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Yong Zheng, Yonggui Luo, Kuihan Tang Department of Orthopedics, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, 550014, People’s Republic of ChinaCorrespondence: Kuihan Tang, Email tkh5200520@163.comBackground: Endoplasmic reticulum stress (ERS) is closely associated with Osteoporosis (OP). In order to explore the role of ERS related genes in OP and its molecular mechanism.Methods: OP-related transcriptome data were retrieved from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was applied to screen OP-related genes. Differentially expressed ERS-related genes (DE-ERSGs) between OP and controls were identified by overlapping OP-related, differentially expressed genes (DEGs), and ERS-related genes. ERS-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore their functions. Receiver operating characteristic (ROC) curves assessed the diagnostic value of DE-ERSGs, and comparative toxicogenomics database (CTD) was used to predict targeting agents for key DE-ERSGs. Finally, biomarker expression was verified by real time quantitative polymerase chain reaction (RT-qPCR).Results: A total of 10 DE-ERSGs were screened in OP patients. GO and KEGG analyses indicated their enrichment in Alcoholic liver disease, Endometrial cancer, and Glycerolipid metabolism. ROC curve analysis revealed that RPN2, FOXO3, ERGIC2, and MYO9A had significant diagnostic value, thus being identified as key DE-ERSGs. Moreover, the key DE-ERSGs-drug interaction network showed that some drugs such as bisphenol A, Cisplatin, Cyclosporine, and Valproic Acid might play roles by targeting key DE-ERSGs in OP. The expression validation analysis of key DE-ERSGs revealed that RPN2, ERGIC2, and MYO9A was significantly expressed in the GSE62402. Ultimately, The blood samples RT-qPCR verification results show that RPN2, ERGIC2, and MYO9A were significantly lower in OP samples compared to normal samples (p < 0.05), whereas there was no difference in the expression levels of FOXO3.Conclusion: RPN2, FOXO3, ERGIC2 and MYO9A as the biomarkers associated with ERS in OP by bioinformatics analysis, which may provide new biological targets for clinical treatment.Keywords: osteoporosis, endoplasmic reticulum stress, bioinformatics analysis, biomarkers

Jia Zhou,1,&ast; Wenwen Wang,1,&ast; Qiyu Zhang,1,&ast; Hanlin Zhang,1 Keyun Tang,1 Chenhui Mao,2 Mingli Li,3 Jun Li1 1Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, People’s Republic of China; 2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Li, Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Disease, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86-010-69151500, Fax +86-010-69151502, Email lijun35@hotmail.comPurpose: Syphilis, caused by Treponema pallidum, presents a diagnostic challenge due to its diverse clinical manifestations. Neurosyphilis has seen a resurgence in recent years, particularly among men who have sex with men and those living with HIV. Diagnosis of neurosyphilis in emergency settings is challenging due to its varied neurological presentations. This study aims to serve as a reference for dermatologists and neurologists in diagnosing and treating neurosyphilis.Patients and Methods: This retrospective study analyzed patients who presented with neuropsychiatric symptoms and were ultimately diagnosed with neurosyphilis. These patients were collected from the emergency department in Peking Union Medical College Hospital between January 2018 and November 2023. The medical history, clinical symptoms, laboratory examinations, cranial MRI characteristics, and treatment regimens of these patients were investigated.Results: Among the included 12 neurosyphilis patients, memory deterioration was observed in 8 out of the 12 neurosyphilis patients. Diagnosis often resulted in delays, with misdiagnoses mainly including Alzheimer’s disease, stroke, and epilepsy. Neuroimaging revealed various abnormalities, predominantly affecting ventricular and temporal regions. Treatment with penicillin-based regimens varied in compliance, with only a minority of patients adhering to guidelines. Treatment outcomes were inconsistent, with some patients experiencing irreversible neurological damage and fluctuating serum rapid plasma reagin (RPR) titers.Conclusion: Diagnosis of neurosyphilis in the emergency department remains challenging, necessitating awareness of its varied neurological presentations. Enhanced diagnostic strategies are imperative to accelerate treatment initiation and improve outcomes for affected individuals.Keywords: neurosyphilis, emergency department, neuropsychiatric symptoms, cerebrospinal fluid, serologic tests

Jinglei Wang,1 Dehong Qiao,2 Yunzhu Wang,3 Rui Xiong,1 Xinyi Ding,1 Wei Zhang,3 Tingting Wang,1 Kai Tang1 1Department of Gastroenterology, Zhejiang Rongjun Hospital, Jiaxing, People’s Republic of China; 2Minimally Invasive Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, People’s Republic of China; 3Endoscopy Center, Zhejiang Rongjun Hospital, Jiaxing, People’s Republic of ChinaCorrespondence: Kai Tang, Department of Gastroenterology, Zhejiang Rongjun Hospital, Jiaxing, People’s Republic of China, +86 15858363565, Email 15858363565@sohu.comPurpose: Helicobacter pylori (Hp)-related gastropathies are accompanied by alterations in gastric secretion function, but the effects of infection of different Hp strains on gastric function are not yet well-elucidated. Our cross-sectional clinical study aim to research the effects of infection with different Hp types on gastric function.Patients and Methods: We analyzed 525 patients’ serum cytotoxin-associated protein gene A (CagA), vacuolating cytotoxin-associated protein gene A (VacA), urease (Ure), Gastrin-17 (G-17), Pepsinogen I (PGI), Pepsinogen II (PGII) and PGI/PGII ratio (PGR).Results: The PGII levels (8.19 ± 5.44 vs 5.98 ± 10.75, P = 0.013) were higher in the Hp infected group than in the uninfected, while the PGR levels (16.81 ± 8.22 vs 23.23 ± 8.36, P < 0.001) were lower. The PGR levels were higher in the uninfected group (23.23 ± 8.36, P < 0.001) than in Hp-I (16.47 ± 7.45) and Hp-II infected groups (17.39 ± 8.98). In the uninfected group, the G-17 level was positively correlated with the levels of PGI (Pearson coefficient = 0.177, P = 0.001), PGII (Pearson coefficient = 0.140, P = 0.008) and age (Pearson coefficient = 0.121, P = 0.022), negatively with the PGR levels (Pearson coefficient = − 0.201, P < 0.001). In the Hp-I (Pearson coefficient = − 0.003, P = 0.975) and Hp-II (Pearson coefficient = 0.018, P = 0.161) infected groups, the G-17 levels were not correlated with age.Conclusion: Hp-I with CagA and/or VacA positive and Hp-II without cytotoxicity can reduce gastric secretion function regardless of age and sex. Gastric function in patients with Hp eradication was similar to that in those without Hp infection. G-17 rises physiologically with age, but infection with Hp will affect it.Keywords: Helicobacter pylori, Pepsinogen I, Pepsinogen II, Gastrin-17, cytotoxin-associated protein gene A, vacuolating cytotoxin-associated protein gene A

Jing Yu,1 Yike Zhang,1 Zhixiong Ye,1 Kun Tang,1 Yiming Ma,1 Linlin Fu,1 Tongtong Cui,1 Hening Kang,2 Yadong Yuan,1 Wensen Pan1 1Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2College of Basic Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Wensen Pan, Email 27400010@hebmu.edu.cnBackground: Despite ongoing interventions, SARS-CoV-2 continues to cause significant global morbidity and mortality. Early diagnosis and intervention are crucial for effective clinical management. However, prognostic features based on transcriptional data have shown limited effectiveness, highlighting the need for more precise biomarkers to improve COVID-19 treatment outcomes.Methods: We retrospectively analyzed 149 clinical features from 189 COVID-19 patients, identifying prognostic features via univariate Cox regression. The cohort was split into training and validation sets, and 77 prognostic models were developed using seven machine learning algorithms. Among these, the least absolute shrinkage and selection operator (Lasso) method was employed to refine the selection of prognostic variables by ten-fold cross-validation strategy, which were then integrated with random survival forests (RSF) to build a robust COVID-19-related prognostic model (CRM). Model accuracy was evaluated across training, validation, and entire cohorts. The diagnostic relevance of interleukin-10 (IL-10) was confirmed in bulk transcriptional data and validated at the single-cell level, where we also examined changes in cellular communication between mononuclear cells with differing IL-10 expression and other immune cells.Results: Univariate Cox regression identified 43 prognostic features. Among the 77 machine learning models, the combination of Lasso and RSF produced the most robust CRM. This model consistently performed well across training, validation, and entire cohorts. IL-10 emerged as a key prognostic feature within the CRM, validated by single-cell transcriptional data. Transcriptome analysis confirmed the stable diagnostic value of IL-10, with mononuclear cells identified as the primary IL-10 source. Moreover, differential IL-10 expression in these cells was linked to altered cellular communication in the COVID-19 immune microenvironment.Conclusion: The CRM provides accurate prognostic predictions for COVID-19 patients. Additionally, the study underscores the importance of early IL-10 level testing upon hospital admission, which could inform therapeutic strategies.Keywords: SARS-CoV-2, machine learning, IL-10, therapeutic guidance, clinical decision making

Kehua Jiang,1 Qing Wang,1 Xiao-Long Chen,1 Xiaodong Wang,1 Xiaoya Gu,1 Shuangshuang Feng,1 Jian Wu,2 Haojie Shang,2 Xiaozhuo Ba,2 Yanlong Zhang,1 Kun Tang2 1Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 2Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of ChinaCorrespondence: Yanlong Zhang, Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China, Email ylzhang3030@163.com Kun Tang, Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Qiaokou District, Wuhan, 430030, People’s Republic of China, Email tangsk1990@163.comAbstract: Tryptophan (Trp) metabolism plays a vital role in cancer immunity. Indoleamine 2.3-dioxygenase 1 (IDO1), is a crucial enzyme in the metabolic pathway by which Trp is degraded to kynurenine (Kyn). IDO1-mediated Trp metabolites can inhibit tumor immunity and facilitate immune evasion by cancer cells; thus, targeting IDO1 is a potential tumor immunotherapy strategy. Recently, numerous IDO1 inhibitors have been introduced into clinical trials as immunotherapeutic agents for cancer treatment. However, drawbacks such as low oral bioavailability, slow onset of action, and high toxicity are associated with these drugs. With the continuous development of nanotechnology, medicine is gradually entering an era of precision healthcare. Nanodrugs carried by inorganic, lipid, and polymer nanoparticles (NPs) have shown great potential for tumor therapy, providing new ways to overcome tumor diversity and improve therapeutic efficacy. Compared to traditional drugs, nanomedicines offer numerous significant advantages, including a prolonged half-life, low toxicity, targeted delivery, and responsive release. Moreover, based on the physicochemical properties of these nanomaterials (eg, photothermal, ultrasonic response, and chemocatalytic properties), various combination therapeutic strategies have been developed to synergize the effects of IDO1 inhibitors and enhance their anticancer efficacy. This review is an overview of the mechanism by which the Trp-IDO1-Kyn pathway acts in tumor immune escape. The classification of IDO1 inhibitors, their clinical applications, and barriers for translational development are discussed, the use of IDO1 inhibitor-based nanodrug delivery systems as combination therapy strategies is summarized, and the issues faced in their clinical application are elucidated. We expect that this review will provide guidance for the development of IDO1 inhibitor-based nanoparticle nanomedicines that can overcome the limitations of current treatments, improve the efficacy of cancer immunotherapy, and lead to new breakthroughs in the field of cancer immunotherapy.Keywords: indoleamine 2, 3-dioxygenase 1, IDO1, IDO1 inhibitors, nanodrugs, nanodelivery, cancer immunotherapy, combination therapy

Hailing Yu,1,&ast; Yongquan Huang,2,&ast; Zhisheng Nong,3,&ast; Xi Lin,1 Kexin Tang,1 Zeyu Cai,1 Kaichen Huang,4 Ting Yu,1 Huimin Lan,1 Qianqian Zhang,1 Qiang Wang,5 Lei Yang,6 Jingchuan Zhu,7 Lili Wu,8 Hui Luo1 1Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3School of Materials Science and Engineering, Shenyang Aerospace University, Shenyang, Liaoning, People’s Republic of China; 4Department of Clinical laboratory, The Third People’s Hospital of Zhuhai, Zhuhai, Guangdong, People’s Republic of China; 5The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, People’s Republic of China; 6Center for Composite Materials and Structures, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 7School of Materials Science and Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 8Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, School of Physics and Electronic Engineering, Harbin Normal University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Luo; Lili Wu, Email luoh53@mail.sysu.edu.cn; wll790107@hotmail.comIntroduction: Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo.Methods: Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth.Results: Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment.Discussion: These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.Keywords: nanozyme, sonodynamic therapy, Ti3C2/TiO2, ROS

Qiu Huang,&ast; Yue Ge,&ast; Yu He, Jian Wu, Yonghua Tong, Haojie Shang, Xiao Liu, Xiaozhuo Ba, Ding Xia, Ejun Peng, Zhiqiang Chen, Kun Tang Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqiang Chen; Kun Tang, Email zhqchen8366@163.com; tangsk1990@163.comAbstract: Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in the tumor microenvironment (TME), especially in solid tumors. It has been confirmed that it can not only interact with tumor cells to promote cancer progression and metastasis, but also affect the infiltration and function of immune cells to induce chemotherapy and immunotherapy resistance. So, targeting CAF has been considered an important method in cancer treatment. The rapid development of nanotechnology provides a good perspective to improve the efficiency of targeting CAF. At present, more and more researches have focused on the application of nanoparticles (NPs) in targeting CAF. These studies explored the effects of different types of NPs on CAF and the multifunctional nanomedicines that can eliminate CAF are able to enhance the EPR effect which facilitate the anti-tumor effect of themselves. There also exist amounts of studies focusing on using NPs to inhibit the activation and function of CAF to improve the therapeutic efficacy. The application of NPs targeting CAF needs to be based on an understanding of CAF biology. Therefore, in this review, we first summarized the latest progress of CAF biology, then discussed the types of CAF-targeting NPs and the main strategies in the current. The aim is to elucidate the application of NPs in targeting CAF and provide new insights for engineering nanomedicine to enhance immune response in cancer treatment.Keywords: nanoparticles, cancer therapy, cancer-associated fibroblasts, drug delivery, cancer, nanomedicine

Kuihan Tang,1 Li Sun,2 Long Chen,2 Xiaobo Feng,1 Jiarui Wu,2 Hao Guo,2 Yong Zheng1 1Department of Orthopedics, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, 550014, People’s Republic of China; 2Department of Orthopedics, Guizhou Provincial People’s Hospital, Guiyang, 550000, People’s Republic of ChinaCorrespondence: Yong Zheng, Email 1210244258@qq.comBackground: Mitochondrial autophagy is closely related to the pathogenesis of osteoarthritis, In order to explore the role of mitochondrial autophagy related genes in knee osteoarthritis (KOA) and its molecular mechanism.Methods: KOA-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed mitochondrial autophagy gene (DEMGs) were screened in patients with KOA by differential expression analysis. The STRING website was used to construct a protein-protein interaction (PPI) network among DEMGs. Molecular complex detection (MCODE) method in Cytoscape software was performed to identify hub DEMGs. Support vector machine recursive feature elimination (SVM-RFE) method was used to construct the hub DEMG diagnosis model. Genes with diagnostic value were identified as biomarkers by plotting receiver operating characteristic (ROC) curves and Expression validation. CIBERSORT algorithm was used to calculate the proportion of 22 immune cells in each sample in the GSE114007 dataset. Finally, biomarker expression was verified by qPCR.Results: A total of 15 DEMGs were obtained and enrichment analyses showed that these DEMG strains were mainly enriched in the mitophagy-animal, shigellosis, autophagy-animal and FoxO signal pathways. The PPI network unveiled 13 DEMGs with interactions. In addition, 8 hub DEMGs (ULK1, CALCOCO2, MAP1LC3B, BNIP3L, GABARAPL1, BNIP3, FKBP8 and FOXO3) were obtained for KOA. And 5 model DEMGs (BNIP3L, BNIP3, MAP1LC3B, ULK1 and FOXO3) were screened. The ROC curves revealed that BNIP3 and FOXO3 has strong diagnostic value in these models of DEMG. Immune-infiltration and correlation analysis showed that BNIP3 and FOXO3 were significantly correlated with three different immune cells, including primary B cells, M0 macrophage and M2 macrophage. The cartilage tissue samples qPCR verification results show that FOXO3 and BNIP3 were all down-regulated in KOA (p < 0.01), and the validation results are consistent with the above analysis.Conclusion: BNIP3 and FOXO3 have been identified as biomarkers for the diagnosis of KOA, which might supply a new insight for the pathogenesis and treatment of KOA.Keywords: Gene Expression Omnibus, diagnostic, bioinformatics analysis, immune infiltration, biomarkers

Wenwen Wang,1,&ast; Yuanyuan Peng,2,&ast; Keqiang Tang,3 Ziwei Zheng,1 Lan He,1 Shaoling Yang1 1Department of Ultrasound Medicine, Shanghai Eighth People’s Hospital, Shanghai, 200235, People’s Republic of China; 2Department of Imaging Medicine and Nuclear Medicine, Anhui University of Science and Technology, School of Medicine, Huainan, Anhui, 232001, People’s Republic of China; 3Department of Intensive Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital, Shanghai, 201619, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaoling Yang, Department of Ultrasound Medicine, Shanghai Eighth People’s Hospital, Shanghai, 200235, People’s Republic of China, Tel +86-18930240812, Email drysl@163.comPurpose: This study aimed to assess the knowledge, attitudes and practices (KAP) among middle-aged and elderly population towards ultrasound screening for strokes.Patients and Methods: This web-based cross-sectional study was conducted between March, 2023, and May, 2023 at Shanghai Eighth People’s Hospital. A self-designed questionnaire was developed to collect demographic information of middle-aged and elderly population and assess their knowledge, attitudes and practices toward ultrasound screening for strokes.Results: A total of 552 participants enrolled in this study, among them 151 (27.36%) aged above 60 years old, 306 (55.43%) resided in rural area, 239 (43.30%) possessed educational attainment at the level of junior college, college or above. The mean knowledge, attitudes and practice scores were 5.53 ± 2.56, 40.22 ± 5.60 and 38.30 ± 7.38, respectively. Pearson’s analysis was performed to assess the relationship between knowledge, attitudes, and practices. It was shown that knowledge and attitudes were positively correlated (r = 0.544, P < 0.001), and knowledge and practices were also positively correlated (r = 0.404, P < 0.001). Additionally, there was a positive correlation between attitude and practice scores (r = 0.566, P < 0.001).Conclusion: The results of this study demonstrate that the middle-aged and elderly population exhibited insufficient knowledge, positive attitudes, and moderate practices towards ultrasound screening for strokes. There is a need to improve the understanding of stroke risk factors, symptoms, and emergency measures among this population.Keywords: knowledge, attitudes, practice, stroke, ultrasound imaging, middle-aged, elderly

Li Liu,&ast; Jie Chen,&ast; Kangheng Tang, Feng Li, Si Li, Xiaojie Ding Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaojie Ding, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, 1st Maoyuan South Road, Shunqing District, Nanchong, Sichuan Province, 637000, People’s Republic of China, Tel +8615881788808, Fax +8681715881788808, Email pfkdxj@126.comAbstract: Psoriasis and atopic dermatitis are relatively common in clinical practice, but it is rare for the two diseases to co-occur in the same patient. Dupilumab, an anti-IL-4/IL-13 monoclonal antibody, has been approved for treating moderate to severe AD. In addition to its therapeutic effects, dupilumab may induce new cutaneous adverse reactions. We report a rare case of pustular psoriasis induced during the treatment of atopic dermatitis with dupilumab. This case demonstrates the need for caution while treating patients with moderate to severe atopic dermatitis and staying vigilant for the emergence of new symptoms, especially with biological agents.Keywords: psoriasis, atopic dermatitis, dupilumab, case report

Congying Zheng,&ast; Chengliang Mao,&ast; Kai Tang, Hang Shu Department of Neurosurgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hang Shu, Department of Neurosurgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan Er Road, Guangzhou City, Guangdong Province, 510080, People’s Republic of China, Tel +86- 13902204543, Email zhengcongying@gdph.org.cnBackground: Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. VSIG4 has been identified to be associated with GBM. We aimed to determine the downstream regulatory mechanisms of VSIG4 in GBM.Methods: Differential expression of VSIG4 was analysed using GEPIA. The expression of VSIG4 was assessed by RT-qPCR and its downstream genes were screened by transcriptome sequencing. The expression of pyroptosis-related proteins and the JAK2/STAT3 pathway was measured by Western blotting. GBM cell viability, migration, and invasion were detected using CCK-8, scratch, and Transwell assays. The levels of pyroptosis-related factors were measured using ELISA. The effect of VSIG4 on GBM tumour growth in vivo was explored by constructing a xenograft tumour model.Results: VSIG4 expression was upregulated in GBM. Functionally, silencing of VSIG4 inhibited proliferation, invasion, and migration of U251 and LN229 cells, and promoted pyroptosis. Mechanically, transcriptome sequencing revealed that the JAK2/STAT3 pathway might be a downstream regulator of VSIG4. Further studies proved that silencing of VSIG4 enhanced the expression of p-JAK2 and p-STAT3, and the JAK2/STAT3 pathway inhibitor relieved the suppression of VSIG4 silencing on GBM cell viability, invasion, and migration. Furthermore, in vivo experiments further validated that knockdown of VSIG4 inhibited the growth of GBM tumors.Conclusion: In GBM, silencing VSIG4 promoted pyroptosis and inhibited tumor progression by regulating the JAK2/STAT3 signaling pathway.Keywords: glioblastoma, VSIG4, JAK2/STAT3 pathway, pyroptosis

Hailing Yu,1,&ast; Kexin Tang,1,&ast; Zeyu Cai,2,&ast; Xi Lin,1 Yongquan Huang,3 Ting Yu,1 Qianqian Zhang,1 Qiang Wang,4 Lili Wu,5 Lei Yang,6 Hong Shan,1 Hui Luo1 1Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Radiology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, People’s Republic of China; 5Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, School of Physics and Electronic Engineering, Harbin Normal University, Harbin, Heilongjiang, People’s Republic of China; 6Center for Composite Materials and Structures, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Luo; Hong Shan, Email luoh53@mail.sysu.edu.cn; shanhong@mail.sysu.edu.cnBackground: Nanomaterials exhibited intrinsic enzyme-like properties due to the unique properties compared with natural enzyme. Carbon dots (CDs) are an important kind of quantum-sized nanomaterials, which have enormous application potential in bio-imaging, drug carrier, and nanosystems. Carbon dots possess intrinsic enzyme-like properties, such as glutathione (GSH) oxidase or peroxidase activities.Methods: A co-delivery nanosystem that could carry siRNA and doxorubucin (DOX) simultaneously has been studied in this work. The co-delivery based on carbon dots was surface-modified with poly-ethylenimine (PEI) and loaded the siMRP1 with chemotherapeutics on the surface with pH-triggered drug release. The CD-PEI was synthesized by one-step microwave assisted method; the PEI was raw materials and passivator during the reaction process that makes CDs exhibit excellent optical property.Results: The CD-PEI was capable of loading and delivering siMRP1 and DOX to tumors and releasing them synchronously in cells in an acid-triggered manner. The particles exhibited GSH oxidase-like catalytic property, oxidizing GSH to oxidized glutathione with concomitant increase of reactive oxygen species (ROS). We found that silencing of MRP1 by co-delivery system antagonized chemoresistance by increasing DOX accumulation and significantly enhancing the inhibitory effect of cell viability induced by CD-PEI-DOX. The co-delivery system dramatically inhibited tumor growth in xenograft model, and CDs counteracted MRP1 function by siRNA-mediated knockdown of MRP1.Conclusion: Taken together, we uncover the potential role of CDs with a combination of siRNA and chemotherapeutics in overcoming chemoresistance of lung cancer by suppressing MRP1 and oxidation of GSH. Our findings imply its potential of antagonizing chemoresistance to enhance therapeutic efficiency of doxorubicin in clinical practices of lung cancer treatment.Keywords: carbon dots, chemoresistance, co-delivery, siRNA

Kai Tang, Heng Zhao Fujian Provincial Key Laboratory of Innate Immune Biology, Fujian Normal University, Fujian, People’s Republic of ChinaCorrespondence: Heng Zhao, Fujian Provincial Key Laboratory of Innate Immune Biology, Fujian Normal University, Fujian, People’s Republic of China, Tel +86-17689970104, Email QBX20200151@yjs.fjnu.edu.cnAbstract: The clinical application of quinolone antibiotics is particularly extensive. In addition to their high efficiency in infectious diseases, the treatment process brings multiple hidden dangers or side effects. In this regard, drug resistance becomes a major challenge and is almost unavoidable in the clinical application of quinolones. Both genetic and phenotypic variations contribute to bacterial survival resistance under antibiotic therapy. This review is focusing on the drug discovery history, compound structure, and bactericidal mechanism of quinolone antibiotics. Recent studies bring a more in-depth insight into the research progress of quinolone antibiotics in the causes of death, drug resistance formation, and closely related SOS response after disease treatment at this stage. Combined with the latest clinical studies, we summarize the clinical application of quinolone antibiotics and further lay a theoretical foundation for the mechanism study of resistant or sensitive bacteria in response to quinolone treatment.Keywords: quinolone antibiotics, disease treatment, SOS response, lethality, bacteria

Sijie Chen,1,2 Jiahao Wang,3– 6 Haiqin Liao,1,2 Kui Tang,1,2 Yan Xu,1,2 Long Wang,3– 6 Chengcheng Niu1,2 1Department of Ultrasound Diagnosis, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China; 2Research Center of Ultrasonography, The Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China; 3Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Chengcheng Niu, Department of Ultrasound Diagnosis and Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China, 410011, Email niuchengcheng@csu.edu.cnBackground: Many nanocarriers currently developed have potential in tumor targeting, but there are still several limitations to their applications in clinical treatment. It is crucial to explore novel nanocarriers with higher biocompatibility and targeting efficiency to overcome the barriers of the tumor microenvironment to penetrate deeply into the tumor.Methods: In this work, we designed multilayer sonoresponsive M1/IR780@PLGA nanoparticles, which can actively target tumor tissues, and repolarize M2 macrophages in the tumor microenvironment into M1 macrophages to stimulate antitumor immune effects. When the nanoparticles reach the tumor site, ultrasound (US) irradiation is applied to the tumor site, and the sonosensitizer consumes oxygen and generates ROS, thereby triggering local tumor cell death.Results: The M1/IR780@PLGA nanoparticle-based antitumor sonodynamic therapy (SDT) significantly inhibited tumor growth, triggered a great number of M2 tumor-associated macrophages to convert into M1 macrophages in the tumor microenvironment and promoted dendritic cell maturation to activate the antitumor immune response.Conclusion: M1/IR780@PLGA nanoparticles potentiate antitumoral efficacy through SDT and antitumor immune responses by activating dendritic cells maturation and M1 macrophage repolarization in the tumor microenvironment.Keywords: M1 macrophage, sonodynamic therapy, antitumor therapy, reactive oxygen species, tumor microenvironment

Sijie Chen,1,2,&ast; Jiahao Wang,3– 6,&ast; Kui Tang,1,2 Haiqin Liao,1,2 Yan Xu,1,2 Long Wang,3– 6 Chengcheng Niu1,2 1Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengcheng Niu, Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China, Email niuchengcheng@csu.edu.cnBackground: MRSA with high morbidity and mortality is prone to cause serious infection, SDT has become a new antibiotic-free modality for bacterial infection treatment. Switching from proinflammatory M1 macrophages to anti-inflammatory M2 macrophages dominant could activate the immune system to generate an anti-infection immune response.Methods: Herein, we developed M2 macrophages derived cell membranes coated PLGA nanoparticles with IR780 encapsulation (M2/IR780@PLGA) for antibacterial SDT and subsequent M2 macrophage polarization to enhance the therapeutic efficacy of MRSA myositis. For in situ visualization of antibacterial SDT, both diagnostic high-frequency US and magnetic resonance imaging (MRI) were introduced to monitor the sono-therapeutic progression of M2/IR780@PLGA nanoparticles in mice with bacterial myositis.Results: Our developed M2/IR780@PLGA nanoparticles exhibited excellent antibacterial effects due to the IR780 under low-frequency US irradiation in vitro. In an MRSA-infected mice model, a great deal of M2/IR780@PLGA nanoparticles accumulated at the site of inflammation due to M2 macrophage coating. The infected legs in the M2/IR780@PLGA nanoparticles-based SDT group were significantly smaller, fewer blood flow signals, a slight muscular edema without obvious intermuscular abscesses under high-frequency US and MR images guidance. Histopathology proved the infected legs in the M2/IR780@PLGA nanoparticles-mediated SDT group had less clumped bacteria infiltration, more M2 macrophage expression and less M1 macrophage expression. The percentage of mature dendritic cells in spleens was much higher in the group of mice with M2/IR780@PLGA nanoparticles-based SDT.Conclusion: This study provides a promising nanoparticles-based SDT anti-bacterial strategy, which could effectively enhance the antibacterial SDT and subsequent promote M2 macrophage polarization to boost the therapeutic efficacy of MRSA myositis.Keywords: M2 macrophage, sonodynamic therapy, multidrug-resistant bacterial infections, antibacterial therapy, reactive oxygen species

Abstract Background Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial–mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. Methods The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. Results The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients’ survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. Conclusions Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.

Hanlin Zhang,&ast; Dingyue Zhang,&ast; Keyun Tang,&ast; Qiuning Sun Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, National Clinical Research Center for Skin and Immune Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiuning Sun Tel/Fax +86-10-69156114Email doctorjenny1@163.comAbstract: Alzheimer’s disease is the most common type of dementia placing a heavy burden on the healthcare system worldwide. Skin diseases are also one of the most common health problems. Several skin diseases are associated with Alzheimer’s disease through different mechanisms. This review summarizes the relationship between Alzheimer’s disease and several types of skin diseases, including bullous pemphigoid, hidradenitis suppurativa, psoriasis, skin cancer, and cutaneous amyloidosis, and provides suggestions based on these associations. Neurologists, dermatologists, and general practitioners should be aware of the relationship between Alzheimer’s disease and skin diseases. Dermatology/neurology consultation or referral is necessary when needed.Keywords: Alzheimer’s disease, dementia, skin disease, bullous pemphigoid, hidradenitis suppurativa, psoriasis

Fengqi Liu,1,2,&ast; Li Zhong,1,2,&ast; Feifei Zhou,3,&ast; Cheng Zheng,1,4 Kai Zhang,1 Jiachang Cai,5 Hongwei Zhou,5 Kankai Tang,2 Zhaohui Dong,2 Wei Cui,1 Gensheng Zhang1 1Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2Department of Critical Care Medicine, First Affiliated Hospital, Huzhou Teachers College, The First People’s Hospital of Huzhou, Huzhou, 313000, Zhejiang, People’s Republic of China; 3Department of Critical Care Medicine, Ningbo Medical Center, Li Huili Hospital, Ningbo, Zhejiang, 315040, People’s Republic of China; 4Department of Critical Care Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang, 318000, People’s Republic of China; 5Department of Clinical Microbiology Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gensheng Zhang; Wei CuiDepartment of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, cc88 Jiefang Road, Hangzhou, 310009, People’s Republic of ChinaTel +86-571-8778-3636; +86-571-8778-3551Fax +86-571- 87022776Email genshengzhang@zju.edu.cn; zricu@zju.edu.cnPurpose: Candida albicans (C. albicans) candidemia has been well reported in previous studies, while research on non-albicans Candida (NAC) bloodstream infections remains poorly explored. Therefore, the present study aimed to investigate the clinical characteristics and outcomes of patients with NAC candidemia.Patients and Methods: We recruited inpatients with candidemia from January 2013 to June 2020 in a tertiary hospital for this retrospective observational study.Results: A total of 301 patients with candidemia were recruited in the current study, including 161 (53.5%) patients with NAC candidemia. The main pathogens in NAC candidemia were Candida tropicalis (C. tropicalis) (23.9%), Candida parapsilosis (15.6%) and Candida glabrata (10.3%). Patients with NAC candidemia had more medical admissions (P=0.034), a higher percentage of hematological malignancies (P=0.007), a higher frequency of antifungal exposure (P=0.012), and more indwelling peripherally inserted central catheters (P=0.002) than those with C. albicans candidemia. In a multivariable analysis, prior antifungal exposure was independently related to NAC candidemia (adjusted odds ratio [aOR], 0.312; 95% confidence interval [CI], 0.113– 0.859). Additionally, NAC was obviously resistant to azoles, especially C. tropicalis had a high cross-resistance to azoles. However, no significant differences were noted in the mortality rates at 14 days, 28 days and 60 days between these two groups.Conclusion: NAC is dominant in candidemia, and prior antifungal exposure is an independent risk factor. Of note, although the outcomes of NAC and C. albicans candidemia are similar, drug resistance to specific azoles as well as cross-resistance frequently occurs in patients with NAC candidemia, and this drug resistance deserves attention in clinical practice and further in-depth investigation.Keywords: non-albicans candidemia, clinical features, risk factor, cross-resistance

Hanlin Zhang,* Keyun Tang,* Yuanzhuo Wang, Rouyu Fang, Qiuning Sun Department of Dermatology, Peking Union Medical College Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiuning Sun Tel +86-10-69156114Fax +86-10-69156114Email doctorjenny1@163.comBackground: Rosacea is a chronic skin disorder characterized by erythema, flushing, telangiectasia, papules and pustules, phymatous changes, and ocular involvement. The aim of this study was to examine all published research articles in which botulinum toxin was used to treat rosacea and to evaluate the efficacy and safety of this treatment.Methods: PubMed, Embase, Cochrane Library, and Web of Science database were used to identify articles eligible for systematic review on March 26, 2021. Prospective or retrospective studies which directly used botulinum toxin to treat rosacea were included and reviewed.Results: Nine studies were included in this systematic review. Two were randomized controlled trials, graded as Level 2 for the quality of evidence. The total number of participants was 130, and the number of participants in each study ranged from 1 to 25. The improvement was observed in all studies in signs and symptoms compared with baseline. Adverse events were transitory and self-limited.Conclusion: Botulinum toxin could have overall satisfying efficacy and safety in the treatment of rosacea, though limited by small sample size, imperfect study design, and short follow-up visits.Keywords: botulinum toxin, rosacea, systematic review

Hailang Liu,1 Kun Tang,1 Ejun Peng,1 Liang Wang,2 Ding Xia,1 Zhiqiang Chen1 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People’s Republic of China; 2Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People’s Republic of ChinaCorrespondence: Ding Xia; Zhiqiang ChenTongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, People’s Republic of ChinaEmail 3012904661@qq.com; lhl20180129@163.comObjective: This study aimed to develop a machine learning (ML)-assisted model capable of accurately predicting the probability of biopsy Gleason grade group upgrading before making treatment decisions.Methods: We retrospectively collected data from prostate cancer (PCa) patients. Four ML-assisted models were developed from 16 clinical features using logistic regression (LR), logistic regression optimized by least absolute shrinkage and selection operator (Lasso) regularization (Lasso-LR), random forest (RF), and support vector machine (SVM). The area under the curve (AUC) was applied to determine the model with the highest discrimination. Calibration plots and decision curve analysis (DCA) were performed to evaluate the calibration and clinical usefulness of each model.Results: A total of 530 PCa patients were included in this study. The Lasso-LR model showed good discrimination with an AUC, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.776, 0.712, 0.679, 0.745, 0.730, and 0.695, respectively, followed by SVM (AUC=0.740, 95% confidence interval [CI]=0.690– 0.790), LR (AUC=0.725, 95% CI=0.674– 0.776) and RF (AUC=0.666, 95% CI=0.618– 0.714). Validation of the model showed that the Lasso-LR model had the best discriminative power (AUC=0.735, 95% CI=0.656– 0.813), followed by SVM (AUC=0.723, 95% CI=0.644– 0.802), LR (AUC=0.697, 95% CI=0.615– 0.778) and RF (AUC=0.607, 95% CI=0.531– 0.684) in the testing dataset. Both the Lasso-LR and SVM models were well-calibrated. DCA plots demonstrated that the predictive models except RF were clinically useful.Conclusion: The Lasso-LR model had good discrimination in the prediction of patients at high risk of harboring incorrect Gleason grade group assignment, and the use of this model may be greatly beneficial to urologists in treatment planning, patient selection, and the decision-making process for PCa patients.Keywords: prostate cancer, biopsy cores, Gleason grade group, upgrading, machine learning

The centrosome is composed of a pair of centrioles and serves as the major microtubule-organizing center (MTOC) in cells. Centrosome dysfunction has been linked to autosomal recessive primary microcephaly (MCPH), which is a rare human neurodevelopmental disorder characterized by small brain size with intellectual disability. Recently, several mouse models carrying mutated genes encoding centrosomal proteins have been generated to address the genotype–phenotype relationships in MCPH. However, several human-specific features were not observed in the mouse models during brain development. Herein, we generated isogenic hiPSCs carrying the gene encoding centrosomal CPAP-E1235V mutant protein using the CRISPR-Cas9 genome editing system, and examined the phenotypic features of wild-type and mutant hiPSCs and their derived brain organoids. Our results showed that the CPAP-E1235V mutant perturbed the recruitment of several centriolar proteins involved in centriole elongation, including CEP120, CEP295, CENTROBIN, POC5, and POC1B, onto nascent centrioles, resulting in the production of short centrioles but long cilia. Importantly, our wild-type hiPSC-derived brain organoid recapitulated many cellular events seen in the developing human brain, including neuronal differentiation and cortical spatial lamination. Interestingly, hiPSC-CPAP-E1235V-derived brain organoids induced p53-dependent neuronal cell death, resulting in the production of smaller brain organoids that mimic the microcephaly phenotype. Furthermore, we observed that the CPAP-E1235V mutation altered the spindle orientation of neuronal progenitor cells and induced premature neuronal differentiation. In summary, we have shown that the hiPSC-derived brain organoid coupled with CRISPR/Cas9 gene editing technology can recapitulate the centrosome/centriole-associated MCPH pathological features. Possible mechanisms for MCPH with centriole/centrosome dysfunction are discussed.

Yu Zhang, Kaiqi Tang, Lizhu Chen, Meng Du, Zhi Qu Department of Prosthetics, The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of ChinaCorrespondence: Zhi QuDepartment of Prosthetics, The Second Affiliated Hospital of Jinzhou Medical University, No. 49, Section 2, Shanghai Road, Guta District, Jinzhou City, Liaoning Province 121000, People’s Republic of ChinaTel +86 41 62655049Email wangkang2137@163.comBackground: Exosomes are small membrane vesicles that are secreted by most cell types. Circular RNAs (circRNAs) have recently been identified in exosomes, and exosomal circRNAs exert important biological activities in human cancers, including oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate whether circRNA GDP dissociation inhibitor 2 (circGDI2) was transferred by exosomes and how exosomal circGDI2 regulated OSCC cell malignant behaviors.Methods: The levels of circGDI2, miR-424-5p and suppressor of cancer cell invasion (SCAI) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Transwell assays were performed to detect cell migration and invasion. Measurement of glucose consumption and lactate production were conducted using a corresponding assay kit. Targeted correlations among circGDI2, miR-424-5p and SCAI were confirmed by dual-luciferase reporter assays. Xenograft assays were used to observe the role of circGDI2 in tumor growth in vivo.Results: Our data indicated that circGDI2 was down-regulated in OSCC, and it could be transferred by the exosomes in OSCC cells. The up-regulation of exosomal circGDI2 weakened OSCC cell proliferation, migration, invasion and glycolysis. CircGDI2 functioned as a molecular sponge of miR-424-5p, and SCAI was a direct target of miR-424-5p. MiR-424-5p mediated the repression of exosomal circGDI2 overexpression on OSCC cell malignant behaviors, and miR-424-5p silencing mitigated OSCC cell progression by up-regulating SCAI. Moreover, exosomal circGDI2 regulated SCAI expression through sponging miR-424-5p. Additionally, the overexpression of exosomal circGDI2 inhibited tumor growth in vivo.Conclusion: The present study had led to the identification of exosomal circGDI2 that regulated OSCC cell malignant behaviors through targeting the miR-424-5p/SCAI axis, highlighting circGDI2 as a novel exosome-based cancer biomarker and therapeutic agent for OSCC treatment.Keywords: OSCC, exosome, circGDI2, miR-424-5p, SCAI

Hailang Liu,1 Kun Tang,1 Ding Xia,1 Xinguang Wang,1 Wei Zhu,1 Liang Wang,2 Weimin Yang,1 Ejun Peng,1 Zhiqiang Chen1 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People’s Republic of China; 2Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, People’s Republic of ChinaCorrespondence: Ejun Peng; Zhiqiang Chen Email qingyangfeng60@gmail.com; d201981784@hust.edu.cnObjective: To develop novel models for predicting extracapsular extension (EPE), seminal vesicle invasion (SVI), or upgrading in prostate cancer (PCa) patients using clinical parameters, biparametric magnetic resonance imaging (bp-MRI), and transrectal ultrasonography (TRUS)-guided systematic biopsies.Patients and Methods: We retrospectively collected data from PCa patients who underwent standard (12-core) systematic biopsy and radical prostatectomy. To develop predictive models, the following variables were included in multivariable logistic regression analyses: total prostate-specific antigen (TPSA), central transition zone volume (CTZV), prostate-specific antigen (PSAD), maximum diameter of the index lesion at bp-MRI, EPE at bp-MRI, SVI at bp-MRI, biopsy Gleason grade group, and number of positive biopsy cores. Three risk calculators were built based on the coefficients of the logit function. The area under the curve (AUC) was applied to determine the models with the highest discrimination. Decision curve analyses (DCAs) were performed to evaluate the net benefit of each risk calculator.Results: A total of 222 patients were included in this study. Overall, 83 (37.4%), 75 (33.8%), and 107 (48.2%) patients had EPE, SVI, and upgrading at final pathology, respectively. The addition of bp-MRI data improved the discrimination of models for predicting SVI (0.807 vs 0.816) and upgrading (0.548 vs 0.625) but not EPE (0.766 vs 0.763). Similarly, models including clinical parameters, bp-MRI data, and information on systematic biopsies achieved the highest AUC in the prediction of EPE (0.842), SVI (0.913), and upgrading (0.794), and the three corresponding risk calculators yielded the highest net benefit.Conclusion: We developed three easy-to-use risk calculators for the prediction of adverse pathological features based on patient clinical parameters, bp-MRI data, and information on systematic biopsies. This may be greatly beneficial to urologists in the decision-making process for PCa patients.Keywords: prostate cancer, extracapsular extension, seminal vesicle invasion, upgrading, biparametric MRI, systematic biopsy, predictive model

Tingfang Sun,1,* Man Liu,2,* Sheng Yao,1 Yanhui Ji,1 Lei Shi,3 Kai Tang,1 Zekang Xiong,1 Fan Yang,1 Kaifang Chen,1 Xiaodong Guo1 1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 2Department of Gastroenterology and Hepatology, Taikang Tongji Hospital, Wuhan 430050, China; 3State Key Laboratory of Materials Processing and Die & Mould Technology, School of Materials Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074, China *These authors contributed equally to this work Introduction: At present, the treatment of osteoporotic defects poses a great challenge to clinicians, owing to the lower regeneration capacity of the osteoporotic bone as compared with the normal bone. The guided bone regeneration (GBR) technology provides a promising strategy to cure osteoporotic defects using bioactive membranes. The decellularized matrix from the small intestinal submucosa (SIS) has gained popularity for its natural microenvironment, which induces cell response. Materials and methods: In this study, we developed heparinized mineralized SIS loaded with bone morphogenetic protein 2 (BMP2)-related peptide P28 (mSIS/P28) as a novel GBR membrane for guided osteoporotic bone regeneration. These mSIS/P28 membranes were obtained through the mineralization of SIS (mSIS), followed by P28 loading onto heparinized mSIS. The heparinized mSIS membrane was designed to improve the immobilization efficacy and facilitate controlled release of P28. P28 release from mSIS-heparin-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells from ovariectomized rats (rBMSCs-OVX) were investigated in vitro. Furthermore, a critical-sized OVX calvarial defect model was used to assess the bone regeneration capability of mSIS-heparin-P28 in vivo. Results: In vitro results showed that P28 release from mSIS-heparin-P28 occurred in a controlled manner, with a long-term release time of 40 days. Moreover, mSIS-heparin-P28 promoted cell proliferation and viability, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes in rBMSCs-OVX without the addition of extra osteogenic components. In vivo experiments revealed that mSIS-heparin-P28 dramatically stimulated osteoporotic bone regeneration. Conclusion: The heparinized mSIS loaded with P28 may serve as a potential GBR membrane for repairing osteoporotic defects. Keywords: osteoporotic defect, guided bone regeneration, decellularized matrix, heparin, BMP2-related peptide, control release

Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis.

Mutations in many centriolar protein-encoding genes cause primary microcephaly. Here the authors show that human microcephaly protein RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles

CPAP is required for centriole elongation during S/G2 phase, but the role of CPAP in mitosis is incompletely understood. Here, we show that CPAP maintains spindle pole integrity through its phosphorylation by Aurora-A during mitosis. Depletion of CPAP induced a prolonged delay in mitosis, pericentriolar material (PCM) dispersion, and multiple mitotic abnormalities. Further studies demonstrated that CPAP directly interacts with and is phosphorylated by Aurora-A at serine 467 during mitosis. Interestingly, the dispersal of the PCM was effectively rescued by ectopic expression of wild-type CPAP or a phospho-mimic CPAP-S467D mutant, but not a non-phosphorylated CPAP-S467A mutant. Finally, we found that CPAP-S467D has a low affinity for microtubule binding but a high affinity for PCM proteins. Together, our results support a model wherein CPAP is required for proper mitotic progression, and phosphorylation of CPAP by Aurora-A is essential for maintaining spindle pole integrity.

Xiong Liu,1 Kaizhi Tang,1 Stacey Harper,2 Bryan Harper,2 Jeffery A Steevens,3 Roger Xu1 1Intelligent Automation, Inc., Rockville, MD, USA; 2Department of Environmental and Molecular Toxicology, School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USA; 3ERDC Environmental Laboratory, Vicksburg, MS, USA Background: Predictive modeling of the biological effects of nanomaterials is critical for industry and policymakers to assess the potential hazards resulting from the application of engineered nanomaterials. Methods: We generated an experimental dataset on the toxic effects experienced by embryonic zebrafish due to exposure to nanomaterials. Several nanomaterials were studied, such as metal nanoparticles, dendrimer, metal oxide, and polymeric materials. The embryonic zebrafish metric (EZ Metric) was used as a screening-level measurement representative of adverse effects. Using the dataset, we developed a data mining approach to model the toxic endpoints and the overall biological impact of nanomaterials. Data mining techniques, such as numerical prediction, can assist analysts in developing risk assessment models for nanomaterials. Results: We found several important attributes that contribute to the 24 hours post-fertilization (hpf) mortality, such as dosage concentration, shell composition, and surface charge. These findings concur with previous studies on nanomaterial toxicity using embryonic zebrafish. We conducted case studies on modeling the overall effect/impact of nanomaterials and the specific toxic endpoints such as mortality, delayed development, and morphological malformations. The results show that we can achieve high prediction accuracy for certain biological effects, such as 24 hpf mortality, 120 hpf mortality, and 120 hpf heart malformation. The results also show that the weighting scheme for individual biological effects has a significant influence on modeling the overall impact of nanomaterials. Sample prediction models can be found at http://neiminer.i-a-i.com/nei_models. Conclusion: The EZ Metric-based data mining approach has been shown to have predictive power. The results provide valuable insights into the modeling and understanding of nanomaterial exposure effects. Keywords: nanomaterial exposure effects, biological response, toxicity, embryonic zebrafish, data mining, numerical prediction

Kaizhi Tang,1 Xiong Liu,1 Stacey L Harper,2 Jeffery A Steevens,3 Roger Xu1 1Intelligent Automation, Inc, Rockville, MD, USA; 2Department of Environmental and Molecular Toxicology, School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USA; 3US Army Engineer Research and Development Center, Vicksburg, MS, USA Abstract: As more engineered nanomaterials (eNM) are developed for a wide range of applications, it is crucial to minimize any unintended environmental impacts resulting from the application of eNM. To realize this vision, industry and policymakers must base risk management decisions on sound scientific information about the environmental fate of eNM, their availability to receptor organisms (eg, uptake), and any resultant biological effects (eg, toxicity). To address this critical need, we developed a model-driven, data mining system called NEIMiner, to study nanomaterial environmental impact (NEI). NEIMiner consists of four components: NEI modeling framework, data integration, data management and access, and model building. The NEI modeling framework defines the scope of NEI modeling and the strategy of integrating NEI models to form a layered, comprehensive predictability. The data integration layer brings together heterogeneous data sources related to NEI via automatic web services and web scraping technologies. The data management and access layer reuses and extends a popular content management system (CMS), Drupal, and consists of modules that model the complex data structure for NEI-related bibliography and characterization data. The model building layer provides an advanced analysis capability for NEI data. Together, these components provide significant value to the process of aggregating and analyzing large-scale distributed NEI data. A prototype of the NEIMiner system is available at http://neiminer.i-a-i.com/. Keywords: nanomaterial environmental impact, data integration, data management, content management system, data mining, modeling, model composition

Qingyi He,2,* Xiaohui Wang,3,* Xing Zhang,4 Huifang Han,4 Baosan Han,5 Jianzhong Xu,2 Kanglai Tang,2 Zhiren Fu,1 Hao Yin1,4 1Department of Surgery, Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai Second Military Medical School, 2Department of Orthopedic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 3Department of General Surgery, Bayinguoleng Mengguzizhizhou People's Hospital, Korla, Xinjiang, People's Republic of China; 4Department of Surgery, The University of Chicago, Chicago, IL, USA; 5Department of Surgery, Shanghai Xinhua Hospital, Shanghai, People's Republic of China*These authors contributed equally to this workAbstract: The traditional xenograft subcutaneous pancreatic cancer model is notorious for its low incidence of tumor formation, inconsistent results for the chemotherapeutic effects of drug molecules of interest, and a poor predictive capability for the clinical efficacy of novel drugs. These drawbacks are attributed to a variety of factors, including inoculation of heterogeneous tumor cells from patients with different pathological histories, and use of poorly defined Matrigel®. In this study, we aimed to tissue-engineer a pancreatic cancer model that could readily cultivate a pancreatic tumor derived from highly homogenous CD24+CD44+ pancreatic cancer stem cells delivered by a well defined electrospun scaffold of poly(glycolide-co-trimethylene carbonate) and gelatin. The scaffold supported in vitro tumorigenesis from CD24+CD44+ cancer stem cells for up to 7 days without inducing apoptosis. Moreover, CD24+CD44+ cancer stem cells delivered by the scaffold grew into a native-like mature pancreatic tumor within 8 weeks in vivo and exhibited accelerated tumorigenesis as well as a higher incidence of tumor formation than the traditional model. In the scaffold model, we discovered that oxaliplatin-gemcitabine (OXA-GEM), a chemotherapeutic regimen, induced tumor regression whereas gemcitabine alone only capped tumor growth. The mechanistic study attributed the superior antitumorigenic performance of OXA-GEM to its ability to induce apoptosis of CD24+CD44+ cancer stem cells. Compared with the traditional model, the scaffold model demonstrated a higher incidence of tumor formation and accelerated tumor growth. Use of a tiny population of highly homogenous CD24+CD44+ cancer stem cells delivered by a well defined scaffold greatly reduces the variability associated with the traditional model, which uses a heterogeneous tumor cell population and poorly defined Matrigel. The scaffold model is a robust platform for investigating the antitumorigenesis mechanism of novel chemotherapeutic drugs with a special focus on cancer stem cells.Keywords: pancreatic cancer, cancer stem cell, electrospun scaffold, gemcitabine, oxaliplatin

A high temperature process for recycling spent nickel-metal hydride rechargeable batteries has been recently developed at SINTEF/NTNU. The spent battery modules were first frozen with liquid nitrogen for the de-activation and brittle fracture treatment. The broken steel scraps and plastics were then separated by the mechanical classification and magnetic separation. The remaining positive and negative electrodes, together with the polymer separator, were heated to 600-800oC in order to remove the organic components and further separate the Ni-based negative electrode. XRF analyses indicate that the heat-treated materials consist mainly of nickel, rare earth and cobalt oxides. The valuable rare earth oxides were further recovered by the high-temperature slagging treatment. The waste metallurgical slags, consist mainly of SiO2 and CaO, were used as the rare earth oxide absorbent. After the high temperature slagging treatment, over 98% of nickel and cobalt oxides were reduced to the metal phase; meanwhile almost all rare earth oxides remain in the molten slags. Furthermore, EPMA and XRF analyses of the slag samples indicate that the rare earth oxides selectively precipitate in the forms of solid xSiO2•yCaO•zRe2O3. The matrix of slag phase is Re2O3 deficient, typically being less than 5 wt%. This provides a sound basis to further develop the high-temperature process of concentrating the Re2O3 oxides in slags.

We report the differentiation of neural stem and progenitor cells solely induced by direct current (DC) pulses stimulation. Neural stem and progenitor cells in the adult mammalian brain are promising candidates for the development of therapeutic neuroregeneration strategies. The differentiation of neural stem and progenitor cells depends on various in vivo environmental factors, such as nerve growth factor and endogenous EF. In this study, we demonstrated that the morphologic and phenotypic changes of mouse neural stem and progenitor cells (mNPCs) could be induced solely by exposure to square-wave DC pulses (magnitude 300 mV/mm at frequency of 100-Hz). The DC pulse stimulation was conducted for 48 h, and the morphologic changes of mNPCs were monitored continuously. The length of primary processes and the amount of branching significantly increased after stimulation by DC pulses for 48 h. After DC pulse treatment, the mNPCs differentiated into neurons, astrocytes, and oligodendrocytes simultaneously in stem cell maintenance medium. Our results suggest that simple DC pulse treatment could control the fate of NPCs. With further studies, DC pulses may be applied to manipulate NPC differentiation and may be used for the development of therapeutic strategies that employ NPCs to treat nervous system disorders.

Summary The primary cilium is a microtubule-based structure protruded from the basal body analogous to the centriole. CPAP (centrosomal P4.1-associated protein) has previously been reported to be a cell cycle-regulated protein that controls centriole length. Mutations in CPAP cause primary microcephaly (MCPH) in humans. Here, using a cell-based system that we established to monitor cilia formation in neuronal CAD (Cath.a-differentiated) cells and hippocampal neurons, we found that CPAP is required for cilia biogenesis. Overexpression of wild-type CPAP promoted cilia formation and induced longer cilia. In contrast, an exogenously expressed CPAP-377EE mutant that lacks tubulin-dimer binding significantly inhibited cilia formation and caused cilia shortening. Furthermore, depletion of CPAP inhibited ciliogenesis and such effect was effectively rescued by expression of wild-type CPAP, but not by the CPAP-377EE mutant. Taken together, our results suggest that CPAP is a positive regulator of ciliogenesis whose intrinsic tubulin-dimer binding activity is required for cilia formation in neuronal cells.

The meiotic generation of haploid gametes with equal contents of genetic material is important for sexual reproduction in mammals. Errors in the transmission of chromosomes during meiosis may lead to aneuploidy, which is the leading cause of miscarriage and congenital birth defects in humans. The Aurora kinases, which include Aurora-A, Aurora-B, and Aurora-C, are highly conserved serine-threonine kinases that play essential roles in centrosome function, chromosome segregation, and cytokinesis during mitosis and meiosis. While Aurora-A and Aurora-B have been extensively studied in mitosis, the role of Aurora-C in meiosis is only now starting to be revealed. For example, the perturbation of Aurora-C kinase activity by microinjection of Aurora-C-kinase-dead mutant mRNAs into mouse oocytes induced multiple defects, including chromosome misalignment, abnormal kinetochore-microtubule attachment, premature chromosome segregation, and failure of cytokinesis during meiotic division. However, the analysis of such defects is complicated by the possibility that Aurora-B may be present in mammalian germ cells. Interestingly, a homozygous mutation of Aurora-C in humans leads to the production of large-headed polyploid spermatozoa and causes male infertility, but homozygous females are fertile. Mouse studies regarding the roles of Aurora-B and Aurora-C in female meiotic divisions have yielded inconsistent results, and it has proven difficult to explain why homozygous human females have no significant clinical phenotype. In this review, we will discuss the controversial status of Aurora-B in oocytes and the possible role of Aurora-C during meiotic division.

Phase-transition materials provide exciting opportunities for controlling optical properties of photonic devices dynamically. Here, we systematically investigate the infrared emission from a thin film of vanadium dioxide (VO2). We experimentally demonstrate that such thin films are promising candidates to tune and control the thermal radiation of an underlying hot body with different emissivity features. In particular, we studied two different heat sources with completely different emissivity features, i.e. a black body-like and a mirror-like heated body. The infrared emission characteristics were investigated in the 3.5-5.1 μm spectral range using the infrared thermography technique which included heating the sample, and then cooling back. Experimental results were theoretically analyzed by modelling the VO2 film as a metamaterial for a temperature range close to its critical temperature. Our systematic study reveals that VO2 thin films with just one layer 80 nm thick has the potential to develop completely different dynamic tuning of infrared radiation, enabling both black-body emission suppression and as well as mirror emissivity boosting, in the same single layer device. Understanding the dynamics and effects of thermal tuning on infrared emission will benefit wide range of infrared technologies including thermal emitters, sensors, active IR filters and detectors.

We present BVRI and unfiltered light curves of 93 Type Ia supernovae (SNe Ia) from the Lick Observatory Supernova Search (LOSS) follow-up program conducted between 2005 and 2018. Our sample consists of 78 spectroscopically normal SNe Ia, with the remainder divided between distinct subclasses (3 SN 1991bg-like, 3 SN 1991T-like, 4 SNe Iax, 2 peculiar, and 3 super-Chandrasekhar events), and has a median redshift of 0.0192. The SNe in our sample have a median coverage of 16 photometric epochs at a cadence of 5.4 d, and the median first observed epoch is ∼4.6 d before maximum B-band light. We describe how the SNe in our sample are discovered, observed, and processed, and we compare the results from our newly developed automated photometry pipeline to those from the previous processing pipeline used by LOSS. After investigating potential biases, we derive a final systematic uncertainty of 0.03 mag in BVRI for our data set. We perform an analysis of our light curves with particular focus on using template fitting to measure the parameters that are useful in standardizing SNe Ia as distance indicators. All of the data are available to the community, and we encourage future studies to incorporate our light curves in their analyses.