Hongrong Mao1 1Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 2Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China; 3Clinical Laboratories, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 4Department of Rehabilitation, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 5Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USACorrespondence: Hongrong Mao, Department of Acupuncture, Wuhan First Hospital, 215 Zhongshan Avenue, Wuhan, Hubei Province, 430030, People’s Republic of China, Tel +86-13277912052, Email 1838269751@qq.comPurpose: The ultrapotent transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX) induces small-fiber sensory neuropathy, which has been widely used model of postherpetic neuralgia to study mechanisms of neuropathic pain and new analgesics. The long non-coding RNA (lncRNA) and mRNA expression profiles in spinal dorsal horn tissues of rats six weeks after RTX injection to identify new RNAs related to neuropathic pain.Methods: Microarray technology was applied to determine lncRNA expressions in spinal dorsal horn samples of adult rats 6 weeks after treatment with RTX or vehicle. The lncNA/mRNA co-expression network was constructed, and differential expression patterns of lncRNA and mRNA in RTX-treated rats were identified. Differential expressions of lncRNAs and mRNAs between RTX-treated samples and control samples were examined by RT-qPCR.Results: Microarray analyses showed that 745 mRNA and 139 lncRNAs were upregulated, whereas 590 mRNA and 140 lncRNAs were downregulated in spinal dorsal horn tissues after RTX exposure. TargetScan was used to predict mRNA targets for these lncRNAs, which showed that the transcripts with multiple predicted target sites were related to neurologically important pathways. In addition, differential expressions of lncRNA (ENSRNOG00000022535, ENSRNOG00000042027, NR_027478, NR_030675) and Apobec3b mRNA in spinal cord tissue samples were validated, which confirmed the microarray data. The association between NR_030675 and Apobec3b levels was confirmed, which may be related to neuropathic pain.Conclusion: Our study reveals lncRNA and mRNA of molecule targets that are enriched in the spinal cord dorsal horn and provides new information for further investigation on the mechanisms and therapeutics of neuropathic pain.Keywords: postherpetic neuralgia, lncRNAs, microarray, spinal dorsal horn

Hongqiang Lou, Xusheng Li, Suhua Gao, Yanfang Zhang, Haohao Chen, Xia Zhai Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua City, Zhejiang Province, 330700, People’s Republic of ChinaCorrespondence: Xia Zhai, Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, 1188 Wuzhou Street, Jinhua City, Zhejiang Province, 321000, People’s Republic of China, Email 20211049@jhc.edu.cnAbstract: Background: Coronavirus disease 2019 (COVID-19) greatly affects cancer patients, especially those with lung cancer. This study aimed to identify potential drug targets for lung adenocarcinoma (LUAD) patients with COVID-19.Methods: LUAD samples were obtained from public databases. Differentially expressed genes (DEGs) related to COVID-19 were screened. Protein–protein interactions among COVID-19-related genes, the traditional Chinese medicine (TCM) and TCM target genes were analyzed by CytoScape. The correlation between tumor microenvironment and COVID-19 target genes were assessed by Pearson correlation analysis. Unsupervised consensus clustering was conducted to categorize molecular subtypes.Results: We filtered 26 COVID-19 target genes related to TCM for LUAD. Interleukin (IL)-17 signaling pathway and tumor necrosis factor (TNF) signaling pathway were significantly enriched in these 26 genes. A strong correlation was found between COVID-19 target genes and tumor microenvironment (TME), cell death. Importantly, interleukin-1beta (IL1B) was identified as a core gene in the protein–protein interactions (PPI) network. Based on the 26 target genes, two molecular subtypes showing distinct overall survival, TME and response to target therapy were developed.Conclusions: This study explored 26 COVID-19 target genes, which could serve as potential therapeutic drug targets for LUAD. IL1B was verified as a critical target for developing new molecular drugs. Furthermore, two novel molecular subtypes showed the potential to guide personalized therapies in clinical practice.Keywords: COVID-19, lung adenocarcinoma, traditional Chinese medicine, drug targets, tumor microenvironment, molecular subtypes

Wanbing Feng,1– 6 Di Zhang,1– 6 Linlin Fu,1– 6 Jingmei Hu,1– 6 Shanshan Gao,1– 6 Xiaocui Song,1 Linlin Cui1– 6 1Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, People’s Republic of China; 4Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China; 5Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, People’s Republic of China; 6National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Linlin Cui; Xiaocui Song, Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 157, Jingliu Road, Shizhong District, Jinan, Shandong, People’s Republic of China, 250001, Tel +86 531 85651598, Fax +86 531 87068226, Email fdclear3@126.com; babyjuncong@163.comObjective: To investigate the effect of maternal estradiol (E2) elevation on long-term metabolic manifestations in the offspring.Study Design and Setting: This was a retrospective cohort study. Overall, 3690 children conceived by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) between July 2014 and December 2017 were recruited and divided into four groups categorized by maternal E2 quartiles (Q1, < 2420; Q2, 2420– 3839; Q3, 3839– 5599; and Q4, ≥ 5599 pg/mL). The metabolic profiles were measured during childhood. Linear mixed models were used to evaluate the association between maternal E2 elevation and metabolic phenotypes of the offspring.Results: Lipoprotein cholesterol (LDL-C) was significantly higher in the highest quartile group than in the lowest quartile group during infancy (adjusted mean difference [95% confidence interval, CI]): 0.11 [0.02, 0.20], P = 0.005), but the difference disappeared in the later childhood phase. In children born after fresh embryo transfer, LDL-C showed an increasing trend with the increase in maternal E2 level (adjusted mean difference [95% CI]: Q2 vs Q1, − 0.01 [− 0.11, 0.08], Q3 vs Q1, 0.06 [− 0.04, 0.15], Q4 vs Q1, 0.10 [0, 0.20]). Other metabolic variables were comparable across increasing quartiles of maternal E2 levels.Conclusion: This study demonstrates a temporary increase in LDL-C levels in infants with higher levels of maternal preconception E2 levels. However, the long-term safety of hyperestrogens after ovarian stimulation in the next generation is favorable. The mechanism underlying the transiently increased metabolic dysfunction risk in infants conceived by IVF/ICSI requires investigation in future studies.Keywords: offspring, supraphysiologic estradiol, controlled ovarian hyperstimulation, assisted reproductive technology

Xiaonan Meng,1 Liping Wang,1 Chunying Li,1 Sen Gao,2 Haikuo Yu,3 Lufen Zhang,4 Jie Sun5 1Acupuncture Department, Beijing Huguosi TCM Hospital, affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Rehablitation Department, Beijing Huguosi TCM Hospital, affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Rehabilitation Department, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China; 4School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Rehabilitation Department of Integrated Chinese and Western Medicine, Beijing Xiaotangshan Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jie Sun, Rehabilitation Department of Integrated Chinese and Western Medicine, Beijing Xiaotangshan Hospital, No. 390 Spring Road, Changping District, Beijing, 102211, People’s Republic of China, Email jiesun1109@gmail.comObjective: This study aims to evaluate the safety and efficacy of various levels of moxibustion smoke concentration (MSC), represented by particulate matter 10mm (PM10), on pain and motor dysfunction in patients with stage 1 post-stroke shoulder-hand syndrome (SHS).Materials and Methods: In this multi-center, sham-controlled, single-blind, randomized controlled trial (RCT), a total of 140 eligible patients with stage 1 post-stroke SHS will be recruited from March 2022 to February 2023 and randomly allocated to five groups in a ratio of 1:1:1:1:1. Moxibustion, in addition to standard medical care, will be applied to subjects in all groups. No acupoints on the affected upper limb will be utilized. Moxibustion smoke therapy, with varying levels of MSC, will be applied to the five groups as follows: (A) sham control group, (B) zero MSC group, (C) low MSC group, (D) medium MSC group, and (E) high MSC group. Patients in each group will be treated for 20 minutes per session, with five sessions each week, over a course of six weeks, with a total follow-up interval of eight weeks. The primary outcome measure will be a visual analog scale (VAS) assessment of the intensity of regionalized pain in the affected upper limb. Secondary outcome measures will include scoring on the Fugl-Meyer Assessment of the Upper Extremity Scale (FMA-UE), the Modified Barthel Index (MBI) and the measurement of somatosensory evoked potential (SEP). All participants will be evaluated before treatment, during treatment (ie, at two weeks and four weeks), immediately after concluding treatment (ie, at six weeks) and at two weeks post-treatment (ie, at eight weeks). Intention-to-treat analysis will be applied.Trial Registration Number: ChiCTR2100043076.Keywords: moxibustion smoke concentration, shoulder-hand syndrome, stroke, protocol, randomized controlled trial

Siqi Gao,&ast; Yifeng Yu,&ast; Zheng Wang, Yifan Wu, Xingan Qiu, Chao Jian, Aixi Yu Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Chao Jian, Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China, Tel +86-27-6781-3120 ; +86-27-6781-3120, Email yuaixi@whu.edu.cn; chaojian@whu.edu.cnPurpose: Currently, skin avulsion–injury reconstruction is mainly based on subjective evaluation of traditional clinical signs. It frequently results in unnecessary tissue loss and incomplete debridement-related infection. This pilot study aimed to develop a novel near-infrared (NIR) II fluorescence imaging method to assess avulsed skin–perfusion status and thus predict its outcome early.Methods: Skin avulsion–injury models were established by avulsing 10× 4 cm pedicled flaps on porcine hindlimbs. A clinically available improved NIR-&Igr;/II multispectral imaging system was applied for NIR imaging using indocyanine green (ICG) fluorescence. Continuous NIR-wavelength filters and dynamic imaging were used to investigate optimal imaging conditions and time window. NIR-&Igr;/II imaging was synchronously conducted for quality comparison of the two methods. Visual inspection and histological studies were used for assessing the final outcome of avulsed skin.Results: NIR-II fluorescence imaging with a 1,100 nm filter obtained satisfactory performance and reached maximum fluorescence intensity at 1 minute after ICG injection. NIR-II imaging clearly visualized the microvascular network in vascularized avulsed skin and revealed “dark areas” in nonvascularized avulsed skin in a real-time fashion. NIR-II fluorescence imaging demonstrated higher resolution than NIR-I imaging, as indicated by ae higher signal-to-background ratio (2.11) and lower full width at half maximum (6.50614). The dark area of avulsed skin on imaging finally developed to necroses that were confirmed by histology.Conclusion: NIR-II real-time fluorescence imaging clearly maps the microvascular network and shows the perfusion status of avulsed skin at higher resolution than traditional NIR-I imaging, and thus precisely predicts the outcome of avulsed skin early.Keywords: ICG, near-infrared fluorescence imaging, skin avulsion-injury, swine model

Jiaqiang Wang,1 Shilei Gao,1 Yonghao Yang,2 Xu Liu,1 Peng Zhang,1 Shuping Dong,1 Xin Wang,1 Weitao Yao1 1Department of Orthopedics, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of China; 2Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaCorrespondence: Jiaqiang WangDepartment of Orthopaedics, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaTel +86-18737187831Fax +86-371-65961505Email doctorwangjiaqiang@126.comPurpose: Advanced clear cell sarcoma (CCS) is a rare subtype of sarcoma with few effective treatments. Evidence shows that apatinib is efficacious and safe for CCS. This study aimed to assess the safety and efficacy of apatinib and/or camrelizumab (a PD-1 inhibitor) in treating advanced CCS.Methods: We retrospectively reviewed 12 patients with advanced CCS who received apatinib and/or camrelizumab therapy between November 2018 and July 2021. Standard descriptive statistics were employed for continuous variables and categorical variables (number and percentage).Results: Of the 12 CCS patients, 3 had a partial response (PR), and 4 had stable disease (SD). Among the 5 patients treated with apatinib monotherapy, 1 PR and 2 SD were found, and the addition or replacement of camrelizumab after progressive disease (PD) did not work. In the 4 patients who received apatinib plus camrelizumab combination therapy, 1 PR and 1 SD were found. All 3 patients who received camrelizumab first had PD, and 1 PR and 1 SD were found after adding apatinib. Grade 3 or 4 adverse events were significantly more common in the apatinib plus camrelizumab combination therapy than in the apatinib or camrelizumab monotherapy, and these included increased aspartate aminotransferase and increased alanine aminotransferase levels.Conclusion: Apatinib has promising effectiveness for CCS. Camrelizumab efficacy for the treatment of clear cell sarcoma is inconclusive. The efficacy of apatinib and PD-1 inhibitors in CCS need to be further investigated in prospective clinical trials.Keywords: clear cell sarcoma, apatinib, camrelizumab, sarcoma, tyrosine kinase inhibitor, PD-1 inhibitor

Shenghan Gao,1,2 Xinyu Zhang,1,2 Jie Liu,3 Yonggang Lv,2 Wenzhen Shi3 1The College of Life Sciences, Northwest University, Xi’an, 710069, People’s Republic of China; 2Department of Thyroid Breast Surgery, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China; 3Clinical Medical Center, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi’an, People’s Republic of ChinaCorrespondence: Yonggang Lv, Department of Thyroid Breast Surgery, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China, Email lvygwytt@163.com Wenzhen Shi, Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, School of Life Sciences and Medicine, Northwest University, Xi’an, People’s Republic of China, Tel +8615037916770, Email shiwenzhen736@163.com

Jiaqiang Wang,1 Shuping Dong,1 Jianpo Zhang,2 Shilei Gao,1 Zhehuang Li,1 Po Li,1 Junhui Yuan,3 Zhichao Tian1 1Department of Bone and Soft Tissue, the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of China; 2Pathology Department, the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of China; 3Medical Imaging Department, the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaCorrespondence: Zhichao TianDepartment of Bone and Soft Tissue, the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Dongming Road, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaTel +86-13592413731Fax +86-371-65961505Email tianzhichaoyy@163.comBackground: Although the annual incidence of undifferentiated pleomorphic sarcoma (UPS) is extremely low, it can be subdivided into different subtypes. UPS with fever of unknown origin (also known as neoplastic fever) is a specific subtype of UPS, which shows certain clinical features that differentiate it from other UPS subtypes. However, no studies have focused on this rare UPS subtype. This study retrospectively analyzed the clinical data of patients with UPS to provide a reference for the diagnosis and treatment of UPS with neoplastic fever.Methods: This study included patients with UPS who were diagnosed and treated between June 2012 and June 2018. We examined whether these patients had a history of neoplastic fever. The characteristics of patients with UPS with neoplastic fever were summarized and analyzed.Results: We reviewed the medical records of 183 patients with UPS. Seven (3.83%) of these patients had neoplastic fever. In patients with UPS with neoplastic fever, the primary lesions were located in the extremities and across the muscle space. In these patients, magnetic resonance imaging showed necrosis within the tumor body and extensive soft tissue edema around the tumor body. Patients with UPS with neoplastic fever had a lower metastasis rate (14.29% vs 44.94%) and a higher 3-year survival rate (85.71% vs 59.55%) than those without neoplastic fever.Conclusion: UPS with neoplastic fever is characterized by intratumoral necrosis and extensive edema of the surrounding soft tissues. Patients with UPS with neoplastic fever may have a better prognosis than those without neoplastic fever.Keywords: undifferentiated pleomorphic sarcoma, neoplastic fever, fever of unknown origin, sarcoma

Ruirui Zhang,1 Shanjun Gao,2 Shenghui Wang,3 Jiewen Zhang,1,3 Yingying Bai,3 Shuang He,3 Pan Zhao,3 Hongju Zhang1,3 1Department of Neurology, Henan Provincial People’s Hospital Affiliated to Henan University, Zhengzhou, Henan, People’s Republic of China; 2Microbiome Laboratory, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 3Department of Neurology, Henan Provincial People’s Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Hongju ZhangDepartment of Neurology, Henan Provincial People’s Hospital Affiliated to Henan University, Zhengzhou, Henan, People’s Republic of ChinaEmail hongjuz@sina.comPurpose: To explore the characteristics of gut microbiota and its relationship between clinical manifestations in patients with type 1 narcolepsy (NT1).Patients and Methods: Scale and polysomnography were performed in 20 NT1 patients and 16 healthy controls (HC group) to evaluate the clinical characteristics of NT1. Illumina sequencing was performed on bacterial 16S ribosomal RNA gene using V3-V4 regions to compare the fecal microbiota in all subjects. Associations between clinical characteristics and gut microbiota were analyzed using partial correlation analysis.Results: Compared with the HC group, the NT1 group had a significantly higher ESS score, longer total sleep time, increased wakefulness, decreased sleep efficiency, disturbance of sleep structure, shorter mean sleep latency, and increased sleep-onset REM periods (all P < 0.05). No differences in alpha and beta diversity were observed between the two groups. In contrast, there were significant differences at the level of class, order, family, and genus (all P < 0.05). LEfSe analysis showed that the relative abundance of Klebsiella in the NT1 group was higher than that in the HC group (P < 0.05), while the relative abundance of Blautia, Barnesiellaceae, Barnesiella, Phocea, Lactococcus, Coriobacteriia, Coriobacteriales, Ruminiclostridium_5, and Bilophila were lower (all P < 0.05). Partial correlation analysis revealed that partial differential bacteria in the NT1 group were correlated with total sleep time, sleep efficiency, stage 1 sleep, arousal index, and sleep latency (all P < 0.05).Conclusion: Our data revealed differences in intestinal flora structure between NT1 patients and the normal population, thus providing a theoretical basis for future microecological therapy for narcolepsy. However, future larger sample size studies and different study designs are needed to further clarify the possible pathogenesis and potential causality of intestinal flora in NT1 patients and explore the new treatment strategies.Keywords: type 1 narcolepsy, gut microbiota, 16SrRNA, high throughput sequencing

Yanyun Li,1,&ast; Ying-Xin Gong,1,&ast; Qing Wang,1 Shujun Gao,1 Hongwei Zhang,1 Feng Xie,1 Qing Cong,1 Limei Chen,1 Qi Zhou,1 Zubei Hong,2 Lihua Qiu,2 Fang Li,3 Yu Xie,1 Long Sui1 1Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Gynecology and Obstetrics, Renji Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Gynecology and Obstetrics, Shanghai Dongfang Hospital of Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Long Sui; Yu XieObstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200011, People’s Republic of ChinaTel +86-21-33189900Fax +86-21-63450900Email suilong@fudan.edu.cn; yuxie18@fudan.edu.cnPurpose: Early-stage cervical cancer is usually diagnosed by colposcopy-directed biopsy (CDB) and/or endocervical curettage (ECC), but some neglected lesions must be detected by conization because they are occult. This study aimed to explore the optimal method for detecting these “occult” cervical cancers.Patients and Methods: A total of 1299 patients who were high-risk for early-stage cervical cancer from five centres in China were prospectively included. We evaluated the diagnostic performance of cytology, HPV testing, colposcopy and CDB&ECC for detecting “occult” cervical cancer and discussed the diagnostic importance of transformation zone (TZ) type, conization length and the proportion of cervical cone excision.Results: The diagnostic agreement between colposcopy impression and conization was 64.5% and 72.4% between CDB&ECC and conization. Forty-two patients were finally diagnosed with pathologic cancer, and the sensitivities of cytology, colposcopy, CDB&ECC were 4.8%, 7.1%, and 47.4%, respectively. Twenty cases were neglected by CDB&ECC but further diagnosed as cancer by conization, considered to be occult cervical cancer, accounting for 1.6%. Cytologic high-grade squamous intraepithelial lesion (HSIL)+, positive HPV, biopsy HSIL+ and cervical TZ type 3 were considered risk factors for developing HSIL+, while colposcopy impression HSIL+ was not. There was a significant difference between cancerous and HSIL patients in the proportion of cervical cone excision (P< 0.001), which was recognized as a risk factor (P< 0.001) for detecting cancer, while the length of cervical cone excision was not. The average proportion was 0.62, and the minimal effective proportion was 0.56.Conclusion: Since the incidence of occult cervical cancer neglected by CDB&ECC, colposcopy and cytology was far beyond expectations, conization is necessary, especially in patients with TZ type 3, high-grade cytology and biopsy results. As the cervical length varies in patients, the proportion of cervical cone excision might be a better indicator for detecting occult cervical cancer.Keywords: cervical conization, colposcopy-directed biopsy, high-grade intraepithelial lesion, length proportion, occult cervical cancer, transformation zone