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Jin Zhang,1 Luxin Li,1 Jing Yu,2 Fan Zhang,1 Jiayi Shi,1 Meiyun LI,1 Jianyong Liu,3 Haitao Li,3 Jie Gao,4 Yan Wu1 1College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China; 2Department of Endocrinology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China; 3Department of Vascular Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Yan Wu, College of Life Science, Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157001, People’s Republic of China, Tel/Fax +86-453-6984647, Email wuyan@mdjmu.edu.cn; Jie Gao, Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China, Tel/Fax +86 21-31166666, Email jmsx2021@shu.edu.cnAbstract: Autophagy, a self-renewal mechanism, can help to maintain the stability of the intracellular environment of organisms. Autophagy can also regulate several cellular functions and is strongly related to the onset and progression of several diseases. Wound healing is a biological process that is coregulated by different types of cells. However, it is troublesome owing to prolonged treatment duration and poor recovery. In recent years, biomaterials have been reported to influence the skin wound healing process by finely regulating autophagy. Biomaterials that regulate autophagy in various cells involved in skin wound healing to regulate the differentiation, proliferation and migration of cells, inflammatory responses, oxidative stress and formation of the extracellular matrix (ECM) have emerged as a key method for improving the tissue regeneration ability of biomaterials. During the inflammatory phase, autophagy enhances the clearance of pathogens from the wound site and leads to macrophage polarization from the M1 to the M2 phenotype, thus preventing enhanced inflammation that can lead to further tissue damage. Autophagy plays important roles in facilitating the formation of extracellular matrix (ECM) during the proliferative phase, removing excess intracellular ROS, and promoting the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes. This review summarizes the close association between autophagy and skin wound healing and discusses the role of biomaterial-based autophagy in tissue regeneration. The applications of recent biomaterials designed to target autophagy are highlighted, including polymeric materials, cellular materials, metal nanomaterials, and carbon-based materials. A better understanding of biomaterial-regulated autophagy and skin regeneration and the underlying molecular mechanisms may open new possibilities for promoting skin regeneration. Moreover, this can lay the foundation for the development of more effective therapeutic approaches and novel biomaterials for clinical applications.Keywords: wound healing, autophagy, biomaterial, antibacterial effects, inflammatory response, oxidative stress

Jifen Hu,1,2,* Jian Gao,1,2,* Chunlin Wang,1,2,* Wuling Liu,1,2 Anling Hu,1,2 Xiao Xiao,1,2 Yi Kuang,1,2 Kunlin Yu,1,2 Babu Gajendran,1– 3 Eldad Zacksenhaus,4 Weidong Pan,1,2 Yaacov Ben-David1,2 1State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People’s Republic of China; 2The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, People’s Republic of China; 3School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou Province, 550025, People’s Republic of China; 4Department of Medicine, University of Toronto, Toronto, Ontario, Canada, and Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada*These authors contributed equally to this workCorrespondence: Yaacov Ben-David, State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Province Science City, High Tech Zone, Baiyun District, Guiyang, 550014, People’s Republic of China, Email yaacovbendavid@hotmail.comAim: Histamine decarboxylase (HDC) catalyzes decarboxylation of histidine to generate histamine. This enzyme affects several biological processes including inflammation, allergy, asthma, and cancer, although the underlying mechanism is not fully understood. The present study provides a novel insight into the relationship between the transcription factor FLI1 and its downstream target HDC, and their effects on inflammation and leukemia progression.Methods: Promoter analysis combined with chromatin immunoprecipitation (ChIp) was used to demonstrate binding of FLI1 to the promoter of HDC in leukemic cells. Western blotting and RT-qPCR were used to determine expression of HDC and allergy response genes, and lentivirus shRNA was used to knock-down target genes. Proliferation, cell cycle, apoptosis assays and molecular docking were used to determine the effect of HDC inhibitors in culture. An animal model of leukemia was employed to test the effect of HDC inhibitory compounds in vivo.Results: Results presented herein demonstrate that FLI1 transcriptionally regulates HDC by direct binding to its promoter. Using genetic and pharmacological inhibition of HDC, or the addition of histamine, the enzymatic product of HDC, we show neither have a discernable effect on leukemic cell proliferation in culture. However, HDC controls several inflammatory genes including IL1B and CXCR2 that may influence leukemia progression in vivo through the tumor microenvironment. Indeed, diacerein, an IL1B inhibitor, strongly blocked Fli-1-induced leukemia in mice. In addition to allergy, FLI1 is shown to regulate genes associated with asthma such as IL1B, CPA3 and CXCR2. Toward treatment of these inflammatory conditions, epigallocatechin (EGC), a tea polyphenolic compound, is found strongly inhibit HDC independently of FLI1 and its downstream effector GATA2. Moreover, the HDC inhibitor, tetrandrine, suppressed HDC transcription by directly binding to and inhibiting the FLI1 DNA binding domain, and like other FLI1 inhibitors, tetrandrine strongly suppressed cell proliferation in culture and leukemia progression in vivo.Conclusion: These results suggest a role for the transcription factor FLI1 in inflammation signaling and leukemia progression through HDC and point to the HDC pathway as potential therapeutics for FLI1-driven leukemia.Graphical Abstract: Keywords: HDC, histamine, FLI1, inflammation, allergy, asthma, leukemia progression

Jiaoping Mi,1,2,&ast; Yijie Fang,3,&ast; Jianzhong Xian,4 Guojie Wang,3 Yuanqing Guo,5 Haiyu Hong,2 Mengshi Chi,2 Yong-Fang Li,2 Peng He,2 Jiebing Gao,3 Wei Liao2 1Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4Department of Ultrasound, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 5Department of Spinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Liao, Department of Otolaryngology Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, 519020, People’s Republic of China, Email liaowei23@mail.sysu.edu.cn Jiebing Gao, Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China, Email Gaojb@mail.sysu.edu.cnObjective: Accurate preoperative localization of abnormal parathyroid glands is crucial for successful surgical management of secondary hyperparathyroidism (SHPT). This study was conducted to compare the effectiveness of preoperative MRI, 4D-CT, and ultrasonography (US) in localizing parathyroid lesions in patients with SHPT.Methods: We performed a retrospective review of prospectively collected data from a tertiary-care hospital and identified 52 patients who received preoperative MRI and/or 4D-CT and/or US and/or 99mTc-MIBI and subsequently underwent surgery for SHPT between May 2013 and March 2020. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each imaging modality to accurately detect enlarged parathyroid glands were determined using histopathology as the criterion standard with confirmation using the postoperative biochemical response.Results: A total of 198 lesions were identified intraoperatively among the 52 patients included in this investigation. MRI outperformed 4D-CT and US in terms of sensitivity (P < 0.01), specificity (P = 0.455), PPV (P = 0.753), and NPV (P = 0.185). The sensitivity and specificity for MRI, 4D-CT, and US were 90.91%, 88.95%, and 66.23% and 58.33%, 63.64%, and 50.00%, respectively. The PPV of combined MRI and 4D-CT (96.52%) was the highest among the combined 2 modalities. The smallest diameter of the parathyroid gland precisely localized by MRI was 8× 3 mm, 5× 5 mm by 4D-CT, and 5× 3 mm by US.Conclusion: MRI has superior diagnostic performance compared with other modalities as a first-line imaging study for patients undergoing renal hyperparathyroidism, especially for ectopic or small parathyroid lesions. We suggest performing US first for diagnosis and then MRI to make a precise localization, and MRI proved to be very helpful in achieving a high success rate in the surgical treatment of renal hyperparathyroidism in our own experience.Keywords: MRI, 4D-CT, ultrasonography, SHPT, preoperative localization, parathyroidectomy

Rui Zhong,&ast; Gang Yu,&ast; Yingming Wang,&ast; Chao Fang, Shuai Lu, Zhilin Liu, Jingyu Gao, Chengyuan Yan, Qichun Zhao Department of Sports Medicine, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qichun Zhao, Department of Sports Medicine, The Affiliated Provincial Hospital of Anhui Medical University, No. 17 Lujiang Road, Luyang District, Hefei, 230001, People’s Republic of China, Tel/Fax +86 13965050622, Email qichzhao@163.comPurpose: To compare the effects of an allogeneic bone graft and a non-filled bone graft on the rate of osteotomy gap union in medial opening wedge high tibial osteotomy (MOWHTO) with an opening width less than 10 mm.Methods: A total of 65 patients undergoing MOWHTO between January 2018 and December 2020 were enrolled in this retrospective study. The patients were divided into two groups: the allograft group (MOWHTO with allogeneic bone grafting, 30 patients) and the non-filling group (MOWHTO without bone void fillers, 35 patients). The clinical outcomes, including the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), Lysholm score, and post-operative complications, were compared. The radiographic evaluation included changes in hip–knee–ankle angle (HKA), medial proximal tibial angle (MPTA), femorotibial angle (FTA), and weight-bearing line ratio (WBLR) at pre-operation, at two-day post-operation, and the last follow-up. Radiographs were obtained at three, six and twelve months post-surgery, and at the time of the last follow-up to assess the fill area of the osteotomy gap. The union rate of the osteotomy gap was calculated and compared, and risk factors that may affect the rate of osteotomy gap union were also discussed.Results: The rate of osteotomy gap union at 3 and 6 months after the operation in the allograft group was significantly higher compared with the non-filling group (all P< 0.05), while no significant difference was found after the 1-year post-operative and at the last follow-up. Also, the WOMAC and Lysholm scores of the allograft group were significantly higher than those of the non-filling group (all P< 0.05), and there was no significant difference between the two groups at the last follow-up.Conclusion: Filling the gaps with the allograft bones may accelerate the union of osteotomy gap, improve clinical outcomes, and have important implications for patient rehabilitation in the early post-operative course. Bone grafting did not affect the final rate of osteotomy gap union and the clinical score of patients.Keywords: MOWHTO, osteotomy gap, bone union, allogenic bone graft

Shiyuan Han,1 Zimu Zhang,2 Wenbin Ma,1 Jun Gao,1 Yongning Li1,3 1Department of Neurosurgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital (Dongdan Campus), Beijing, People’s Republic of China; 2Department of General Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital (Dongdan Campus), Beijing, People’s Republic of China; 3Department of International Medical Service, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital (Dongdan campus), Beijing, People’s Republic of ChinaCorrespondence: Yongning Li, Department of Neurosurgery and Department of International Medical Service, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital (Dongdan campus), No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, People’s Republic of China, Tel +86 13901074129, Fax +86 1069152530, Email 13901074129@139.comPurpose: Glioblastoma multiforme (GBM) remains the deadliest primary brain tumor. We aimed to illuminate the role of nucleotide‐binding oligomerization domain (NOD)-like receptor subfamily C (NLRC) in GBM.Patients and Methods: Based on public database data (mainly The Cancer Genome Atlas [TCGA]), we performed bioinformatics analysis to visually evaluate the role and mechanism of NLRCs in GBM. Then, we validated our findings in a glioma tissue microarray (TMA) by immunohistochemistry (IHC), and the prognostic value of NOD1 was assessed via random forest (RF) models.Results: In GBM tissues, the expression of NLRC members was significantly increased, which was related to the low survival rate of GBM. Additionally, Cox regression analysis revealed that the expression of NOD1 (among NLRCs) served as an independent prognostic marker. A nomogram based on multivariate analysis proved the effective predictive performance of NOD1 in GBM. Enrichment analysis showed that high expression of NOD1 could regulate extracellular structure, cell adhesion, and immune response to promote tumor progression. Then, immune infiltration analysis showed that NOD1 overexpression correlated with an enhanced immune response. Then, in a glioma TMA, the results of IHC revealed that the increase in NOD1 expression indicated high recurrence and poor prognosis of human glioma. Furthermore, the expression level of NOD1 showed good prognostic value in the TMA cohort via RF.Conclusion: The value of NOD1 as a biomarker for GBM was demonstrated. The possible mechanisms may lie in the regulatory role of NLRC-related pathways in the tumor microenvironment.Keywords: glioblastoma multiforme, NLRC family, biomarker, tumor microenvironment, prognostic model, tissue microarray

Wen-Shang Liu,1,&ast; Yu Liu,2,&ast; Jie Gao,3,&ast; Hao Zheng,4 Zheng-Mao Lu,4 Meng Li1 1Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 2Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China; 3Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 4Department of General Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng Li, Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China, Tel +086-15000879978, Fax +086-021-23271699, Email lemonlives_dr@163.com Zheng-Mao Lu, Department of General Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China, Tel +086-13651688596, Fax +086-021-31161589, Email luzhengmao1982@163.comAbstract: Wound healing is a complex and dynamic process, and metabolic disturbances in the microenvironment of chronic wounds and the severe symptoms they cause remain major challenges to be addressed. The inherent properties of hydrogels make them promising wound dressings. In addition, biomembrane-based nanostructures and microstructures (such as liposomes, exosomes, membrane-coated nanostructures, bacteria and algae) have significant advantages in the promotion of wound healing, including special biological activities, flexible drug loading and targeting. Therefore, biomembrane-based nanostructure- and microstructure-loaded hydrogels can compensate for their respective disadvantages and combine the advantages of both to significantly promote chronic wound healing. In this review, we outline the loading strategies, mechanisms of action and applications of different types of biomembrane-based nanostructure- and microstructure-loaded hydrogels in chronic wound healing.Keywords: biomembrane, nanostructures, microstructures, hydrogels, chronic wound healing

Huijuan Wang,1 Yinmin Shi,2 Jiying Ma,1 Wenxia Wang,2 Jianrong Gao,3 Lili Zhao,1 Ting Zhao,2 Guifeng Ding4 1The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, Shaanxi, 710069, People’s Republic of China; 2Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, Shaanxi, 710069, People’s Republic of China; 3Department of Obstetrics, Xi’an International Medical Center Hospital, Xi’an, Shaanxi, 710018, People’s Republic of China; 4Department of Obstetrics and Gynecology, Urumqi Maternal and Child Health Care Hospital, Urumqi, Xinjiang, 830001, People’s Republic of ChinaCorrespondence: Guifeng Ding, Department of Obstetrics and Gynecology, Urumqi Maternal and Child Health Care Hospital, No. 344 Jiefang South Road, Urumqi, Xinjiang, People’s Republic of China, Tel +86 1 331 988 0258, Fax + 86 991-8554656, Email dingguifeng123@126.comBackground: Preeclampsia (PE) is a multi-system disorder of pregnancy that poses a serious threat to maternal and perinatal health worldwide. This study aims to evaluate the global alterations of protein expression and N-glycosylations that are crucial for PE pathogenesis. Here, tandem mass tag labeling combined with LC-MS/MS was employed to determine the global expression of all proteins and intact glycopeptide in placentas from three healthy pregnant women, three patients with early-onset severe PE, and three patients with late-onset severe PE.Results: A total of 2260 proteins were quantified across 9 placental tissues, of which 37 and 23 were differentially expressed in the early-onset and late-onset PE groups, compared to the controls. A total of 789 glycopeptides were accurately quantified, which were derived from 204 glycosylated sites in 159 glycoproteins and were modified by 59 N-Linked glycans. A total of 123 differently expressed glycopeptides, which were from 47 glycoproteins were identified among three groups. Through a combined analysis of proteomic and glycoproteomic data, it was found that the changes in 10 glycoproteins were caused by the difference in glycosylation level but not in the protein abundance level.Conclusion: This is the first study to conduct an integrated proteomic and glycoproteomic characterization of placental tissues of PE patients. Our findings suggest that glycosylation modification may affect the molecular function of proteins through changes in the glycosylation structure or the occupancy of glycosylation, which will provide new insights to help elucidating the pathogenic mechanism of PE.Keywords: preeclampsia, placenta, proteomics, glycoproteomics, glycosylation

Wenqi Qin,1 Yan Wu,1 Jieting Liu,1 Xiaohuan Yuan,1 Jie Gao2 1College of Life Science, Mudanjiang Medical University, Mudanjiang, People’s Republic of China; 2Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of ChinaCorrespondence: Xiaohuan Yuan, College of Life Science, Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157001, People’s Republic of China, Tel/Fax +86 453 6984647, Email yuanxiaohuan@mdjmu.edu.cn Jie Gao, Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China, Tel/Fax +86 021 31166666, Email gaojiehighclea@163.comAbstract: Diabetic wounds are one of the most challenging public health issues of the 21st century due to their inadequate vascular supply, bacterial infections, high levels of oxidative stress, and abnormalities in antioxidant defenses, whereas there is no effective treatment for diabetic wounds. Due to the distinct properties of nanoparticles, such as their small particle size, elevated cellular uptake, low cytotoxicity, antibacterial activity, good biocompatibility, and biodegradability. The application of nanoparticles has been widely used in the treatment of diabetic wound healing due to their superior anti-inflammatory, antibacterial, and antioxidant activities. These nanoparticles can also be loaded with various agents, such as organic molecules (eg, exosomes, small molecule compounds, etc.), inorganic molecules (metals, nonmetals, etc.), or complexed with various biomaterials, such as smart hydrogels (HG), chitosan (CS), and hyaluronic acid (HA), to augment their therapeutic potential in diabetic wounds. This paper reviews the therapeutic potential and future perspective of nanoparticles in the treatment of diabetic wounds. Together, nanoparticles represent a promising strategy in the treatment of diabetic wound healing. The future direction may be to develop novel nanoparticles with multiple effects that not only act in wound healing at all stages of diabetes but also provide a stable physiological environment throughout the wound-healing process.Keywords: nanoparticles, biomaterials, wound healing, diabetic wound, diabetic complications

Yongchao Zhang,1 Hualei Chen,1 Shanshan Chen,1 Youjia Duan,1 Long Cheng,1 Jie Gao,2,&ast; Wei Li1,3,&ast; 1Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, People’s Republic of China; 3Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Gao, Department of Hepatobiliary Surgery, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Email gjpk898@126.com Wei Li, Cancer Center, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, People’s Republic of China, Email weili8989@ccmu.edu.cnBackground: The liver resection for solitary large hepatocellular carcinoma (SLHCC) remains controversial due to the high risk of complications and recurrence after resection. This study aimed to compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus microwave ablation (MWA) with resection for SLHCC.Methods: We retrospectively analyzed a total of 148 patients who were treated with either TACE-MWA (n = 94) or resection (n = 54) for SLHCC (≥ 5 cm). A matched cohort composed of 86 patients was included after propensity score matching (PSM). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and safety.Results: The TACE-MWA group was older with higher ALT and AST (all P < 0.05). After PSM, the 1-, 3-, and 5-year OS were 100%, 80.3%, and 51.0% in the TACE-MWA group, and 88.3%, 66.7%, and 39.4% in the liver resection group, respectively. The 1-, 3-, and 5-year PFS were 76.7%, 48.8%, and 19.6% in the TACE-MWA group, and 72%, 40.2%, and 22.6% in the liver resection group, respectively. There was no significant difference in OS and PFS between the two groups (all P > 0.05). For SLHCC patients with tumor size ≥ 7cm, TACE-MWA showed favorable OS than liver resection. The TACE-MWA group exhibited a lower rate of major complications and shorter hospital stay than the resection group.Conclusion: TACE-MWA showed comparable efficacy to liver resection in patients with SLHCC, but better safety and shorter hospital stay. TACE-MWA might provide a longer OS than liver resection for SLHCC patients with tumor size ≥ 7cm.Keywords: transarterial embolization, microwave ablation, hepatocellular carcinoma, liver resection

Liu Tang,1 Jiefang Gao,2 Xiaolei Li,2 Xiaoqin Cao,3 Benhong Zhou1 1Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2School of Pharmaceutical Sciences, Wuhan University, Wuhan, People’s Republic of China; 3School of Medicine, Jianghan University, Wuhan, People’s Republic of ChinaCorrespondence: Liu Tang; Benhong Zhou, Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email tangliu900402@whu.edu.cn; benhongzh@whu.edu.cnPurpose: To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation.Methods: TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB).Results: A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin.Conclusion: Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.Keywords: atopic dermatitis, luteolin, network pharmacology, target prediction, experimental validation

Hao Wang, Xin Yin, Tianyi Fang, Shenghan Lou, Bangling Han, Jialiang Gao, Yufei Wang, Daoxu Zhang, Xibo Wang, Zhanfei Lu, Junpeng Wu, Jiaqi Zhang, Yimin Wang, Yao Zhang, Yingwei Xue Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of ChinaCorrespondence: Yingwei Xue, Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China, Email xueyingwei@hrbmu.edu.cnBackground: Aging has a negative impact on the immune function of patients. The purpose of this study was to construct an age-related specific immune index according to the immune aging phenomenon of gastric cancer (GC) and explore its prognostic value.Methods: This study retrospectively analyzed patients who underwent radical GC surgery in the Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Harbin Medical University, from August 2014 to December 2016 and divided them into a training cohort and a validation cohort. A new immune score, the GC-specific immune index (GSII), was developed as a series of lymphocyte subsets associated with the prognosis of patients with GC. Then, the receiver operating characteristic (ROC) curve was used to compare the prediction performance. The Kaplan‒Meier method and Log rank test were used to analyze the overall survival of patients. Cox hazard regression models were used to identify independent risk factors associated with prognosis. Finally, a nomogram model was constructed by combining the GSII and clinicopathological characteristics, and the calibration chart, consistency index, and decision curve were used to test the performance of the model.Results: Aging did not significantly affect CD8 cell counts but decreased CD4 and CD19 cell counts. Based on the Cox analysis, the GSII of patients ≤ 60 years old was 0.079×lg CD4+0.348×lg CD19, and the GSII of patients > 60 years old was 0.058×lg CD4. A decreased GSII was indicative of a poor prognosis and was an independent risk factor associated with patient outcomes. The nomogram constructed based on the GSII and clinicopathological features accurately predicted patient prognosis. Furthermore, the GSII was well validated in the validation cohort.Conclusion: The GSII constructed for the special immune aging phenomenon of GC can accurately predict patient prognosis.Keywords: gastric cancer, lymphocyte subsets, age, prognosis

Mingming Deng1– 4&ast;, Liming Yan5 &ast;, Run Tong1– 4&ast;, Joseph Zhao,6 Yanxia Li,7 Yan Yin,8 Qin Zhang,8 Jinghan Gao,8 Qiuyue Wang,8 Gang Hou,1– 4 Xiaoming Zhou9,10 1Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Center for Respiratory Medicine, Beijing, People’s Republic of China; 3Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Fourth Hospital of China Medical University, Shenyang, People’s Republic of China; 6Sage Hill High School, Newport Coast, CA, USA; 7Institute of Respiratory Diseases, Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 8Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, People’s Republic of China; 9Respiratory Department, Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 10Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gang Hou, Department of Pulmonary and Critical Care Medicine, Centre of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China, Email hougangcmu@163.com Xiaoming Zhou, Respiratory Department, Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China, Email zhouxmcmu@163.comPurpose: Sarcopenia, an age-related loss of skeletal muscle mass and function, is frequent in patients with chronic obstructive pulmonary disease (COPD) and is linked to a poor prognosis. The diagnosis of sarcopenia requires specific equipment and is inconvenient to introduce into clinical practice. Ultrasound is an innovative method to assess muscle quantity. The objective of this research was to evaluate the use of ultrasound for prospectively screening for sarcopenia in COPD patients.Patients and Methods: A total of 235 stable patients with COPD were included in this observational study and divided into development and validation sets. The Asian Working Group for Sarcopenia standards were used to define sarcopenia. The thickness (RFthick) and cross-sectional area (RFcsa) of the rectus femoris were measured using ultrasound. Receiver operating characteristic curve analysis of RFthick and RFcsa was used to predict sarcopenia. Nomogram models were constructed based on RFthick, RFcsa, age and body mass index to identify sarcopenia.Results: Sarcopenia was present in 83 (35.32%) patients. Patients with sarcopenia had advanced age, decreased pulmonary function, decreased physical function and poor clinical outcomes. RFthick and RFcsa showed good predictive ability for sarcopenia in the development and validation sets. The nomogram based on RFthick and RFcsa could detect sarcopenia in COPD patients, and all had significant predictive performance in the development and validation sets. The calibration plot showed good agreement between the nomogram predictions and actual observations.Conclusion: The ultrasound measurement of the rectus femoris has potential for the clinical assessment of sarcopenia in patients with COPD.Keywords: chronic obstructive pulmonary disease, sarcopenia, ultrasound, rectus femoris, nomogram

Yitian Zheng,1– 3,&ast; Yu Qi,1,&ast; Samuel Seery,4,5 Jie Yang,2,3 Chen Li,2,3 Wenyao Wang,1 Jun Gao,1 Xiangbin Meng,1 Chunli Shao,1 Yi-Da Tang1 1Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, People’s Republic of China; 2Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4School of Humanities and Social Sciences, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China; 5Faculty of Health and Medicine, Division of Health Research, Lancaster University, Lancaster, UK&ast;These authors contributed equally to this workCorrespondence: Yi-Da Tang, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, People’s Republic of China, Email tangyida@bjmu.edu.cnObjective: Anti-inflammatory therapies are reported to have additional benefits beyond lipid control for patients with cardiovascular disease. However, no study has focused on the relationship between inflammation status and long-term outcomes for chronic obstructive pulmonary disease (COPD) patients, after percutaneous coronary intervention (PCI).Methods: 277 COPD-PCI patients were divided into two groups according to hsCRP status upon admission. Major adverse cardiac events (MACE) in high hsCRP patients were compared to patients with low hsCRP. Restricted cubic spline (RCS) analysis was performed using MACE hazard ratios (HR) to investigate interrelations with hsCRP, as a continuous variable.Results: Patients in the high hsCRP group incurred more inflammation activation, in terms of higher white blood cell counts, neutrophil, lymphocytes, and had higher smoking rates, compared to those with lower hsCRPs. A significant increase in MACEs was observed in hsCRP high group, compared to the low hsCRP group (HR: 2.47, 95% CI: 1.22– 5.00; p = 0.012). RCS curves suggest that HRs rise beyond 1.0, after the 0.24 juncture for Lg HsCRP (base 10 logarithm with hsCRP), HR per SD: 1.19 (95% CI: 0.96– 1.48). Further subgroup analysis implies that elevated hsCRP is associated with a higher risk of MACEs across the sub-groups tested.Conclusion: HsCRP could be a useful indicator for COPD-CAD patient prognosis, after PCI. This is because hsCRP highlights inflammation activation. More multi-center research, designed for COPD-CAD patients should be conducted to more accurately determine the cut-off value for hsCRP.Keywords: HsCRP, chronic obstructive pulmonary disease, coronary artery disease, percutaneous coronary intervention, outcomes

Jin Gao,1,2 Tingting Liu,1 Xingyu Xiong,1 Mei Zhao,1 Kun Du,1,2 Jiwei Li2,3 1Department of Neonates; 2Yunnan Province Clinical Research Center for Children’s Health and Disease, Kunming, People’s Republic of China; 3Department of Pathology, Kunming Children’s Hospital, The Affiliated Children’s Hospital of Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Kun Du; Jiwei Li, Email Dukun@etyy.cn; 360623155@qq.comAbstract: Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi, which is transmitted by larval trombiculid mites. Due to nonspecific clinical presentation, scrub typhus is grossly underdiagnosed in pregnant women, fetuses and neonates. Here, we present a congenital infection case and hope to provide more insight into this disease.Keywords: neonatal scrub typhus, vertical transmission, congenital infection, Orientia tsutsugamushi, meningitis

Hongliang Zhang,1 Jie Gao,1 Wenxiang Fang,1 Yujie Tang,1 Xuan Fang,1 Tengchuan Jin,2 Jinhui Tao1 1Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People’s Republic of China; 2Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, People’s Republic of ChinaCorrespondence: Jinhui Tao; Tengchuan Jin, Email taojinhui@ustc.edu.cn; jint@ustc.edu.cnObjective: To determine the role of nerve injury-induced protein 1 (NINJ1) introduced plasma membrane rupture (PMR) and damage-associated molecular patterns (DAMPs) release in the pathogenesis and progression of gout and to explore the potential of NINJ1 as a therapeutic target in gout.Methods: Both peripheral blood mononuclear cells (PBMCs) and serum sample from gout patients (n = 58) and healthy controls (n = 16) were collected and processed to NINJ1 expression, lactate dehydrogenase (LDH) detection, NINJ1 inhibition, and NINJ1 expression experiments, respectively. NINJ1 knockdown was carried out by lentivirus in a monosodium urate (MSU) induced rat model, and NINJ1 neutralizing antibody was applied in a MSU induced mouse model.Results: Our results found that NINJ1 was upregulated during a gout flare, and the resulting induction of PMR correlated with gout progression. NINJ1 knockdown significantly reduced the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and joint swelling in the rat model, and NINJ1 neutralizing antibody also significantly reduced gout flare in the mouse model and PBMCs. Moreover, NINJ1 expression is under NLRP3 inflammasome produced interleukin (IL)-1β control.Conclusion: These results support the notion of a pathogenic role of NINJ1 introduced PMR in gout and provide a detailed mechanism for gout pathogenesis involving inflammatory cell death and DAMPs release introduced by IL-1β. In addition, targeting NINJ1 might be a potential therapeutic approach for gout.Keywords: gout arthritis, NINJ1, NLRP3 inflammasome, plasma membrane rupture, therapeutic target

Junwei Gao,1 Ziyun Li,1 Jing Li,2 Ping Song,3 Jinsheng Yang,1 Wei Xiao,4 Ning Li,1 Ruodan Xu1 1Department of Biomedical Engineering and Technology, Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Nephropathy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 4Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang, People’s Republic of ChinaCorrespondence: Ruodan Xu; Ning Li, Email ruodanxu@gmail.com; lili.li.ning@gmail.comPurpose: Peptide-based high-density lipoprotein (pHDL) structurally and functionally resembles the natural HDL as anti-atherosclerosis (AS) therapies. Since pHDL contains a large hydrophobic core, this study aims to evaluate the potentials of pHDL as a hydrophobic drug carrier and the efficiency of drug-loaded pHDL in the control of AS.Methods: The pHDL encapsulation of hydrophobic components from natural plants, including curcumin (Cur) and tanshinone IIA (TanIIA), was achieved using one-step microfluidics. Then, morphological features and loading efficiencies of pHDL-Cur and pHDL-TanIIA were determined by TEM and high-performance liquid chromatography (HPLC), respectively. Taking the fluorescence advantage of Cur, localizations of loaded Cur in pHDL were investigated by fluorescence quenchers, and recruitments of Cur to AS plaques were assessed with ex vivo imaging. Based on anti-inflammatory properties of TanIIA, pHDL-TanIIA was accordingly developed to evaluate the anti-AS effects through examinations of plasma lipid parameters and pathological alterations of plaque-associated regions.Results: Both lipophilic Cur and TanIIA can be efficiently loaded into pHDL carriers. The resultant pHDL-Cur and pHDL-TanIIA inherit the homogeneous nano-disk structure of pHDL. By using pHDL-Cur, the encapsulated hydrophobics are tracked in the core of pHDL, and incorporations of Cur with pHDL vehicles greatly improve the bioavailability and association of Cur with AS plaques. Moreover, when loaded with TanIIA, which has established its role in anti-AS as an anti-inflammatory candidate, synergistic effects in reducing AS lesions and improving pathological alterations of main organs related to AS were achieved.Conclusion: The pHDL system could potentially be applied for both imaging and therapy in animal models of AS. Benefits of pHDL-based drug delivery will potentially extend the application scenarios of bioactive chemicals from natural plants which are underutilized due to features like low bioavailability and facilitate the clinical translation of synthetic HDL therapies in HDL-associated disorders, including but not limited to AS.Graphical Abstract: Keywords: HDL, peptide-based HDL, atherosclerosis, drug delivery, natural plants, antiatherogenic therapy

Xiaona Guo,1,&ast; Xia Geng,1,&ast; Yunchao Chu,2 Jianfei Gao,1 Linkai Jiang1 1Pain Department, Dongying People’s Hospital, Dongying, Shandong, People’s Republic of China; 2Pain Department, Shengli Oilfield Central Hospital, Dongying, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linkai Jiang, Pain Department, Dongying People’s Hospital, No. 317, Dongcheng Nanyi Road, Dongying, Shandong, 257091, People’s Republic of China, Tel +86 546-8901234, Email jianglinkai12@163.comPurpose: The pathogenesis of neuropathic pain is complex, and previous studies have found that microRNAs are important regulators of neuropathic pain and are associated with the progression of neuropathic pain. This study aims to explore the level and role of miR-204-5p in the chronic constrictive injury (CCI) model of rats.Patients and Methods: The CCI rat model was constructed to evaluate paw withdrawal threshold (PWT), paw withdrawal latency (PWL), the expressions of miR-204-5p, and the contents of inflammatory factors in the model. Overexpression of miR-204-5p in rat spinal cord was induced by intrathecal injection of miR-204-5p mimics. PWT and PWL were used to estimate mechanical and thermal pain thresholds. IL-6 and TNF-α were determined by ELISA. Luciferase reporter gene was conducted to verify the targeting relationship between miR-204-5p and BRD4.Results: miR-204-5p was abnormally down-regulated in the CCI group. The thresholds of mechanical and thermal pain stimulation in the CCI group were lower, and the levels of inflammatory factors were higher than those in the sham group. Overexpression of miR-204-5p alleviated PWT, PWL and inflammatory factors. Besides, the luciferase reporter gene showed that BRD4 was a target gene of miR-204-5p.Conclusion: These results suggested that miR-204-5p may alleviate neuropathic pain and inflammation through targeted regulation of BRD4 expression.Keywords: neuropathic pain, miR-204-5p, chronic constrictive injury model, BRD4

Mingyue Wang, Yan Wu, Yue Zhou, Junqiang Dong, Shenshen Hu, Ping Hou, Jianbo Gao Department of Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Jianbo Gao, Email cjr.gaojianbo@vip.163.comIntroduction: Early detection and treatment of osteoporosis through bone mineral density (BMD) measurement could aid in the prevention of osteoporosis-related fractures. We aimed to assess the parameter of dual-energy spectral CT (DesCT) consistency with BMD determination using quantitative computed tomography (QCT), thereby establishing a basis for further DesCT application for BMD determination.Methods: We subjected the European spine phantom, which contains three vertebral bodies (V1, V2, and V3), to DesCT with different radiation doses. The basis material pairs were hydroxyapatite (water), calcium (water), and hydroxyapatite (fat). Additionally, the medical records of 152 patients who underwent QCT and DesCT for chest scans in a two-month period were reviewed to measure BMD values.Results: No significant differences were found in the basis pair values of the V1, V2, or V3 vertebrae under different radiation doses in the phantom; in particular, the hydroxyapatite (water), hydroxyapatite (fat), relative error values of V1, V2, and V3 under different radiation doses were not significantly different (all p > 0.05). For patients, the hydroxyapatite (water), hydroxyapatite (fat), and hydroxyapatite (average) values measured by DesCT had a significant correlation with BMD measured by QCT Among 242 vertebrae (152 T12 and 90 L1 vertebrae), there was no significant difference between the BMD measured by QCT and the HAP (average) measured by DesCT (p = 0.071). The interclass correlation coefficient (ICC) value was 0.925 between the HAP (average) and HAP (average) with DesCT and BMD measured by QCT (p < 0.001). Bland-Altman diagram indicated that both measurements were in good agreement.Discussion: We showed that BMD values measured by DesCT were stable and repeatable under different radiation doses. DesCT and QCT measurements of human BMD were highly correlated. Thus, DesCT-based BMD assessment of the spine in a clinical setting could be considered feasible.Keywords: dual-energy spectral computed tomography, quantitative computed tomography, bone mineral density, European spine phantom, spine

Hengqing Cui,1,&ast; Yidan Su,1,&ast; Wei Wei,2,&ast; Fei Xu,3 Jie Gao,2 Wenjun Zhang2 1Department of Burns and Plastic Surgery, Shanghai Changzheng Hospital, Shanghai, 200003, People’s Republic of China; 2Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China; 3Department of Plastic Surgery, Naval Medical Center, Naval Medical University, Shanghai, 200052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun Zhang, Department of Burns and Plastic Surgery, Shanghai Changzheng Hospital, Shanghai, 200001, People’s Republic of China, Tel +86 21 81885775, Fax +86 21 81886000, Email gift1013@163.com Jie Gao, Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China, Tel +86 21 81871290, Fax +86 21 81871290, Email gaojiehighclea@163.comAbstract: Hypoxia can aggravate the conditions of many oxygen-deficiency-aggravated diseases (ODAD), such as cancer, ischemic heart disease, and chronic wounds. Photosynthetic microalgae can alleviate the hepatotoxicity of the local microenvironment by producing oxygen. In addition, microalgae extracts have antitumor, anti-inflammatory, antibacterial, and antioxidant effects. These properties make them attractive candidates for developing methods to treat ODAD. Although researchers have exploited the advantages of microalgae and developed a variety of microalgae-based biomaterials to treat ODAD, a comprehensive review of this topic has not been presented previously. Therefore, in this review, we summarize the development and progress made in the field of developing microalgae-based biomaterials toward the treatment of ODAD. The challenges and prospects of this field are also discussed.Keywords: chronic wounds, tumors, ischemic heart disease, hypoxia, oxygen generation

Yuling Lai,1,2 Fuling Zeng,1 Zhenyue Chen,1 Min Feng,1 Yanxi Huang,3 Pin Qiu,3 Lihua Zeng,1 Yan Ke,4 Gaopi Deng,3,&ast; Jie Gao3,&ast; 1First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Sports Medicine, Guangzhou Sport University, Guangzhou, People’s Republic of China; 3Department of Gynaecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Department of Gynaecology, Shenzhen Chinese and Western Medicine Hospital, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Gao; Gaopi Deng, Email gaojie1769@gzucm.edu.cn; denggaopi@126.comBackground: Albeit oxidative stress has been implied in the pathogenesis of tubal pregnancy (TP), there are scant data to suggest that ferroptosis occurs in TP. Shikonin plays a pivotal role in redox status, but whether it can regulate ferroptosis to treat TP remains unknown.Methods: We collected and analyzed ferroptosis-related indices from the villous tissue (VT) of women suffering from TP and from women with a normal pregnancy. In vitro, we used shikonin and/or RAS-selective lethal 3 (RSL3) to intervene HTR-8/SVneo cells and further detected ferroptosis indices and cell functions. Finally, the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) is pharmacologically activated to explore the effect of Nrf2 on shikonin regulating ferroptosis.Results: Increased malondialdehyde content, reduced levels of glutathione and glutathione peroxidase (GPx), and upregulated protein expression which promoted ferroptosis were observed in the VT of TP patients, suggesting that ferroptosis occurred during TP. In vitro, shikonin enhanced ferroptosis sensitivity in HTR-8/SVneo cells induced by RSL3 via amplifying lipid peroxidation, which mainly included increasing cellular reactive oxygen species (ROS), lipid ROS and Fe2+ level. RSL3 and/or shikonin inhibited Nrf2 and downregulated protein expression of SLC7A11 and GPx4 caused by RSL3 + shikonin co-treatment, which could be reversed under activation of Nrf2. Hence, shikonin facilitated lipid peroxidation by inhibiting Nrf2 signaling. Additionally, shikonin and/or RSL3 potently inhibited the invasion and migration of HTR-8/SVneo cells.Conclusion: This study firstly showed that ferroptosis may be involved in TP pathogenesis and shikonin potentially targeted ferroptosis to treat TP.Keywords: ectopic pregnancy, shikonin, lipid peroxidation, iron dependent

Wang J, Gao J, Chen Q, et al. Onco Targets Ther. 2020;13:9333–9347. At the authors request, we the Editor and Publisher of OncoTargets and Therapy are retracting the published article. Concerns were raised to the authors attention regarding the duplication of images in Figures 2 and 5. Specifically, Images from Figure 2E, Invasion, si-LINC1116 1# and si-LINC01116 2#, were duplicated. Images from Figure 5E, Migration, Empty vector and Invasion, Empty vector and pcDNA-LINC0116 were duplicated. The authors explained that errors had been made during the preparation of the figures, but no original data was provided to the journal. As verifying the validity of published work is core to the integrity of the scholarly record, the authors requested to retract the article. The editor agreed with this decision. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Jia Gao,1,&ast; Sifu Yang,2,&ast; Guanqun Xie,3 Jieli Pan,4 Feiye Zhu4 1The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 2Medical Oncology Department, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, 310014, People’s Republic of China; 3College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 4Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jieli Pan; Feiye Zhu, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Email panjieli_zj@163.com; zhufeiye@163.comPurpose: This study was designed to evaluate the pharmacological mechanisms of Aloin against gastric cancer (GC) via network pharmacology analysis combined with experimental verification.Methods: Using network pharmacology methods, the potential targets of Aloin and targets related to GC were screened from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against GC. The expressions of major targets predicted by network pharmacology in normal stomach tissues and GC tissues and their relationships with overall survival of GC were searched in GEPIA, HPA and DriverDBv3 database. The results of network pharmacology analysis were verified by in vitro experiments.Results: A total of 129 potential targets were retrieved by searching the intersection of Aloin and GC targets. PPI network analysis indicated that 10 targets, including AKT1 and CASP3, were hub genes. GO enrichment analysis involved 93 biological processes, 19 cellular components, and 37 molecular functions. KEGG enrichment analysis indicated that the anti-cancer effect of Aloin was mediated through multiple pathways, such as PI3K-AKT, FoxO and Ras signaling pathway. Among them, the PI3K-AKT signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of GC. The validation of key targets in GEPIA, HPA and DriverDBv3 database showed that the verification results for most core genes were consistent with this study. Then, the results of in vitro experiment indicated that Aloin could inhibit proliferation of NCI-N87 cells and induce cell apoptosis. The results also showed that Aloin could decrease the mRNA and protein expressions of PI3K and AKT, suggesting that Aloin can treat GC by inducing cell apoptosis and regulating the PI3K-AKT signaling pathway.Conclusion: This study identified the potential targets of Aloin against GC using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Aloin in treatment of GC.Keywords: gastric cancer, Aloin, pharmacological mechanisms, network pharmacology, experimental verification

Zhiyuan Zhang,&ast; Nan Zhang,&ast; Jing Yu,&ast; Wenting Xu, Jiameng Gao, Xin Lv, Zongmei Wen Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Lv; Zongmei Wen, Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, People’s Republic of China, Email xinlvg@126.com; wzm1103@126.comAbstract: Podoplanin is a small cell-surface mucin-like glycoprotein that participates in multiple physiological and pathological processes. Podoplanin exerts an important function in the immune response and is upregulated in fibroblasts, macrophages, T helper cells, and epithelial cells during inflammation. Herein, we summarize the latest knowledge on the functional expression of podoplanin in the immune system and review the contribution of podoplanin to several inflammatory diseases. Furthermore, we discuss podoplanin as a novel therapeutic target for various inflammatory diseases.Keywords: podoplanin, immune system, inflammation

Xueying Zhang,1– 3,* Chen He,1– 3,* Peijun Ju,4,* Qingrong Xia,1– 3 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Xuequan Chen,1– 3 Hui Yuan,1– 3 Hua Gao,1– 3 Yang Zhang,1– 3 Junwei Yan,1– 3 Wen Xie,1– 3,* Cuizhen Zhu1– 3,* 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aimed to clarify the cognitive impairments of schizophrenia with metabolic syndrome while evaluating their potential as risk factors.Patients and Methods: We recruited 153 participants and divided them into three groups according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and the guideline standards for the prevention and treatment of dyslipidemia in Chinese adults in 2007 for metabolic syndrome, as follows: healthy control group (n = 47); nonmetabolic syndrome group (n = 58); and metabolic syndrome group (n = 48). Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale. Cognitive function and automatic thinking were estimated using the Montreal Cognitive Assessment Scale, Verbal Fluency Test, and Automatic Thoughts Questionnaire. Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: One-way ANOVA analysis revealed that differential cognition impairments in schizophrenia patients compared to controls. Furthermore, results of multiple comparisons showed that more serious barriers in orientation, language fluency, and negative automatic thinking existed in the metabolic syndrome group than in the healthy and non-metabolic syndrome groups. Spearman correlation and stepwise linear regression analyses showed that psychopathological symptoms, high waist circumference, and high triglyceride were the predictive factors for negative automatic thoughts, orientation, and language fluency. Those results collectively revealed that high waist circumference, high triglyceride and negative automatic thinking had validity and effectiveness in predicting the cognitive function impairments of the metabolic syndrome group.Conclusion: The present findings strongly supported the notion that aberrant parameters of high waist circumference, high triglyceride and high negative automatic thoughts had validity and effectiveness predictive role for cognitive impairments in the schizophrenics with metabolic syndrome. The schizophrenia patients with metabolic syndrome should receive regular monitoring and adequate treatment for metabolic and psychological risk factors.Keywords: second-generation antipsychotics, negative symptoms, diet, Montreal Cognitive Assessment Scale, Verbal Fluency Test

Ruhai Bai,1 Jianmin Gao,2 Wanyue Dong3 1School of Public Affairs, Nanjing University of Science and Technology, Nanjing, People’s Republic of China; 2School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of ChinaCorrespondence: Wanyue Dong, School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Qixia District, Nanjing, 210023, People’s Republic of China, Tel +86 25 858 11301, Email wanyuedong@njucm.edu.cnPurpose: Northwest China has a large area, low population density, and few health resources, which makes the utilization of health resources in this region difficult. The objective of this study was to assess utilization of health services and its association with travel time in Shaanxi Province.Patients and Methods: Data were obtained from the fifth Household Health Service Survey of Shaanxi Province conducted in 2013. Binary logistic regression was used to assess the relationship between travel time and health service utilization, and negative binomial regression was conducted to assess the relationship between travel time and the frequency of health service utilization.Results: A total of 42.6% of patients used health services, with a higher use rate among rural residents than among urban residents (47.0% and 27.4%, respectively). A total of 30.9% of patients traveled more than 15 min to the nearest medical facility (33.3% in rural areas and 22.6% in urban areas). A total of 12.4% of patients traveled more than 30 min to the nearest medical facility (15.1% in rural areas and 3.0% in urban areas). Urban residents living farthest from health care facilities (more than 30 min) had a 2.12-fold higher probability of health service utilization and expected to have a health service utilization rate 1.77 times greater than that of residents with a travel time of less than 5 min. Among the rural population, there was no significant correlation between travel time and health service utilization.Conclusion: Urban patients living farthest from hospitals were more likely to use health services and used health services more frequently. This suggests that more attention should be given to urban patients who live far away from health service providers in Shaanxi Province.Keywords: health equity, accessibility, travel time, health service utilization

Wenjun Sun,1 Jing Gao,1 Ranran Fan,2 Ting Zhang,3 Yang Tian,1 Zengming Wang,1 Hui Zhang,1 Aiping Zheng1 1Department of Pharmaceutics, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, People’s Republic of China; 2Bengbu Medical College, Bengbu, People’s Republic of China; 3School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Hui Zhang; Aiping Zheng, Department of Pharmaceutics, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, People’s Republic of China, Tel +86 10 66931694, Email zhhui58@126.com; apzheng@163.comBackground: Cyclosporin A (CsA) is a hydrophobic drug widely used as an immunosuppressant and anti-rejection drug in solid organ transplantation. On the market, there are two oral CsA formulations available containing polyoxyethylene castor oil, which can cause serious allergic reactions and nephrotoxicity. In order to eliminate polyoxyethylene castor oil, CsA was formulated into a nanosuspension. This study aimed to design an oral cyclosporin A nanosuspensions (CsA-NSs) and investigate the effect of particle size on absorption of CsA-NSs.Methods: CsA-NSs were prepared using a wet bead milling method. Particle size, morphology and crystallinity state of CsA-NSs were characterized. The in vitro dissolution, the intestinal absorption properties and pharmacokinetic study of CsA-NSs were investigated.Results: CsA-NSs with sizes of 280 nm, 522 nm and 2967 nm were prepared. The shape of CsA-NSs with smaller size was similar to that of spheres. The crystallinity of CsA in nanocrystals was reduced. The dissolution rate of CsA-NSs (280 nm) was greater than that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). CsA-NSs (280 nm) showed higher absorption rate constants (Kα) and effective permeability coefficients (Peff) of different intestinal segments compared with that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). AUC0-48h of 280 nm CsA-NSs was about 1.12-fold of that of 522 nm CsA-NSs, and about 1.51-fold of that of 2967 nm CsA-NSs. In particular, the particle size of CsA-NSs was nanoscale, and their bioavailability was bioequivalent with marked self-microemulsion (Sandimmun Neoral®).Conclusion: It is feasible to prepare CsA-NSs. The dissolution rate, gastrointestinal transport properties and the oral absorption of CsA-NSs were promoted by reducing size. Considering the cost, efficiency and energy consumption, there should be an optimal particle size range in industrial production.Keywords: wet bead milling, in vitro dissolution, in situ single-pass intestinal perfusion, pharmacokinetics

Xudong Liu,1– 3 Jie Gao,1– 3 Yaohui Sun,1– 3 Feng Zhang,1– 3 Wenzhi Guo,1– 3 Shuijun Zhang1– 3 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Henan Research & Development International Joint Laboratory for Organ Transplantation Immunomodulation, Zhengzhou, Henan Province, People’s Republic of China; 3National Regional Medical Treatment Centre of Henan Organ Transplantation, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Shuijun Zhang, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan Province, People’s Republic of China, Tel/Fax +8637166913032, Email zhangshuijun@zzu.edu.cnPurpose: Hepatocellular carcinoma (HCC), has a very high mortality rate and is the most common type of liver cancer. Clotrimazole, a traditional antifungal drug, has garnered considerable attention as a therapeutic strategy for HCC. However, its effects against the migration and invasion of HCC cells as well as the associated underlying mechanisms remain unclear. Therefore, in this study, we investigated its effects on HCC and attempted to elucidate the underlying molecular mechanisms.Methods: CCK-8 was used to investigate the inhibitory effect of clotrimazole on the proliferation of different types of HCC cells, and wound healing and transwell assays were performed to investigate its inhibitory effect on the invasion and migration of the HCC cells. Further, western blotting was employed to detect changes in the expression levels of epithelial mesenchymal transition (EMT)-related proteins, extracellular-regulated protein kinases (ERK), p-ERK, p65, and p-p65. We also used ERK activators in combination with clotrimazole to treat the HCC cell lines.Results: Clotrimazole inhibited the invasion and migration of HCC cells, and mechanistically, it exerted these anti-tumor effects via EMT by repressing ERK phosphorylation.Conclusion: These findings suggest that clotrimazole inhibits HCC metastasis by repressing EMT in an ERK dephosphorylation-dependent manner.Keywords: hepatocellular carcinoma, clotrimazole, extracellular-regulated protein kinases, migration, invasion, cancer

Haoze Li, Ce Guo, Jiale Gao, Hongwei Yao Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, Beijing, 100050, People’s Republic of ChinaCorrespondence: Hongwei YaoDepartment of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, People’s Republic of China, Email yaohongwei@ccmu.edu.cnObjective: To identify, systematically review and synthesize the evidence on the effectiveness of biofeedback therapy in patients with bowel dysfunction following rectal cancer surgery.Data Sources: Four electronic databases (PubMed 1974– 2021; Embase1980– 2021; Cochrane databases and the trial registers) were systematically searched by reviewers from inception through March 2021.Study Selection: Randomized controlled trials (RCTs), cohort studies, and case series studies were included for adults with bowel dysfunction following rectal cancer surgery. All participants received an intervention of biofeedback treatment. Any outcomes that can evaluate the patient’s bowel function were the primary research endpoint, while the quality of life was the second endpoint. The disagreements between the two reviewers were resolved after discussion and the third independent reviewer’s ruling. As a result, 12 of 185 studies met selection criteria and were included in the review.Data Extraction: We designed an electronic data extraction form and data were extracted independently. The methodological quality of included studies was assessed using the Cochrane Risk of Bias, the MINORS scale, and the Institute of Health Economics scale.Data Synthesis: Meta-analyses were conducted for case series only and narrative syntheses were completed. Key findings included significant improvements in bowel function as well as health-related quality of life after biofeedback therapy. (Wexner score: t=7, MD=3.33; 95% CI [2.48, 4.18]) and (Vaizey score: t=3, MD=2.46; 95% CI [1.98, 2.93]). Subgroup analysis of Wexner score: receiving electrical stimulation therapy (t=3, MD=2.36; 95% CI [1.51, 3.22]), not receiving electrical stimulation (t=4, MD=3.79;95% CI[2.66, 4.93]); not receiving adjuvant chemoradiotherapy (t=3, MD=2.42;95% CI[1.61, 3.24]), chemotherapy and radiotherapy (t=1, MD=4.10; 95% CI [2.90, 5.30]), radiotherapy and chemotherapy on parts of patients (t=2, MD=3.46;95% CI [1.41, 5.51]), chemotherapy (t=1, MD=4.81; 95% CI [3.38, 6.24]); performing ISR (t=2, MD=3.32;95% CI [0.37, 6.27]), performing AR (t=4, MD=3.08; 95% CI [2.12, 4.04]), performing PLRAS surgery (t=1, MD=4.10;95% CI[2.90, 5.30]).Conclusion: Although biofeedback therapy may improve intestinal function and quality of life as well as anal function reflected by ARM after surgery, patient satisfaction is still unclear. Due to the scarcity of data, good-quality research is required to delve deeper.Clinical Trial Registration Number: CRD42020192658.Keywords: biofeedback, fecal incontinence, rectal neoplasms, surgery, rehabilitation

Zhihong Wang,1,&ast; Peng Tang,2,&ast; Surong Hua,1 Junyi Gao,1 Bin Zhang,3 Hua Wan,4 Qixi Wu,4 Jiaxin Zhang,5 Ge Chen1 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Breast and Thyroid Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 3Department of General Surgery, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 4Research and Development Department, Beijing USCI Medical Laboratory, Beijing, People’s Republic of China; 5Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ge ChenDepartment of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuai Fu Yuan Hu Tong, Beijing, 100730, People’s Republic of China, Tel +86 156 1123 3738, Fax +86 156 69152600, Email chenge@pumch.cn; Jiaxin ZhangDepartment of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, No. 99, Huaihai West Road, Xuzhou, 221004, People’s Republic of China, Tel +86 180 5226 8693, Fax +86 180 85802306, Email zhangjiaxin1969@163.comPurpose: To describe the genetic landscape and clinical characteristics of Chinese patients diagnosed with papillary thyroid cancer (PTC) and to determine which high-risk genetic characteristics suggest a likelihood of lymph node metastasis (LNM) and lateral lymph node metastasis (LLNM).Patients and Methods: Data from previously untreated patients with PTC collected between May 2018 and December 2020 from 14 hospitals in China were analyzed retrospectively. High-risk pathologic characteristics were defined as T3/T4, N(+), and N1b(+) stages. All patients were tested for 57 genes by second-generation sequencing. The t-test, chi-square test, and Fisher’s exact test were performed for statistical analysis.Results: Overall, 395 patients were enrolled in this study. The prevalence of BRAF mutation was 78.53%. BRAF mutant allele frequency (MAF) > 16.93% was associated with a significantly higher risk of LNM, LLNM, and T3 + T4 stage compared with a low-risk group, defined by a MAF < 2.54% (odd ratios [ORs] for each risk=3.38, 3.46, and 8.54, respectively), and an intermediate-risk group, defined by a MAF of 2.54% to 16.93% (ORs=2.04, 2.07, and 4.07, respectively). The population with RET fusion had higher T, N, and N1b stages (ORs for each stage=10.40, 7.60, and 8.77, respectively) compared with a RET-negative population. Similar conclusions about T, N, and N1b stages were observed in relation to multiple driver gene mutations (ORs for each stage=7.48, 2.80, and 7.04, respectively) compared with population without multiple driver mutations. These genetic characteristics may be suggestive of high clinical risk. However, regardless of genetic profiles, patients younger than age 45 years had greater rates of LNM and LLNM.Conclusion: The main driver gene in this study, BRAF, differs significantly between the United States (79% vs 51%) and other countries. The Chinese population in this study that experienced more aggressive tumor biology had a BRAF MAF greater than 16.93%, exhibited RET fusion events, and had multiple driver gene mutations; thus, these traits may be considered high-risk genetic characteristics in PTC that could warrant aggressive treatment in such population.Keywords: papillary thyroid cancer, lymph node metastasis, high risk clinicopathological characteristics, genotypes

Yongmei Lv, Yamei Gao, Na Lan, Minghui Sun, Chenchen Zhang, Jing Gao, Na Wang, Xingyu Yang Departments of Dermatology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of ChinaCorrespondence: Yongmei Lv, Department of Dermatology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei Economic and Technological Development Zone, Hefei, Anhui Province, 230601, People’s Republic of China, Email yongmei_lv830@163.comPurpose: To understand the distribution characteristics of onset time, onset age and gender of pityriasis alba (PA) patients in the dermatology clinic of our hospital and to further explore the pathogenesis of the disease to provide a scientific basis for the prevention and treatment of this disease.Patients and Methods: The clinical data of 2726 outpatients with PA diagnosed for the first time from January 2016 to December 2020 were collected and descriptively analyzed.Results: The number of patients with PA was less from January to March. The peak was reached in July and August. The number of cases affected by the COVID-19 epidemic in 2020 was significantly lower than that in previous years. Furthermore, the onset age of the patients ranged from 0 to 64 years old, and the median age of the total population was 7 (3, 13) years old, including 1566 males (57.45%) and 1160 females (42.55%). The ratio of male to female was 1.35:1. The number of male patients before 18 years old was higher than that of female patients, especially in the high paroxysmal age group.Conclusion: PA can be seen all the year round, and the onset peak of the disease is from July to August every year. It occurs frequently at the age of 1 to 14 before puberty. In the season of high incidence of PA, the protection from sun and moisture retention should be strengthened for infants and adolescents.Keywords: pityriasis alba, epidemic characteristics, pathogenic factors

Wei Zhang,1,&ast; Yuyang Zhang,1,&ast; Jingjing Gao,1 Dangwei Peng,1 Yao Zhang,1 Xu Wu,1 Guodong Liu,1 Yutian Dai,2 Hui Jiang,3 Xiansheng Zhang1 1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Urology, Gulou Hospital of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Reproductive Medicine Center, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiansheng Zhang; Hui Jiang, Email xiansheng-zhang@163.com; jianghui55@163.comPurpose: To determine the role of poor sleep quality as a risk factor for acquired premature ejaculation (APE) after considering the various risk factors, such as ages, lower urinary tract symptoms (LUTS), anxiety, depression, and erectile dysfunction.Methods: This study presents a multivariate analysis to identify risk factors for PE, including the covariate of age, International Prostate Symptom Score (IPSS), General Anxiety Disorder-7 (GAD-7) score, Patient Health Questionnaire-9 (PHQ-9) score, International Index of Erectile Function (IIEF) score, and Pittsburgh Sleep Quality Index (PSQI). Acquired PE was defined as self-reported intravaginal ejaculation latency time ≤ 3 minutes, and poor sleep quality was diagnosed using the Pittsburgh Sleep Quality Index tool.Results: A total of 349 men were enrolled in the study after completing the questionnaires and the medical history survey. Among 349 men, 203 individuals (58.17%) suffered from acquired PE. The IIEF-5 score, IPSS, GAD-7 score, PHQ-9 score, and PSQI score of the population with PE were significantly different from the non-PE group. Further multivariate analysis showed that erectile dysfunction, depression, severe prostatitis-like symptoms, and poor sleep quality were high-risk factors of APE. Additionally, our study showed that premature ejaculation diagnostic tool (PEDT) score was associated with IPSS/GAD-7/PHQ-9/PSQI scores positively and associated with IIEF-5 scores negatively. The stratified analysis of sleep quality showed that APE patients with different sleep qualities have different prevalence rates of anxiety, depression, prostatitis-like symptoms, and erectile function.Conclusion: In general, sleep quality may be a potential risk factor for patients with acquired premature ejaculation. Our research revealed the impact of sleep quality on premature ejaculation and provided new viewpoints for further understanding and perfecting the pathogenesis of premature ejaculation.Keywords: sleep quality, acquired premature ejaculation, multivariate analysis

Yue-Jiao Lan,1,2 Napoleon Bellua Sam,3 Ming-Han Cheng,1 Hai-Feng Pan,4,5 Jian Gao1 1Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 3Department of Medical Research and Innovation, School of Medicine, University for Development Studies, Tamale, Ghana; 4Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, People’s Republic of ChinaCorrespondence: Jian GaoPediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, People’s Republic of ChinaEmail gaojian@scmc.com.cn; gaojianayfy@163.comHai-Feng PanDepartment of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaEmail panhaifeng@ahmu.edu.cnAbstract: Progranulin (PGRN), a secretory glycoprotein consisting of 593 amino acid residues, is a key actor and regulator of multiple system functions such as innate immune response and inflammation, as well as tissue regeneration. Recently, there is emerging evidence that PGRN is protective in the development of a variety of immune-mediated diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) by regulating signaling pathways known to be critical for immunology, particularly the tumor necrosis factor alpha/TNF receptor (TNF-α/TNFR) signaling pathway. Whereas, the role of PGRN in psoriasis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is controversial. This review summarizes the immunological functions of PGRN and its role in the pathogenesis of several immune-mediated diseases, in order to provide new ideas for developing therapeutic strategies for these diseases.Keywords: PGRN, TNF-α, TNFR, immune-mediated diseases, therapeutic

Zhangying Feng, Jinglin Gao, Xiaonan Gao, Li Hua, Xuyang Nie, Yaqi Sun, Mingxia Wang Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Mingxia WangDepartment of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of ChinaTel +86311-66696233Email mxia_wang@163.comPurpose: A simple, rapid and reliable method to quantify methotrexate (MTX) in human plasma by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was established and validated in two laboratories.Patients and Methods: Sample separation was achieved on a Synergi Hydro-RP column (50 mm× 2.0 mm, 2.5 μm) with a gradient elution program in 3.5 min after a simple protein precipitation with methanol (MeOH) and acetonitrile (ACN) (1:1). About 5 mM ammonium formate aqueous solution with 0.2% formic acid and ACN were used as mobile phase with a flow rate of 0.5 mL/min at 40 °C. Mass spectrometry detection using AB Sciex Triple Quad 4500 mass spectrometer (4500 QQQ) and Qtrap 5500 mass spectrometer (5500 Q-trap) were both characterized by electrospray ionization (ESI) for positive ions in multiple reaction-monitoring (MRM) mode. Quantitative ion pairs were m/z 455.1→m/z 308.0 for MTX and m/z 248.1→m/z 121.0 for tinidazole (TNZ) used as internal standard (IS).Results: Linear calibration curves were generated over the range of 5– 1000 ng/mL (r2> 0.99) on both the 4500 QQQ and 5500 Q-trap, both of the intra- and inter-batch precision were less than 7.67% and accuracy ranged from 96.33% to 108.94%. The recovery and matrix effect were 82.20– 93.98% and 102.69– 105.28%, respectively.Conclusion: An analytical method transfer was achieved by re-verification in two laboratories to ensure stability and reproducibility and this method has been applied for therapeutic drug monitoring (TDM) successfully in children and adults with NHL, and during routine TDM, two delayed elimination of MTX cases were observed and analyzed.Keywords: methotrexate, therapeutic drug monitoring, non-Hodgkin lymphoma, children, adult

Daofang Zhu,1 Jingjing Gao,1 Xianming Dou,2 Dangwei Peng,1 Yao Zhang,1 Xiansheng Zhang1 1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Department of Urology, Anhui No. 2 Provincial People’s Hospital, Heifei, 230041, People’s Republic of ChinaCorrespondence: Xiansheng Zhang Tel +86- 551-62922114Email xshzhang1013@126.comBackground: Benign prostatic hyperplasia (BPH) is a frequent-occurring disease in middle-aged and elderly men. This work is a prospective study and aims at exploring the incidence of post-operative depression and the potential risk factors of depression in a cohort of patients with BPH in China.Methods: In this survey, 611 men who underwent transurethral resection of the prostate (TURP) were strictly selected at our institution from January 2016 to August 2019. Zung Self-rating Depression Scale was used for evaluation of depressive symptoms. Sociodemographic, clinical and other data were also collected.Results: We found that 152/611 (24.9%) patients suffered from different degree of depression at 6 months after TURP, including mild symptoms (20.9%) and moderate/severe symptoms (3.9%). A total of 421 (68.9%) patients developed post-TURP erectile dysfunction (ED). The occurrence of depression was closely associated with marital status, education level, cigarette smoking, alcohol consumption, severity of lower urinary tract symptoms (LUTS), duration of BPH, erectile function, and comorbidities (such as diabetes, dyslipidaemia and bladder stone). The risk factors related to the severity of depression included widowed or single marital status, frequent alcohol consumption, moderate or severe LUTS, longer duration (> 5 years) of BPH, ED, urinary continence, and comorbidities such as diabetes and bladder stone.Conclusion: Many risk factors are related to the occurrence of depression in patients undergoing TURP. Widowed or single marital status, frequent alcohol consumption, moderate or severe LUTS, longer duration of BPH, ED, urinary incontinence and comorbidities such as diabetes and bladder stone are connected with the increase odds of moderate or severe depressive symptom.Keywords: benign prostate hyperplasia, BPH, transurethral resection of the prostate, TURP, depression, prevalence rate, risk factors

Liangliang Yan,1 Jinrong Qu,2 Jing Li,2 Hongkai Zhang,2 Yanan Lu,2 Jianbo Gao1 1The Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Radiology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Jianbo Gao Tel +86 15188330092Email jbgao1231@126.comObjective: To explore the feasibility of the whole tumor histogram analysis parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) based on stack-of stars (StarVIBE) to predict T and N staging of resectable gastric cancer (GC).Methods: Eighty-seven patients confirmed as GC by histopathology were enrolled in this prospective study. DCE-MRI were performed before surgery, and quantitative DCE parameters (Ktrans, Kep, Ve) and histogram metrics (Skewness, Kurtosis and Entropy) were measured by Omni-Kinetics software. Intraclass correlation coefficient (ICC) testing was used to determine the consistency of Ktrans, Kep and Ve values and histogram metrics values between two radiologists using Bland–Altman analysis. The quantitative DCE parameters or histogram metrics values between T stage or N stage were compared using ANOVA or Kruskal–Wallis testing. Receiver operating characteristic (ROC) analyses was performed to find out the best parameters for identifying T and N staging.Results: There was statistical difference in Ktrans, Kep, Ve and entropy to identify T staging (P=0.015, 0.033, < 0.001, and 0.007, respectively), and in pairwise comparisons of Ve values showed statistically difference between T1+2 and T3 group (P< 0.001), T1+2 and T4 group (P< 0.001). There were statistical differences in Ve to identify N staging (P=0.041). In ROC analysis, Ve was the best parameter for identifying T staging (AUC: 0.788, the sensitivity and specificity was 0.929 and 0.578, respectively) and N staging (AUC: 0.590, the sensitivity and specificity was 0.714 and 0.899, respectively).Conclusion: The whole tumor histogram analysis parameters derived from StarVIBE DCE-MRI may be able to quantitatively evaluate T and N staging of GC, so as to help clinical treatment decision optimization.Keywords: magnetic resonance imaging, quantitative DCE parameters, histogram metrics, starVIBE, T and N staging, stomach neoplasms

Shuo Zhang,1 Jingtao Gao,1 Shibo Liu,1 Lu Yu,1 Wen Zhang,1 Yinming Liang,1,2 Hui Wang1,2 1Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan Province, 453003, People’s Republic of China; 2Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan Province, 453003, People’s Republic of ChinaCorrespondence: Hui WangHenan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan Province, 453003, People’s Republic of ChinaTel/Fax +86 373 3831203Email wanghui@xxmu.edu.cnBackground and Purpose: Transcriptional coactivator B-cell lymphoma-3 (BCL3) is a member of the IκB family of NF-κB inhibitors and regulates the activity of the NF-κB pathway. However, the relationship between BCL3 and lipid metabolism remains unclear. The present study investigates the effects of BCL3 in immune and metabolism in obese mice.Animals and Methods: Construct Bcl3-KO mice through CRISPR/Cas9 technology. Obesity model was induced in Bcl3-KO mice by feeding a high-fat diet for 16 weeks, and some metabolic-related indicators were analysed.Results: The results showed that the KO mice gained significantly less body weight on a high fat diet without a change in food intake. There was significant improvement in hepatic steatosis and adipose tissue hypertrophy in KO mice. The expression of SREBP1 and its downstream fatty acid synthetase FAS and ACC were down-regulated in KO mice, and the inflammation in adipose tissue and liver was further reduced.Conclusion: These results suggest that BCL3 may be a novel factor in regulating lipid metabolism in the development of obesity.Keywords: inflammation, obesity, BCL3, lipid metabolism, SREBP1

Huipu Li,1,&ast; Shasha Shi,1,&ast; Meng Wu,2,&ast; Wei Shen,1 Jianli Ren,3 Zhechuan Mei,1 Haitao Ran,3 Zhigang Wang,3 Yi Tian,4 Jian Gao,1 Hongyun Zhao1,3 1Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Plastic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongyun Zhao; Jian Gao Email zhychina@cqmu.edu.cn; 982213482@qq.comPurpose: Prepare a multifunctional ultrasound molecular probe, cell-penetrating peptide-modified 10-hydroxycamptothecin-loaded phase-transformation lipid nanoparticles (iRGD-ICG-10-HCPT-PFP-NPs), and to combine iRGD-ICG-10-HCPT-PFP -NPs with low-intensity focused ultrasound (LIFU) for precision theranostics against hepatocellular carcinoma (HCC).Materials and Methods: The morphology of nanoparticles (NPs) and iRGD-ICG-10-HCPT-PFP-NPs was detected. In vitro, we examined targeting ability by flow cytometry and confocal laser scanning microscopy (CLSM), assessed penetration ability into hepatoma cells, and assessed killing ability. In vivo, we examined the targeting ability of the NPs with a photoacoustic (PA) imager and fluorometer (FL), while LIFU irradiation was used to trigger the release of chemotherapeutic drugs, which had a therapeutic effect on tumors.Results: The particle size of iRGD-ICG-10-HCPT-PFP-NPs was 298.4 ± 10.42 nm. In vitro, iRGD-ICG-10-HCPT-PFP-NPs bound more to SK-Hep1 cells than ICG-10-HCPT-PFP-NPs. iRGD-ICG-10-HCPT-PFP-NPs could achieve PA/ultrasound imaging. The percentage of antiproliferative and apoptotic cells in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly higher. In vivo, iRGD-ICG-10-HCPT-PFP-NPs can target tumor sites and achieve PA/ultrasound imaging. The tumor volume in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly smaller, and the antiproliferative and proapoptotic effects were higher.Conclusion: We successfully prepared a novel molecular probe that has good targeting, can perform ultrasound/PA dual-modality imaging, and can penetrate deep into tumors to achieve better therapeutic tumor effects, providing a new idea and method for theranostics of HCC.Keywords: molecular probe, homing membrane peptide, precision diagnosis and treatment, dual-modality imaging

Taiyong Bi,1 Qinhong Xie,1,2 Jianhui Gao,1 Tao Zhang,1 Hui Kou1 1Center for Mental Health Research in School of Management, Zunyi Medical University, Zunyi, People’s Republic of China; 2School of Criminal Justice, China University of Political Science and Law, Beijing, People’s Republic of ChinaCorrespondence: Taiyong Bi; Hui Kou Email bitaiyong@126.com; kouhuizmu@163.comBackground: Empathy is shown to affect the attentional processing of painful stimuli and emotional stimuli. However, whether the attentional effects on emotional stimuli depend on emotional valence and the nature of the relationship between the attentional effects on different stimuli are still unknown.Methods: In the present study, 25 high-empathy (HE) participants and 25 low-empathy (LE) participants were recruited to perform dot-probe tasks on painful stimuli and emotional stimuli.Results: The results showed that HE individuals had weak attentional disengagement to painful pictures. More importantly, regarding emotional pictures, HE individuals showed attentional avoidance to negative emotion pictures, while LE individuals showed attentional bias to positive emotion pictures. Correlation analysis showed that the attentional bias score and attentional disengagement score were only associated with each other within the same category of stimuli (painful, positive or negative stimuli).Conclusion: These results revealed that HE individuals mainly showed attentional avoidance to negative stimuli, while LE individuals mainly showed attentional bias to positive stimuli.Keywords: empathy, attentional bias, attentional disengagement, painful stimuli, emotional stimuli

Zhe Shi,&ast; Qiang Zhong,&ast; Yuhang Chen, Jian Gao, Xin Pan, Qiang Lian, Rong Chen, Pinkai Wang, Jian Wang, Zhanjun Shi, Hao Cheng Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhanjun Shi; Hao Cheng Tel +86 2062787924Email shizhanjun111@gmail.com; haocool317@gmail.comPurpose: Given that autologous bone graft for bone defects is limited by insufficient supply and morbidity at the donor site, developing biomimetic graft materials as an alternative has gained consistent attention. However, obstacles in designing bone-mimetic materials that could integrate the biomimetic nature of the bone extracellular matrix, osteogenic cells, and osteoinductive ingredients with a fast and convenient strategy still exist.Methods: This study designed and fabricated a mesenchymal stem cell (MSC)-laden, nanohydroxyapatite (HAP), and nanosilicate (SN)-loaded bone mimetic and injectable gelatin-methacryloyl hydrogel (GelMA-HAP-SN) system for bone tissue engineering, and systemically investigated the osteogenic capacity of GelMA-HAP-SN in vitro and in vivo.Results: Introducing HAP enhanced the compositional similarity to the natural bone extracellular matrix, and SN loading endowed the hydrogel with injectable and osteogenic ability. As a result, the GelMA-HAP-SN hydrogel demonstrated an increase in cellular viability, proliferation, and spreading behavior. The GelMA-HAP-SN hydrogel also amplified the embedded MSCs’ osteogenic biomarkers’ expression and matrix mineralization. Furthermore, the MSC-encapsulated GelMA-HAP-SN hydrogel was injected into rats’ critical-sized calvaria defect, and micro-CT and histomorphometry staining results further confirmed its excellent bone regeneration ability.Conclusion: These MSC-loaded GelMA-HAP-SN hydrogels are potential graft materials for bone defect treatment.Keywords: GelMA, injectable, biomimetic, nanohydroxyapatite, nanosilicate, bone regeneration

Ye Hu, Jiyue Gao, Meiling Wang, Man Li Department of Oncology & Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of ChinaCorrespondence: Man LiDepartment of Oncology & Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, People’s Republic of ChinaTel +86-411-84671291Fax +86-411-84671230Email man_li@dmu.edu.cnAbstract: Triple-negative breast cancer (TNBC) is an aggressive, difficult-to-treat subtype of cancer with a poor prognosis; there is an urgent need for effective, targeted molecular therapies. The cyclin D/cyclin-dependent kinase (CDK)4/6–retinoblastoma protein (Rb) pathway plays a critical role in regulating cell cycle checkpoints, a process which is often disrupted in cancer cells. Selective CDK4/6 inhibitors can prevent retinoblastoma protein phosphorylation by invoking cell cycle arrest in the first growth phase (G1), and may therefore represent an effective treatment option. In this article, we review the molecular mechanisms and therapeutic efficacy of CDK4/6 inhibitors in combination with other targeted therapies for the treatment of triple-negative breast cancer. Three selective CDK4/6 inhibitors have so far received the approval of the Food and Drug Administration (FDA) for patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2) breast cancer. Trilaciclib, a small molecule short-acting inhibitor of CDK4/6, has also been approved recently for people with small cell lung cancer, and is also expected to be clinically effective against breast cancer. Although the efficacy of CDK4/6 inhibitors in patients with triple-negative breast cancer remains uncertain, their use in conjunction with other targeted therapies may improve outcomes and is therefore currently being explored. Identifying biomarkers for response or resistance to CDK4/6 inhibitor treatment may optimize the personalization of treatment strategies for this disease. Ongoing and future clinical trials and biomarker studies will shed further light on these topics, and help to realize the full potential of CDK4/6 inhibitor treatment in triple-negative breast cancer.Keywords: triple-negative breast cancer, palbociclib, biomarkers, combination therapy

Jinghai Gao,* Jianhong Dang,* Jing Chu,* Xiaojun Liu, Jing Wang, Jiahao You, Zhijun Jin Department of Obstetrics and Gynecology, Shanghai ChangZheng Hospital, Naval Medical University, Shanghai, 200003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaojun LiuDepartment of Obstetrics and Gynecology, Shanghai ChangZheng Hospital, Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai, 200003, People’s Republic of ChinaTel +8621-81885873Email liuxiaojun@smmu.edu.cnPurpose: To compare perioperative outcomes between robotic single-site surgical technique and conventional laparoendoscopic single-site surgical technique.Methods: This was a retrospective cohort study involving 67 patients who received robotic single-site surgery or laparoendoscopic single-site surgery for the treatment of stage IB1 cervical squamous carcinoma. The robotic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 32 patients while the laparoendoscopic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 35 patients.Results: The enrolled patients had been diagnosed with stage IB1 cervical squamous carcinoma. The perioperative outcomes were mean age (51.63± 8.32 years in the lymph node dissection (RSS group) and 53.14± 8.14 years in the lymph node dissection (LESS group), p=0.453); BMIs (23.76± 2.72 in the RSS group and 23.46± 2.28 in the LESS group, p=0.629); shorter operative times (223.56± 15.43 min in the RSS group and 248.61± 20.89 min in the LESS group, p< 0.01) and less estimated blood loss (217.25± 16.77 mL in the RSS group and 294.74± 24.00 mL in the LESS group, p< 0.01). None of the study participants exhibited postoperative pain. There were no statistically significant differences in the length of hospital stay (p=0.865), perioperative complications (p=0.602), duration of closure and removal of catheter (p=0.518) as well as in pathological diagnoses between the two groups.Conclusion: Robotic single-site surgery can be used in the treatment of early stage cervical cancer as it exhibits acceptable operative times and perioperative outcomes. This surgical technique is feasible and safe.Keywords: cervical squamous cancer, robotic single-site surgery, laparoendoscopic single-site surgery

Min Xu,1,2,* Chong Yao,3,* Wei Zhang,1 Shen Gao,1 Hao Zou,1 Jing Gao1,4 1School of Pharmacy, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Pharmacy, Changzheng Hospital, Shanghai, 200003, People’s Republic of China; 3Clinical Pharmacy Center, Department of Pharmacy, Chinese PLA General Hospital, Beijing, 100850, People’s Republic of China; 4State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Gao; Hao ZouSchool of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Yangpu District, Shanghai, People’s Republic of ChinaTel +86-10-6687-4665Email gjsmmu@126.com; haozou@smmu.edu.cnPurpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research.Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo.Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.Keywords: poly(2-oxazoline)s, micelle, docetaxel, high loading, anti-cancer activity

Hua Yang,1,* Jian Gao,2,* Shuyu Li,1 Huiling Xia,1 Zhangyan Chen,1 Shanzhu Zhu,1 Zhigang Pan1 1Department of General Practice, Zhongshan Hospital of Fudan University, Shanghai, 200030, People’s Republic of China; 2Department of Nutrition, Zhongshan Hospital of Fudan University, Center of Clinical Epidemiology and Evidence-Based Medicine, Fudan University, Shanghai, 200030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shanzhu Zhu; Zhigang PanDepartment of General Practice, Zhongshan Hospital of Fudan University, No. 180, Road Fenglin, Shanghai, 200030, People’s Republic of ChinaTel +86 13501770447; +86 13681971967Email shanzhu_zhu@163.com; zhigang_pan@163.comBackground and Objectives: Serum uric acid (sUA) level has been reported to be associated with arteriosclerotic cardiovascular risk, yet remains poorly defined in Chinese type 2 diabetes patients. The purpose of the current study was to evaluate gender differences in the association between sUA level and arteriosclerotic cardiovascular risk in Chinese type 2 diabetes patients.Methods: The cross-sectional study was conducted in six community health service centers in Shanghai, China from December 2014 to December 2016. A stratified random sampling method was used to recruit participants. From a total of 3977 type 2 diabetic patients, 2537 were included for the analysis of the association between sUA level and arteriosclerotic cardiovascular risk. Clinical and biochemical data were obtained from participants. Arteriosclerotic cardiovascular risk was evaluated by the ten-year risk profile for arteriosclerotic cardiovascular disease. The associations between sUA level and arteriosclerotic cardiovascular risk were assessed via multiple logistic regression.Results: Of the 2537 participants, the average sUA level was 317± 77umol/L in men and 294± 73 umol/L in women, and 54.8% (1391/2537) of participants had high ten-year risk of arteriosclerotic cardiovascular disease (ASCVD), which was ≥ 20%. High ten-year risk of ASCVD odds ratio was increased by 1.596 (95% CI, 1.113– 2.289, p for trend 0.004) comparing fourth to first quartiles of sUA in women. However, no significant association was found between sUA and high ten-year risk of ASCVD in men.Conclusion: This community-based study indicated that sUA levels were independently associated with high ten-year risk of ASCVD in women with type 2 diabetes mellitus, but not in men.Keywords: serum uric acid, ten-year risk, arteriosclerotic cardiovascular disease, type 2 diabetes mellitus

Wencui Wan,1,* Zhen Wu,2,* Jia Lu,2,* Weiwei Wan,1 Jing Gao,3 Hongxia Su,4 Wei Zhu5 1Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Ear, Nose, and Throat, Changshu No. 2 People’s Hospital, Changshu, People’s Republic of China; 3Department of Ophthalmology, First Hospital Affiliated to Soochow University, Suzhou, Jiangsu Province, People’s Republic of China; 4Department of Rhinology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 5Department of Ophthalmology, Changshu No. 2 People’s Hospital, Changshu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongxia SuDepartment of Rhinology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaTel +86-137726129234Email hxs_ent@163.comWei ZhuDepartment of Ophthalmology, Changshu No. 2 People’s Hospital, No. 99, Xiannan Street, Changshu, Jiangsu, 215000, People’s Republic of ChinaTel +86-13776212565Email shzhuwei0722@163.comBackground: Retinal vein occlusion (RVO) was a vision-threatening retinal vascular disorder, however, the relationship between obstructive sleep apnea (OSA) and RVO risk remained unclear.Methods: A total of 45 RVO cases and 45 controls between April 2018 and April 2020 were included. All the participants underwent full-night polysomnography (PSG) and thus detected the severity of OSA. Besides, the relationship between the apnea–hypopnea index (AHI) and oxidative and inflammatory biomarkers, including 8-hydroxy-2 deoxyguanosine (8-OHdG), C-reactive protein (CRP), interleukin 1 beta (IL1β), interleukin 6 (IL6) and tumor necrosis factor alpha (TNFα) were detected. The incidences of macular edema (ME) and neovascular glaucoma (NVG) were detected in a three-months follow-up.Results: In this case–control study, it was found that OSA incidence was increased in the RVO cases comparing with the cataract controls. Advanced analyses about the RVO subtypes demonstrated that incidence of OSA was higher in the central RVO (CRVO) cases comparing with branch RVO (BRVO) cases. Plasma samples from OSA cases demonstrated relatively higher concentrations of oxidative stress parameters and inflammatory biomarkers, including 8-OHdG, CRP, IL1β, and IL6, in the RVO cases. Significant linear correlations between AHI and oxidative/inflammatory biomarkers were detected, and advanced analyses on the OSA subtypes demonstrated that these biomarkers were significantly higher in cases with later stages of OSA. In a three months follow-up, an impaired visual activity improvement rate and increased ME incidence in the OSA group among all the RVO cases were detected.Conclusion: OSA was related with an increased incidence of RVO. Besides, OSA would lead to increased oxidative and inflammatory biomarkers concentrations in the RVO cases. OSA could be used as a harmful prognostic factor of visual activity improvement and ME incidences. These findings highlighted the role of OSA in the development of RVO.Keywords: obstructive sleep apnea, retinal vein occlusion, risk factor, prognosis, oxidative stress

Wen-Cai Li,1,* Zhen Wang,2,* Jie Gao,2 Han Zhou,2 Jing Li,2 Xi-Xu Zhu3 1Department of Radiation Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Medical Radiation Oncology, Jinling Hospital, Nanjing, Jiangsu, 210002, People’s Republic of China; 3Department of Medical Radiation Oncology, Jinling Hospital, First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu, 210002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi-Xu ZhuDepartment of Medical Radiation Oncology, Jinling Hospital, First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu, 210002, People’s Republic of ChinaTel/Fax +86-025-80860078Email zhuxixu@hotmail.comPurpose: The study aimed to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) using CyberKnife (CK) in patients with postoperative thoracic oligo-recurrence/metastasis of non-small-cell lung cancer (NLCLC), and to analyze the prognostic factors affecting overall survival after SBRT.Patients and Methods: A total of 44 patients with postoperative thoracic oligo-recurrence/metastatic of NLCLC treated with SBRT were reviewed. Thoracic oligo-recurrence/was defined as 1– 3 loco-regional confined to lung lobe, hilar/mediastinal lymph nodes, bronchial stump, or chest wall. Primary endpoints included local control (LC), overall survival (OS), progression-free survival (PFS) and toxicity. Prognostic factors that affected these patients were analyzed by the univariate and multivariate analysis by Kaplan–Meier methods and Cox regression models, respectively.Results: The median follow-up time after salvage SBRT was 48.5 months. Measuring from the date of salvage SBRT, the median OS of the 44 patients was 52.60 (95% CI: 29.59– 75.60) months. 1-,3-and 5-year OS rates were 97.7%, 65.3% and 47.7%, respectively. The 1-,3-year and 5-year LC rates were 97.7%, 85.1% and 80.1%, respectively. At 1, 3 and 5 years, the PFS rates were 77.1%, 28.8% and 5.3%, respectively. Multivariate analysis demonstrated that pre-SBRT neutrophil-to-lymphocyte ratio (NLR) and Charlson comorbidity index (CCI) were independent prognostic factors (p < 0.05). The treatment-related side-effects were well tolerated. No patients developed grade 3 or greater pulmonary toxicity.Conclusion: SBRT is a promising salvage therapeutic option for postoperative thoracic oligo-recurrence/metastasis of non-small-cell lung cancer with acceptable toxicity. Low pre-SBRT neutrophil-to-lymphocyte ratio (NLR) and low Charlson comorbidity index (CCI) were associated with a better prognosis and longer survival and might be considered as reliable and independent prognostic factors in these patients treated with SBRT.Keywords: oligo-recurrence, NSCLC, post-surgical recurrence, CyberKnife

Jie Gao,1,* Ying Zhao,1,* Mingyang Du,2,* Hongquan Guo,3 Ting Wan,1 Min Wu,3 Ling Liu,1 Huaiming Wang,1,4 Qin Yin,1 Xinfeng Liu1 1Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Cerebrovascular Disease Treatment Center, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 3Department of Neurology, Jinling Hospital, Southern Medical University, Nanjing, 210000, People’s Republic of China; 4Department of Neurology, The 80th Group Army Hospital, Weifang, Shandong, 261000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Neurology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, People’s Republic of ChinaTel +86 2584801861Fax +86 2584805169Email wanghm89@163.comQin YinDepartment of Neurology, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, People’s Republic of ChinaTel +86 2584801861Fax +86 2584805169Email yinqin9912@163.comBackground and Aims: Albumin levels have been reported to be associated with all-cause and cardiovascular mortality. The aim of this study was to investigate the association between serum albumin and prognosis of ischemic stroke patients after endovascular thrombectomy (EVT) treatment.Methods: Patients with EVT due to large artery occlusion in anterior circulation were selected from ACTUAL (endovascular treatment for acute anterior circulation) ischemic stroke multicenter registry in China. Serum albumin levels were measured within 24 h of admission. The primary outcome was poor functional outcome (modified Rankin scale score of 3– 6) at three months. Secondary outcomes were symptomatic intracranial hemorrhage (sICH) and three-month mortality.Results: A total of 605 patients (mean age, 64.2 years; 59.3% male) were enrolled. Up to three months after stroke, 342 patients (56.5%) developed poor functional outcome. After multivariate adjustment for demographic characteristics, National Institutes of Health stroke score, and other potential confounders, the odds ratio for the lowest tertile of serum albumin levels was 2.43 (95%CI, 1.18− 5.01; P=0.046) for poor functional outcome, compared with the highest category. Restricted cubic spline regression demonstrated a linear association between albumin levels and poor functional outcome (P for linearity=0.017). Subgroup analyses further confirmed these results. Similar significant findings were also found in the association of serum albumin with mortality, but not with sICH.Conclusion: Decreased serum albumin levels were independently associated with poor prognosis at 90 days after acute large vessel occlusion stroke in anterior circulation treated with EVT.Keywords: albumin, ischemic stroke, endovascular treatment, prognosis

Yake Zhang,1,2,* Fangyuan Xie,3,* You Yin,4,* Qin Zhang,1,* Hong Jin,5 Yan Wu,6 Liying Pang,7 Jun Li,2 Jie Gao1,2 1Institute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China; 2Laboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of China; 3Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China; 4Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 5Department of Laboratory Medicine, Hongqi Hospital of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 6Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 7The First Clinical Medical College of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie GaoInstitute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email gaojiehighclea@163.comJun LiLaboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email lijun1982@lcu.edu.cnPurpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity.Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo.Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth.Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.Keywords: RNA lipid nanoparticles, tumor vaccine, dendritic cells, cancer immunotherapy

Jian He,1,2,* Liping Yang,1,2,* Zhenchao Tao,1,2 Jing Yang,1,2 Yan Zhou,1,2 Ru Wang,1,2 Yangyang Zhang,1,2 Yifan Huang,1,2 Lingran Zhou,1,2 Bin Sun,1,2 Jin Gao1,2 1Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province 230031, People’s Republic of China; 2Department of Radiation Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui Province 230031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin GaoDepartment of Radiation Oncology, Anhui Provincial Cancer Hospital, No. 107 Huan Hu East Road, Hefei 230031, Anhui Province, People’s Republic of ChinaTel +86 15395005376Email gaojinUSTC@126.comIntroduction: The present study investigated hospitalization data of patients receiving radiotherapy at Anhui Cancer Hospital during the COVID-19 epidemic and analyzed the impact of the epidemic on the clinical data of radiotherapy patients to provide references for the feasibility and safety of radiotherapy at other medical institutions.Methods: The present study performed a retrospective analysis of hospitalization data of patients undergoing radiotherapy at the Radiation Department (from January 5 to March 19, 2020 according to the Chinese lunar calendar), who were defined as the epidemic group. Hospitalization data for patients undergoing radiotherapy during the same period in 2019 were used as the control group for comparison with the epidemic group in terms of sex, age, distribution of various cancer types, hospitalization costs, average length of stay, completion rate of radiotherapy, treatment mode, and purpose of radiotherapy.Results: A total of 79 and 115 patients received radiotherapy in the epidemic group and control group, respectively. The number of patients who received radiotherapy declined 31.3% during the epidemic period. The number of head and neck cancer patients who received radiotherapy was 36 (45.57%) in the epidemic group and 32 (27.83%) in the control group, which was a significant difference (χ2=6.476, P=0.011). The proportions of patients with other types of cancer decreased, with no significant difference between the two groups (P> 0.05). No significant differences between the two groups were found in terms of other hospitalization data (P> 0.05).Conclusion: The total number of patients who received radiotherapy decreased during the epidemic period, but the proportion of head and neck cancer increased. The epidemic had no significant effect on other hospitalization data. While strengthening prevention and control measures, we should actively perform radiotherapy to ensure that cancer patients receive timely and safe treatment.Keywords: COVID-19, radiation therapy, malignant cancer

Ziqi Jin,1,* Qiong Wu,1,* Shuohua Chen,2,* Jingli Gao,3 Xiaolan Li,3 Xuhui Zhang,4 Yaohan Zhou,1 Di He,1 Zongxue Cheng,1 Yimin Zhu,1,5,6 Shouling Wu7 1Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou 310058, Zhejiang, People’s Republic of China; 2Health Care Center, Kailuan Group, Tangshan 063000, People’s Republic of China; 3Department of Intensive Medicine, Kailuan General Hospital, Tangshan 063000, People’s Republic of China; 4Hangzhou Center for Disease Control and Prevention, Hangzhou 310051, Zhejiang, People’s Republic of China; 5Department of Respiratory Diseases, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310060, People’s Republic of China; 6Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, People’s Republic of China; 7Department of Cardiology, Kailuan General Hospital, Tangshan, 063000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shouling WuDepartment of Cardiology, Kailuan General Hospital, 57 Xinhua East Road, Tangshan, People’s Republic of ChinaEmail drwusl@163.comYimin ZhuDepartment of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou, 310058 Zhejiang, People’s Republic of ChinaTel + 0086-571-88208194Email zhuym@zju.edu.cnBackground: SII and SIRI are two novel systemic inflammation indexes that were suggested in predicting poor outcomes in cancers. However, no studies have examined their effect on cardiovascular diseases (CVDs) and all-cause mortality. Thus, this study aims to investigate associations between SII, SIRI, and the risks for CVDs and all-cause mortality.Methods: A total of 85,154 participants from the Kailuan cohort were included and followed up for incidents of CVDs (including MI, stroke) and all-cause death for 10 years. Multiple Cox regression was used to calculate the adjusted hazard ratios (HRs).Results: During the follow-up period, 4262 stroke events, 1233 MI events, and 7225 all-cause deaths were identified, respectively. Compared with the lowest quantile (Q1) of SII or SIRI, after adjusted for most cardiovascular risk factors, both indexes showed positive associations with the risk for stroke (adjusted HRs in Q4 were 1.264 (95% CI: 1.157,1.382) for SII, 1.194 (95% CI: 1.087,1.313) for SIRI), and all-cause death (adjusted HRs in Q4 were 1.246 (95% CI: 1.165,1.331) for SII, 1.393 (95% CI: 1.296,1.498) for SIRI). Additionally, higher SII and SIRI are also associated with increased risk of hemorrhagic stroke and ischemic stroke. Higher SIRI but not SII exhibited a higher MI risk, the adjusted HR in Q4 was 1.204 (1.013,1.431). The significant association remained after additional adjustment for CRP. Subgroup analysis and sensitivity analysis displayed consistent results except for SIRI with MI, where the association did not arrive at significance in subjects aged ≥ 60.Conclusion: Elevated SII and SIRI increased the risk of stroke, two stroke subtypes, and all-cause death. Higher SIRI, but not SII associated with increased MI incidence, and the association of SIRI was only significant in subjects aged < 60.Keywords: systemic inflammation, prospective study, risk factors, cardiovascular events, mortality

Jie Gao,* Hai Gui Wu,* Feng Wu Department of Pulmonary and Critical Care Medicine, Huizhou the Third People’s Hospital, Guangzhou Medical College, Huizhou 516002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng WuHuizhou the Third People’s Hospital, 1# Xuebei Ave., Huizhou 516002 Guangdong, People’s Republic of ChinaTel +86-13502436132Fax +86-7522359648Email huizhouwufeng@126.comBackground: Cough variant asthma (CVA) is one kind of atypical asthma. The study was to compare spirometric parameters of small airways and the degree of bronchial hyper-responsiveness (BHR) between CVA and classic asthma (CA), and examine the relationship between BHR and small airways to determine the accuracy of these markers as indicators of CVA.Methods: A total of 825 asthmatic patients were screened for the study, and 614 were included. All patients performed spirometry and underwent a bronchial challenge with methacholine.Results: The number of small airways dysfunctions in the CVA group was less than those of the CA group with MMEF% predicted (70% vs 80.91%, P=0.002) and FEF50% predicted (62.71% vs 73.5%, P=0.004). The degree of small airways dysfunction was less in the CVA group compared with the CA group (P< 0.001). Significant positive correlations were observed between the FEV1 level below 20% of the baseline value (PD20) and MMEF% predicted (r=0.282, P< 0.001), FEF50% predicted (r=0.2522, P< 0.001), and FEF75% predicted (r=0.2504, P< 0.001) in patients with CVA. The area under curve (AUC) of MMEF, FEF50, and FEF75 (% predicted) was 0.615, 0.621, and 0.606, respectively. In addition, 0.17 mcg of PD20 was the best diagnostic value for CVA, with an AUC of 0.582 (P=0.001).Conclusion: Small airway dysfunction is milder in CVA. The value of BHR combined with small airways in CVA prediction, which was significant, but not enough to be clinically useful.Keywords: small airways, bronchial hyper-responsiveness, cough-variant asthma, classic asthma