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Xiaojing Wang, Qinli Guo, Zhaoxiang Liu, Yanlei Wang, Chenxiang Cao, Lixia Jin, Caihong Li, Jianzhong Xiao, Wenhui Zhao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Wenhui Zhao, Department of Endocrinology, Beijing Tsinghua Changgung Hospital, LiTang Lu No. 168, Chang Ping District, Beijing, 102218, People’s Republic of China, Tel +86-13810719795, Email zwha01637@btch.edu.cnPurpose: Obesity has become a major public health concern worldwide, increasing the risk of T2DM. Growing evidence indicates gut microbiota dysbiosis is related to metabolic disorders. We aimed to firstly investigate the compositional and functional features of the gut microbiome between obesity with and without T2DM in the Chinese population.Methods: A total of 32 obese individuals accompanied with T2DM and 18 age and gender-matched obesity with normal glucose tolerance (NGT) were enrolled. Fecal samples were collected, and the gut microbiota profile was determined using the Illumina MiSeq platform based on V3-V4 bacterial 16S rRNA gene.Results: Compared with obesity- NGT, obesity-T2DM showed a significantly higher alpha diversity. Principal coordinates analysis based on both Bray-Curtis distance and weighted Unifrac revealed that the global microbial composition was significantly different between the two groups (P = 0.007 and P = 0.005, respectively). At the phylum level, Obesity-T2DM patients exhibited a significant decrease in Bacteroidetes, and a pronounced increase in Firmicutes. Regarding the genus level, Bacteroides and Escherichia-Shigella were found to increase considerably, while Prevotella_9 and Sutterella had an evident decrease in Obesity-T2DM. Furthermore, Spearman correlation analysis revealed that Prevotella_9 and Sutterella were negatively associated with HbA1c and fasting blood glucose.Conclusion: We found clear differences in the gut microbiota composition in obesity-T2DM compared with obesity-NGT. Obesity accompanied with T2DM may aggravate the obesity-associated gut microbiota, and gut microbiota is expected to be a promising novel intervention target for obese management. However, larger sample size and more in-depth taxonomic identification studies are warranted.Keywords: gut microbiota, obesity, type 2 diabetes

Xiangan Gong,1,2 Qian Zhao,1,2 Huimin Zhang,1,2 Rui Liu,1,2 Jie Wu,1,2 Nanxin Zhang,3 Yuanxian Zou,1,2 Wen Zhao,1,2 Ran Huo,1,2,4 Rongtao Cui1– 4 1Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 2Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 3School of Clinical Medicine, Shandong Second Medical University, Weifang, People’s Republic of China; 4Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Rongtao Cui, Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China, Tel +86 18653170822, Email cuirt1986@outlook.comAbstract: Pathological scarring results from aberrant cutaneous wound healing due to the overactivation of biological behaviors of human skin fibroblasts, characterized by local inordinate inflammation, excessive extracellular matrix and collagen deposition. Yet, its underlying pathogenesis opinions vary, which could be caused by increased local mechanical tension, enhanced and continuous inflammation, gene mutation, as well as cellular metabolic disorder, etc. Metabolic reprogramming is the process by which the metabolic pattern of cells undergoes a systematic adjustment and transformation to adapt to the changes of the external environment and meet the needs of their growth and differentiation. Therefore, the abnormality of metabolic reprogramming in cells within wounds and scars attaches great importance to scar formation. Mesenchymal stem cells-derived exosomes (MSC-Exo) are the extracellular vesicles that play an important role in tissue repair, cancer treatment as well as immune and metabolic regulation. However, there is not a systematic work to detail the relevant studies. Herein, we gave a comprehensive summary of the existing research on three main metabolisms, including glycometabolism, lipid metabolism and amino acid metabolism, and MSC-Exo regulating metabolic reprogramming in wound healing and scar formation for further research reference.Keywords: mesenchymal stem cells-derived exosomes, metabolic reprogramming, scar, wound healing, fibroblast

Jing Wang,1,* Lei Tian,2,* Weilong Zhang,1,* Shuhan Tang,1 Wei Zhao,1 Yu Guo,1 Chaoling Wu,1 Yuansheng Lin,1 Xiaoyan Ke,1 Hongmei Jing1 1Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Health Management Center, Peking University Third Hospital, Beijing, 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyan Ke; Hongmei Jing, Email xykbysy@163.com; hongmeijing@bjmu.edu.cnBackground: The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL).Methods: Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases.Results: Our findings highlighted significantly elevated mutation frequencies of TP53, MEF2B and CD58 in diagnostic biopsies from patients who progressed to relapse or refractory disease, with CD58 mutations exclusively observed in the rrDLBCL group. In assessing the predictive power of mutation profiles for treatment responses in primary DLBCL patients, we found that the frequency of CARD11 mutations was substantially higher in non-response group as compared with those who responded to immunochemotherapy. In addition, we revealed mutations in HIST2H2AB, BCL2, NRXN3, FOXO1, HIST1H1C, LYN and TBL1XR1 genes were only detected in initial diagnostic biopsies, mutations in the EBF1 gene were solely detected in the rrDLBCL patients.Conclusion: Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of CD58 mutations might serve as a powerful predictive marker for relapse/refractory outcomes in primary DLBCL patients.Keywords: targeted sequencing, mutation profile, relapse/refractory disease, diffuse large B-cell lymphoma

Tingting Wang,1 Juntao Tan,2 Tiantian Wang,2 Shoushu Xiang,2 Yang Zhang,1 Chang Jian,1 Jie Jian,1 Wenlong Zhao1,3 1College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Operation Management Office, Affiliated Banan Hospital of Chongqing Medical University, Chongqing, 401320, People’s Republic of China; 3Medical Data Science Academy, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wenlong Zhao, College of Medical Informatics, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-13883163651, Email cqzhaowl@163.comPurpose: Hospitalized hypertensive patients rely on blood pressure medication, yet there is limited research on the sole use of amlodipine, despite its proven efficacy in protecting target organs and reducing mortality. This study aims to identify key indicators influencing the efficacy of amlodipine, thereby enhancing treatment outcomes.Patients and Methods: In this multicenter retrospective study, 870 hospitalized patients with primary hypertension exclusively received amlodipine for the first 5 days after admission, and their medical records contained comprehensive blood pressure records. They were categorized into success (n=479) and failure (n=391) groups based on average blood pressure control efficacy. Predictive models were constructed using six machine learning algorithms. Evaluation metrics encompassed the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). SHapley Additive exPlanations (SHAP) analysis assessed feature contributions to efficacy.Results: All six machine learning models demonstrated superior predictive performance. Following variable reduction, the model predicting amlodipine efficacy was reconstructed using these algorithms, with the light gradient boosting machine (LightGBM) model achieving the highest overall performance (AUC = 0.803). Notably, amlodipine showed enhanced efficacy in patients with low platelet distribution width (PDW) values, as well as high hematocrit (HCT) and thrombin time (TT) values.Conclusion: This study utilized machine learning to predict amlodipine’s effectiveness in hypertension treatment, pinpointing key factors: HCT, PDW, and TT levels. Lower PDW, along with higher HCT and TT, correlated with enhanced treatment outcomes. This facilitates personalized treatment, particularly for hospitalized hypertensive patients undergoing amlodipine monotherapy.Keywords: anti-hypertensive drugs, hypertension, machine learning, shapley additive explanations

Jiachen Yu,1,* Yingchun Zhang,1,* Rong Ran,2,* Zixiao Kong,3 Duoyi Zhao,1 Wei Zhao,1 Yingxin Yang,4 Lianbo Gao,5 Zhiyu Zhang1 1Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China; 2Department of Anesthesia, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China; 3China Medical University, Shen Yang, 110032, People’s Republic of China; 4General Hospital of Northern Theater Command, China Medical University, Shen Yang, 110032, People’s Republic of China; 5Department of Neurology, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyu Zhang; Lianbo Gao, The Fourth Affiliated Hospital of China Medical University, No. 4 Chongshan Road, Huanggu District, Shenyang, Liaoning, People’s Republic of China, Email zyzhang@cmu.edu.cn; lbgao@cmu.edu.cnAbstract: The development of therapeutic drugs and methods has been greatly facilitated by the emergence of tumor models. However, due to their inherent complexity, establishing a model that can fully replicate the tumor tissue situation remains extremely challenging. With the development of tissue engineering, the advancement of bioprinting technology has facilitated the upgrading of tumor models. This article focuses on the latest advancements in bioprinting, specifically highlighting the construction of 3D tumor models, and underscores the integration of these two technologies. Furthermore, it discusses the challenges and future directions of related techniques, while also emphasizing the effective recreation of the tumor microenvironment through the emergence of 3D tumor models that resemble in vitro organs, thereby accelerating the development of new anticancer therapies.Keywords: bioprinting, bioink, organoids, tumor spheroids, tumor chips

Jing Luo,1,2 Yi Luo,2 Maoru Zhao,3 Yulong Liu,2 Jiayin Liu,2 Zhulin Du,2 Hong Gong,2 Lian Wang,2 Jinghui Zhao,2 Xiaqing Wang,2 Zhanjun Gu,3 Wenhui Zhao,1 Tianyao Liu,2 Xiaotang Fan2 1School of Life Sciences, Chongqing University, Chongqing, 401331, People’s Republic of China; 2Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China; 3Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, Institute of High Energy Physics and National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100049, People’s Republic of ChinaCorrespondence: Xiaotang Fan; Tianyao Liu, Email fanxiaotang2005@163.com; squall277@163.comBackground: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment. Keywords: fullerenols, BTBR, neurogenesis, autism spectrum disorder, hippocampus

Yanzhi Feng,1– 4,* Litao Liang,1– 4,* Wenbo Jia,1– 4 Jinyi Wang,1– 4 Chao Xu,1– 4 Deming Zhu,1– 4 Bin Xu,1– 4 Wenhu Zhao,1– 4 Xiangyu Ling,1– 4 Yongping Zhou,5 Lianbao Kong,1– 4,* Wenzhou Ding1– 4,* 1Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, People’s Republic of China; 3Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, People’s Republic of China; 4Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, People’s Republic of China; 5Jiangnan University Medical Center, JUMC, Department of Hepatobiliary, Wuxi, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenzhou Ding; Lianbao Kong, Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Email dingwenzhou@njmu.edu.cn; lbkong@njmu.edu.cnBackground: Circular RNAs (circRNAs) have been shown to play a crucial role in the initiation and development of Hepatocellular carcinoma (HCC). However, the mechanism and function of circ_0007386 in HCC are still unknown.Methods: Circ_0007386 expression level in HCC tissues, and HCC cell lines was further analyzed by qRT-PCR. Agarose gel electrophoresis and Sanger sequencing were used to figure out the structure of circ_0007386. The involvement of circ_0007386 in HCC development was evaluated by experimental investigations conducted in both laboratory settings (in vitro) and living organisms (in vivo). RNA immunoprecipitation, Western blotting, luciferase reporter assay and fluorescence in situ hybridization (FISH) were applied for finding out the interaction among circ_0007386, miR-507 and CCNT2. To assess the connection between circ_0007386 and lenvatinib resistance, lenvatinib-resistant HCC cell lines were employed.Results: The expression of circ_0007386 was found to increase in HCC tissues, and it was observed to be associated with a worse prognosis. Overexpression of circ_0007386 stimulated HCC cells proliferation, invasion, migration and the epithelial–mesenchymal transition (EMT) while silencing of circ_0007386 resulted in the opposite effect. Mechanistic investigations revealed that circ_0007386 acted as a competing endogenous RNA of miR-507 to prevent CCNT2 downregulation. Downregulating miR-507 or overexpressing CCNT2 could reverse phenotypic alterations that originated from inhibiting of circ_0007386. Importantly, circ_0007386 determines the resistance of hepatoma cells to lenvatinib treatment.Conclusion: Circ_0007386 advanced HCC progression and lenvatinib resistance through the miR-507/ CCNT2 axis. Meanwhile, circ_0007386 served as a potential biomarker and therapeutic target in HCC patients. Keywords: hepatocellular carcinoma, circ_0007386, miR-507, CCNT2, Lenvatinib

Jufei Wu,1,&ast; Jishi Wu,2,&ast; Yan Zhou,3 Xiaohua Lu,4 Wane Zhao,4 Fengmei Xu1 1Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2Department of General Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Department of Interventional Radiology & Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 4Department of Endocrinology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Zhou, Department of Interventional Radiology & Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China, Email 992054881@qq.com Xiaohua Lu, Department of Endocrinology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China, Email yhlu@163.comPurpose: To develop a prediction model for hypoglycemia in type 2 diabetes mellitus (T2DM) patients treated with an insulin pump during enteral nutrition.Methods: This retrospective study included T2DM patients treated with an insulin pump during enteral nutrition at the First Affiliated Hospital of Jinan University, Guangzhou Red Cross Hospital, Foshan First People’s Hospital, and Guangdong Provincial Hospital of Traditional Chinese Medicine between January 2016 and December 2023. The patients were randomized 3:1 to the training and validation sets. The risk factors for hypoglycemia were analyzed. A prediction model was developed.Results: This study included 122 patients, and 57 patients had at least one hypoglycemic event during their hospitalization (46.72%). The multivariable logistic regression analysis showed that the time to reach the glycemic targets (odds ratio (OR)=1.408, 95% confidence interval (CI)=1.084– 1.825, P=0.006), average glycemia (OR=0.387, 95% CI=0.233– 0.643, P=0.010), coronary heart disease (OR=0.089, 95% CI=0.016– 0.497, P< 0.001), and the administration of hormone therapy (OR=6.807, 95% CI=1.128– 41.081, P=0.037) were independently associated with hypoglycemia. A nomogram was built. The receiver operating characteristics analysis showed that the area under the curve of the model was 0.872 (95% CI=0.0.803– 0.940) for the training set and 0.839 (95% CI=0.688– 0.991) in the validation set.Conclusion: A nomogram was successfully built to predict hypoglycemia in T2DM patients treated with an insulin pump during enteral nutrition, based on the time to reach the glycemic targets, average glycemia, coronary heart disease, and the administration of hormone therapy.Keywords: T2DM, hypoglycemia, enteral nutrition, insulin pump therapy, nomograms

Lang Liu,1,&ast; Binghua Zhang,1,&ast; Zhenwei Zhou,2 Jie Yang,1 Ailin Li,1 Yongji Wu,1 Zeyu Peng,1 Xiangyan Li,2 Zhonghua Liu,3 Xiangyang Leng,1 Changwei Zhao,4 Haisi Dong,2 Wenhai Zhao4 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Orthopaedics, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 4Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisi Dong, Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China, Tel/Fax +86 431-18604361976, Email adonghaisi@163.com Wenhai Zhao, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China, Tel/Fax +86 431-86177836, Email zwh9899@163.comBackground: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA.Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments.Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats.Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.Keywords: knee osteoarthritis, RAR, cartilage degeneration, network pharmacology, Mapk1

Qinghao Liu,&ast; Weiwen Zhao,&ast; Hao Yin Department of Orthopedic, The First Affiliated Hospital of Hunan Normal University Hunan Provincial People’s Hospital, Changsha, China Mainland (PRC)&ast;These authors contributed equally to this workCorrespondence: Hao Yin, Email ehour@hunnu.edu.cnBackground: Spontaneous spinal epidural hematoma (SSEH) presenting in the context of JAK2 V617F-positive myeloproliferative neoplasms is a rare condition, characterized by the compression of the spinal cord leading to various symptoms. The etiology, pathogenesis, and optimal treatment strategies for this condition remain undetermined. The occurrence of spontaneous spinal epidural hematoma (SSEH) in the context of JAK2 V617F-positive myeloproliferative neoplasms (MPNs) represents a rare manifestation. Magnetic Resonance Imaging (MRI) plays a crucial role in the definitive diagnosis of this condition. With a good understanding of the pathogenic characteristics and clinical presentations of this disease, a diagnosis can be reasonably made, even in the absence of MRI, based on physical examinations indicating the affected area. Once diagnosed, immediate surgery is recommended to attempt the restoration of spinal cord function. Postoperatively, the use of hydroxyurea has proven effective in disease control.Case Presentation: We report a case of a 65-year-old male patient who presented with progressive lumbar back pain and bilateral lower limb paralysis lasting for 36 hours. CT imaging revealed an intraspinal lesion at the L1-3 level, and genetic testing confirmed the presence of the JAK2V617F mutation. Following surgery, there was a significant recovery of sensory and motor function in the lower limbs. At one-year follow-up, the patient demonstrated good functional status, and blood tests indicated a platelet count within the normal range.Conclusion: The presented case adds to the existing literature on SSEH by highlighting the association with myeloproliferative neoplasms (MPNs), as evidenced by the JAK2V617F mutation. MPNs constitute a group of hematologic malignancies, and the association with SSEH is a rare occurrence. The exact interplay between MPNs and SSEH warrants further investigation, as the underlying mechanisms linking these conditions remain elusive. The case also underscores the importance of a multidisciplinary approach, involving hematologists and neurosurgeons, in the comprehensive management of such complex cases.Keywords: myeloproliferative neoplasms, spinal epidural hematoma, JAK2V617F

Yanlei Wang,&ast; Zhaoxiang Liu,&ast; Wenhui Zhao, Chenxiang Cao, Luqi Xiao, Jianzhong Xiao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianzhong Xiao, Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, People’s Republic of China, Tel/Fax +8610-5611-9057, Email xjza01150@btch.edu.cnBackground: Von Hippel-Lindau (VHL) syndrome is characterized by tumorous lesions affecting multiple organs. Pancreatic involvement in VHL syndrome can present as endocrine tumors and pancreatic cysts, which can interfere with both exocrine and endocrine functions of the pancreas. Diabetes is an uncommon complication of VHL syndrome.Purpose: This study aims to summarize the various mechanisms of diabetes in VHL syndrome by reporting two cases and conducting a literature review.Methods: We analyzed the clinical and imaging data of two patients with VHL syndrome and diabetes. Additionally, we reviewed the existing literature to explore the clinical diversities and management strategies for VHL syndrome complicated with diabetes.Results: The first patient presented with liver metastasis of pancreatic neuroendocrine tumor and multiple pheochromocytoma. After surgery, the patient’s diabetic control improved, as evidenced by a significant reduction in insulin dosage. This indicates a potential insulin resistance due to elevated metanephrine levels prior to surgery and partial insulin deficiency caused by distal pancreatectomy. The second patient had multiple hemangioblastomas, as well as multiple pancreatic cysts and positive pancreatic islet autoantibodies. Diabetes in this case may be attributed to pancreatic lesions and the coexistence of autoimmune insulitis. A literature review of other patients with VHL combined with diabetes revealed multiple mechanisms, including increased catecholamine levels, pancreatic lesions, surgical removal of pancreatic tissue, endocrine treatment, and possibly the coexistence of autoimmune insulitis.Conclusion: VHL syndrome complicated with diabetes involves diverse mechanisms.Keywords: von Hippel-Lindau syndrome, diabetes, pancreatic neuroendocrine tumor

Jing Zhang,1,2 Ke Ma,3 Jun Yan,4 Pingsheng Pan,5 Jiangshan Yin,6 Fuqing Lin,7 Hui Chen,8 Weiwei Zhao,1,2 Menglei Chen,1,2 Zhe Zhang,1,2 Minghui Liu,1,2 Xiaoli Gu,1,2 Xinghe Liao,1,2 Chenyue Zhang,1,2 Wenwu Cheng1,2 1Department of Integrated Therapy, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pain Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 5Department of Oncology, Fangta Hospital of Traditional Chinese Medicine in Songjiang District, Shanghai, People’s Republic of China; 6Department of Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, People’s Republic of China; 7Department of Anaesthesiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 8Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Wenwu Cheng, Email cwwxxm@sina.comPurpose: This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai.Methods: From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China.Results: A total of 238 responses participated in the survey. This survey reports physicians’ understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors’ knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff’s understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training.Conclusion: Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.Keywords: refractory cancer pain, breakthrough cancer pain, pain management, opioid drugs

Yi He,1,2 Lejia Zhang,1,2 Siyuan Huang,1,2 Yuquan Tang,3 Yiming Li,1,2 Hongyu Li,1,2 Guanhui Chen,4 Xun Chen,1,2 Xiliu Zhang,1,2 Wei Zhao,1,2 Feilong Deng,1,2 Dongsheng Yu1,2 1Hospital of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, GuangZhou, 510080, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, GuangZhou, 510080, People’s Republic of China; 3Zhujiang Hospital, Southern Medical University, Guangzhou, 510080, People’s Republic of China; 4Department of Stomatology, the Seventh Affiliated Hospital, Sun Yat-sen University, ShenZhen, 518107, People’s Republic of ChinaCorrespondence: Feilong Deng; Dongsheng Yu, Email dengfl@mail.sysu.edu.cn; yudsh@mail.sysu.edu.cnBackground: The ability of nanomaterials to induce osteogenic differentiation is limited, which seriously imped the repair of craniomaxillofacial bone defect. Magnetic graphene oxide (MGO) nanocomposites with the excellent physicochemical properties have great potential in bone tissue engineering. In this study, we aim to explore the craniomaxillofacial bone defect repairment effect of MGO nanocomposites and its underlying mechanism.Methods: The biocompatibility of MGO nanocomposites was verified by CCK8, live/dead staining and cytoskeleton staining. The function of MGO nanocomposites induced osteogenic differentiation of BMSCs was investigated by ALP activity detection, mineralized nodules staining, detection of osteogenic genes and proteins, and immune-histochemical staining. BMSCs with or without MGO osteogenic differentiation induction were collected and subjected to high-throughput circular ribonucleic acids (circRNAs) sequencing, and then crucial circRNA circAars was screened and identified. Bioinformatics analysis, Dual-luciferase reporter assay, RNA binding protein immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) and osteogenic-related examinations were used to further explore the ability of circAars to participate in MGO nanocomposites regulation of osteogenic differentiation of BMSCs and its potential mechanism. Furthermore, critical-sized calvarial defects were constructed and were performed to verify the osteogenic differentiation induction effects and its potential mechanism induced by MGO nanocomposites.Results: We verify the good biocompatibility and osteogenic differentiation improvement effects of BMSCs mediated by MGO nanocomposites. Furthermore, a new circRNA-circAars, we find and identify, is obviously upregulated in BMSCs mediated by MGO nanocomposites. Silencing circAars could significantly decrease the osteogenic ability of MGO nanocomposites. The underlying mechanism involved circAars sponging miR-128-3p to regulate the expression of SMAD5, which played an important role in the repair craniomaxillofacial bone defects mediated by MGO nanocomposites.Conclusion: We found that MGO nanocomposites regulated osteogenic differentiation of BMSCs via the circAars/miR-128-3p/SMAD5 pathway, which provided a feasible and effective strategy for the treatment of craniomaxillofacial bone defects. Keywords: nanomaterials, MGO nanocomposites, craniomaxillofacial bone repair, circular RNAs, circAars

Shuling Wang,1,2,&ast; Yuqin Chen,1– 3,&ast; Weidong Li,2,4,&ast; Chunfang Hao,1,2 Li Zhang,1,2 Weipeng Zhao,1,2 Yehui Shi,1,2 Zhongsheng Tong1,2 1Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 2Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, People’s Republic of China; 3Department of Respiratory Center, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, People’s Republic of China; 4Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yehui Shi; Zhongsheng Tong, Email shiyehui@tjmuch.com; tongzhongsheng_on@163.comBackground: The purpose of this study was to investigate the therapeutic efficacy and prognosis of serum HER2 (sHER2) in patients with advanced breast cancer.Methods: We analyzed the sHER2 levels of 200 patients with advanced breast cancer receiving first or second line treatment, the tissue HER2 (tHER2) level was also analyzed. Indicators of therapeutic efficacy and prognosis were objective response rate (ORR), disease control rate (DCR), and time to progression (TTP).Results: The baseline sHER2 level was high in 132 patients and low in 68 patients. The high level of sHER2 is correlated with molecular subtype (p=0.016), visceral metastasis (p< 0.001), liver metastasis (p< 0.001), tissue HER-2 (tHER2) (p=0.001), and, among tHER2-low tumors (59 patients), the baseline sHER2 high level was associated with a higher proportion of brain metastasis. The ORR of patients with baseline sHER2 high level is higher than those with baseline sHER2 low level (p=0.026). The TTP of patients with baseline sHER2 low level is longer than the patients with baseline sHER2 high level (p=0.024). For patients with baseline sHER2 high level, a significant decrease in sHER2 after two cycles of treatment indicates higher ORR, DCR, and an extension of TTP. After multiple cycles of treatment, for patients with tHER-2 positive and baseline sHER2 high level, the DCR in the sHER2 decrease in the negative group was higher than that in the continuous positive group (p=0.037). Patients with a rapid decline type of sHER2 dynamic change curve had higher ORR and prolonged TTP compared with patients with other types of sHER2 dynamic change curve. There is no correlation between OS and sHER2 levels.Conclusion: Our study showed that patients with advanced breast cancer had a high level of sHER2 at recurrence, regardless of whether they are tHER2 positive or negative. Dynamic detection of sHER2 can help predict therapeutic efficacy and prognosis, regardless of whether tHER-2 is positive or negative.Keywords: serum HER2, advanced breast cancer, clinicopathological characteristics, therapeutic efficacy, prognosis

Xingqiang Wang,1,2,&ast; Xianna Yang,3,&ast; Shiqi Wang,3,&ast; Xiaofang Tian,1 Jianmei Yin,3 Nian Liu,3 Pengtao Di,1 Jipeng Qi,3 Ya Li,3 Jimin Chen,3,4 Yang Wu,1 Jingjin Wu,1,2 Weiqing Zhao,5 Jiangyun Peng,1,2 Ling Zhang,1,2 Lingli Gu1 1Department of Rheumatology, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 2Yunnan Provincial Clinical Medicine Research Center of Rheumatism in TCM, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 3The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 4Department of Integrative Internal Medicine, The Lijiang Hospital of Traditional Chinese Medicine, Lijiang, Yunnan, 674100, People’s Republic of China; 5Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province and The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650034, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Zhang; Lingli Gu, Email zebaiyuan@126.com; guyuxin82@126.comAbstract: Glucocorticoids (GC) are crucial in the treatment of rheumatoid arthritis (RA), but discontinuing GC effectively in RA patients poses a significant challenge for rheumatologists. In this two-stage, single-center, non-randomized controlled trial, we investigated the benefits of combining Chinese traditional herbal treatment with csDMARDs to aid GC discontinuation in terms of GC tapering, disease control, and safety. A total of 231 participants were enrolled, of which 150 eligible subjects were included in the first phase and allocated to three groups (control group, treatment group 1, and treatment group 2) based on their willingness to take traditional Chinese medicine and syndrome differentiation, in a 1:1:1 ratio. All groups received basic treatment consisting of methotrexate tablets (10 mg, qw), leflunomide (10 mg, qd), and stratified GC bridging therapy and tapering regimen (The intervention regimen was developed based on rigorous adherence to available evidence). Treatment group 1 received basic treatment combined with Juanbi Granule, while treatment group 2 received basic treatment combined with Yupingfeng Guizhi Decoction Granule. Efficacy was evaluated after a 12-week follow-up, with slightly adjustments to the treatment group based on efficacy and change of syndrome, followed by continued observation until 24 weeks to complete the study. The efficacy evaluation and data analysis were conducted in a blinded manner, including group label concealment, data cleaning, confounder and control regimen analysis, and outcome analysis. This project has received ethical approval from the Ethics Committee of Yunnan Provincial Hospital of Traditional Chinese Medicine (YLZ [2022] Ethical Review No. (006)-01) and has been registered with the China Clinical Trials Registry (Registration number: ChiCTR2300067676, Registered 17 January 2023, https://www.chictr.org.cn/showproj.html?proj=184908). This trial was the first to evaluate the clinical efficacy of combining Chinese herbal medicines with standard Western medicines to facilitate the discontinuation of glucocorticoid (GC) therapy in patients with rheumatoid arthritis (RA).Keywords: rheumatoid arthritis, glucocorticoids tapering, clinical trial, traditional Chinese medicine, Yupingfeng Guizhi Decoction, Juanbi Decoction

Antao Lin,&ast; Yan Wang,&ast; Hao Zhang, Kai Zhu, Dan Zhou, Jianwei Guo, Wenhao Zhao, Chuanli Zhou, Xuexiao Ma Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuexiao Ma; Chuanli Zhou, Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266000, People’s Republic of China, Tel +8618661807895 ; +8618661809796, Email maxuexiaospinal@163.com; justin_5257@hotmail.comObjective: We explore the endoscopic revision and surgical techniques for L4/5 recurrent disc herniation (rLDH) after percutaneous endoscopic transforaminal discectomy (PETD).Methods: A retrospective study was conducted. From January 2016 to September 2022, 96 patients who underwent percutaneous endoscopic lumbar discectomy for L4/5 rLDH after PETD were enrolled in the study. Based on the revision approach, the patients were divided into PETD group (57 cases) and percutaneous endoscopic interlaminar discectomy (PEID) group (39 cases). Visual Analogue Scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), and modified MacNab standard were recorded to evaluate the clinical outcomes.Results: No significant differences were found in the demographic data and intraoperative blood loss between the two groups (P> 0.05), but the time of operation and intraoperative X-ray fluoroscopy exposures in the PEID group were significantly less than that in the PETD group (P< 0.05). The patients’ postoperative clinical indexes gradually improved, and the VAS score, ODI index, and JOA score of the patients in both groups showed significant improvement compared with the preoperative period at the 1-week, 1-month, and 6-month postoperative follow-ups (P < 0.05). There was no serious complication observed during the follow-up.Conclusion: For recurrent LDH after PETD of L4/5 segments, percutaneous endoscopic revision can achieve satisfactory results. Among them, PEID has a shorter operative and fluoroscopy time and allows avoidance of the scar that forms after the initial surgery, so it can be considered preferred when both procedures can remove the disk well. However, for some specific types of herniation, a detailed surgical strategy is required.Keywords: endoscopic revision, recurrent lumbar disc herniation, percutaneous endoscopic lumbar discectomy

Weichao Zhao,1,2,&ast; Huqin Yang,1,&ast; Yong Huang,3,&ast; Xin Fan,4 Zhaohui Tong1 1Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory Medicine, Strategic Support Force Medical Center, Beijing, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, People’s Republic of China; 4Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaohui Tong; Xin Fan, NO. 8 Gong Ti South Road, Beijing, 10020, People’s Republic of China, Tel +86 1085231297 ; +86 13521438062, Email tongzhaohuicy@sina.com; fanxin123356@163.comPurpose: Cupriavidus gilardii is an emerging multidrug-resistant pathogen found in many environments and few clinical samples. The clinical infectiousness, pathogenicity, and resistance mechanisms of C. gilardii are still unclear due to the lack of clinical and sequencing data. We need to obtain insight into the clinical characteristics, virulence, and resistance mechanisms of C. gilardii.Patients and Methods: We isolated five C. gilardii isolates from hospitalized patients and carried out assay, culture and genome sequencing. We analyzed the genomic features of clinical C. gilardii isolates and took insight into their clinical characteristics, virulence, and resistance mechanisms.Results: These isolates were resistant to meropenem, gentamicin, and other antimicrobials due to intrinsic resistance genes. Furthermore, the sequencing results revealed the widespread presence of the MCR-5.1 gene in C. gilardii. The virulence magnitude of C. gilardii is closely correlated with the number of virulence factors they carry. Some C. gilardii strains can acquire resistance to levofloxacin through gyrA gene mutation during treatment. The diverse antimicrobial resistance mechanisms challenge the treatment of C. gilardii infections.Conclusion: We present the genomic characteristics of clinically isolated C. gilardii to improve (i) our understanding of this pathogen and (ii) treatment options.Keywords: Cupriavidus gilardii, clinical characteristics, antimicrobial resistance, MCR-5.1, gyrA

Yanbei Duo,1 Shuoning Song,1 Xiaolin Qiao,2 Yuemei Zhang,3 Jiyu Xu,4 Jing Zhang,5 Zhenyao Peng,6 Yan Chen,2 Xiaorui Nie,2 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Zechun Lu,8 Tao Yuan,1,&ast; Weigang Zhao1,&ast; 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Yuan; Weigang Zhao, Email t75y@sina.com; xiehezhaoweigang@163.comObjective: Gestational diabetes mellitus (GDM) is a condition of glucose intolerance, which may be accompanied with inflammation. The levels of hematological parameters during pregnancy can reflect inflammatory conditions in pregnant women. This study aims to describe the dynamic change of blood cell parameters from the first trimester (6– 12 weeks of gestation) to the second trimester (24– 28 weeks of gestation) and to investigate the associations of these biomarkers with the risk of GDM.Methods: This study was a prospective double-center study conducted in Beijing, China (clinical trial number: NCT03246295). Hematological parameters were tested four times during the follow-up. Logistic regression analysis and Receiver Operating Characteristic (ROC) curve analysis were used to explore the association and predictive ability of hematological parameters for GDM.Results: There were 258 of 1027 pregnant women in our study developed GDM. Among the 1027 pregnant women, white blood cells (WBC) gradually increased, and red blood cells (RBC), hemoglobin (HGB), and platelet (PLT) tended to decrease from the first trimester to second trimester. After adjusting for confounding factors, higher levels of RBC, HGB, and PLT in both early and middle pregnancy were positively associated with GDM risk, whereas the level of WBC was associated with GDM risk only in early pregnancy. WBC, RBC, HGB, and PLT in early and middle pregnancy were all correlated with fasting insulin (FINS) in early pregnancy.Conclusion: Higher levels of hematological parameters in early and middle pregnancy were associated with glucose metabolism in early pregnancy and the subsequent risk of GDM.Keywords: hematological parameters, gestational diabetes mellitus, inflammation, insulin resistance, prospective study

Guangxin Zhou,1,2 Wei Zhao,2 Yi Zhang,2 Wenli Zhou,2 Haizhou Yan,2 Yongli Wei,1 Yuming Tang,1 Zijing Zeng,2 Hanrong Cheng1 1Department of Sleep Medicine, Institute of Respiratory Diseases, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China; 2OPPO Health, Guangdong OPPO Mobile Telecommunications Co. Ltd., Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Hanrong Cheng, Department of Sleep Medicine, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China, Email cheng.hanrong@szhospital.comObjective: To evaluate the clinical performance of the OPPO Watch (OW) Sleep Analyzer (OWSA) on OSA screening with polysomnography reference.Methods: We recruited 350 participants using OWSA and PSG simultaneously in a sleep laboratory. The respiratory event index (REI) derived from OWSA and the apnea-hypopnea index (AHI) provided by PSG were compared. SHapley Additive exPlanation (SHAP) values were calculated to explain the model of OWSA.Results: The OWSA-REI (26.5± 18.5 events/h) correlated well with PSG-AHI (33.2± 25.7 events/h; r = 0.91, p < 0.001), with an intraclass correlation coefficient (ICC) of 0.83. Using a threshold of AHI ≥ 15 events/h, the sensitivity, specificity, accuracy, and area under the curve (AUC) were 86.1%, 86.7%, 86.3%, and 0.94, respectively. Bland-Altman analysis showed that OWSA-REI and PSG-AHI were in good agreement (Mean Difference: − 6.7, 95% CI:16.0 to − 29.3 events/h). In addition, the effectiveness of the models in OWSA were also explained by visualizing SHAP values.Conclusion: The OWSA demonstrated a reasonable performance for OSA screening in the clinical setting. In light of this, it is possible for smartwatches to become a complementary tool to PSG, which is particularly useful for larger-scale preliminary screenings.Plain Language Summary: OPPO Watch Sleep Analyzer (OWSA), an emerging sleep-tracking method based on a wearable device, uses a machine learning model to analyze physiological signals including snoring recordings, and other basic anthropometric information to estimate REI. The study evaluated the OSA screening performance of OWSA with PSG-AHI and interpreted the results of the pre-trained machine learning model.OWSA demonstrated consistent clinical diagnostic performance for OSA. The interpretive machine learning models used in OWSA highlighted the impact of multi-modal data on estimation results. Therefore, these types of models are likely to be more widely accepted and promoted in clinical practice.Keywords: obstructive sleep apnea, photoplethysmography, polysomnography, smartwatch

Dapeng Hu,1,2 Junwen Huang,1 Wenqu Zhao,1 Maosheng Xu,1 Yanyan Ma,1 Zhaoqian Gong,1 Qian Zhang,1 Haijin Zhao1 1Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, NanFang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Emergency Medicine, Dalian Municipal Friendship Hospital, Dalian, Liaoning, 116001, People’s Republic of ChinaCorrespondence: Haijin Zhao, Chronic Airway Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Tel/Fax +86-2062787112, Email zhjin@smu.edu.cnPurpose: Identifying prognosis for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is challenging. Eosinophils and platelet are involved in the development of COPD, which may predict adverse events. The objective of this study was to determine the effect of the eosinophil to platelet ratio (EPR) in predicting adverse events in patients with AECOPD who visited the emergency department.Patients and Methods: The records of patients with AECOPD treated at Dalian Municipal Friendship Hospital from January 2018 to December 2020 were retrospectively reviewed. The relationship between the clinical characteristics and EPR, as cut-off value of 0.755, was evaluated.Results: A total of 508 patients with an AECOPD (316 male, 192 female) were included. An optimal AUC cutoff of 0.755 for the EPR segregated the patients into 2 groups with significantly different mortality (25.3% vs 5.5%, P < 0.001). The same mortality risk with lower EPR was observed among the patients with emergency room attendance (35.6% vs 11.1%, P < 0.001). A model including EPR < 0.755, exacerbation history, PaO2 < 60mmHg, PaCO2 > 50 mm Hg, hypoalbuminemia and age ≥ 80 was developed to predict death risk and showed good performance.Conclusion: During severe COPD exacerbation, an EPR < 0.755 preceding therapy can predict worse outcomes in patients with an AECOPD.Keywords: eosinophil, COPD, eosinophil to platelet ratio, emergency department

Yurun Liu,1,&ast; Shengnan Yu,2,&ast; Sha Ma,2 Juan Yu,2 Dachen Zuo,2 Weiqing Zhao,2 Juan Wang,2 Jing Wang2 1Department of Rheumatology and Immunology, The Affiliated Hospital of Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, People’s Republic of China; 2Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Wang, Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China, Email wjing1981@163.comBackground: An overlap of systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibodies- (ANCA-) associated vasculitis (AAV) is extremely uncommon and no clear definition has been proposed. The SLE/AAV overlap syndrome mainly affects kidney, blood count, nervous system and lung. However, few previous cases reported nasal septal and palatal perforation in this disorder.Case Presentation: We presented a case of a 16-year-old female with a 6-month history of SLE, developed perforation of the nasal septum and palate. She was diagnosed with SLE due to facial malar rash, oral ulcer, increased erythrocyte sedimentation rate (ESR), low complement levels, and positive anti-Smith antibody. Approximately 6 months later, she had a perforation of the nasal septum and palate with positive anti-proteinase 3 antibody (anti-PR3-ANCA). A nasal endoscopic biopsy revealed an inflammatory polyp with chronic suppurative inflammation and inflammatory granulomatous hyperplasia. In this case, the clinical, biological, radiological, and histological findings substantiated the diagnosis of AAV. Infections, drug abuse, malignancies, IgG4-related disease (IgG4-RD) and trauma were excluded. So we diagnosed her with SLE/AAV overlap syndrome.Conclusion: When a patient’s symptoms cannot be explained by one disease, we need to consider the overlapping of two diseases, especially in patients with autoimmune diseases.Keywords: perforation of palate, systemic lupus erythematosus, ANCA-associated vasculitis, SLE/AAV overlap syndrome

Jiwen Xu,1,&ast; Chang Liu,1,2,&ast; Weixiu Zhao,1 Weihua Lou1 1Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weixiu Zhao; Weihua Lou, Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200127, People’s Republic of China, Email zhaowxiu12@163.com; louweihua@renji.comAbstract: Diabetic ketoacidosis (DKA) is rare in pregnancy, especially in pregnant women with normal glucose tolerance examined in early pregnancy. Once DKA occurs in pregnancy, the disease progresses rapidly and can be life-threatening for both mother and fetus. We concluded three cases of DKA in late pregnancy. The clinical manifestations, progression, and prognosis of the three cases are different, but all of the cases have normal glucose tolerance. We summarized the characteristics of pregnant women with DKA and analyzed and discussed them in conjunction with literature for reference by clinical doctors.Keywords: diabetic ketoacidosis, pregnancy, gestational diabetes mellitus

Xiaorong Xu,&ast; Jing Cheng,&ast; Yeping Zhang, Xin Wang, Mulei Chen, Lin Xu, Wenshu Zhao Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenshu Zhao; Lin Xu, Email zhaowenshu1965@126.com; xul853@126.comBackground: The efficacy of chronic heart failure (CHF) checklist management in reducing adverse outcomes of heart failure patients is still uncertain. This study explores whether CHF checklist management is more useful than usual care in reducing adverse health outcomes in the medium- and long-term among CHF patients.Methods: In our prospective study, 132 patients with CHF were randomly assigned to CHF management group and usual care group by random number method. Patients in CHF management group were conducted through CHF checklist by cardiologists and general practitioner. Patients assigned to usual care were treated by non-stationary medical group without checklist. All groups were followed up for 18 months.Results: There was no significant difference in overall mortality rate between management group and control group during 18 months (12.3% [8/65] vs. 11.7% [7/60], P = 0. 912]). The re-hospitalization rate of heart failure in management group (18.5% [12/65]) was significantly lower than that in usual care group (38.3% [23/60]) after 18 months of follow-up (P = 0.013). Median NT-proBNP level (632.3 ng/l vs. 1678 ng/l, p = 0.004) was lower in management group than that in usual care group. Cardiac ultrasonography was performed at 18 months between the management and usual care group. LVEDD (55.88± 7.11 mm vs. 60.92± 8.06 mm) and LVESD (43.25± 8.42mm vs. 48.41± 9.02mm) were decreased (P< 0.01). LVEF was increased (45.36± 10.64% vs. 39.96 ± 10.15%, P< 0.01). The utilization rate of ACEI/ARB/ARNI, β-blocker were high in management group.Conclusion: CHF checklist management by cardiologists and general practitioners can significantly reduce the re-hospitalization and improve cardiac function. CHF management through heart failure checklist may improve prognosis in patients with CHF in the medium- and long-term.Keywords: chronic heart failure, heart failure management, heart failure checklist, prognosis, re-hospitalization rate, CHF

Huimin Zhang,1,&ast; Chengyu Zang,1,2,&ast; Wen Zhao,1 Linfeng Zhang,1 Rui Liu,1 Zhang Feng,1 Jie Wu,1 Rongtao Cui1– 3 1Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 2Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, People’s Republic of China; 3Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongtao Cui, Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China, Tel +86 18653170822, Email cuirt1986@outlook.comBackground: Mesenchymal stem cell-derived exosomes (MSC-exo) have been shown to have significant potential in wound healing and scar relief processes. According to reports, TNFSF13 and HSPG2 are associated with various fibrotic diseases. The aim of this study is to investigate how TNFSF13 and HSPG2 affect the formation of hypertrophic scar (HS) and the mechanism by which exosomes regulate HS.Methods: Immunohistochemistry, qRT-PCR, Western blot, and immunofluorescence were performed to measure TNFSF13 expression in HS skin tissues and hypertrophic scar fibroblast (HSF). HSF were treated with recombinant TNFSF13 protein and TNFSF13 siRNAs to probe the effect of TNFSF13 on the activity of HSF. The CCK-8, EdU, Transwell, and Western blot were used to investigate the role of TNFSF13 in viability, proliferation and inflammation. The influence of MSC-exo on the proliferation and function of HSF was determined by scratch and Western blot.Results: TNFSF13 was dramatically up-regulated in HS skin tissues and HSF. Recombinant TNFSF13 protein increased cell viability, proliferation, migration, fibrosis, inflammation, and the binding between TNFSF13 and HSPG2 of HSF. The opposite results were obtained in TNFSF13 siRNAs transferred HSF. Furthermore, TNFSF13 activated the nuclear factor-κB (NF-κB) signaling pathway. Silencing of HSPG2 and inhibition of NF-κB remarkably eliminated the promoting effects of TNFSF13 on cell viability, proliferation, migration, fibrosis and inflammation of HSF. MSC-exo reduced α-SMA and COL1A1 inhibited the proliferation and migration of HSF by inhibiting TNFSF13 and HSPG2.Conclusion: TNFSF13 activates NF-κB signaling pathway by interacting with HSPG2, which regulates the proliferation, migration, fibrosis and inflammatory response of HSF. Through the above mechanisms, knocking out TNFSF13 can inhibit the proliferation, migration, fibrosis and inflammatory response of HSF, whereas MSC-exo could reverse this process. These results suggest that MSC-exo alleviates HS by inhibiting the fibroblasts via TNFSF-13/HSPG2 signaling pathway.Keywords: TNFSF13, HSPG2, hypertrophic scar(HS), MSC-exo, fibroblasts

Mei Cong,1,&ast; Houjun Pang,1,2,&ast; Guangxing Xie,1 Feifei Li,3 Chunxiao Li,3 Hao Sun,3 Shaoyou Yang,1 Weidong Zhao3 1School of Pharmacy, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2Department of Pharmacy, Dazhou Women and Children’s Hospital, Dazhou, People’s Republic of China; 3Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weidong Zhao, Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China, Tel +86 0373 3029977, Fax +86 0373 3029977, Email 141051@xxmu.edu.cnPurpose: Molecular targeted therapy is one of the most pivotal strategies in the treatment of non-small cell lung cancer, yet its curative effect is severely compromised by the poor aqueous solubility, low bioavailability and inadequate tumor accumulation of targeted agents. To enhance the efficacy of targeted agents, we demonstrate a novel self-assemble amphiphilic molecule based on erlotinib as an effective nanodrug for anti-cancer treatment.Methods: An amphiphilic molecule composed of hydrophobic erlotinib and hydrophilic biotin block was synthesized and characterized by nuclear magnetic resonance (NMR) as well as high-resolution mass spectrometry (HRMS). Then, nanoassemblies of the amphiphilic molecules are formulated by using nanoprecipitation method. Subsequently, the size, morphology, cell uptake, the anticancer activity and in vivo distribution of the newly constructed erlotinib nanodrug were systematically assessed by some methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), flow cytometry, in vivo imaging system etc.Results: We developed a novel nanoformulation of erlotinib, which possesses a high drug loading of 45%. With the features of well-defined structure and small size, the obtained nanodrug could be effectively accumulated in tumor sites and rapidly internalized by cancer cells. Finally, the erlotinib-based nanoformulation showed considerably better anticancer activity compared to free erlotinib both in vitro and in vivo. Moreover, the nanodrug displayed great tolerability.Conclusion: Combining the advantageous features of both nanotechnology and self-assemble, this novel erlotinib nanomedicine constitutes a promising therapeutic candidate for cancer treatment. This study also underlines the potential use of amphiphilic molecule for improving drug efficacy as well as reducing drug toxicity, which could become a general strategy for the preparation of nanodrugs of active agents.Keywords: erlotinib, amphiphilic molecule, self-assembling, drug self-delivery system, non-small cell lung cancer

Yifei Zeng,1,2 Dongxiao Zhang,1 Na Fu,1 Wenjie Zhao,1 Qiao Huang,1 Jianchun Cui,3 Yunru Chen,4 Zhaolan Liu,4 Xiaojun Zhang,5 Shiyun Zhang,6 Khattak Mazher Mansoor3 1Department of Galactophore, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Liaoning Provincial People’s Hospital (Department of Thyroid and Breast Surgery, People’s Hospital of China Medical University), Shenyang, People’s Republic of China; 4Centre for Evidence-Based Chinese Medicine, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 6Guang’ Anmen Hospital, China Academy of Chinese Medical Science, Beijing, People’s Republic of ChinaCorrespondence: Dongxiao Zhang, Department of Galactophore, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Art Museum Back Street, Dongcheng District, Beijing, 100010, People’s Republic of China, Tel +86 17862968916, Email morningdong@163.comBackground: This study aimed to explore the risk factors and clinical characteristics of granulomatous mastitis (GM) using a case-control study and establish and validate a clinical prediction model (nomogram).Methods: This retrospective case-control study was conducted in three hospitals in China from June 2017 to December 2021. A total of 1634 GM patients and 186 healthy women during the same period were included and randomly divided into the modeling and validation groups in a 7:3 ratio. To identify the independent risk factors of GM, univariate and multivariate logistic analyses were conducted and used to develop a nomogram. The prediction model was internally and externally validated using the Bootstrap technique and validation cohort. The receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the discrimination and calibration of the prediction model. Decision curve analysis (DCA) and clinical impact curve (CIC) were used to evaluate the clinical significance of the model.Results: The average age of GM patients was 33.14 years (mainly 20– 40). The incidence was high within five years from delivery and mainly occurred in the unilateral breast. The majority of the patients exhibited local skin alterations, while some also presented with systemic symptoms. On multivariate logistic analysis, age, high prolactin level, sex hormone intake, breast trauma, nipple discharge or invagination, and depression were independent risk factors for GM. The mean area under the curve (AUC) in the modeling and validation groups were 0.899 and 0.889. The internal and external validation demonstrated the model’s predictive ability and clinical value.Conclusion: Lactation-related factors are the main risk factors of GM, leading to milk stasis or increased ductal secretion. Meanwhile, hormone disorders could affect the secretion and expansion of mammary ducts. All these factors can obstruct or injure the duct, inducing inflammatory reactions and immune responses. Additionally, blunt trauma, depressed mood, and diet preference can accelerate the process. The nomogram can effectively predict the risk of GM.Keywords: granulomatous mastitis, risk factors, case-control study, nomogram, prediction model

Xi-Qing Pan, Jin-Hui Liu, Jiang-Li Zhang, An Chai, Feng Li, Lei Shu, Wei Zhao Department of Joint Surgery, Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Jin-Hui Liu, Department of Joint Surgery, Third Hospital of Shijiazhuang, No. 15 Tiyu South Street, Shijiazhuang, Hebei, 050011, People’s Republic of China, Tel +86 13191872146, Fax +86 31185990628, Email jinhuiauliu6@126.comObjective: In this study, we aim to examine the effects of osteotomy under varying posterior slope angles on knee joint function recovery following knee arthroplasty.Methods: We conducted a retrospective analysis from September 2015 to September 2018 on 240 patients who underwent knee arthroplasty three years previously. The study participants were categorized based on changes in the angle of the posterior slope before and after surgery: Group 1, > 5°; Group 2, 3°– 5°; Group 3, 0°– 3°; Group 4, − 3°– 0°; Group 5, < − 3°. All participants were affected with knee osteoarthritis. The Knee Society Clinical Rating System (KSS) knee function score, Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee function score, Visual Analogue Scale (VAS) pain score, and postoperative complications were measured 3 years after surgery.Results: The level of pain experienced by the patients decreased significantly than before, with pain scores ranging from 1.0– 3.0, and there was a statistical difference between groups (H = 93.400, P

Kang He,1,&ast; Taiwei Wang,1,&ast; Junyu Chen,2,&ast; Xuemiao Huang,1 Zeyu Wang,1 Zhaoyun Yang,1 Kai Wang,1 Weixin Zhao,2 Jian Jiang,1 Lijing Zhao1 1Department of Rehabilitation, School of Nursing, Jilin University, Changchun, Jilin, 130021, People’s Republic of China; 2Department of Gynaecology and Obstetrics, The Second Hospital, Jilin University, Changchun, Jilin, 130041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijing Zhao; Jian Jiang, School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin, 130021, People’s Republic of China, Email zhao_lj@jlu.edu.cn; jiangjian91@jlu.edu.cnIntroduction: Raddeanin A (RA), a potent triterpenoid extracted from Anemone raddeana Regel, has a moderate therapeutic effect on prostate cancer (PCa), correlating with serious biological toxicity. Therefore, a RA-loaded PEGylated liposome drug delivery system was devised in this study.Methods: Hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-Polyethyleneglycol-2000 (sodium salt) (DSPE-PEG2k), cholesterol (CHO), and RA were utilised to prepare a RA-loaded liposome (LRA) drug delivery system via the thin film hydration technique., The drug loading content was confirmed by high performance liquid chromatography. Dynamic light scattering was employed to evaluate the drug’s particle size and stability. Methyl tetrazolium, colony formation, and Western blot (WB) were used in vitro to elucidate the inhibitory effect and mechanism of LRA on prostate cancer cells. Finally, xenograft model was used to confirm the tumor-inhibiting efficacy, clarify the mechanism, and determine the biosafety in mice.Results: LRA has stable physicochemical properties and a diameter of 173.5 15.3 nm. LRA inhibited the growth of prostate cancer cells in a dose- and time-dependent manner. LRA can substantially reduce the expression of AR and HMGB1, induce apoptosis, regulate the expression of cell cycle-related proteins in vitro and in vivo. The results of the biosafety tests demonstrated that LRA effectively reduced the adverse effects of RA.Conclusion: As a drug delivery system, LRA could effectively and safely inhibit the progression of prostate cancer.Graphical Abstract: Keywords: prostate cancer, liposome, Raddeanin A, HMGB1, AR

Yifei Zeng,1,2 Dongxiao Zhang,1 Wenjie Zhao,1 Na Fu,1 Qiao Huang,1 Shuqi Li,2 Chang Gao,2 Jiale Yu2 1Department of Galactophore, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Dongxiao Zhang, Department of Galactophore, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Art Museum Back Street, Dongcheng District, Beijing, People’s Republic of China, Tel +86 13811077684, Email morningdong@163.comBackground: Despite the rising incidence rate of granulomatous lobular mastitis (GLM), uncertainties persist about its etiologic and predisposing factors to guide clinical treatment and early prevention. The objective of this study is to explore the predisposing factors for GLM.Patients and methods: This case-control study was conducted from 2018 to 2021 at Beijing Hospital of Traditional Chinese Medicine, Capital Medical University. Patients with GLM (cases) were matched with healthy examinees (controls) in a 1:1 ratio according to gender and living area. We analyzed their demographic features and investigated 75 factors that may be relevant to GLM using a standard questionnaire. Univariate and multivariable binary conditional logistic regression analyses were used to compare the differences between the two groups and evaluate the predisposing factors that may induce GLM.Results: There were 594 female GLM patients and 594 matched controls included in the study. The average age of the cases was 32.78 years (mainly 20 to 40). The incidence was high within five years after childbirth, and lesions were mainly in the unilateral breast. Univariate and multivariable conditional logistic regression analyses obtained six relevant factors and six high-risk factors. The six relevant factors included age, marriage, emotional abnormality, high prolactin, psychiatric drug intake, and sex hormone intake. Additionally, the independent high-risk factors for GLM included gestation, nipple invagination, blunt trauma, non-iatrogenic massage, lactation disorder, and nipple discharge (odds ratio (OR)=17.378, 8.518, 4.887, 3.116, 2.522, 1.685, P< 0.05). Menopause was an independent protective factor (OR=0.249, P< 0.05).Conclusion: The factors that increase milk and secretion production in the mammary duct are the main risk factors of GLM, especially when the nipples are invaginated. These factors can obstruct the duct and induce inflammation. Additionally, hormonal disorders, extrinsic trauma, and emotional abnormalities can accelerate the occurrence of GLM.Keywords: granulomatous lobular mastitis, GLM, predisposing factor, risk factor, case-control study, etiology

Wen Zhao,1,2,&ast; Huimin Zhang,1,2,&ast; Rui Liu,1,2 Rongtao Cui1– 3 1Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 2Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 3Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongtao Cui, Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China, Tel +86 18653170822, Email cuirt1986@outlook.comAbstract: Pathological scars are the result of over-repair and excessive tissue proliferation of the skin injury. It may cause serious dysfunction, resulting in psychological and physiological burdens on the patients. Currently, mesenchymal stem cells-derived exosomes (MSC-Exo) displayed a promising therapeutic effect on wound repair and scar attenuation. But the regulatory mechanisms are opinions vary. In view of inflammation has long been proven as the initial factor of wound healing and scarring, and the unique immunomodulation mechanism of MSC-Exo, the utilization of MSC-Exo may be promising therapeutic for pathological scars. However, different immune cells function differently during wound repair and scar formation. The immunoregulatory mechanism of MSC-Exo would differ among different immune cells and molecules. Herein, this review gave a comprehensive summary of MSC-Exo immunomodulating different immune cells in wound healing and scar formation to provide basic theoretical references and therapeutic exploration of inflammatory wound healing and pathological scars.Keywords: exosomes, inflammation, immune cells, immunoregulation, scars

Han Li,1,&ast; Lu Guo,2,&ast; Ke Su,1,&ast; Changlun Li,3 Yi Jiang,1 Pan Wang,4 Jiali Chen,1 Zhenying Wu,1 Ke Xu,5 Tao Gu,1 Hao Zeng,1 Kun He,6 Hao Chi,1 Wenxi Zhao,7 Lei Han,3 Yunwei Han1 1Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, 272000, People’s Republic of China; 4Clinical Skills Center, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 5Department of Oncology, Chongqing General Hospital, Chongqing, 401147, People’s Republic of China; 6Clinical Research Institute, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 7Clinical Medical College, Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunwei Han, The Affiliated Hospital of Southwest Medical University, 25 TAIPING Street, Luzhou City, Sichuan Province, People’s Republic of China, Tel +86-830-3165598, Email Lanpaoxiansheng@126.com Lei Han, Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, 272000, People’s Republic of China, Email hanleixxf@126.comBackground: TACE and TACE with or without targeted immunotherapy are crucial comprehensive therapies for middle and advanced HCC. However, a reasonable and concise score is needed to evaluate TACE and TACE combined with systemic therapy in HCC treatment.Methods: The HCC patients were grouped into two groups: training group (n = 778) (treated with TACE) and verification group (n = 333). The predictive value of baseline variables on overall survival was analyzed using COX model, and easy-to-use ALR (AST and Lym-R) scores. The best cut-off value of AST and Lym-R were determined using X-Tile software based on total survival time (OS) and further verified via a restricted three-spline method. Meanwhile, the score was further verified using two independent valid sets: TACE combined with targeted therapy and TACE with targeted combined immunotherapy.Results: In multivariate analysis, baseline serum AST> 57.1 (p < 0.001) and Lym-R≤ 21.7 (p < 0.001) were identified as independent prognostic factors. The OS of patients in the TACE pooled cohort with 0, 1, and 2 scores were 28.1 (95% CI 24– 33.8) months, 15 (95% CI 12.4– 18.6) months, and 7.4 (95% CI 5.7– 9.1) months, respectively. The time-varying ROC curve based on ALR showed that the AUC values for predicting 1, -2-and 3-year OS were 0.698, 0.718, and 0.636, respectively. These results are confirmed in two independent valid sets of TACE combined with targeted therapy and TACE with targeted combined immunotherapy. And we established a nomogram after COX regression to predict the 1 -, 2- and 3-year survival time.Conclusion: Our study confirmed that ALR score can predict the prognosis of HCC treated with TACE or TACE combined with systemic therapy.Keywords: TACE, immunotherapy, targeted therapy, nomogram

Songhui Li,1,&ast; Wenfeng Zhao,2,&ast; Lei Xia,3 Lingyi Kong,1 Lei Yang1 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China; 2Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China; 3Bloomage Biotechnology Corporation Limited, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lingyi Kong, Jiangning Campus, China Pharmaceutical University, No. 639 Longmian Avenue, Chunhua Street, Jiangning District, Nanjing City, Jiangsu Province, People’s Republic of China, Fax +86-25-8327-1405, Email cpu_lykong@126.com Lei Yang, Jiangning Campus, China Pharmaceutical University, No. 639 Longmian Avenue, Chunhua Street, Jiangning District, Nanjing City, Jiangsu Province, People’s Republic of China, Tel +86-13813925076, Email dorothy19802003@gmail.comAbstract: Helicobacter pylori infection often occurs in early childhood, and can last a lifetime if not treated with medication. H. pylori infection can also cause a variety of stomach diseases, which can only be treated with a combination of antibiotics. Combinations of antibiotics can cure H. pylori infection, but it is easy to relapse and develop drug resistance. Therefore, a vaccine is a promising strategy for prevention and therapy for the infection of H. pylori. After decades of research and development, there has been no appearance of any H. pylori vaccine reaching the market, unfortunately. This review summarizes the aspects of candidate antigens, immunoadjuvants, and delivery systems in the long journey of H. pylori vaccine research, and also introduces some clinical trials that have displayed encouraging or depressing results. Possible reasons for the inability of an H. pylori vaccine to be available over the counter are cautiously discussed and some propositions for the future of H. pylori vaccines are outlined.Graphical Abstract: Keywords: Helicobacter pylori vaccines, antigen, adjuvant, delivery system, clinical trials

Wenzhe Zhao,1 Haiqin Zhu,1 Xiaoqing Zhao,1 Xinyi Wu,1 Fei Sun,1 Meng Pan,1,&ast; Shengru Zhou2,&ast; 1Department of Dermatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 2Department of Dermatology, Dushu Lake Hospital Affiliated to Soochow University (Medical Center of Soochow University, Suzhou Dushu Lake Hospital), Suzhou, 215123, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shengru Zhou, Department of Dermatology, Dushu Lake Hospital Affiliated to Soochow University, (Medical Center of Soochow University, Suzhou Dushu Lake Hospital), No. 9, Chongwen Road, Suzhou, 215123, People’s Republic of China, Tel +86-17717453465, Fax +86-2164669691, Email zhoushengru1989@foxmail.comPurpose: Direct immunofluorescence (DIF) on frozen sections (DIF-F) plays a key role in the identification and differential diagnosis of bullous dermatoses, which are a group of critical autoimmune diseases that include pemphigus, bullous pemphigoid (BP), and epidermolysis bullosa acquisita (EBA). However, this technique requires specialized laboratory equipment conditions, sample acquisition and sample preservation. In this study, the application value of DIF on paraffin-embedded tissue sections (DIF-P) detecting IgG using heat-induced antigen retrieval (HIAR) in the diagnosis of bullous dermatosis was explored.Patients and Methods: Samples from 12 patients with pemphigus vulgaris (PV), 10 patients with pemphigus foliaceus (PF), 17 patients with BP, and 4 patients with EBA were retrospectively studied for DIF-P IgG detection. Formalin-fixed, paraffin-embedded tissue (FFPE) was used, and the antigen retrieval method used in the experiment was HIAR. All patients were diagnosed with the autoimmune bullous disease (AIBD) based on clinical presentation, histopathology, DIF-F, and enzyme-linked immunosorbent assay (ELISA).Results: Intercellular staining for IgG in the epidermis was successful in paraffin-embedded tissue sections in 11 of 12 PV samples and in all 10 PF samples. IgG at the basement membrane zone (BMZ) was not detected by immunofluorescent staining in 17 BP samples and 4 EBA samples.Conclusion: The detection of IgG by DIF-P using HIAR can be used for the diagnosis of pemphigus as an alternative method to DIF-F.Keywords: pemphigus, bullous dermatoses, direct immunofluorescence, IgG, paraffin-embedded section, heat-induced antigen retrieval

Fen Pan,1,2,&ast; Na Zhao,3,&ast; Wantong Zhao,1 Chun Wang,1 Yan Sun,1 Haomin Zhang,3 Juanxiu Qin,3 Qian Liu,3 Hong Zhang1,2 1Department of Clinical Laboratory, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, People’s Republic of China; 3Department of Laboratory Medicine, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Zhang, Department of Clinical Laboratory, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86 189 1712 8200, Email schjyk2015@126.com Qian Liu, Department of Laboratory Medicine, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People’s Republic of China, Email qq2005011@163.comBackground: Due to similar colony morphology among viridans group streptococci (VGS), the differentiation of VGS species remains difficult in routine clinical microbiology. Recently, matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS) has been described as a fast method for identifying various bacteria at species level, and also for the VGS strains.Methods: A total of 277 VGS isolates were identified with the two MALDI-TOF MS systems (VITEK MS and Bruker Biotyper). The tuf and rpoB gene sequencing was used as the reference identification method for comparison.Results: Based on tuf and rpoB gene sequencing, 84 isolates were S. pneumoniae and 193 strains were other VGS isolates including S. anginosus group (n=91, 47.2%), S. mitis group (n=80, 41.5%), S. bovis group (n=11, 5.7%), S. salivarius group (n=10, 5.2%), and S. mutans group (n=1, 0.5%). VITEK MS and Bruker Biotyper accurately identified 94.6% and 89.9% of all VGS isolates, respectively. VITEK MS showed better identification results than Bruker Biotyper for S. mitis group including S. pneumoniae and S. bovis group, but for other VGS isolates, two MALDI-TOF MS systems showed comparable identification performance. However, VITEK MS was able to identify S. gallolyticus to the subspecies level with high-confidence (S. gallolyticus ssp. pasteurianus), while the Bruker Biotyper system could not. While Bruker Biotyper system could be able to correctly differentiate the subspecies of S. salivarius from S. vestibularis, VITEK MS poorly identify.Conclusion: This study demonstrated that two MALDI-TOF MS systems allowed discrimination for most VGS isolates with different identification performance, but Bruker Biotyper could produce more misidentifications and VITEK MS system. It is crucial to be familiar with the performance of MALDI-TOF MS systems used in clinical microbiology.Keywords: MALDI-TOF MS, viridans group streptococci, identification, Streptococcus pneumoniae

Ye Mao,&ast; Wei Zhao,&ast; Mengxiao Hao, Rui Xing, Ming Yan Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Yan, Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221000, People’s Republic of China, Tel +86 18052268329, Email yjy3001@163.comPurpose: Many studies confirmed that several approaches of quadratus lumborum block (QLB) were superior to transversus abdominis plane block (TAPB) in reducing opioid consumption during postoperative period. As a new QLB approach at the lateral supra-arcuate ligament (QLB-LSAL), the analgesic efficacy and safety in patients undergoing open hepatectomy are still unknown. This study aims to compare postoperative analgesia between the blocks in open hepatectomy.Patients and Methods: Sixty-two patients undergoing open hepatectomy were enrolled and randomly allocated into the QLB-LSAL group (group Q) and the subcostal TAPB group (group T). Preoperatively, patients received ultrasound-guided bilateral QLB-LSAL or subcostal TAPB with injection of 0.5% ropivacaine (a total volume of 40 mL). The primary outcome was cumulative total morphine equivalent consumption in the first postoperative 24 h. Other outcomes included numerical rating scale (NRS) scores at rest and coughing, cumulative total morphine equivalent consumption at 2, 6, 12, 48 h, Quality of Recovery-15 (QoR-15) scores, time to first patient-controlled intravenous analgesia (PCIA) request, time to first ambulation and adverse effects.Results: The cumulative total morphine equivalent consumption in group Q was decreased significantly at all postoperative time points (P < 0.01). The postoperative NRS scores at rest and coughing in group Q were lower than those in group T at all postoperative time points except 48 h (P < 0.05). A significant increase was also observed in the QoR-15 scores among patients in group Q. Time to first PCIA request was significantly prolonged in group Q than in group T, and time to first ambulation was shortened. Adverse effects showed no statistical significance between the two groups.Conclusion: Compared with subcostal TAPB, preoperative bilateral QLB-LSAL provided superior analgesic properties and promoted early postoperative recovery quality in patients undergoing open hepatectomy.Trial Registration: China Clinical Trials Registration Center (http://www.chictr.org.cn) ChiCTR2200063291, 3/9/2022.Keywords: quadratus lumborum block, transversus abdominis plane block, open hepatectomy, analgesia

Xijier Qiaolongbatu,1,&ast; Wenjuan Zhao,1,&ast; Xucong Huang,2,3,&ast; Feng Qian,1 Xinyi Yang,1 Jiaqi Wu,2 Cui Ma,2 Han Qu,1,2 Li Wang,3 Guorong Fan,2 Zhenghua Wu2 1Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3School of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenghua Wu; Guorong Fan, Department of Clinical Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, No. 85 Wujin Road, Shanghai, 200080, People’s Republic of China, Tel +86-133-0177-7863 ; +86-21-36123711, Email zhenghua.wu@shgh.cn; fanguorong@sjtu.edu.cnBackground: Schisandrol A (Sch A) is the main active ingredient of Schisandra chinensis (Turcz.) Baill. Our previous study showed that Sch A has anti-pulmonary fibrosis (PF) activity, but its metabolic-related mechanisms of action are not clear.Methods: Here, we explored the therapeutic mechanisms of Sch A on PF by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) metabolomics approach and network analysis. The metabolites of Sch A in mice (bleomycin + Sch A high-dose group) plasma were identified based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS).Results: 32 metabolites were detected reversed to normal level after treating bleomycin (BLM)-induced PF mice with Sch A. The 32 biomarkers were enriched in energy metabolism and several amino acid metabolisms, which was the first report on the therapeutic effects of Sch A on PF through rescuing the disordered energy metabolism. The UPLC-Q-TOF/MS analysis identified 17 possible metabolites (including isomers) of Sch A in mice plasma. Network analysis revealed that Sch A and 17 metabolites were related to 269 genes, and 1109 disease genes were related to PF. The construction of the Sch A/metabolites-target-PF network identified a total of 79 intersection genes and the TGF-β signaling pathway was determined to be the main signaling pathway related to the treatment of PF by Sch A. The integrated approach involving metabolomics and network analysis revealed that the TGF-β 1-ID3-creatine pathway, TGF-β 1-VIM-carnosine pathway were two of the possible pathways Sch A regulated to modulate metabolic disorders, especially energy metabolism, and the metabolite of Sch A M5 was identified as a most likely active metabolite.Conclusion: The results suggested the feasibility of combining metabolomics and network analysis to reflect the effects of Sch A on the biological network and the metabolic state of PF and to evaluate the drug efficacy of Sch A and its related mechanisms.Graphical Abstract: Keywords: schisandrol A, pulmonary fibrosis, mechanism of action, network analysis, metabonomics

Wenming Zhao,1,2,&ast; Chengwei Yang,1,&ast; Ning Zhang,3,&ast; Yuanyuan Peng,3 Ying Ma,3 Keru Gu,3 Xia Liu,3 Xiaohui Liu,3 Xijian Liu,3 Yumin Liu,4 Songkai Li,1 Linjing Zhao3 1Department of Spinal Surgery, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, People’s Republic of China; 2Department of Orthopedics, Zhangye Second People’s Hospital, Zhangye, People’s Republic of China; 3College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People’s Republic of China; 4Instrumental Analysis Centre, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linjing Zhao, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People’s Republic of China, Email ljzhao@sues.edu.cn Songkai Li, Department of Spinal Surgery, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, People’s Republic of China, Email lisongkai@gmail.comObjective: The characteristic constituents of essential oils from aromatic plants have been widely applied as antimicrobial agents in the last decades. However, their mechanisms of action remain obscure, especially from the metabolic perspective. The aim of the study was to explore the antimicrobial effect and mechanism of menthone, a main component of peppermint oil, against methicillin resistant Staphylococcus aureus (MRSA).Methods: An integrated approach including the microbiology and the high-coverage lipidomics was applied. The changes of membrane properties were studies by the fluorescence and electron microscopical observations. The lipid profile was analyzed by ultra-high performance liquid chromatography coupled with quadruple Exactive mass spectrometry (UHPLC-QE-MS). The lipid-related key targets which were associated with the inhibitory effect of menthone against MRSA, were studied by network analysis and molecular docking.Results: Menthone exhibited antibacterial activities against MRSA, with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of 3,540 and 7,080 μg/mL, respectively. The membrane potential and membrane integrity upon menthone treatment were observed to change strikingly. Further, lipids fingerprinting identified 136 significantly differential lipid species in MRSA cells exposed to menthone at subinhibitory level of 0.1× MIC. These metabolites span 30 important lipid classes belonging to glycerophospholipids, glycolipids, and sphingolipids. Lastly, the correlations of these altered lipids, as well as the potential metabolic pathways and targets associated with menthone treatment were deciphered preliminarily.Conclusion: Menthone had potent antibacterial effect on MRSA, and the mechanism of action involved the alteration of membrane structural components and corresponding properties. The interactions of identified key lipid species and their biological functions need to be further determined and verified, for the development of novel antimicrobial strategies against MRSA.Keywords: menthone, MRSA, antimicrobial activity, cell membrane, lipid homeostasis, microbial lipidomics, UHPLC-QE-MS

Bin Liang,1,&ast; Huiyu Chen,2,&ast; Donghong Yu,3,4 Wantong Zhao,1,3 Xiaoling Cai,1,3 Huahong Qiu,2 Liangpu Xu1 1Medical Genetic Diagnosis and Therapy Center, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 2Laboratory Department, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 3Fujian Obstetrics and Gynecology Hospital, Fuzhou, Fujian, People’s Republic of China; 4Medical Research Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangpu Xu; Huahong Qiu, Fujian Maternity and Child Health Hospital, Fuzhou, 350001, People’s Republic of China, Tel +86-0591-87554929 ; +86-0591-87604121, Email xiliangpu@fjmu.edu.cn; 722hhq@sina.comObjective: This study investigated the molecular epidemiology of Group B Streptococcus (GBS) in pregnant women with premature rupture of membranes (PROM) in Fuzhou region of China as a source of clinical reference.Methods: GBS isolates were obtained from pregnant women with PROM. All isolates were genotyped, serotyped, and tested for drug-resistance and virulence genes using PCR and DNA sequencing. Antibiotic susceptibility testing was performed using the Vitek® 2 automated system.Results: Among the 140 GBS isolates, seventeen sequence types (STs) were identified, of which ST19 (20.0%) was the most prevalent, followed by ST862, ST10, and ST12. Three clonal complexes (CC19, CC10 and CC1) were identified. The predominant serotype was III (45.7%), followed by V (23.6%), Ib (18.6%), Ia (7.1%), and II (3.6%). The prevalence of multidrug resistance was 72.8% (102/140). All isolates were susceptible to penicillin G, ampicillin, quinupristin, linezolid, vancomycin, and tigecycline. The majority of isolates were resistant to erythromycin (70.0%), clindamycin (72.1%), and tetracycline (81.4%), and 28.6% of isolates were resistant to levofloxacin and moxifloxacin. Of the 98 erythromycin-resistant strains, mreA, ermB, mefA, mefE, ermA, and ermTR were detected in 100%, 70.4%, 49.0%, 22.4%, 13.3%, and 9.2%, respectively. No linB was detected among 101 clindamycin-resistant strains. Of the 114 tetracycline-resistant strains, tetM, tetK, tetL and tetO were detected in 52.6%, 61.4%, 7.9%, and 23.7%, respectively. Regarding virulence genes, all strains carried rib and hylB, followed by scpB (98.6%), and bca (80.7%), whereas only one strain carried bac.Conclusion: ST19/III and ST862/III were the most prevalent GBS subtypes. Penicillin G remains a first-line antibiotic for intrapartum antibiotic prophylaxis and treatment of GBS infections. The prevalence of resistance to clindamycin, erythromycin, and tetracycline is high among GBS isolates in the Fuzhou region. ST862 and ST651 are emerging animal origin STs in human infections, and may become potential zoonotic threats.Keywords: Group B Streptococcus, molecular epidemiology, premature rupture of the membranes, antibiotic resistance, China

Daniel H Chang,1 Jerry Hu,2 Kevin M Miller,3 Srividhya Vilupuru,4 Wuchen Zhao4 1Empire Eye and Laser Center, Bakersfield, CA, USA; 2Texas Eye & Laser Center, Hurst, TX, USA; 3Department of Ophthalmology, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, CA, USA; 4Johnson & Johnson Surgical Vision, Inc., Irvine, CA, USACorrespondence: Daniel H Chang, Empire Eye & Laser Center, 4105 Empire Dr, Bakersfield, CA, 93309, USA, Email dchang@empireeyeandlaser.comPurpose: To evaluate 3-month rotational stability, and visual and refractive outcomes of a toric intraocular lens (IOL) with frosted haptics.Patients and Methods: A post-market, prospective, multi-center, single-arm, open-label study conducted at seven clinical sites in the United States. Two hundred and two eyes of 133 subjects with unilateral or bilateral cataracts and corneal astigmatism were implanted with the Tecnis Toric II IOL, Models ZCU150 to 600 (Johnson & Johnson Surgical Vision, Inc.). Lens axis misalignment/rotation, visual acuity, manifest refraction, and surgeon and patient satisfaction were evaluated 3 months postoperatively. Lens rotation was determined with operative and postoperative visit photographs and was analyzed by two independent masked analysts.Results: Mean absolute lens rotation was 0.82° ± 1.00° and 0.94° ± 0.71° at 1 day (n = 189 eyes) and 3 months (n = 185 eyes), respectively. Absolute lens rotation was ≤ 5° in 98.9% and 100% of eyes at 1 day and 3 months, respectively. At 3 months, postoperative monocular uncorrected and corrected distance visual acuities were 0.004 ± 0.115 LogMAR (20/20) and − 0.066 ± 0.092 LogMAR (20/17), mean spherical equivalent was − 0.25 D ± 0.35 D and residual refractive cylinder was +0.27 D ± 0.33 D. Surgeons were satisfied/very satisfied with overall clinical outcomes and rotational stability in 99% of eyes, and with uncorrected distance vision in 98.5% of eyes.Conclusion: The study results demonstrate that the Tecnis Toric II IOL has excellent rotational stability with a high percentage of study eyes being within 5° of intended orientation. The study lens demonstrated excellent uncorrected distance visual acuity, reduction of cylinder, and exceptional patient and surgeon satisfaction.Keywords: toric IOL, lens rotation, IOL misalignment, residual astigmatism

Xiao Chen,1,&ast; Wenjuan Zhao,2,&ast; Jie Yuan,3 Wei Qin,1 Yuhong Zhang,1 Yuxia Zhang1 1Department of Nursing, Zhongshan Hospital of Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Nursing, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 3Department of Nursing, Shanghai Fengxian District Hospital of Traditional Chinese Medicine, Shanghai, 201499, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuxia Zhang; Yuhong Zhang, Department of Nursing, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China, Tel +86 13816881925, Fax +86 64041990, Email zhang.yx@aliyun.com; zhang.yuhong@zs-hospital.sh.cnPurpose: When creating and managing patient loyalty, medical institutes always focus on medical technicians, overall healthcare quality, and hospital brands, and the role of nursing seems to be underappreciated. Empirical evidence about the relationship between patient experience with nursing care and patient loyalty is limited, especially in the Chinese healthcare system. This study aimed to explore to what extent patient experience with nursing care influences patient loyalty to the hospital and the impact routes.Patients and Methods: This study is a multicenter cross-sectional survey. The STROBE was selected as the checklist in this study. Patient experience with nursing care, patient satisfaction and patient loyalty were collected from 1469 inpatients in three hospitals in China through a paper-based survey. Data were analyzed using SPSS and AMOS software; a structural equation model was established to explore the effect of patient experience with nursing care and satisfaction on patient loyalty using the PROCESS macro.Results: There were significant direct and indirect effects between patient experience with nursing care and patient loyalty, explaining 32.0% of patient loyalty variance. Patient experience with nursing care had a direct and positive impact on patient loyalty (β=0.298, P< 0.01), and better patient experience with nursing care was directly associated with better patient loyalty. In addition, the results also revealed the effect of patient experience with nursing care on patient loyalty was partially mediated by patient satisfaction with nursing care and overall hospital services (β=0.162, P< 0.01).Conclusion: This study confirmed the importance of nursing care in creating patient loyalty; improving the patient experience with nursing care would be beneficial to patient loyalty. When creating patient loyalty, hospital administrators and nursing managers should make efforts to develop positive patient experience of nursing care in daily clinical practice through organizational changes, culture shaping and staff education.Keywords: patient experience, nursing care, patient satisfaction, patient loyalty

Yumeng Wei,1– 3,&ast; Mingtang Zeng,1– 4,&ast; Chao Pi,1– 3 Hongping Shen,2,5 Jiyuan Yuan,2,5 Ying Zuo,2,6 Jie Wen,1– 3 Pu Guo,7 Wenmei Zhao,1– 3 Ke Li,1– 3 Zhilian Su,1– 3 Xinjie Song,8,9 Shaozhi Fu,10 Robert J Lee,11 Ling Zhao2,3 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Clinical Trial Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 6General Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 7Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 8School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, People’s Republic of China; 9Department of Food Science and Technology, Yeungnam University, Gyeongsan-si, Gyeongsangbuk-do, 38541, Republic of Korea; 10Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 11Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA&ast;These authors contributed equally to this workCorrespondence: Shaozhi Fu, Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel +86 830-3165698, Fax +86 830-3165690, Email shaozhifu513@swmu.edu.cn Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling-998@163.comPurpose: Paclitaxel (PTX) has been widely utilized for the treatment of breast cancer. However, drawbacks, such as poor aqueous solubility, rapid blood clearance and severe toxicity, greatly reduce its efficacy and safety. Herein, a novel self-developed curcumin derivative (CUD) was chosen as the carrier to develop a long-acting PTX nano-delivery system (PTX-Sln@CUD) in order to improve its pharmacokinetic behavior, anti-breast cancer efficacy and safety.Methods: PTX-Sln@CUD was prepared using solid dispersion and ultrasonic technology. Relevant physical and chemical properties, including stability and release behavior, were characterized. The clearance of PTX-Sln@CUD in vivo was studied by pharmacokinetic experiments. The anti-tumor activity of PTX-Sln@CUD was investigated in vitro and in vivo. Hemolysis experiments, acute toxicity and cumulative toxicity studies were performed in mice to determine the safety of PTX-Sln@CUD.Results: The average particle size, PDI, Zeta potential, encapsulation efficiency and loading efficiency of the PTX-Sln@CUD were 238.5 ± 4.79 nm, 0.225 ± 0.011, − 33.8 ± 1.26 mV, 94.20 ± 0.49% and 10.98 ± 0.31%, respectively. PTX-Sln@CUD was found to be stable at room temperature for half a year. The cumulative release rates of PTX-Sln@CUD at 24, 96 and 168 h were 17.98 ± 2.60, 57.09 ± 2.32 and 72.66 ± 4.16%, respectively, which were adherent to zero-order kinetics. T1/2, MRT (0-t) and AUC (0-t) of the PTX-Sln@CUD group were 4.03-fold (44.293 h), 7.78-fold (38.444 h) and 6.18-fold (14.716 mg/L&ast;h) of the PTX group, respectively. PTX-Sln@CUD group demonstrated stronger anti-breast cancer activity than the PTX group. Importantly, the PTX-Sln@CUD group was safer compared to the PTX group both in vitro and in vivo.Conclusion: PTX-Sln@CUD was verified as promising therapeutic nanoparticles for breast cancer and provided a novel strategy to solve the problem of low efficacy and poor safety of clinical chemotherapy drugs.Graphical Abstract: Keywords: breast cancer, long-acting, paclitaxel nanoparticles, curcumin derivative

Hang Yu,1,&ast; Wenwei Zhao,2,&ast; Yongqing Ni,1,&ast; Linlin Li1,&ast; 1Department of Pediatric, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010030, People’s Republic of China; 2Office of the Director, Hohhot People’s Mediation Committee for medical Disputes, Hohhot, Inner Mongolia Autonomous Region, 010030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linlin Li, Department of Pediatric, The Affiliated Hospital of Inner Mongolia Medical University, No. 1 Tongdao North Road, Hohhot, Inner Mongolia Autonomous Region, 010030, People’s Republic of China, Tel +86 13848185400, Email 1135315688@qq.comObjective: Analyze the different clinical manifestations and genetic characteristics of Shwachman diamond syndrome (SDS).Methods: The clinical data of a case of neonatal onset Shwachman diamond syndrome with arrhythmia as the first manifestation were retrospectively analyzed, and the relevant literature was reviewed to summarize the clinical manifestations, genetic characteristics and treatment of Shwachman diamond syndrome.Results: The patient, female, age 1 month 24 days, with ventricular arrhythmia as the first manifestation, accompanied by growth retardation, liver damage, and persistent decrease in peripheral blood neutrophil count (< 1.5 × 109/l), no pancreatic exocrine gland dysfunction at the initial stage of the disease. Gene detection showed that the SBDS gene chr7:66,459,197, c.258+2T > C homozygous variation.Conclusion: Although the classic manifestations of Shwachman diamond syndrome are pancreatic exocrine insufficiency, pancreatic adiposis and unexplained neutropenia, its clinical manifestations are complex and diverse, involving multiple systems. For suspected children, early genetic examination is helpful for subsequent diagnosis and treatment.Keywords: Shwachman diamond syndrome, arrhythmia, case report

Gabriel A Quesada,1 Rodrigo A Quesada,1 Jason J Jones,2 Benjamin JK Straker,3 Wuchen Zhao,3 Linda Tsai,3 Srividhya Vilupuru3 1Centro de Oftalmología y Cirugía Plástica, San Salvador, El Salvador; 2Jones Eye Clinic, Sioux City, IA, USA; 3Johnson & Johnson Surgical Vision, Inc, Irvine, CA, USACorrespondence: Srividhya Vilupuru, Johnson & Johnson Surgical Vision, 31 Technology Dr Suite 200, Irvine, CA, 92618, USA, Tel +1-949-581-5799, Email SVilupur@ITS.JNJ.comPurpose: To evaluate the reproducibility of magnitude of postoperative IOL rotation following implantation of a toric intraocular lens (IOL) with modified haptics, in comparison with a Proof-of-Concept (POC) study of prototype IOLs featuring the same haptic design.Patients and Methods: A post-market, prospective, multicenter, single-arm, open-label clinical study was conducted. TECNIS Toric II IOL (Johnson & Johnson Vision, Irvine, CA, USA, Models ZCU150 to 600) were implanted in 125 subjects and evaluated at 1-day and 1-week postoperatively. An objective photographic method was used to determine postoperative IOL rotation. Uncorrected distance visual acuity (UCDVA), postoperative astigmatism, and surgeon satisfaction were also assessed. Rotation data were compared to the POC study in which two prototype non-toric monofocal IOLs, one with the same haptic design as Model ZCU, were studied.Results: Mean absolute rotation was 0.82° ± 1.0° and 0.84° ± 0.92°at 1-day and 1-week visits, respectively. The percentage of eyes with ≤ 5° of absolute rotation was 98.9% and 99.5% at the 1-day and 1-week visits, respectively. The magnitude of rotation was similar to the POC study prototype IOLs. At 1-week, mean monocular UCDVA was 0.026 ± 0.135 (~20/21) logMAR and mean residual manifest refractive cylinder was 0.30 D ± 0.35 D. The mean signed axis difference (postoperative minus operative) of the TECNIS Toric II IOL was 0.23° ± 1.27° at 1-day and − 0.07° ± 1.25° at 1-week, indicating a clockwise drift. At 1-week, surgeons were very satisfied or satisfied with overall clinical outcomes and rotational stability in 98% of implanted eyes.Conclusion: The TECNIS Toric II IOL, with frosted, squared haptics, demonstrated low magnitude of postoperative IOL rotation, excellent uncorrected distance vision, and minimal residual astigmatism. The POC study design was supported, demonstrating that prototype non-toric monofocal IOLs can predict clinical performance of toric IOLs with the same haptic design.Keywords: toric IOL, astigmatism, IOL rotation, cataract, surgery, axis misalignment

Weiguo Zhao,1 Xinning Wang,1 Jiazheng Li,1 Qingtian Li,1 Chen Chen2 1School of Psychology, Shandong Normal University, Jinan, People’s Republic of China; 2Linyi Suhe Experimental School, Linyi, People’s Republic of ChinaCorrespondence: Weiguo Zhao, School of Psychology, Shandong Normal University, No. 1, Daxue Road, Changqing District, Jinan, 250358, People’s Republic of China, Tel +86 18765411698, Email wgzhao512sys@163.comPurpose: Previous studies have shown that academic procrastination not only affects middle school students’ academic performance but also causes them physical and psychological stress, as well as negative emotions. Therefore, it is necessary to explore the influencing factors of academic procrastination and its internal mechanisms. This study aims to explore the relationship between perceived parental autonomy support and academic procrastination, as well as the role of autonomous motivation and time management disposition.Participants and Methods: Cross-sectional data from 662 middle school students were collected using the Parental Autonomy Support Scale, Academic Procrastination Inventory for Middle School Students, Academic Self-Regulation Questionnaire and Adolescence Time Management Disposition Scale. SPSS and its PROCESS macro were used for data analysis.Results: After gender and age were controlled, the results showed that perceived parental autonomy support could not only directly predict middle school students’ academic procrastination but also predict three paths of procrastination: (1) the mediating role of autonomous motivation, (2) the mediating role of time management disposition, and (3) the chain mediating role of autonomous motivation and time management disposition.Conclusion: Autonomous motivation and time management disposition played a chain mediating role in the relationship between perceived parental autonomy support and academic procrastination in middle school students.Keywords: middle school students, academic procrastination, perceived parental autonomy support, autonomous motivation, time management disposition

Wen Zhao,1 Rui Zhang,1 Chengyu Zang,1 Linfeng Zhang,1 Ran Zhao,1 Qiuchen Li,1 Zhanjie Yang,1 Zhang Feng,1 Wei Zhang,1 Rongtao Cui1,2 1Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 2Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Rongtao Cui, Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China, Tel +86 18653170822, Email cuirt1986@outlook.comIntroduction: The therapies of using exosomes derived from mesenchymal stem cells (MSC-Exo) for wound healing and scar attenuation and micro RNAs (miRNAs) for regulation of genes by translational inhibition and mRNA destabilization obtained great achievements. Silent information regulator 1 (SIRT1) is the silent information, which has an intricate role in many biological processes. However, the effects of SIRT1 and miR-138-5p loaded in MSC-Exo on pathological scars remain unclear.Methods: MSC-Exo was isolated and identified by ultracentrifugation, transmission electron microscopy, nanoparticle size measuring instrument and Western blot assays. The relationship between SIRT1 and miR-138-5p was verified by a double-luciferase reporter assay. Cell Counting Kit-8, &Tgr;ranswell, scratch, and Western blot assays were used to evaluate the proliferation and migration of human skin fibroblasts (HSFs), and the protein expression of SIRT1, NF-κB, α-SMA and TGF-β 1 in HSFs, respectively. Flow cytometry was used to assess the apoptosis and cell cycle of HSFs affected by SIRT1.Results: Our study demonstrated that miR-138-5p loaded in MSC-Exo could attenuate proliferation, migration and protein expression of HSFs-derived NF-κB, α-SMA, and TGF-β 1 by targeting to SIRT1 gene, which confirmed the potential effects of MSC-Exo in alleviating pathological scars by performing as a miRNA’s delivery vehicle.Conclusion: Exosomes derived from MSCs acting as a delivery vehicle to deliver miR-138-5p can downregulate SIRT1 to inhibit the growth and protein expression of HSFs and attenuate pathological scars.Keywords: mesenchymal stem cell-derived exosomes, miR-138-5p, SIRT1, human skin fibroblasts, pathological scars

Jingnuo Ding, Weifeng Zhao Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People’s Republic of ChinaCorrespondence: Weifeng Zhao, Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Gusu District, Suzhou, JiangSu Province, 215000, People’s Republic of China, Tel +86 13360518767, Email zhaoweifeng@suda.edu.cnAbstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.Keywords: liquid biopsy techniques, hepatocellular carcinoma, high-risk population

Zhaoxiang Liu, Luqi Xiao, Chenxi Jin, Jianzhong Xiao, Wenhui Zhao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Wenhui Zhao, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, People’s Republic of China, Tel +86 10-5611-9057, Fax +86 10-5611-9057, Email zwha01637@btch.edu.cnBackground: Bariatric surgery is an effective therapy for type 2 diabetes mellitus (T2DM) and obesity. Euglycaemic ketoacidosis (EKA) has been reported in patients taking sodium-glucose cotransporter 2 (SGLT2) inhibitors after bariatric surgery. Cases of T2DM complicated with EKA without SGLT2 inhibitors after bariatric surgery are rarely reported.Purpose: To present a case report of a T2DM patient (without SGLT2 inhibitor use) who developed EKA soon after laparoscopic sleeve gastrectomy.Methods: Clinical records and interviews were used.Results: A 35-year-old female patient was diagnosed with T2DM and obesity. The patient underwent laparoscopic sleeve gastrectomy to lose weight and control her blood glucose levels. Her daily fluid intake was 800– 1000 mL, and her daily caloric intake was less than 500 kcal during the first days after the surgery. She was prescribed degludec insulin, metformin and dulaglutide and her blood sugar was lower than 13.9 mmol/L. On postoperative Day 6, the patient complained of fatigue and vomiting. Blood gas analysis and urine analysis supported the diagnosis of ketoacidosis. Fluid resuscitation, insulin and glucose were administered to the patient immediately. On postoperative Day 8, the patient recovered without any symptoms.Conclusion: We report an extremely rare case of T2DM in which the patient developed EKA after laparoscopic sleeve gastrectomy owing to extremely low-calorie intake and dehydration. Physicians should be on alert for ketoacidosis in patients with T2DM after bariatric surgery with an euglycaemic status, even without the use of SGLT2 inhibitors or the presence of stresses, such as infection.Level V: Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.Keywords: bariatric surgery, euglycaemic ketoacidosis, type 2 diabetes mellitus

Hongmei Chen,1,&ast; Shanshan Li,2,&ast; Weijie Zhao,3,&ast; Jiaheng Deng,4,&ast; Zhuohong Yan,5 Tingting Zhang,2 Shu’ an Wen,2 Haiping Guo,2 Lei Li,6 Jianfeng Yuan,6 Hongtao Zhang,5 Liping Ma,1 Jianhua Zheng,4,&ast; Mengqiu Gao,1 Yu Pang2 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 2Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 3Clinical Trial Agency Office, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 4Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Central Laboratory, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 6Electral Safety Research & Development Center, Beijing Normal University, Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Pang, Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/ Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel +86 10 8950 9359, Email pangyupound@163.com Mengqiu Gao, Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/ Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel +86 10 8950 9302, Email gaomqwdm@aliyun.comBackground: Here, we conducted a peptidomic study in murine model to identify novel antigen biomarkers for the diagnosis of tuberculosis (TB) with improved performance.Methods: Four recombinant proteins, including Mycobacterium tuberculosis protein 32 (MPT32), Mycobacterium tuberculosis protein 64 (MPT64), culture filtrate protein 10 (CFP10), and phosphate ABC transporter substrate-binding lipoprotein (PstS1) were expressed and intravenously injected into BALB/c mice. The serum were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The concentrations of candidate peptides in serum of suspected TB patients were determined using competitive enzyme-linked immunosorbent assay.Results: A total of 65 peptides from 4 MTB precursor recombinant proteins were identified in mouse serum by LC-MS/MS, of which 5 peptides were selected as candidates for serological analysis. The concentrations of peptides MPT64-2, CFP10-2 and PstS1-2 in TB patients were significantly higher than those in non-TB patients. MPT64-2 exhibited the most promising sensitivity (81.4%), followed by PstS1-2 and CFP10-2. In addition, PstS1-2 had the highest specificity (93.3%), followed by CFP10-2 and MPT64-2. According to the area under the curve (AUC), MPT64-2 (AUC = 0.863), PstS1-2 (AUC = 0.812) and CFP10-2 (AUC = 0.809) exhibited better diagnostic validity.Conclusion: We develop an effective approach to identify new antigen biomarkers via LC-MS/MS-based peptidomics. Multiple peptides exhibit promising efficacy in diagnosis of active TB patients.Keywords: tuberculosis, peptidomics, enzyme-linked immunosorbent assay, Mycobacterium tuberculosis protein 64, diagnostics

Weidong Zhao,1,2,&ast; Shaoyou Yang,3,&ast; Chunxiao Li,1,2 Feifei Li,1,2 Houjun Pang,3 Guangling Xu,1,2 Yuxin Wang,3 Mei Cong3 1Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China; 3School of Pharmacy, Xinxiang Medical University, Xinxiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei Cong, School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China, Tel +86 0373 3029879, Fax + 86 0373 3029879, Email 151051@xxmu.edu.cnPurpose: Gemcitabine is the first line and the gold standard drug for pancreatic cancer. However, the anticancer efficacy is severely limited by its instability and poor cellular uptake. To enhance the clinical efficacy of gemcitabine, we constructed a novel nanodrug delivery system based on amphiphilic dendrimers and aliphatic gemcitabine prodrug.Methods: An aliphatic gemcitabine prodrug and a small amphiphilic dendrimer were synthesized and characterized by high resolution mass spectrometry (HRMS) as well as nuclear magnetic resonance (NMR). Then the aliphatic gemcitabine prodrug was encapsulated into the small amphiphilic dendrimer by film dispersion method, resulting in a novel nanodrug delivery system. Subsequently, the size, morphology, drug loading, stability, drug release profiles, cell uptake, toxicity, the anticancer activity and in vivo distribution of the new developed gemcitabine delivery system were systematically evaluated by different technical methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), ultraviolet spectrophotometer, flow cytometry, in vivo imaging system etc.Results: We developed a novel nanodrug delivery system of gemcitabine using amphiphilic dendrimer. This dendrimer-based gemcitabine nanoformulation reported here possess a high drug loading of 33%. With the features of small size, stable formulation and pH-responsive drug release, the obtained gemcitabine nanoformulation could effectively accumulate in tumor site and rapid uptake in cells. Finally, the gemcitabine nanoformulation displayed more potent anticancer activity compared to free gemcitabine both in vitro and in vivo. Moreover, the nanodrug displayed greatly reduced adverse effects and satisfactory biocompatibility.Conclusion: Benefiting the advantageous features of both amphiphilic dendrimers and nanotechnology-based drug delivery, this gemcitabine nanosystem constitutes a promising therapeutic candidate for pancreatic cancer treatment. This study also underlines the potential use of self-assembling amphiphilic dendrimer-based nanotechnology for improving drug efficacy as well as reducing drug toxicity.Graphical Abstract: Keywords: gemcitabine, amphiphilic dendrimer, self-assembling, pancreatic cancer, anticancer candidate

Fang Wei,1 Qiuyue Wang,1 Hang Liu,1 Xuejing Yang,1 Wenyu Cao,1 Weiman Zhao,1 Yingying Li,1 Lijie Zheng,1 Tao Ma,1,2 Qingqing Wang1– 3 1School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China; 2Engineering Research Center for Biochemical Pharmaceuticals of Anhui Province, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China; 3Bengbu BBCA Medical Science Co., Ltd., Bengbu, Anhui Province, 233030, People’s Republic of ChinaCorrespondence: Qingqing Wang; Tao Ma, School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China, Tel +86 15605528300 ; +86 13855266592, Email qingqingwang@bbmc.edu.cn; matao1992@foxmail.comIntroduction: Methotrexate (MTX) is the first-line drug for the treatment of rheumatoid arthritis (RA) in several countries. However, MTX has an extremely low solubility in water, and the side effects caused by its delivery mode restrict its curative effect. In this study, we designed a dissolving microneedles array (DMNA) containing MTX nanocrystals (MTX-NCs) (MTX-NC@DMNA) to improve the treatment of RA. DMNA-based drug delivery combines the advantages of patient compliance with the use of transdermal drug delivery systems and high-efficiency injection administration; thus, it can mitigate the side effects that result from current administration routes. Carrier-free and surfactant-free MTX-NCs were prepared to overcome bioavailability limitations and poor drug loading problems.Methods: The MTX-NCs prepared by reverse solvent precipitation method was encapsulated in the DMNA. The morphology, mechanical properties, safety, stability and in vivo dissolution were evaluated, and its pharmacodynamic characteristics were assessed in a rat model of RA.Results: The particle size of the MTX-NCs was 148.1 ± 10.1 nm. The MTX-NC@DMNA were found to be rigid enough to penetrate the skin and deliver the drug successfully. The results indicated effective skin recovery after removal of the DMNA. It was found that the MTX-NC@DMNA significantly reduced foot swelling in the rats and regulated the balance in the levels of related cytokines. It also reduced pathological damage to the synovium, joint, and cartilage, and effectively alleviated organ injury in the rats.Conclusion: Transdermal administration of MTX-NC@DMNA may be an effective approach for treating RA.Graphical Abstract: Keywords: nanocrystals, inflammation, dissolving microneedles array, transdermal, rheumatoid arthritis