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Guojun Shen,1,* Xueying Li,2,3,* Anqi Zheng,2 Mingxing Gong,4 Zhanhui Wang,2 Baolin Liao5 1Hepatology Unit, the Third People′s Hospital of Jiujiang City, Jiujiang, People’s Republic of China; 2Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Gastroenterology, Shenzhen Qianhai Taikang Hospital, Shenzhen, People’s Republic of China; 4Department of Infectious Diseases, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 5Department of Hepatology, Guangzhou Medical Research Institute of Infectious Diseases, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baolin Liao, Department of Hepatology, Guangzhou Medical Research Institute of Infectious Diseases, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, No. 8 Huaying Road, Guangzhou, 510440, People’s Republic of China, Email polinlbl@163.com Zhanhui Wang, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Blvd, Guangzhou, 510515, People’s Republic of China, Email wangzhh@smu.edu.cnBackground: Nucleos(t)ide analogues (NAs) as the first-line treatment for chronic hepatitis B (CHB) have been shown to partially restore the antiviral immunity of the patients. However, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) patients have a relatively longer duration of HBV infection and lower level of HBV DNA. Whether NAs treatments have a different effect on their immune repertoires between CHB and HCC patients remains to be determined.Patients and Methods: In this study, 126 CHB patients and 85 HBV-related HCC patients who received or did not receive NAs treatment, as well as 361 healthy individuals were enrolled to analyze the effect of NAs treatment on T cell receptor β chain (TCRβ) and B cell receptor heavy chain (BCRh) repertoires in peripheral blood of the patients.Results: We found that after NAs therapy, the richness and evenness of TCRβ and BCRh repertoires in CHB patients were significantly lower than those in untreated patients and healthy controls, while the diversity of TCRβ and BCRh repertoires was stable in HCC patients. The alanine aminotransferase and HBV DNA levels were not correlated with the TCR or BCR diversity in CHB and HCC patients.Conclusion: The results suggest that NAs therapy could influence the overall T cell and B cell repertoires diversity in CHB patients but has minimal impact on HCC patients, indicating a significant difference in the potential to restore antiviral immunity between CHB and HCC patients by NAs treatment.Keywords: chronic hepatitis B, Nucleos(t)ide analogue, T cell receptor, immune repertoire, hepatocellular carcinoma

Mingjun Gong,1 Min Sun,1 Yaqi Sun,2 Lijuan Jin,1 Shen Li3 1Sports Training College, Tianjin University of Sport, Tianjin, People’s Republic of China; 2Mental Health Institute, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Psychoneuromodulation Center, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Shen Li, Psychoneuromodulation Center, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, No. 13, Liulin Road, Hexi District, Tianjin, 300222, People’s Republic of China, Tel +86-22-88188875, Email lishen@tmu.edu.cnObjective: Using meta-analysis to comprehensively and quantitatively evaluate the impact of acute sleep deprivation on different sports performance of athletes, this study aims to provide scientific guidance for coaches in optimizing and adjusting training and competition arrangements.Methods: Establishing literature inclusion and exclusion criteria, we conducted searches in both Chinese and English databases. Using stata 14.0, we analyzed 75 indicators from 27 included literature, focusing on three aspects: the impact of acute sleep deprivation on overall athletic performance, the impact on sporting performance across various athletic abilities, and the disparities in athletic performance between morning and afternoon following acute sleep deprivation.Results: The effect size of acute sleep deprivation on overall athletic performance was − 0.56 (P< 0.05). Sub-analyses revealed effect sizes of − 0.23 (P< 0.05) for whole night sleep deprivation, − 1.17 (P< 0.05) for partial sleep deprivation at the end of the night, and − 0.25 (P> 0.05) for partial sleep deprivation in the beginning of the night. The effect sizes of acute sleep deprivation on high intensity intermittent exercise, skill control, speed, aerobic endurance, and explosive power indicators were − 1.57, − 1.06, − 0.67, − 0.54, and − 0.39 respectively (P< 0.05). The effect sizes of acute sleep deprivation on the overall athletic performance in the morning and afternoon were − 0.30, and − 1.11, respectively (P< 0.05).Conclusion: Acute sleep deprivation significantly impairs the overall athletic performance of athletes, with a more pronounced negative impact observed with partial sleep deprivation at the end of the night. Various types of exercise performance are adversely affected by acute sleep deprivation, with magnitude of impact ranking high intensity intermittent, skill control, speed, aerobic endurance, and explosive power. Following acute sleep deprivation, athletes’ overall sporting performance in the afternoon is inferior to that in the morning.Keywords: acute sleep deprivation, athletes, athletic ability, sporting performance, meta-analysis

Chenglin Xu,1,&ast; Song Wen,1,2,&ast; Min Gong,1,&ast; Meiyuan Dong,1,3,&ast; Yue Yuan,1 Yanyan Li,1 Mingyue Zhou,4 Ligang Zhou1,3,5 1Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China; 2Fudan Zhangjiang Institute, Fudan University, Shanghai, 201203, People’s Republic of China; 3Hebei Medical University, Shijiazhuang, 050013, People’s Republic of China; 4Clinical Research OB/GYN REI Division, University of California, San Francisco, CA, USA; 5Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Shanghai, 201399, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ligang Zhou, Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China, Tel +8613611927616, Email zhouligang1n1@163.comObjective: To investigate the implications of elevated myoglobin (MYO) in acute diabetic conditions of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).Materials and methods: This study integrates in-patient data from Shanghai Pudong Hospital from 2019 to 2023. Laboratory data were compared between stable T2D patients (without acute diabetic complications), DKA, and HHS patients. The multilinear regression explored variables relevant to the elevated MYO in DKA and HHS. The dynamics of MYO, the survival rate, and associated risk factors in HHS were determined.Results: Except for triglyceride, procalcitonin, low-density lipoprotein, islet cell autoimmune antibodies, N-terminal Pro-brain natriuretic peptide (NT-ProBNP), and brain natriuretic peptide (BNP), there were significant differences in age, gender distribution, duration of diabetes, type of diabetes, and other referred laboratory data (p< 0.05). The age, gender, creatine kinase (CK), estimated glomerular filtration rate (eGFR), and free triiodothyronine (FT3) in DKA, whereas osmolar, uric acid (UA), and cardiac troponin I (cTNI) in the HHS, were significant determinants of elevated MYO, respectively (p< 0.05). The dynamic of MYO in HHS was in line with the survival trend, where the percentage of death was 29.73%, and aging with higher procalcitonin levels was a key risk factor. Besides, the cumulative survival rates between patients with or without bone fracture or muscle injury were substantially different.Conclusion: This real-world study demonstrated DKA and HHS potentially have unique causes for increased MYO. By utilizing the appropriate regression parameters, we could forecast the progression of increased MYO in groups of DKA and HHS, while based on risk factors of aging, severity of infection, and different MYO sources, we could predict the prognosis of HHS.Keywords: diabetes mellitus, diabetic ketoacidosis, hyperosmolar hyperglycemic state, myoglobin, survival

Dawei Ren,1 Yan Zhang,1 Bo Du,1 Lina Wang,2 Meiheng Gong,1 Wei Zhu1 1Department of Otorhinolaryngology, the First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Pediatric Respiration, the First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Wei Zhu, Email zhuwei@jlu.edu.cnBackground: Electrical stimulation (ES) can effectively promote skin wound healing; however, single-electrode-based ES strategies are difficult to cover the entire wound area, and the effectiveness of ES is often limited by the inconsistent mechanical properties of the electrode and wound tissue. The above factors may lead to ES treatment is not ideal.Methods: A multifunctional conductive hydrogel dressing containing methacrylated gelatin (GelMA), Ti3C2 and collagen binding antimicrobial peptides (V-Os) was developed to improve wound management. Ti3C2 was selected as the electrode component due to its excellent electrical conductivity, the modified antimicrobial peptide V-Os could replace traditional antibiotics to suppress bacterial infections, and GelMA hydrogel was used due to its clinical applicability in wound healing.Results: The results showed that this new hydrogel dressing (GelMA@Ti3C2/V-Os) not only has excellent electrical conductivity and biocompatibility but also has a durable and efficient bactericidal effect. The modified antimicrobial peptides V-Os used were able to bind more closely to GelMA hydrogel to exert long-lasting antibacterial effects. The results of cell experiment showed that the GelMA@Ti3C2/V-Os hydrogel dressing could enhance the effect of current stimulation and significantly improve the migration, proliferation and tissue repair related genes expression of fibroblasts. In vitro experiments results showed that under ES, GelMA@Ti3C2/V-Os hydrogel dressing could promote re-epithelialization, enhance angiogenesis, mediate immune response and prevent wound infection.Conclusion: This multifunctional nanocomposite hydrogel could provide new strategies for promoting infectious wound healing. Keywords: MXene, GelMA, electrical stimulation, antimicrobial peptides, wound healing

Tao Sun,1,2 Shilin Xiao,1 Miaomiao Wang,1 Qian Xie,1 Liang Zhang,1 Mingfu Gong,1 Dong Zhang,1 Chunyu Zhou1 1Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, People’s Republic of ChinaCorrespondence: Dong Zhang; Chunyu Zhou, Department of Radiology, Xinqiao Hospital, Army Medical University, No. 183, Xinqiao Street, Shapingba District, Chongqing, People’s Republic of China, Tel +86 23 68763842, Email hszhangd@tmmu.edu.cn; zhouchy@tmmu.edu.cnAbstract: Acute liver injury (AIL), a fatal clinical disease featured with a swift deterioration of hepatocyte functions in the short term, has emerged as a serious public health issues that warrants attention. However, the effectiveness of existing small molecular antioxidants and anti-inflammatory medications in alleviating AIL remains uncertain. The unique inherent structural characteristics of liver confer it a natural propensity for nanoparticle capture, which present an opportunity to exploit in the formulation of nanoscale therapeutic agents, enabling their selective accumulation in the liver and thereby facilitating targeted therapeutic interventions. Significantly increased reactive oxygen species (ROS) accumulation and inflammation response have been evidenced to play crucial roles in occurrence and development of AIL. Nanozymes with ROS-scavenging capacities have demonstrated considerable promise in ROS elimination and inflammation regulation, thereby offering an appealing therapeutic instrument for the management of acute liver injury. In this review, the mechanisms of different type of ALI were summarized. In addition, we provide a comprehensive summary and review of the available ROS-scavenging nanozymes, including transition metal-based nanozymes, noble metal nanozymes, carbon-based nanozymes, and some other nanozymes. Furthermore, the challenges still need to be solved in the field of ROS-scavenging nanozymes for ALI alleviation are also discussed.Keywords: acute liver injury, nanozyme, ROS-scavenging, antioxidant, anti-inflammation

Xiucai Li,1,&ast; Song Wen,1,&ast; Meiyuan Dong,1,2 Yue Yuan,1 Min Gong,1 Congcong Wang,1 Xinlu Yuan,1 Jianlan Jin,1 Mingyue Zhou,3 Ligang Zhou1,2,4 1Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, People’s Republic of China; 2Hebei Medical University, Shijiazhuang, 050013, People’s Republic of China; 3Clinical Research OB/GYN REI Division, University of California, San Francisco, CA, USA; 4Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Shanghai, 201399, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ligang Zhou, Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, People’s Republic of China, Tel +8613611927616, Email zhouligang@yahoo.comBackgrounds and Objective: Diabetic foot is a relatively severe complication in patients with type 2 diabetes (T2D), with peripheral neuropathy and angiopathy frequently serving as risk factors. However, it is unknown how the other major systemic metabolic factors impacted the profile of these patients, besides glucose management. Thus, we investigated the distinct characteristics of patients with diabetic foot ulcers and their relationships with angiopathy.Materials and Methods: We obtained the laboratory data of 334 diabetic patients at Shanghai Pudong Hospital from 2020 to 2023. The comparisons were performed between the groups with or without diabetic foot, including glucose metabolism, lipids profile, liver and kidney function, thyroid function, and serum iron. The association between metabolic factors and lower extremity computed tomography angiography (CTA) was analyzed.Results: We found significant disparities between groups in relation to age, serum protein content, liver transferase, serum creatinine, estimated glomerular filtration rate (eGFR), serum uric acid (UA), small dense low-density lipoprotein (sdLDL), lipoprotein A (LP(a)), apolipoprotein A1 (APOA1), thyroid function, serum iron, and hemoglobin (Hb) (p< 0.05). The Spearman correlational analyses showed that the severity of CTA, categorized by the unilateral or bilateral plaque or occlusion, was positively significantly correlated with UA (r=0.499), triglyceride (TG) (r=0.751), whereas inversely correlated with serum albumin (r=− 0.510), alanine aminotransferase (r=− 0.523), direct bilirubin (DBil) (r=− 0.494), total bilirubin (TBil) (r=− 0.550), Hb (r=− 0.646).Conclusion: This cross-section investigation showed that compared to T2D only, the patients with diabetic foot ulcer (DFU) might display similar glucose metabolic control context but adverse metabolic profiles, and this profile is associated with macrovascular angiopathy characteristics and their severity.Keywords: diabetic foot, macrovascular angiopathy, CTA, thyroid function, serum iron, serum bilirubin

Mingqiang Gong,1,2,&ast; Yunxia Shen,2,&ast; Wenbin Liang,2 Zhen Zhang,3 Chunxue He,4 Mingwu Lou,2 ZiYu Xu2 1Department of Acupuncture and Moxibustion, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Department of Radiology, Longgang Central Hospital, Shenzhen, People’s Republic of China; 3Department of Radiology, The Third People’s Hospital of Longgang District, Shenzhen, People’s Republic of China; 4Department of Radiology, Shenzhen Clinical Medicine College, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingwu Lou; ZiYu Xu, Department of Radiology, Longgang Central Hospital, No. 6082, Longgang Avenue, Longgang District, Shenzhen, 518000, People’s Republic of China, Tel +86 13808854650 ; +86 13824321925, Email mingwulou@sina.com; xuziyu82@163.comPurpose: Methamphetamine use may cause severe neurotoxicity and cognitive impairment, leading to addiction, overdose, and high rates of relapse. However, few studies have systematically focused on functional impairments detected by neuroimaging in methamphetamine abstainers (MAs) during short-term abstinence. This study aimed to investigate effective connectivity, resting-state networks, and internetwork functional connectivity in MA brains to improve clinical treatment.Methods: Twenty MAs and 27 age- and education-matched healthy controls underwent resting-state functional magnetic resonance imaging. The amplitude of low-frequency fluctuations and Granger causality were analyzed to investigate disrupted brain regions and effective connectivity, respectively. Independent component analysis and functional network connectivity were used to identify resting-state networks and internetwork functional connectivity, respectively.Results: Compared with healthy controls, MAs demonstrated abnormal amplitudes of low-frequency fluctuations in the bilateral precuneus, left posterior cingulate cortex (PCC), left middle frontal gyrus (MFG), left superior parietal lobule, left supplementary motor area (SMA), and left inferior parietal lobule (IPL). Moreover, MAs showed decreased effective connectivity from the left PCC to the left precuneus, increased effective connectivity from the left precuneus to the left MFG and from the right precuneus to the left SMA, and altered functional connectivity within the default mode network (DMN), frontoparietal network, sensorimotor network, ventral attention network, cerebellar network, and visual network. Importantly, hyperconnectivity between the DMN and ventral attention network and hypoconnectivity between the DMN and cerebellar network as well as the DMN and frontoparietal network were demonstrated in MAs.Conclusion: Our study implies that in short-term methamphetamine abstinence, disruptions to the DMN and executive network may a play key role, providing new insights for early rehabilitation.Keywords: methamphetamine, abstinence, network, Granger causality analysis, independent component analysis

Yanju He,1,&ast; Song Wen,1,&ast; Mingyue Zhou,2 Xiucai Li,1 Min Gong,1 Ligang Zhou1,3 1Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, People’s Republic of China; 2Helen Driller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; 3Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ligang Zhou, Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, People’s Republic of China, Tel +8613611927616, Email zhouligang@yahoo.comBackground: The mini-clinical evaluation exercise (mini-CEX) is an excellent tool for assessing the clinical abilities of medical students in intense clinical practice. In this study, the Mini-CEX was adapted to professional questionnaires for Diabetes Mellitus (DM), and examined in medical students completing their clerkship rotation in the department of endocrinology.Methods: From January 2021 to January 2022, all rotating medical students at Shanghai Pudong Hospital completed two mini-CEX exams before and following their rotation under the supervision and guidance of six tutors. The mini-CEX form was modified in this study primarily for inpatient management based on our clinical experience and updated DM guidelines of the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the Chinese Diabetes Society (CDS). Each component of the mini-CEX assessment, including medical interviews, physical examination, clinical judgment, clinical management, and overall clinical competence was evaluated using a nine-item questionnaire.Results: Our findings revealed that the second-round performance on the assessments significantly improved, as indicated by higher scores on each component. The Pearson association analysis revealed that the feedback time of the first examination was markedly associated with improved overall scores (r= 0.391, p< 0.001). However, no correlations were discovered between patient age, gender, disease severity disparity, or the interval between examinations (p> 0.05). Additional regression analysis revealed that the feedback time during the initial examination was the most significant contributor to the increased overall scores (β=0.391, p< 0.001).Conclusion: This newly designed mini-CEX form based on current ADA and EASD guidelines may assist trainees in more effectively diagnosing and managing DM in inpatients, particularly those with macrovascular, microvascular, or peripheral nerve neuropathy. This study aims to assess the efficacy of administering a modified mini-CEX form to rotating trainees participating in an endocrine clerkship.Keywords: mini-clinical evaluation exercise, diabetes, medical student, feedback time

Chuanzhen Hao,&ast; Jiachen Luo,&ast; Baoxin Liu,&ast; Wei Xu, Zhiqiang Li, Mengmeng Gong, Xiaoming Qin, Beibei Shi, Yidong Wei Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yidong Wei, Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China, Tel +86-21-66307249, Fax +86-21-66301771, Email ywei@tongji.edu.cnPurpose: The prognostic impact of new-onset atrial fibrillation (NOAF) among different heart failure (HF) subtypes including HF with preserved (HFpEF, ejection fraction [EF] ≥ 50%), mid-range (HFmrEF, EF 40%∼ 49%), and reduced (HFrEF, EF < 40%) EF following acute myocardial infarction (AMI) remains unclear. We aimed to investigate the incidence and prognostic implication of post-MI NOAF across HF subtypes.Patients and Methods: We included 1413 patients with post-MI HF (743 with HFpEF, 342 with HFmrEF and 328 with HFrEF) between February 2014 and March 2018. NOAF was considered as patients without a preexisting AF who developed AF during the AMI hospitalization. The primary endpoint was all-cause mortality.Results: Of 1413 patients (mean age 66.8 ± 12.6 years, 72.9% men) analyzed, 200 (14.2%) developed post-MI NOAF. Patients with HFrEF were more likely to experience NOAF compared to those with HFmrEF or HFrEF (18.9%, 13.7% and 12.2% in HFrEF, HFmrEF and HFpEF, respectively; p for trend = 0.006). During a median follow-up of 28.5 months, 192 patients died (70 with HFrEF, 35 with HFmrEF and 87 with HFpEF) and 195 patients experienced HF rehospitalization (79 with HFrEF, 37 with HFmrEF and 79 with HFpEF). After multivariable adjustment, NOAF was independently associated with all-cause mortality (hazard ratio [HR]: 1.79, 95% confidence interval [CI]: 1.03– 3.12) only in the HFrEF group compared to sinus rhythm (SR), whereas an increased risk of HF rehospitalization was found in all HF subtypes, particularly in HFmrEF (HR: 5.08, 95% CI: 2.29– 11.25) and HFpEF (HR: 2.83 95% CI: 1.64– 4.90).Conclusion: In patients with post-MI HF, NOAF carried a worse prognosis for all-cause death in the HFrEF group and for HF rehospitalization in all HF subtypes.Keywords: heart failure, acute myocardial infarction, atrial fibrillation, left ventricular ejection fraction, mortality

Jin Chen,1,&ast; Min Gong,1,&ast; Zhuo Huang,1 Fang Wang,2 Yajing Wang,3 Zuquan Hu,1 Zhu Zeng,1 Yun Wang2 1Key Laboratory of Biology and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People’s Republic of China; 2Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, People’s Republic of China; 3The Affiliated Stomatological Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, 550025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhu Zeng, Key Laboratory of Biology and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province, School of Biology and Engineering, Guizhou Medical University, Guiyang, 550025, People’s Republic of China, Email zengzhu@gmc.edu.cn Yun Wang, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, People’s Republic of China, Tel/Fax +86851-88174044, Email wangyun@gmc.edu.cnPurpose: Gastric injury is a major issue for long-term administration of aspirin. In this work, we tried to explore the possibility of using BLG to alleviate aspirin-induced gastric injury, because of excellent abilities of BLG in loading drug molecules.Methods: Various spectroscopic techniques and molecular docking methods were applied to investigate the interaction mechanism between BLG and aspirin. Animal experiments were performed to figure out the effects of taking aspirin-BLG on the stomach.Results: Our results demonstrate that aspirin could bind with BLG to form stable aspirin-BLG complex (the binding constant Kb= 2.051 × 103 M− 1). The formation process is endothermic (∆H> 0) and the main acting force is hydrophobic force. Our data also show that the aspirin-BLG complex is formed with a higher affinity in simulated gastric fluid and could remain stable for several hours, which might arise from its special binding mode under acidic condition and the resistance of BLG to gastric digestion. Furthermore, animal models (rats with aspirin-induced gastric damage) were built. The results of animal experiments reveal that the oral administration of aspirin-BLG could cause less damage to gastric tissue, and it also hardly triggers obvious inflammatory responses.Conclusion: This study would contribute to an in-depth understanding of the interaction mechanism between BLG and aspirin. It is reasonable to believe that using BLG to bind with aspirin would be a potential way to alleviate the aspirin-induced gastric injury.Graphical Abstract: Keywords: beta-lactoglobulin, aspirin, gastric injury, static quenching, molecular docking

Bian Hu,1,2 Jingyu Zhang,3 Mengdan Gong,1 Yongqin Deng,1 Yujie Cao,1 Yizhen Xiang,1 Dong Ye1 1Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, People’s Republic of China; 2Department of Otorhinolaryngology-Head and Neck Surgery, Ninghai First Hospital, Ningbo, 315699, Zhejiang, People’s Republic of China; 3Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of ChinaCorrespondence: Dong Ye, Department of Otorhinolaryngology-Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, 315040, Zhejiang, People’s Republic of China, Tel +86 13819861213, Fax +86 574-87392232, Email yedong518@sina.comAbstract: The olfactory nerve (ON) is the only cranial nerve exposed to the external environment. Hence, it is susceptible to damage from head trauma, viral infection, inflammatory stimulation, and chemical toxins, which can lead to olfactory dysfunction. However, compared with all other cranial nerves, the ON is unique due to its inherent ability to regenerate. This characteristic provides a theoretical basis for treatment of olfactory dysfunction. Olfactory training (OT) is one of the main treatments for olfactory dysfunction. It is easy to apply and has few side-effects, and has been shown to be efficacious for patients with olfactory dysfunction of various causes. To further understand the application value of ON regeneration and OT on olfactory dysfunction, we review the research progress on the mechanism of ON regeneration and OT.Keywords: olfaction, regeneration, olfactory training, olfactory dysfunction

Chenglin Xu,1,&ast; Min Gong,1,&ast; Song Wen,1,&ast; Mingyue Zhou,2 Yanyan Li,1 Ligang Zhou1,3 1Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China; 2Clinical Research OB/GYN REI Division, University of California, San Francisco, CA, USA; 3Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ligang Zhou, Tel +8613611927616, Email zhouligang@yahoo.comPurpose: This study aims to identify changes in bone turnover markers and thyroid function in diabetic ketosis (DK) and diabetic ketoacidosis (DKA).Materials and Methods: We compared data from the Department of Endocrinology at Shanghai Pudong Hospital from 2018 to 2020 on the pancreatic status and previous glucose control, bone transformation, calcium homeostasis, and thyroid function in groups with diabetes (DM alone, n=602), DK (n=232), and DKA (n=60). Similar comparisons were made in recurrent DK (A) (n=17) and single DK (A) (n=272).Results: The fasting C-peptide level decreased significantly, but hemoglobin A1c (HbA1c) levels were higher in DK or DKA (p< 0.05). Blood calcium and 25-hydroxyvitamin D3 (25-OH-VitD3) levels were significantly lower in DKA (p< 0.05), but parathyroid hormone (PTH) levels remained constant across all three groups. The N-terminal middle molecular fragment of osteocalcin (N-MID) and β-C terminal cross-linking telopeptide of type 1 collagen (β-CTX) showed significant inverse alterations in DKA, regardless of gender or age (p< 0.05). Otherwise, DKA significantly inhibited thyroid function (p< 0.05). Furthermore, Spearman correlation analyses revealed a relationship between N-MID and HbA1c in DM alone (r=− 0.27, p< 0.01), while total triiodothyronine (TT3, r=0.62, p< 0.01) or free T3 (FT3, r=0.61, p< 0.01) in DK, and DKA (TT3, r=0.45, p< 0.01; FT3, r=0.43, p< 0.01). Multilinear regression analyses revealed that β-CTX (β=0.564), HbA1c (β=− 0.196), TT3 (β=0.183), and 25-OH-VitD3 (β=− 0.120) were the only independent determinants of N-MID in DM, whereas FT3 (β=0.491), β-CTX (β=0.315) in DK, and FT3 (β=0.420), β-CTX (β=0.367), TG (β=− 0.278) in DKA. Only 25-OH-VitD3 was found to be significantly lower in recurrent DK (A) than in single onset DK (A) (p< 0.05), and β-CTX (β=0.745) was found to be significantly independently associated with N-MID.Conclusion: Our preliminary findings show a dramatic change in bone turnover markers in DM patients with DK and DKA, and this change may be related to thyroid function.Keywords: bone turnover marker, diabetes mellitus, thyroid function, DKA

Chunxue He,1,2,&ast; Mingqiang Gong,3,4,&ast; Gengxiao Li,1,2 Yunxia Shen,2 Longyin Han,5 Bin Han,6 Mingwu Lou2 1Shenzhen Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Department of Radiology, Longgang District Central Hospital of Shenzhen, Shenzhen, People’s Republic of China; 3The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 4Department of Acupuncture, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China; 5Department of Neurology, Beijing Longfu Hospital, Beijing, People’s Republic of China; 6Department of Rehabilitation Medicine, Longgang District Central Hospital of Shenzhen, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Han; Mingwu Lou, Tel +86 13928488998 ; +86 13808854650, Email hhbb08@163.com; mingwulou@sina.comPurpose: To investigate white matter alterations in post-stroke cognitive impairment (PSCI) patients at the subacute stage employing diffusion kurtosis and tensor imaging.Methods: Thirty PSCI patients at the subacute phase and 30 healthy controls (HC) underwent diffusion kurtosis imaging (DKI) scans and neuropsychological assessments. Based on the tract-based spatial statistics and atlas-based ROI analysis, fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), kurtosis fractional anisotropy (KFA), axial kurtosis (AK), and radial kurtosis (RK) were compared in specific white matter fiber bundles between the groups (with family-wise error correction). Adjusting for age and gender, a partial correlation was conducted between neurocognitive assessments and DKI metrics in the PSCI group.Results: In comparison with the HC, PSCI patients significantly showed decreased MK, RK, and FA and increased MD values in the genu of corpus callosum, anterior limb internal capsule, and left superior corona radiata. In addition, DKI detected more white matter region changes in MK (31/48), KFA (40/48), and RK (25/48) than DTI with FA (28/48) and MD (21/48), which primarily consisted of the right cingulum, right superior longitudinal fasciculus, and left posterior limb of internal capsule. In the left anterior limb of internal capsule, MK and RK values were significantly negatively correlated with TMT-B (r = − 0.435 and − 0.414, P < 0.05), and KFA values (r = − 0.385, P < 0.05) of corpus callosum negatively associated with TMT-B.Conclusion: Combing DTI, DKI, and neuropsychological tests, we found extensive damaged white matter microstructure and poor execution performance in subacute PSCI patients. DKI could detect more subtle white matter changes than DTI metrics. Our findings provide added information for exploring the mechanisms of PSCI and conducting cognitive rehabilitation in the subacute stage.Keywords: diffusion kurtosis imaging, diffusion tensor imaging, subacute ischemic stroke, cognitive impairment

Kristin Kostka,1,2 Talita Duarte-Salles,3 Albert Prats-Uribe,4 Anthony G Sena,5,6 Andrea Pistillo,3 Sara Khalid,4 Lana YH Lai,7 Asieh Golozar,8,9 Thamir M Alshammari,10 Dalia M Dawoud,11 Fredrik Nyberg,12 Adam B Wilcox,13,14 Alan Andryc,5 Andrew Williams,15 Anna Ostropolets,16 Carlos Areia,17 Chi Young Jung,18 Christopher A Harle,19 Christian G Reich,1,2 Clair Blacketer,5,6 Daniel R Morales,20 David A Dorr,21 Edward Burn,3,4 Elena Roel,3,22 Eng Hooi Tan,4 Evan Minty,23 Frank DeFalco,5 Gabriel de Maeztu,24 Gigi Lipori,19 Hiba Alghoul,25 Hong Zhu,26 Jason A Thomas,13 Jiang Bian,19 Jimyung Park,27 Jordi Martínez Roldán,28 Jose D Posada,29 Juan M Banda,30 Juan P Horcajada,31 Julianna Kohler,32 Karishma Shah,33 Karthik Natarajan,16,34 Kristine E Lynch,35,36 Li Liu,37 Lisa M Schilling,38 Martina Recalde,3,22 Matthew Spotnitz,14 Mengchun Gong,39 Michael E Matheny,40,41 Neus Valveny,42 Nicole G Weiskopf,21 Nigam Shah,29 Osaid Alser,43 Paula Casajust,42 Rae Woong Park,27,44 Robert Schuff,21 Sarah Seager,1 Scott L DuVall,35,36 Seng Chan You,45 Seokyoung Song,46 Sergio Fernández-Bertolín,3 Stephen Fortin,5 Tanja Magoc,19 Thomas Falconer,16 Vignesh Subbian,47 Vojtech Huser,48 Waheed-Ul-Rahman Ahmed,33,49 William Carter,38 Yin Guan,50 Yankuic Galvan,19 Xing He,19 Peter R Rijnbeek,6 George Hripcsak,16,34 Patrick B Ryan,5,16 Marc A Suchard,51 Daniel Prieto-Alhambra4 1IQVIA, Cambridge, MA, USA; 2OHDSI Center at The Roux Institute, Northeastern University, Portland, ME, USA; 3Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain; 4Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK; 5Janssen Research & Development, Titusville, NJ, USA; 6Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands; 7School of Medical Sciences, University of Manchester, Manchester, UK; 8Regeneron Pharmaceuticals, Tarrytown, NY, USA; 9Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 10College of Pharmacy, Riyadh Elm University, Riyadh, Saudi Arabia; 11National Institute for Health and Care Excellence, London, UK; 12School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 13Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA; 14Unviersity of Washington Medicine, Seattle, WA, USA; 15Tufts Institute for Clinical Research and Health Policy Studies, Boston, MA, USA; 16Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA; 17Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 18Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, South Korea; 19University of Florida Health, Gainesville, FL, USA; 20Division of Population Health and Genomics, University of Dundee, Dundee, UK; 21Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA; 22Universitat Autònoma de Barcelona, Barcelona, Spain; 23O’Brien Institute for Public Health, Faculty of Medicine, University of Calgary, Calgary, Canada; 24IOMED, Barcelona, Spain; 25Faculty of Medicine, Islamic University of Gaza, Gaza, Palestine; 26Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 27Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, South Korea; 28Director of Innovation and Digital Transformation, Hospital del Mar, Barcelona, Spain; 29Department of Medicine, School of Medicine, Stanford University, Redwood City, CA, USA; 30Georgia State University, Department of Computer Science, Atlanta, GA, USA; 31Department of Infectious Diseases, Hospital del Mar, Institut Hospital del Mar d’Investigació Mèdica (IMIM), Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, Spain; 32United States Agency for International Development, Washington, DC, USA; 33Botnar Research Centre, NDORMS, University of Oxford, Oxford, UK; 34New York-Presbyterian Hospital, New York, NY, USA; 35VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA; 36Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; 37Biomedical Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 38Data Science to Patient Value Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 39Institute of Health Management, Southern Medical University, Guangzhou, People’s Republic of China; 40Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA; 41Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; 42Real-World Evidence, TFS, Barcelona, Spain; 43Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 44Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea; 45Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea; 46Department of Anesthesiology and Pain Medicine, Catholic University of Daegu, School of Medicine, Daegu, South Korea; 47College of Engineering, The University of Arizona, Tucson, AZ, USA; 48National Library of Medicine, National Institutes of Health, Bethesda, MD, USA; 49College of Medicine and Health, University of Exeter, St Luke’s Campus, Exeter, UK; 50DHC Technologies Co. Ltd., Beijing, People’s Republic of China; 51Departments of Biostatistics, Computational Medicine, and Human Genetics, University of California, Los Angeles, CA, USACorrespondence: Daniel Prieto-Alhambra, Botnar Research Centre, Windmill Road, Oxford, OX37LD, UK, Email daniel.prietoalhambra@ndorms.ox.ac.ukPurpose: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD.Patients and Methods: We conducted a descriptive retrospective database study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services.Results: We aggregated over 22,000 unique characteristics describing patients with COVID-19. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts and are readily available online. Globally, we observed similarities in the USA and Europe: more women diagnosed than men but more men hospitalized than women, most diagnosed cases between 25 and 60 years of age versus most hospitalized cases between 60 and 80 years of age. South Korea differed with more women than men hospitalized. Common comorbidities included type 2 diabetes, hypertension, chronic kidney disease and heart disease. Common presenting symptoms were dyspnea, cough and fever. Symptom data availability was more common in hospitalized cohorts than diagnosed.Conclusion: We constructed a global, multi-centre view to describe trends in COVID-19 progression, management and evolution over time. By characterising baseline variability in patients and geography, our work provides critical context that may otherwise be misconstrued as data quality issues. This is important as we perform studies on adverse events of special interest in COVID-19 vaccine surveillance.Keywords: OHDSI, OMOP CDM, descriptive epidemiology, real world data, real world evidence, open science

Mingkai Gong,1 Xiangping Liu,2 Wu Yang,3 Hongming Song,1 Xian Zhao,1 Xiancheng Ai,1 Shuo Wang,1 Haibo Wang1 1Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 3Department of International Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaCorrespondence: Haibo WangCenter of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaEmail hbwang66@126.comBackground: Cancer metabolism and specifically lipid metabolism play an important role in breast cancer (BC) progression and metastasis. However, the role of lipid metabolism-associated genes (LMGs) in the prognosis of breast cancer remains unknown.Methods: The expression profiles and clinical follow-up information of 1053 BC were downloaded from The Cancer Genome Atlas (TCGA), and metabolic genes were downloaded from the Gene Set Enrichment Analysis (GSEA) dataset. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed on the differentially expressed metabolism-related genes. Then, the formula of the metabolism-related risk model was composed, and the risk score of each patient was calculated. The breast cancer patients were divided into high-risk and low-risk groups with a cutoff of the median expression value of the risk score, and the prognostic analysis was also used to analyze the survival time between these two groups. Finally, we analyzed the expression, interaction and correlation among the lipid metabolism-associated genes risk model.Results: The results from the prognostic analysis indicated that the survival was significantly poorer in the high-risk group than in the low-risk group in TCGA, and single-sample gene set enrichment analysis (ssGSEA) shows it is plausible that lipid metabolism is highly correlated with tumor immunity.Conclusion: Lipid metabolism-associated genes may become a new prognostic indicator predicting the survival of BC patients. The prognostic genes (n = 16) may help provide new strategies for tumor therapy.Keywords: bioinformatics, lipid metabolism-associated genes, breast cancer, lipid metabolism, TCGA

Xun Kang, Tao Sun, Liang Zhang, Chunyu Zhou, Zhongsheng Xu, Mengmeng Du, Shilin Xiao, Yun Liu, Mingfu Gong, Dong Zhang Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Mingfu Gong; Dong ZhangDepartment of Radiology, Xinqiao Hospital, Army Medical University, No. 183, Xinqiao Street, Shapingba District, Chongqing, People’s Republic of ChinaTel +86 2368763843Fax +86 2368755306Email hummer198625@163.com; hszhangd@163.comBackground: Satisfactory prognosis of breast cancer (BC) is limited by difficulty in early diagnosis and insufficient treatment. The combination of molecular imaging and photothermal therapy (PTT) may provide a solution.Methods: Fe3O4-Aushell nanoparticles (NPs) were prepared by thermal decomposition, seeded growth and galvanic replacement and were comprehensively characterized. After conjugated to PEG, NPs were used as MRI and PTT agents in vitro and in vivo.Results: Fe3O4-Aushell NPs which had uniform Janus-like morphology were successfully synthesized. The Fe3O4 had a size of 18 ± 2.2 nm, and the Aushell had an outer diameter of 25 ± 3.3 nm and an inner diameter of 20 ± 2.9 nm. The NPs showed superparamagnetism, a saturation magnetization of 36 emu/g, and an optical absorption plateau from 700 to 808 nm. The Fe3O4-Aushell NPs were determined to possess good biocompatibility. After PEG coating, the zeta potential of NPs was changed from − 23.75 ± 1.37 mV to − 13.93 ± 0.55 mV, and the FTIR showed the characteristic C–O stretching vibration at 1113 cm− 1. The NPs’ MR imaging implied that the T2 can be shortened by Fe3O4-Aushell NPs in a concentration-dependent manner, and the Fe3O4-Aushell NPs coated with PEG at the molar ratio of 160 (PEG: NPs) showed the highest transverse relaxivity (r2) of 216 mM− 1s− 1. After irradiation at 0.65 W/cm2 for 5 min, all cells incubated with the Fe3O4-Aushell-PEG160 NPs (Fe: 30 ppm, Au: 70 ppm) died. After administrated intratumorally, Fe3O4-Aushell-PEG160 notably decreased the signal intensity of tumor in T2WI images. Under the same irradiation, the temperature of tumors injected with Fe3O4-Aushell-PEG160 quickly rose to 54.6°C, and the tumors shrank rapidly and were ablated in 6 days.Conclusion: Fe3O4-Aushell-PEG NPs show good r2 and PTT performance and are promising synergistic theranostic agents of MRI and PTT for BC.Keywords: magnetic resonance imaging, photothermal therapy, nanoparticle, early breast cancer theranostics, gold nanoshells

Mou-chun Gong,&ast; Wei-qing Chen,&ast; Zhao-qing Jin, Jia Lyu, Li-hao Meng, Hai-yan wu, Fei-hua Chen Department of General Surgery, First People’s Hospital of Hangzhou Lin’an District, Hangzhou, Zhejiang, 311300, People’s Republic of China&ast;These authors contributed equally to this work.Correspondence: Fei-hua ChenDepartment of General Surgery, First People’s Hospital of Hangzhou Lin’an District, 548 Yijin Road, Street Jincheng, Hangzhou, Zhejiang, 311300, People’s Republic of ChinaEmail 13396510518@189.cnBackground: Topoisomerase 2-alpha (TOP2A) has been identified as a hub gene that played an important role in the initiation and progression of thyroid carcinoma (THCA). However, the exact function of TOP2A in papillary thyroid cancer (PTC) remained elusive. The current study aimed to evaluate the TOP2A expression, prognosis significance and key signaling pathways involved in PTC.Methods: We firstly evaluated the expression of TOP2A in PTC via UALCAN, cBioportal, HPA and LinkdedOmics databases. Genetic alteration of TOP2A in PTC was then explored in cBioportal. Prognostic impacts of TOP2A expression on disease-free survival (DFS) of PTC patients were subsequently evaluated using Kaplan–Meier plotter and Gepia databases. Taking gender, age, cancer stage, T, N and M stages into consideration, we compared survival difference between TOP2A high and low expression groups. KEGG pathway analysis in WebGestalt and GSEA analysis were further performed to reveal the potential TOP2A-associated signaling pathways involved in PTC. Finally, the upstream microRNAs of TOP2A were assessed using DIANA, TargetScan, miRDB and miRWALK database, followed by mechanism exploration of upstream microRNAs.Results: 1) The mRNA and protein of TOP2A were highly expressed in PTC tissue compared with normal thyroid tissue. TOP2A expression was associated with patient’s age, N stage and cancer stage (all P< 0.05). TOP2A protein was mainly localized to nucleoplasm. 2) Most of samples occurred the missense substitution, and mutation site was located at K1199E. Nucleotide mutations were mainly presented as G>A (35.29%). 3) TOP2A high expression significantly influenced the DFS of PTC patients (P=0.015). Restricted survival analysis showed that TOP2A high expression caused poorer DFS of female patients (P=0.003) and those with age < 60 years old (P=0.002), early clinical stage (P=0.012), N0 stage (P=0.002) or M0 stage (P=0.040). 4) Pathway analysis suggested that TOP2A positively participated in the cell cycle, oocyte meiosis and p53 signaling pathways (all P< 0.05) involved in thyroid cancer.Conclusion: The expression of TOP2A was higher in PTC tissue, which resulted in a worse DFS of patients with PTC. TOP2A might act as an effective therapeutic target for PTC treatment.Keywords: TOP2A, high expression, poor prognosis, pathway

Xu Zhai,1 Meihua Gong,1,2 Yixuan Peng,1 Daping Yang1 1Department of Plastic Surgery, The 2nd Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Department of Plastic and Cosmetic Surgery, Shenzhen People’s Hospital, Second Affiliated Hospital of Jinan University Medical College, Shenzhen, People’s Republic of ChinaCorrespondence: Daping YangDepartment of Plastic Surgery, The 2nd Hospital of Harbin Medical University, Harbin, People’s Republic of ChinaTel/Fax +86-0451-86297062Email dapingyang1223@hotmail.comPurpose: To study the changes in the hair follicle cycle and related stem cells induced by photoaging to establish a mouse model of senescence in hair follicles.Methods: There were 54 C57BL6/J mice randomly divided into three groups. The UVA group and the UVB group underwent photoaging induced by UV lamps for 8 weeks. Changes in skin and the hair follicle cycle were compared by physical signs, dermoscopy, and hematoxylin and eosin and Masson’s staining in each group. Western blot, immunohistochemistry, and RT-qPCR were carried out to test canonical proteins and gene expression of the Wnt signaling pathway in the samples. Immunofluorescence was chosen to show variations in the stem cells related to the hair follicle cycle.Results: There were more gray hairs in the UVA group than the other groups (P< 0.05). Both diameter of the hair shaft and depth of hair root were significantly decreased in the UV groups (P< 0.05). Stem cells and melanocytes of the hair follicles were reduced in the UVA group. UV, especially UVB, up-regulated the expression of the Wnt signaling pathway and prolonged anagen and telogen phases in the hair follicles, compared with the control group (P< 0.05).Conclusion: By decreasing the number of stem cells related to hair follicles, UVA induces hair follicle photoaging characterized by hair follicle miniaturization and gray hairs. UV up-regulated the expression of the Wnt signaling pathway, and the hair follicle cycle was significantly prolonged by UVB.Keywords: UVA, photoaging, hair follicle cycle, HFSCs, Wnt

Wanli Gu,1 Peng Chen,1 Peng Ren,1 Yanhai Wang,2 Xiaobing Li,3 Mingzhi Gong1 1Department of Orthopaedics, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 2Obstetrical Department, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Mingzhi GongDepartment of Orthopaedics, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, People’s Republic of ChinaTel +86 17660081696Email g17660081699@163.comBackground: Osteosarcoma (OS) is a malignant bone tumor with high metastatic potential. As a regulatory factor of apoptosis, TATA-box binding protein (TBP) associated factor 9B (TAF9B) is rarely studied in tumors.Methods: We investigated the role and mechanism of TAF9B in OS cells by overexpression and knockdown. CCK8, colony formation, transwell, and flow cytometry analysis were performed to detect proliferation, migration, invasion, and apoptosis.Results: TAF9B overexpression promotes the proliferation, migration, and invasion of OS cells, while TAF9B knockdown gives the opposite result. TAF9B inhibits apoptosis by upregulating Bcl-2 and downregulating Bax and Cleaved-caspase-3. Through starBase analysis, it was found that miR-7-5p can bind to the 3ʹUTR region of TAF9B, which is further confirmed by the dual luciferase reporter system assay. MiR-7-5p downregulates the expression of TAF9B in MG63 and U2OS cells. The proliferation and invasion of OS cells are inhibited after miR-7-5p mimics transfection and are promoted after miR-7-5p inhibitor transfection. TAF9B rescues the inhibitory effect of miR-7-5p on OS cells. TAF9B also activates the AKT/mTOR signaling pathway.Conclusion: According to our results, miR-7-5p inhibits the translation of TAF9B and then suppresses growth and metastasis through the AKT/mTOR signaling pathway in OS cells, thereby indicating the potential value of miR-7-5p and TAF9B as therapeutic targets for human OS.Keywords: TAF9B, osteosarcoma, miR-7-5p, 3ʹUTR

Baoxin Liu,1,* Jiachen Luo,1,* Mengmeng Gong,1 Zhiqiang Li,1 Beibei Shi,1 Xingxu Zhang,1 Xinqiang Han,2 Yidong Wei1 1Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Electrophysiology and Arrhythmia Services, Reid Health, Indiana University School of Medicine, Richmond, IN, 47374, USA*These authors contributed equally to this workCorrespondence: Yidong WeiDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Jingan District, Shanghai, People’s Republic of ChinaTel +86-021-66307249Fax +86-021-66301771Email ywei@tongji.edu.cnPurpose: LAAO has been an alternative therapy to oral anticoagulants (OACs) for stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF) with elevated CHA2DS2-Vasc score, but the long-term outcomes of LAAO and its impacts on cardiac electrical and mechanical remodeling remain to be learned. We aimed to describe the impact of left atrial appendage occlusion (LAAO) on atrial remodeling and cardiovascular outcomes within 5-year follow-up.Patients and Methods: A total of 107 patients with nonvalvular atrial fibrillation (NVAF) undergoing LAAO in the Shanghai Tenth People’s Hospital between January 2014 and July 2017 were included. All participants were followed for ECG, transthoracic echocardiography (TTE), and clinical outcomes (including cardiovascular death, heart failure, ischemic stroke/systemic embolism, and pericardial effusion) at 6 and 12 months, and thereafter every 12 months after LAAO discharge until 5 years.Results: After LAAO, the left atrial diameter significantly increased at 6 months (48.6 ± 6.7 vs 46.5 ± 7.0 mm); heart rate decreased immediately after the procedure (78.5 ± 14.7 vs 85.3 ± 21.7 bpm) when compared with the pre-procedure level. The QTc interval prolongated to the highest value of 460.7 ± 46.8 ms at 6 months (pre-procedure level of 433.7± 49.0 ms). All these changes return to the pre-procedure level within the follow-up. For clinical outcomes, 51 patients suffered the composite of cardiovascular death (n=4, 3.7%), heart failure (n=25, 23.4%), ischemic stroke/systemic embolism (n=22, 20.6%), and pericardial effusion (n=26, 26.2%).Conclusion: LAAO did not change ECG or TTE characteristics and nonprocedure-related pericardial effusion is common during long-term follow-up. Further studies are warranted to investigate the optimal time frame of anticoagulation in patients undergoing LAAO.Keywords: atrial fibrillation, left atrial appendage occlusion, ECG, echocardiogram

Liang Zhang, Shilin Xiao, Xun Kang, Tao Sun, Chunyu Zhou, Zhongsheng Xu, Mengmeng Du, Ya Zhang, Guangxian Wang, Yun Liu, Dong Zhang, Mingfu Gong Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Dong Zhang; Mingfu GongDepartment of Radiology, Xinqiao Hospital, Army Medical University, No. 183, Xinqiao Street, Shapingba District, Chongqing, People’s Republic of ChinaTel +86 2368763843Fax +86 2368755306Email hszhangd@163.com; hummer198625@163.comBackground: Manganese Ferrite Nanoparticles (Mn-IONPs) are widely used in biomedical field and their cytotoxicity has been initially explored, but the mechanism remains obscure. The nano-bio interactions are believed to be crucial for cytotoxicity mechanism, while little data have been acquired.Methods: Mn-IONPs were synthesized by thermal decomposition of acetylacetonate precursor. After physicochemical characterization, we analyzed the metabolic conversion and removal of Mn-IONPs in RAW264.7 cells by Prussian blue staining, TEM, HRTEM and elemental quantitative analysis, followed by gene expression evaluation using quantitative RT-PCR.Results: Mn-IONPs were successfully synthesized. Both the uptake and cytotoxicity of Mn-IONPs on RAW264.7 cells were time- and dose-dependent. After internalized, Mn-IONPs were passed to daughter cells with passages on. Meanwhile, Mn-IONPs were exocytosed and digested to metal ions and further excreted out, resulted in the labeling rate and ions contents decreased gradually. As ion influx related genes, the expressions of ZIP14, IRP2, FtH and DMT1 were suppressed within 24 hours but overexpressed to a plateau at the 48th hour in a dose-dependent manner. At the 72nd hour, ZIP14 and DMT1 mRNA levels decreased toward normal, while IRP2 and FtH kept up-regulated. As efflux related genes, FPN, SLC30A10 and Hamp2 genes were up-regulated within 24– 72 hours; SPCA1 was suppressed at the 24th and 72nd hour, while overexpressed at the 48th hour. All the efflux related genes’ mRNA had a dose-dependent increasing manner at the corresponding time points.Conclusion: Mn-IONPs showed time- and dose-dependent cytotoxicity and cell labeling rate in RAW264.7 cells. Accompanying with the intracellular catabolic breakdown and exocytosis of Mn-IONPs, RAW264.7 cells also secreted and re-uptook manganese and iron ions to maintain intracellular homeostasis in the succeeding passages. And the metabolic conversion of Mn-IONPs in RAW264.7 cells can affect the expression of ZIP14, DMT1, FPN, SLC30A10, IRP2, FtH, Hamp2 and SPCA1 genes.Keywords: manganese ferrite nanoparticles, cytotoxicity, metabolism, metal transporter genes, RAW264.7 macrophage cells

Liu J, Yuan W, Wang X, et al. Clin Interv Aging. 2014;9:341–350. The Editor and Publisher of Clinical Interventions in Aging wish to publish an Expression of Concern for the published article. Concerns were raised regarding discrepancies between study details reported in the article and those reported in the corresponding clinical trial registration database. We have contacted the authors requesting they supply information that would confirm the integrity of the data reported in the article but have received no response. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. The authors have been notified about this Expression of Concern. Read the original article

Thiquynhnga Nguyen,* Song Wen,* Min Gong,* Xinlu Yuan, Dongxiang Xu, Chaoxun Wang, Jianlan Jin, Ligang Zhou Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ligang ZhouDepartment of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, People’s Republic of ChinaTel +86 13611927616Email zhouligang@yahoo.comPurpose: This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity.Material and Methods: Thirty-four normal male C57BL/6 mice were randomly assigned to 2 groups to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos, a neural activator. The distributional relationships of SGLT-2 and c-Fos were examined by immunofluorescence.Results: Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin.Conclusion: This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.Keywords: sodium glucose co-transporter-2, dapagliflozin, c-Fos, cardiovascular activity, brain nuclei

Chao Guo, Ming Gong, Zhenling Li Department of Hematology, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Zhenling Li Email zhenlingli_luck@163.comPurpose: The long-noncoding RNA MCM3AP-AS1 has been shown to participate in the tumorigenesis and growth of several types of cancer, but little is known about the role of MCM3AP-AS1 in the chemoresistance of lymphoma.Methods: A series of patients with Burkitt lymphoma were enrolled for clinical analysis. Daudi and Namalwa cells were used for further experiments. CCK-8 and apoptosis assays were used to assess the response to doxorubicin. Mitochondrial membrane potential assays and high-resolution respirometry were used to assess mitochondrial function. Western blotting was used to detect the expression of certain molecules. Luciferase assays and microRNA transfection were used to clarify the regulatory mechanisms of MCM3AP-AS1. An in vivo model using BALB/c nude mice was utilized to investigate the effects of MCM3AP-AS1 on cell proliferation and tumor growth.Results: The expression level of MCM3AP-AS1 was increased in tumors compared with normal lymph nodes, which indicated poor prognosis in patients with Burkitt lymphoma. Moreover, compared with siNC transfection, MCM3AP-AS1 knockdown decreased cell viability and increased apoptosis rates upon doxorubicin treatment compared with siNC. Further studies indicated that upregulation of several antiapoptotic factors, downstream of EIF4E, was partially responsible for MCM3AP-AS1-induced chemoresistance. Moreover, miR-15a functioned as a link between MCM3AP-AS1 and EIF4E, and was sponged by MCM3AP-AS1. Finally, we showed that the MCM3AP-AS1/miR-15a/EIF4E axis regulated the chemoresistance of lymphoma cells in vitro and in vivo.Conclusion: MCM3AP-AS1/miR-15a/EIF4E axis plays a role in the chemoresistance of Burkitt lymphoma, and it might become a promising target for lymphoma therapeutics.Keywords: Burkitt lymphoma, MCM3AP-AS1, microRNA-15a, EIF4E, chemosensitivity

Min Gong, Song Wen, Thiquynhnga Nguyen, Chaoxun Wang, Jianlan Jin, Ligang Zhou Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, People’s Republic of ChinaCorrespondence: Ligang ZhouDepartment of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, ChinaTel +8613611927616Email zhouligang@yahoo.comBackground: Obesity and hyperuricemia mutually influence metabolic syndrome. This study discusses the metabolic relationships between obesity and hyperuricemia in terms of pathophysiology, complications, and treatments.Methods: We searched for preclinical or clinical studies on the pathophysiology, complications, and therapy of obesity and hyperuricemia on the PubMed database.Results: In this systemic review, we summarized our searching results on topics of pathophysiology, complications and therapeutic strategy. In pathophysiology, we firstly introduce genetic variations for obesity, hyperuricemia and their relationships by genetic studies. Secondly, we talk about the epigenetic influences on obesity and hyperuricemia. Thirdly, we describe the central metabolic regulation and the role of hyperuricemia. Then, we refer to the character of adipose tissue inflammation and oxidative stress in the obesity and hyperuricemia. In the last part of this topic, we reviewed the critical links of gut microbiota in the obesity and hyperuricemia. In the following part, we review the pathophysiology of major complications in obesity and hyperuricemia including insulin resistance and type 2 diabetes mellitus, chronic kidney disease, cardiovascular diseases, and cancers. Finally, we recapitulate the therapeutic strategies especially the novel pharmaceutic interventions for obesity and hyperuricemia, which concurrently show the mutual metabolic influences between two diseases.Conclusion: The data reviewed here delineate the metabolic relationships between obesity and hyperuricemia, and provide a comprehensive overview of the therapeutic targets for the management of metabolic syndromes.Keywords: obesity, hyperuricemia, pathophysiology, complication, pharmacotherapy

Mi Gong,1,2,* Chengyan Luo,1,* Huangyang Meng,1,* Siyue Li,1 Sipei Nie,1 Yi Jiang,1 Yicong Wan,1 Huijian Li,3–5 Wenjun Cheng1 1Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China; 2Department of Gynecology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an 223300, People’s Republic of China; 3State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu 211166, People’s Republic of China; 4Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, People’s Republic of China; 5Department of Gynecology, Wuxi Maternal and Child Health Hospital, Wuxi, Jiangsu 214002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjun ChengDepartment of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of ChinaEmail wenjunchengdoc@163.comBackground: Long noncoding RNAs (lncRNAs) have been identified to participate in tumorigenesis. However, the underlying mechanisms of differentially expressed lncRNAs engaged in diseases remain indistinct and need further exploration.Methods: Raw data files downloaded from TCGA and GEO dataset were used to analyze the differentially expressed lncRNAs and LINC00565 was picked out as the potential oncogene. qRT-PCR was used to analyze the LINC00565 level in ovarian tissues and cell lines. Subsequently, the selected ovarian tumor cells were then transfected with LINC00565 siRNA by Lipofectamine 2000 and the cell cycle was detected by flow cytometry. Effect of LINC00565 on tumor growth and cell cycle was verified by tumor formation assay in nude mice. The mechanism of LINC00565 involving in cell cycle regulation was further explored by Western blot.Results: In this research, we discovered that LINC00565, a novel lncRNA, was highly expressed in ovarian cancer (OC). LINC00565 expression level was negatively associated with outcomes of OC patients. Further analysis showed that LINC00565 expression was closely correlated to tumor size, FIGO stage, but not related to other clinical features. In vitro experiments indicated that knockdown of LINC00565 significantly inhibited proliferative, invasive and migratory abilities of ovarian cancer cells. Besides, knockdown of LINC00565 can induce cell cycle arrest in G0/G1 phase. In addition, in vivo assay showed that low expression of LINC00565 inhibited the growth of OC. Further study found that LINC00565 knockdown markedly downregulated the protein expressions of CyclinD1, CyclinE1 and CDK4, but upregulated the expression of P16 and P21. Subsequently, we confirmed that LINC00565 promoted the progression of OC via upregulating GAS6, which has been confirmed to promote tumor progression.Conclusion: In summary, our study firstly reported that the LINC00565 functioned as an oncogene to promote the progression of OC by interacting with GAS6.Keywords: ovarian cancer, OC, LINC00565, GAS6, cell cycle

Shilin Xiao, Xian Yu, Liang Zhang, Ya Zhang, Weijie Fan, Tao Sun, Chunyu Zhou, Yun Liu, Yiding Liu, Mingfu Gong, Dong Zhang Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Mingfu Gong; Dong ZhangDepartment of Radiology, Xinqiao Hospital, Army Medical University, Xinqiao Street, Shapingba District, Chongqing, People’s Republic of ChinaTel +86 23 6876 3843Fax +86 23 6875 5306Email hummer198625@163.com; hszhangd@163.comBackground: Beyond magnetic resonance imaging (MRI), which has been widely used clinically, molecular MRI (mMRI) can further provide qualitative and quantitative information at the cellular and molecular levels. However, the diagnostic accuracy may not be satisfactory via single-contrast mMRI due to some interferences in vivo. T1/T2 dual-contrast MRI using the same contrast agent (CA) could significantly improve the detection accuracy. Therefore, in this study, we fabricated poly(ethylene glycol) (PEG)-coated, manganese-doped iron oxide nanocomposites (Mn-IONPs@PEG) as T1/T2 dual-contrast CA, and evaluated its feasibility of T1/T2 dual-contrast MRI in vitro and in vivo.Methods: Mn-IONPs were prepared by the thermal decomposition of iron-eruciate and manganese-oleate complexes and were coated with 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethylene glycol]-2000) (DSPE-PEG 2000). The physicochemical properties and cytotoxicity of the Mn-IONPs were fully characterized, followed by MRI in vitro and in vivo.Results: Ultrasmall 3 nm-sized nanoparticles were successfully prepared and were identified using transmission electron microscopy (TEM), high-resolution TEM, and X-ray diffraction. After coating with DSPE-PEG, the Mn-IONPs@PEG displayed excellent hydrophilicity and good biocompatibility. Due to the manganese-doping and PEG coating, the Mn-IONPs@PEG showed good relaxivity in vitro. Especially, the Mn-IONPs@PEG coated with DSPE-PEG following a mass ratio to Mn-IONPs of 1:20 showed harmonious longitudinal relaxivity (r1 = 7.1 mM−1s−1) and transversal relaxivity (r2 = 120.9 mM−1s−1), making it a better candidate for T1/T2 dual-contrast mMRI. After administrated via a caudal vein, the Mn-IONPs@PEG can induce significant enhancement in both T1-weighted and T2-weighted MR images and the time at 10 mins after injection was regarded as a suitable time for imaging because both the T1 and T2 enhancement were optimum at that time.Conclusion: The obtained Mn-IONPs@PEG exhibited good r1 and r2 and was a reasonable candidate for T1/T2 dual-contrast mMRI.Keywords: magnetic resonance imaging, manganese-doped iron oxide nanoparticles, T1/T2 dual-contrast, DSPE-PEG coating, high relaxivity

Tian-Yu He, Si-Han Li, Jin Huang, Ming Gong, Guang LiDepartment of Radiation Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaPurpose: Numerous studies have reported that the long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) plays important roles in the tumorigenesis, progression, and prognosis of various types of cancer. However, thus far, a systematic analysis of CRNDE in cancers of the digestive system has not been conducted. Thus, the aim of this meta-analysis was to explore the relationship between CRNDE expression and survival or the clinicopathological features of gastrointestinal cancer.Methods: Eligible studies were collected from nine databases (ie, PubMed, Medline, Embase, Cochrane Library, Ovid, Science Citation Index Expanded, China Biology Medicine, Chinese National Knowledge Infrastructure, and Wanfang). The meta-analysis was conducted using the Stata SE.12 Software. The pooled hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (Cl) was used to assess the clinical value of CRNDE expression in gastrointestinal cancers.Results: A total of 1,053 patients from nine articles were selected. The analysis provided evidence suggesting a significant negative correlation between high CRNDE expression and the rate of overall survival [HR=1.92, 95% CI (1.40–2.64), p5 cm [OR=2.81, 95% CI (1.62–4.88), p

Yuelong Huang,1 Rui Shi,2 Min Gong,3 Jingshuang Zhang,2 Weiyang Li,2 Qingpeng Song,1 Chengai Wu,2 Wei Tian1 1Department of Spine Surgery of Beijing Jishuitan Hospital, The Fourth Clinical Medical College of Peking University, Beijing 100035, China; 2Institute of Traumatology and Orthopaedics, Beijing Laboratory of Biomedical Materials, Beijing Jishuitan Hospital, Beijing 100035, China; 3Beijing Laboratory of Biomedical Materials, State Key Laboratory of Organic–Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, China Background: Epidural adhesion is one of the major reasons attributed to failed back surgery syndrome after a successful laminectomy, and results in serious clinical complications which require management from physicians. Therefore, there is an urgent demand within the field to develop biodegradable anti-adhesion membranes for the prevention of post-operative adhesion. Methods: In this study, icariin (ICA) was initially loaded into polycaprolactone (PCL)/gelatin fibers via electrospinning to fabricate nanofibrous membranes. The effects of the ICA content (0.5wt%, 2wt% and 5wt%) and the bioactivity of ICA in the nanofibrous membranes were investigated in vitro and in vivo. Results: The nanofibrous membranes showed suitable pore size and good properties that were unaffected by ICA concentration. Moreover, the ICA-loaded membranes exhibited an originally rapid and subsequently gradual sustained ICA release profile that could significantly prevent fibroblast adhesion and proliferation. In vivo studies with rabbit laminectomy models demonstrated that the ICA-loaded membranes effectively reduced epidural adhesion by gross observation, histology, and biochemical evaluation. The anti-adhesion mechanism of ICA was found to be via suppression of the TGF-β/Smad signaling proteins and down regulation of collage I/III and a-SMA expression for the first time. Conclusion: We believe that these ICA-loaded PCL/gelatin electrospun membranes provide a novel and promising strategy to resist adhesion formation following laminectomy in a clinical application. Keywords: icariin, polycaprolactone/gelatin, electrospun, epidural adhesion

Heng Zhao,1 Shenghou Liu,1 Chenhua Wang,2 Qingjie Wang,3 Wenguang Liu,1 Mingzhi Gong1 1Department of Orthopedics, The Second Hospital of Shandong University, Jinan, 250033, Shandong, People’s Republic of China; 2Department of Nuclear Medicine, The Second Hospital of Shandong University, Jinan, 250033, Shandong, People’s Republic of China; 3Department of Emergency, The Second Hospital of Shandong University, Jinan, 250033, Shandong, People’s Republic of China Introduction: High comorbidity of osteoarthritis (OA) and neuropathic pain has been reported in aged patients. Evidence shows that central sensitization of pain processing occurs in late-phase OA and may facilitate the development of neuropathic pain. Few studies reveal whether acute monoarthritis (MA) aggravates neuropathic pain on the opposite side of the body from the injury. Methods: To address whether neuropathic pain is affected by contralateral MA through distinct inflammatory pathway, MA was induced by intra-articular injection of complete Freund’s adjuvant (CFA) into the right tibiotarsal joint, and neuropathic pain was established by chronic constriction injury (CCI) of the left sciatic nerve. Results: We observed that MA aggravated mechanical allodynia and thermal hyperalgesia in CCI rats. Furthermore, MA affected the other side of the spinal cord in multiple aspects, including the upregulation of iNOS mRNA and the enhancement of forskolin-induced facilitation of excitatory synaptic transmission in the spinal cord dorsal horn substantia gelatinosa neurons. Discussion: Interestingly, intrathecal injection of 1400W, an antagonist of iNOS, attenuated intensity of pain behaviors in CCI rats with contralateral MA to similar levels in CCI rats without MA, and also normalized the facilitatory effect of forskolin on excitatory synaptic transmission in the spinal cord dorsal horn neurons in contralateral MA rats. Therefore, contralateral MA worsened CCI-induced pain hypersensitivity probably through upregulating iNOS and enhancing the facilitation of synaptic transmission following CCI. Conclusion: Inhibiting the iNOS might be a potential therapeutic strategy for concurrent OA and neuropathic pain. Keywords: osteoarthritis, neuropathic pain, acute monoarthritis, chronic constriction injury

Fang Liu,1,* Ming Gong,2,* Li Gao,2,* Xiaoping Cai,3 Hui Zhang,2 Yigai Ma2 1Department of Oncology, Chinese PLA General Hospital, 2Department of Hematology, China-Japan Friendship Hospital, 3Department of Geriatric Medicine, Army General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Objective: The purpose of this study was to evaluate the frequency of RASSF1A hypermethylation in patients with acute myeloid leukemia (AML), in an attempt to modify the current molecular model for disease prognosis.Materials and methods: Aberrant RASSF1A promoter methylation levels were assessed in 226 newly diagnosed non-M3 AML patients and 30 apparently healthy controls, by quantitative methylation-specific polymerase chain reaction. Meanwhile, RASSF1A mRNA levels were detected by real-time quantitative polymerase chain reaction. Furthermore, hematological characteristics, cytogenetic abnormalities, and genetic aberrations were assessed. Finally, associations of RASSF1A hypermethylation with clinical outcomes were evaluated.Results: RASSF1A hypermethylation was observed in 23.0% of patients with non-M3 AML (52/226), but not in controls. Meanwhile, hypermethylation of the RASSF1A promoter was significantly associated with ASXL1 mutation. Furthermore, the log-rank test revealed that RASSF1A hypermethylation indicated decreased relapse-free survival (RFS) and overall survival (OS) in patients with non-M3 AML (P=0.012 and P=0.014, respectively). In multivariate analysis, RASSF1A hypermethylation was an independent prognostic factor for RFS (P=0.040), but not for OS (P=0.060).Conclusion: Hypermethylation of the RASSF1A promoter is associated with ASXL1 mutation in non-M3 AML patients, likely indicating poor outcome. These findings provide a molecular basis for stratified diagnosis and prognostic evaluation. Keywords: RASSF1A, hypermethylation, acute myeloid leukemia, clinical outcome, survival

Wenjun Ni,1,2 Erlin Song,1 Mancheng Gong,3 Yongxiang Li,4 Jie Yao,5 Ruihua An1 1Department of Urology Surgery, The First Affiliated Hospital of Harbin Medical University, 2Department of Urology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, 3Department of Urology, The People’s Hospital of Zhongshan, Zhongshan, Guangdong, 4Department of Urology, The People’s Hospital of Weifang, Weifang, Shandong, 5Department of Oncology, the 161th Hospital of PLA, Wuhan, Hubei, People’s Republic of China Abstract: Renal cell carcinoma (RCC) is a common type of kidney cancer. Normally, surgical treatment can prolong life, but only for patients with early stage tumors. However, it is difficult for early detection strategies to distinguish between benign and malignant kidney tumors. Therefore, potential biomarkers for early diagnosis and prognosis of RCC are needed. Intriguingly, mounting evidence has demonstrated that many long noncoding RNAs (lncRNAs) are strongly linked to cancers. Indeed, promising RCC-associated lncRNA biomarkers have also been identified. However, the functional and prognostic roles of the antisense (AS) serum deprivation response (SDPR) lncRNA (SDPR-AS) in RCC remain largely unknown. The aims of this study were to investigate the expression and prognostic relevance of SDPR-AS in RCC. We uncovered the downregulated expressions of both lncRNA SDPR-AS and its protein-coding gene, SDPR, in RCC tissues compared to the matched normal tissues. Furthermore, SDPR-AS and SDPR expressions were positively correlated. Overexpression and knockdown experiments suggested that SDPR-AS and SDPR were coregulated in RCC cell lines. In addition, overexpression of SDPR-AS suppressed cell migration and invasion, but not cell growth. Furthermore, expression of SDPR-AS was associated with tumor differentiation and lymphatic metastasis. Kaplan–Meier survival and log-rank tests demonstrated the association of elevated expression of SDPR-AS with increased overall survival. In conclusion, our results suggest that the SDPR-AS may serve as a prognostic biomarker and therapeutic target of RCC. Keywords: long noncoding RNAs, metastasis, prognosis, renal cell carcinoma, suppressor

Gong M, Luo C, Meng H, et al. Upregulated LINC00565 accelerates ovarian cancer progression by targeting GAS6. OncoTargets Ther. 2019;12:10011–10022.Upon reviewing the article, the authors noticed an error in Figure 5D on page 10019, it should be presented as follows: The authors confirm that all of the results and conclusions of the article remain unchanged. The authors apologize for this error. Read the original article

Mingfu Gong,1 Hua Yang,1,2 Song Zhang,1 Yan Yang,1 Dong Zhang,1 Zhaohui Li,3 Liguang Zou1 1Department of Radiology, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 2Department of Radiology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 3Geosciences Department, University of Wisconsin-Parkside, Kenosha, WI, USA Abstract: Tumor angiogenesis plays very important roles for tumorigenesis, tumor development, metastasis, and prognosis. Targeting T1/T2 dual modality magnetic resonance (MR) imaging of the tumor vascular endothelial cells (TVECs) with MR molecular probes can greatly improve diagnostic sensitivity and specificity, as well as helping to make an early diagnosis of tumor at the preclinical stage. In this study, a new T1 and T2 dual modality nanoprobe was successfully fabricated. The prepared nanoprobe comprise peptides CL 1555, poly(ε-caprolactone)-block-poly(ethylene glycol) amphiphilic copolymer shell, and dozens of manganese ferrite (MnFe2O4) nanoparticle core. The results showed that the hydrophobic MnFe2O4 nanoparticles were of uniform spheroidal appearance and narrow size distribution. Due to the self-assembled nanomicelles structure, the prepared probes were of high relaxivity of 281.7 mM-1 s-1, which was much higher than that of MnFe2O4 nanoparticles (67.5 mM-1 s-1). After being grafted with the targeted CD105 peptide CL 1555, the nanomicelles can combine TVECs specifically and make the labeled TVECs dark in T2-weighted MR imaging. With the passage on, the Mn2+ ions were released from MnFe2O4 and the size decreased gradually, making the signal intensity of the second and third passage of labeled TVECs increased in T1-weighted MR imaging. Our results demonstrate that CL-poly(ethylene glycol)-MnFe2O4 can conjugate TVECs and induce dark and bright contrast in MR imaging, and act as a novel molecular probe for T1- and T2-enhanced MR imaging of tumor angiogenesis. Keywords: CL 1555, CL-PEG-MnFe2O4, TVECs, CD105, tumor angio­genesis

Yongzhu Chen,1 Chengkang Tang,2 Jie Zhang,2 Meng Gong,3 Bo Su,2 Feng Qiu4 1Periodical Press, 2Core Facility of West China Hospital, 3Laboratory of Endocrinology and Metabolism, West China Hospital, 4Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Background: Finding a suitable delivery system to improve the water solubility of hydrophobic drugs is a critical challenge in the development of effective formulations. In this study, we used A6K, a self-assembling surfactant-like peptide, as a carrier to encapsulate and deliver hydrophobic pyrene.Methods: Pyrene was mixed with A6K by magnetic stirring to form a suspension. Confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, atomic force microscopy, fluorescence, and cell uptake measurements were carried out to study the features and stability of the nanostructures, the state and content of pyrene, as well as the pyrene release profile.Results: The suspension formed contained pyrene monomers trapped in the hydrophobic cores of the micellar nanofibers formed by A6K, as well as nanosized pyrene crystals wrapped up and stabilized by the nanofibers. The two different encapsulation methods greatly increased the concentration of pyrene in the suspension, and formation of pyrene crystals wrapped up by A6K nanofibers might be the major contributor to this effect. Furthermore, the suspension system could readily release and transfer pyrene into living cells.Conclusion: A6K could be further exploited as a promising delivery system for hydrophobic drugs. Keywords: pyrene, self-assembling peptide, micelles, nanofibers, drug delivery

Dan Hua,1 Weiling Kong,2 Xuemin Zheng,2 Zhixing Zhou,2 Bing Yu,2 Yazhou Li,2 Yuli Wang,2 Xue Yang,2 Changxiao Liu,2 Lida Tang,2 Ying Li,3 Min Gong21School of Pharmacy, Tianjin Medical University, 2Tianjin Institute of Pharmaceutical Research, State Key Laboratory of Drug Delivery and Pharmacokinetics, 3Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of ChinaAbstract: Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.Keywords: matrix metalloproteinase, self-assembly, drug targeting system, paclitaxel

Jian Ding,1,* Dan Li,2,* Minzhen Gong,1 Jinpo Wang,1 Xunru Huang,1 Ting Wu,1 Chengdang Wang11Digestive Department of the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Digestive Department of Union Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workBackground: Highly sensitive markers are urgently needed for the diagnosis and grading of gastric cancer and for managing drug resistance. The recent identification of long-non-coding RNAs (lncRNAs) has provided new approaches for resolving this challenge. The aim of this study was to screen and identify new biomarkers for human gastric cancer from lncRNAs.Methods: First, we used lncRNA microarrays to conduct a preliminary screening for candidate lncRNAs of gastric cancer biomarkers in both human gastric cancer tissues and in two gastric cancer cell lines, SGC7901 cells and paclitaxel-resistant SGC7901 cells. The lncRNA plasmacytoma variant translocation 1 (PVT1) was found to exhibit higher expression in both gastric cancer tissues and the SGC7901 paclitaxel-resistant cell line. Quantitative polymerase chain reaction was used for large-scale analysis in a large number of human gastric cancer tissues to verify the involvement of PVT1 in development of gastric cancer. The relationships between PVT1 expression and clinical features were also analyzed.Results: PVT1 showed higher expression in human gastric cancer tissues than in adjacent non-cancerous tissues and in SGC7901 paclitaxel-resistant cells compared with SGC7901 cells. PVT1 expression was correlated with lymph node invasion of gastric cancer.Conclusion: PVT1 is a new biomarker for human gastric cancer and may indicate lymph node invasion. Therefore, PVT1 shows potential as a novel therapeutic target for the treatment of gastric cancer and enhancement of paclitaxel sensitivity.Keywords: microarray analysis, quantitative polymerase chain reaction, lymph node invasion, tumor biomarkers, paclitaxel resistance

Qiwen Zheng,1,* Shuhong Fu,2,* Dafang Chen,1 Xiaoxia Li,2 Yuru Li,2 Yanyan Li,2 Jihong Yu,2 Meiliang Gong,2 Jie Bai2 1Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, People's Republic of China; 2Nanlou Clinical Lab, Chinese PLA General Hospital, Beijing, People's Republic of China *These authors contributed equally to this work Objective: To estimate the value of the different thromboelastogram indices for predicting hemorrhage and vascular obstruction in an elderly population. Methods: This was a prospective cohort study of patients 65 years and older without hematologic disorders who received thromboelastography (TEG) examination at the Chinese People's Liberation Army General Hospital from January 2007 to December 2010. Detailed information was collected at recruitment including their TEG test results. Subjects were then followed during outpatient visits and hospitalization. The primary outcome measures were hemorrhage and vascular obstruction. Receiver-operating characteristics (ROC) curves were used to compare the predictive value of the four TEG indices, reaction time (R), clot formation time (K), maximal amplitude (MA), alpha angle (ANGLE) and their combination for predicting hemorrhage and vascular obstruction. The maximal Youden's index was used to estimate optimal cut-off values for the indices. Areas under the ROC curves were used to estimate overall predictive accuracies. Results: A total of 403 elderly patients met inclusion criteria and were included: 373 male and 30 females with mean age 83.0 ± 7.3 years and range of 65–103 years. Hemorrhage occurred in 25 (6.2%) patients and vascular obstruction in 78 (19.4%) patients during the 2-year follow up. The currently recommended TEG cut-off values were poorly predictive of vascular obstruction and modestly predictive of hemorrhage. Based on maximal Youden's, the optimal cutoffs of the TEG indices for predicting vascular obstruction were: R = 7, K = 1.5, MA = 63.5, and ANGLE = 67.1. A combination of all four showed the best predictive value (area under the ROC curve of 0.60, sensitivity 85.9%, and specificity 34.7%). The optimal cut-off values for predicting hemorrhage were: R = 7.8, K = 2.3, MA = 50.5, ANGLE = 53.7. A combination of R and MA was also most predictive of hemorrhage (area under ROC curve 0.66, sensitivity 60%, and specificity 71.7%). Conclusion: The currently adopted cut-off values for TEG indices are poorly and modestly predictive of hemorrhage and obstruction, respectively, in the elderly population. Optimal cut-off values determined by ROC curve analysis improved the prediction of vascular obstruction and hemorrhage. Keywords: thromboelastography, TEG, elderly, obstruction, hemorrhage, ROC curve, prediction

Hong Li1, Min Gong1, Aiping Yang1, Jian Ma2, Xiangde Li3, Yonggang Yan11School of Physical Science and Technology, Sichuan University, Chengdu People’s Republic of China; 2Hospital of Stomatology, Tongji University, ShanghaiPeople’s Republic of China; 3Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, People’s Republic of ChinaBackground and methods: A nano calcium-deficient hydroxyapatite (n-CDHA)-multi(amino acid) copolymer (MAC) composite bone substitute biomaterial was prepared using an in situ polymerization method. The composition, structure, and compressive strength of the composite was characterized, and the in vitro degradability in phosphate-buffered solution and preliminary cell responses to the composite were investigated.Results: The composite comprised n-CDHA and an amide linkage copolymer. The compressive strength of the composite was in the range of 88–129 MPa, varying with the amount of n-CDHA in the MAC (ranging from 10 wt% to 50 wt%). Weight loss from the composite increased (from 32.2 wt% to 44.3 wt%) with increasing n-CDHA content (from 10 wt% to 40 wt%) in the MAC after the composite was soaked in phosphate-buffered solution for 12 weeks. The pH of the soaking medium varied from 6.9 to 7.5. MG-63 cells with an osteogenic phenotype were well adhered and spread on the composite surface. Viability and differentiation increased with time, indicating that the composite had no negative effects on MG-63 cells.Conclusion: The n-CDHA-MAC composite had good cytocompatibility and has potential to be used as a bone substitute.Keywords: calcium deficient hydroxyapatite, multi(amino acid) copolymer, biocomposite, degradability, cytocompatibility