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Taoying Lu,1– 3 Mingyue Fan,1 Jianxiong Cai,4 Aolin Liu,1 Qianwen Xie,2,3 Xiaowen Zhou,1 Bei Chang,1 Lingjia Yin,2,3,5 Guli Jiang,6 Bin Sun,7 Wenyi Tang,7 Darong Wu4 1The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Outcome Assessment Research Team in Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Outcome Assessment Research Team in Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 4State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; 6Department of Scientific Research, Guangzhou Cadre Health Management Center, Guangzhou, People’s Republic of China; 7Department of Traditional Chinese Medicine, Guangzhou Cadre Health Management Center, Guangzhou, People’s Republic of ChinaCorrespondence: Darong Wu, State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, People’s Republic of China, Tel +86 13808869436, Email darongwu@gzucm.edu.cnBackground: Dampness syndrome is a basic syndrome of many major and chronic diseases. Early screening and identification of dampness syndrome are important. The Dampness Syndrome Scale of Chinese Medicine (DSSCM) was developed to measure the occurrence and severity of dampness syndrome. The measurement characteristics of the DSSCM should be further validated. The objective of this study is to evaluate the reliability and validity of the DSSCM based on a cross-sectional survey.Methods: The development of DSSCM was based on the traditional Chinese medicine (TCM) theory, expert consensus and clinical investigations. Participants were recruited from Guangdong Provincial Hospital of Chinese Medicine and Guangzhou Cadre Health Management Center in Guangdong Province, China. All participants completed the baseline questionnaire and DSSCM. The reliability of the DSSCM was evaluated by internal consistency reliability and test–retest reliability. The factor structure was tested with confirmatory factor analysis (CFA), while discriminant validity was evaluated by calculating the difference between the total score of the DSSCM and its four dimensions for participants with or without dampness syndrome. We used a clinician’s diagnosis of dampness syndrome as a criterion to evaluate the criterion validity. Multivariate regression analysis was used to analyze the associations among gender, age, height, and weight and dampness syndrome.Results: A total of 880 participants were enrolled for psychometric validation and 869 participants were included in the final analyses after exclusion. The mean age of the participants was 42.62± 12.86 years. The Cronbach’s alpha coefficients for the four dimensions of the DSSCM were 0.809, 0.891, 0.816 and 0.780. The ICCs for the four dimensions of the DSSCM were 0.806, 0.674, 0.780 and 0.760. For validity, the results showed that the DSSCM had good content validity, discriminant validity and criterion validity. For the CFA, the root mean square error of approximation (RMSEA) was 0.091; the standardized root mean square residual (SRMR) was 0.074; the comparative fit index (CFI) was 0.766; and the Tucker–Lewis index (TLI) was 0.745. Weight was found to be associated with the total scores of the DSSCM and its three dimensions.Conclusion: The DSSCM has good reliability and validity to support its use as a tool for assessing the severity of dampness syndrome. This study provides empirical evidence for future updates to the DSSCM.Keywords: dampness syndrome, dampness syndrome scale of Chinese medicine, reliability, validity

Jing Sun,1 Tracy Lu,1 Yan Dang,1 Zigang Xu,2 Ying Liu2 1Medical & Scientific Affairs, Haleon (Formerly GSK Consumer Healthcare), Shanghai, People’s Republic of China; 2Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children‘s Health, Beijing, People’s Republic of ChinaCorrespondence: Ying Liu, Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children’s Health, Beijing, People’s Republic of China, Email ying_lemon@aliyun.comAbstract: Mupirocin, an antibiotic produced by Pseudomonas fluorescens, is mainly used for the topical treatment of various skin and soft tissue infections caused by Staphylococcus (including methicillin-resistant Staphylococcus aureus) and Streptococcus around the world for decades. Nevertheless, the clinical application scope of mupirocin varies in different countries due to differences in their medical policies, prescription types, and drug resistance. According to the experience of Chinese doctors in the past few years, mupirocin presented low drug resistance rates, and could be used as a treatment option for various primary infections and secondary infections, with antibacterial effects in a broad application. In this review, we summarized the experience of mupirocin used in the Chinese population and discussed its clinical value to provide novel insights and inspiration for physicians.Keywords: experience, mupirocin, skin diseases, infectious

Rui Bai,1,2 Yuhang Sui,1,2 Tianqi Lu,1,2 Hua Chen,1,2 Gang Wang,1,2 Rui Kong,1,2 Hongtao Tan,1,2 Yongwei Wang,1,2 Guanqun Li,1,2 Bei Sun1,2 1Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 2Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of ChinaCorrespondence: Guanqun Li; Bei Sun, Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150001, People’s Republic of China, Email liguanqun@hrbmu.edu.cn; sunbei70@hrbmu.edu.cnPurpose: The effects of the step-jump approach on the survival and prognosis of infected pancreatic necrosis (IPN) patients have not yet been determined.Patients and Methods: Between November 2018 and June 2023, 188 patients were included in this study. There were 144 patients in the step-up group (the SU group) and 44 in the step-jump group (the SJ group). In the SU group, patients successfully treated with percutaneous catheter drainage (PCD) alone were classified into the SU-1 group (n=101), while those requiring additional surgery after PCD were categorized into the SU-2 group (n=43). In the SJ group, patients who underwent minimally invasive necrosectomy (MIN) without PCD were assigned to the SJ-1 group (n=34), whereas those who initially underwent PCD followed by immediate open surgery were placed in the SJ-2 group (n=10). Propensity score matching (PSM) was used to mitigate bias.Results: After PSM, a total of 34 pairs were successfully matched. A comparison of the SU group with the SJ-1 group (upfront MIN without PCD) revealed similar mortality rates (P=0.239); however, the incidences of multiple drug-resistant organisms (MDROs) (P=0.029) and surgical complications (P< 0.001) were significantly lower in the SJ-1 group. After comparing the SU-2 and SJ-2 groups (patients who underwent direct open necrosectomy without MIN after PCD failure), the incidences of surgical complications and MDRO in the SJ-2 group were significantly lower (P< 0.05).Conclusion: Compared with the step-up approach, the step-jump approach is safer and more effective and can significantly reduce the incidence of MDRO and surgical complications.Keywords: infected pancreatic necrosis, step-up approach, step-jump approach, propensity score match

Yanyi Wang,1,2,&ast; Juan Wen,1– 3,&ast; Tong Lu,1,2 Wei Han,2,4 Kai Jiao,5 Huang Li1,2 1Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 2Medical School of Nanjing University, Nanjing, People’s Republic of China; 3Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), School of Dentistry, The University of Queensland, Brisbane, Queensland, 4006, Australia; 4Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China; 5Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Han, Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, 30 Central Road, Nanjing, 210008, People’s Republic of China, Email doctorhanwei@hotmail.com Huang Li, Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, 30 Central Road, Nanjing, 210008, People’s Republic of China, Tel +86-25-83620173, Fax +86-25-83620200, Email lihuang76@nju.edu.cnAbstract: Extracellular vesicles (EVs) can deliver various bioactive molecules among cells, making them promising diagnostic and therapeutic alternatives in diseases. Mesenchymal stem cell-derived EVs (MSC-EVs) have shown therapeutic potential similar to MSCs but with drawbacks such as lower yield, reduced biological activities, off-target effects, and shorter half-lives. Improving strategies utilizing biotechniques to pretreat MSCs and enhance the properties of released EVs, as well as modifying MSC-EVs to enhance targeting abilities and achieve controlled release, shows potential for overcoming application limitations and enhancing therapeutic effects in treating bone-related diseases. This review focuses on recent advances in functionalizing MSC-EVs to treat bone-related diseases. Firstly, we underscore the significance of MSC-EVs in facilitating crosstalk between cells within the skeletal environment. Secondly, we highlight strategies of functional-modified EVs for treating bone-related diseases. We explore the pretreatment of stem cells using various biotechniques to enhance the properties of resulting EVs, as well as diverse approaches to modify MSC-EVs for targeted delivery and controlled release. Finally, we address the challenges and opportunities for further research on MSC-EVs in bone-related diseases.Keywords: extracellular vesicles, mesenchymal stem cells, functional modification, bone-related diseases

Zixian Liu, Tianming Lu, Ruoning Qian, Zian Wang, Ruogu Qi, Zhengguang Zhang School of Medicine, Nanjing University of Chinese Medicine, Jiangsu, Nanjing, People’s Republic of ChinaCorrespondence: Zhengguang Zhang; Ruogu Qi, Email zhengguangzhang@njucm.edu.cn; rqi@njucm.edu.cnBackground: Cancer continues to be a prominent issue in the field of medicine, as demonstrated by recent studies emphasizing the significant role of autophagy in the development of cancer. Traditional Chinese Medicine (TCM) provides a variety of anti-tumor agents capable of regulating autophagy. However, the clinical application of autophagy-modulating compounds derived from TCM is impeded by their restricted water solubility and bioavailability. To overcome this challenge, the utilization of nanotechnology has been suggested as a potential solution. Nonetheless, the current body of literature on nanoparticles delivering TCM-derived autophagy-modulating anti-tumor compounds for cancer treatment is limited, lacking comprehensive summaries and detailed descriptions.Methods: Up to November 2023, a comprehensive research study was conducted to gather relevant data using a variety of databases, including PubMed, ScienceDirect, Springer Link, Web of Science, and CNKI. The keywords utilized in this investigation included “autophagy”, “nanoparticles”, “traditional Chinese medicine” and “anticancer”.Results: This review provides a comprehensive analysis of the potential of nanotechnology in overcoming delivery challenges and enhancing the anti-cancer properties of autophagy-modulating compounds in TCM. The evaluation is based on a synthesis of different classes of autophagy-modulating compounds in TCM, their mechanisms of action in cancer treatment, and their potential benefits as reported in various scholarly sources. The findings indicate that nanotechnology shows potential in enhancing the availability of autophagy-modulating agents in TCM, thereby opening up a plethora of potential therapeutic avenues.Conclusion: Nanotechnology has the potential to enhance the anti-tumor efficacy of autophagy-modulating compounds in traditional TCM, through regulation of autophagy.Keywords: autophagy, nano-delivery, anti-cancer, traditional Chinese medicine

Yuling Gao,1 Yanrui Zhao,1 Hanzhou Wang,1 Xiaopei Xu,1 Zhexian Cheng,2 Tianchao Lu,1 Yang Liu,1 Junlin Zhou1 1Orthopedics Department, Affiliated Beijing Chaoyang Hospital of Capital Medical University, Bejing, People’s Republic of China; 2Preventive Dentistry Department, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of ChinaCorrespondence: Junlin Zhou; Yang Liu, Beijing Chaoyang Hospital, Capital Medical University, Gongtinan Road 8&num;, Beijing, 100020, People’s Republic of China, Email junlinzhou_article@outlook.com; y0ring1996@163.comBackground: This study aimed to create three-dimensional heat map and study the characteristic of fracture lines and represented fragments of OTA/AO type 43C pilon fractures.Methods: CT scan was performed in105 fractures diagnosed with OTA/AO type 43C pilon fractures between January 2017 and December 2022. Three-dimensional pilon fracture maps were created and converted into fracture heat maps. CT scan graphic parameters including the fracture line height, α angle, β angle, the ratio of the area and size of bone fragment represented by the fracture line to the total articular surface were measured.Results: The study included 105 patients with 91 males and 14 females. The fractures included C1 (n=16), C2 (n=23), and C3 (n=66). There was no statistically different among the most parameters except in the fracture-line height of the anterior fracture line (p=0.03) and the sagittal fracture line (p=0.02) between C2 and C3 pilon fractures. The average size of the anterolateral fragment, occupied approximately 13.5% of the articular surface area, was (11.5± 2.8) mm × (20.5± 6.3) mm with the average height of 29.8 mm. The average size of the posterolateral fragment, occupied approximately 13.0% of the articular surface area, was (15.7± 4.6) mm × (19.3± 4.0) mm with the average height of 19.1 mm.Conclusion: This study demonstrates that the articular surface fracture lines in the C type pilon fracture are formed by fixed main fracture lines. The understand of morphological and distribution characteristics of the fracture lines and size of fragments in OTA/AO type 43C pilon fractures would help the surgeons take suitable approach and fixation.Keywords: pilon fractures, heat map, three-dimensional reconstruction, classification

Qiuyan Guo,1,2,&ast; Tianming Lu,1,3,&ast; Min Zhang,4,&ast; Qixin Wang,1,2 Minghong Zhao,2,5 Tongchun Wang,6 Maobo Du1 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 2Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 3Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 4Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 5Laboratory Medicine, Guizhou Aerospace Hospital, Zunyi, Guizhou, 563000, People’s Republic of China; 6Traditional Chinese Medicine Orthopedics and Traumatology Department, Shandong Wendeng Orthopedic Hospital, Wendeng, Shandong, 264400, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Maobo Du, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China, Email mbdu@icmm.ac.cnBackground and Objective: Peptic ulcer is a high incidence gastrointestinal disease in China. Berberine (BBR) is a natural product isolated from the Chinese herb Coptis chinensis Franch that has protective effects in digestive diseases. We aimed to evaluate the ability of BBR to attenuate acute gastric ulcer induced by one-time administration of ethanol in the rat.Methods: Tissue pathological morphology, macroscopic score, ulcer healing rate, and serum levels of the inflammatory cytokines nitric oxide (NO), interleukin-6 (IL-6), and prostaglandin E2 (PGE2), and anti-inflammatory interleukin-10 (IL-10) were used to determine the efficacy of BBR and evaluated to identify the optimal dosage. Subsequently, transcriptome and metabolome sequencing were conducted in Control, Model, and optimal dosage groups to explore the pathogenesis of the disease and the mechanism of action of the drug. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), as well as those of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by enzyme-linked immunosorbent assay to verify the results of transcriptomics and metabolomics analyses.Results: BBR significantly improved the pathological morphology of gastric ulcers, increased the macroscopic score and healing rate, decreased serum levels of NO, IL-6, and PGE2, and increased serum levels of IL-10, thus effectively alleviating gastric ulcer severity. Transcriptome results showed that the therapeutic effect of BBR was mainly mediated by the arachidonic acid metabolism pathway at the gene level, which is closely associated with inflammation and increased levels of reactive oxygen species (ROS). The differentially accumulated metabolite prostaglandin E1, which is a negative regulator of ROS, was significantly up-regulated after BBR administration. The validation results indicated that BBR pretreatment increased SOD and GSH-Px enzyme activities, while reducing levels of the oxidative products MDA and MPO.Conclusion: This study demonstrated that BBR exerts a protective effect on acute gastric ulcer by promoting tricarboxylic acid cycle-mediated arachidonic acid metabolism. Keywords: Berberine, acute gastric ulcer, transcriptome, untargeted metabolomics

Xiaopei Xu, Qingnan Sun, Yang Liu, Dong Wang, Shuo Diao, Hanzhou Wang, Yuling Gao, Tianchao Lu, Junlin Zhou Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of ChinaCorrespondence: Junlin Zhou, Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel/Fax +86-01085231227, Email junlinzhou_article@outlook.comObjective: The aim was to evaluate the effects of different glenosphere eccentricities on impingement, range of motion (ROM), and muscle length during standard activities in reverse total shoulder arthroplasty (RSA).Methods: In this study, we utilized computational modeling techniques to create native shoulder and shoulder models undergoing RSA and simulate shoulder movements in all abduction-adduction, flexion-extension, and rotation. We tested a total of 36 different glenosphere configurations, which included three different inferior tilts (0°, +10°, +20°) and two different lateral offsets (0 mm and +4 mm), as well as six different glenosphere eccentricities (concentricity, inferior, posterior, anterior, anteroinferior, and posteroinferior). We evaluated the maximum impingement-free ROM, impingement sites, and muscle lengths.Results: All glenosphere configurations exceeded 50% of native shoulder ROM in three planes and total global ROM. In abduction-adduction, there was no significant difference among the different glenosphere eccentricities (p > 0.05). In flexion-extension, the posteroinferior eccentricity had the maximum ROM among the different eccentricities, but no significant difference among the different glenosphere eccentricities (p > 0.05). In rotation, there was a significant difference overall, and anteroinferior eccentricity had a significant advantage over concentricity (p < 0.05). In total global ROM, anteroinferior eccentricity had a significant advantage over concentricity when lateral offset was 0 mm (p < 0.05). In all models of glenosphere eccentricities, only the elongation of the infraspinatus muscle was statistically significant (p < 0.05).Conclusion: Glenosphere eccentricity significantly influenced rotation, total global ROM, and the length of the subscapularis muscle. Among them, anteroinferior offset achieved the maximum ROM in abduction-adduction, rotation, and total global activities. Both anteroinferior and inferior glenoid eccentricity showed significant advantages over the concentricity in rotation and total global ROM.Level of Evidence: Basic Science Study; Computer Modeling.Graphical Abstract: Keywords: reverse shoulder arthroplasty, glenosphere eccentricities, impingement, notching, range of motion, muscle length

Shan Chen,1 Jie Zhang,1 Chengjia Qian,2 Xiaowei Qi,3 Yong Mao,1 Tingxun Lu1 1Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, 214122, People’s Republic of China; 2Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, 214122, People’s Republic of China; 3Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, 214122, People’s Republic of ChinaCorrespondence: Tingxun Lu, Department of Oncology, Affiliated Hospital of Jiangnan University, 1000, Hefeng Road, Wuxi, 214122, Jiangsu, People’s Republic of China, Email lutingxun@163.comPurpose: We aim to investigate the clinical significance of dynamic changes in the lymphocyte-to-monocyte ratio (LMR) and neutrophil-lymphocyte ratio (NLR) in peripheral blood at different time points combined with CEA in the prediction of postoperative-recurrence-in-patients with colorectal cancer (CRC).Patients and Methods: This study collected 357 patients with stage I–III CRC between 2016 and April 2018. The dynamic changes from preoperative to postoperative LMR (p-LMR-p) and NLR (p-NLR-p) were analyzed using COX regression for multivariate analysis. Logistic regression was used to investigate whether the dynamic changes from post-treatment to pre-end of follow-up LMR (p-LMR-f) and NLR (p-NLR-f) were independent risk factors for CRC recurrence and to construct a predictive model. Internal validation using bootstrapping was performed to validate the discrimination ability of the model. The models’ discriminative effect, calibration degree, and clinical utility were assessed.Results: In both the total cohort and the adjuvant therapy group, the dynamic changes of p-LMR-p (High-High vs Low-Low: p=0.006; HR:2.210, 95% CI: 1.256– 3.890) were found to be independent prognostic factors for recurrence-free survival (RFS) in CRC patients. Additionally, logistic regression analysis revealed that N stage, CEA, LMR of pre-end of follow-up (f-LMR), and p-LMR-f were independent risk factors for CRC recurrence. In the total cohort, the p-LMR-f had an area under the curve (AUC) of 0.704, with a sensitivity of 64% and a specificity of 75.3%. By combining p-LMR-f with CEA, a predictive model was constructed, which showed an AUC of 0.913 (0.986– 0.913) in the total cohort and an AUC of 0.924 (0.902– 0.924) in the adjuvant therapy group during internal validation using bootstrapping.Conclusion: Dynamic changes in LMR can be used to predict the prognosis of CRC and serve as a biomarker for predicting CRC recurrence. Combined with CEA, it can improve the predictive performance for detecting CRC recurrence.Keywords: colorectal cancer, postoperative recurrence, predictive model, inflammatory markers

Jie Zhang,1 Tieshan Wang,2 Yinghui Shi,1 Yansong Liu,1 Tao Lu1 1School of Life Science, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Tao Lu, School of Life Science, Beijing University of Chinese Medicine, 11 Beisanhuandong Road, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +8610 6428 6705, Fax +86 10 6428 6821, Email taolu@bucm.edu.cnPurpose: With the increase in prevalence and decrease in age of the obese population, safer weight loss methods have attracted growing attention. While abdominal massage (AM) has been clinically proven for weight loss, the mechanism thereof has yet to be elucidated. We aimed to investigate the effect of AM on abdominal fat in obese mice fed a high-fat diet and explore the possible mechanisms involved.Materials and Methods: Male C57BL/6J mice were fed a high-fat diet for 16 weeks and then treated with AM for 5 weeks; mice fed a standard diet were used as normal controls. Blood and adipose tissue, including inguinal white adipose tissue (WAT) and epididymal WAT, were collected from the mice after the intervention. We explored the mechanism of weight reduction through inguinal WAT transcriptome sequencing, quantitative real-time polymerase chain reaction (PCR) validation, and Western blot.Results: The results revealed that AM decreased fat mass, weight, glucose, and serum lipid levels. Meanwhile, AM enhanced the expression of the peroxisome proliferator-activated receptor gamma (PPARγ) and other downstream genes (Fabp4, Acox3, Pck1, and Aqp7) in inguinal WAT. In addition, AM increased the expression of PPARγ protein.Conclusion: AM may promote fatty acid oxidation, lipid metabolism, and glucose homeostasis by activating the PPARγ signaling pathway in inguinal WAT, thereby exhibiting therapeutic efficacy against obesity, even in the presence of a persistent high-fat diet.Keywords: abdominal massage, inguinal white adipose tissue, high-fat diet, transcriptome sequencing, PPAR&#x03B3

Shaodan Zhou,1 Yishuang Wen,1 Chao Liu,1 Jian Zhong,1 Manli Liang,1 Yu Wu,2 Sirao Lv,1 Zhuowei Gong,1 Dayuan Lao,1 Taiyan Li,1 Ting Lu,1 Jingqun Tang,1 Xuean Mo,1 Wen Huang1 1Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2University of Pittsburgh School of Medicine, Pittsburgh, PA, USACorrespondence: Wen Huang, Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China, Tel +86-771-5356504, Fax +86-771-5350031, Email hwen1229@163.comPurpose: With the adjustment of prevention strategies in December 2022, coronavirus disease 2019 (COVID-19) became widely prevalent in China. This study is aimed to describe the clinical characteristics of myasthenia gravis (MG) patients with COVID-19 and identify risk factors of exacerbation in MG patients with COVID-19 in Guangxi.Patients and Methods: A total of 489 MG patients and 587 control subjects in Guangxi during the COVID-19 pandemic were enrolled in this case–control study. After contacting the participants, the clinical data of MG patients and the control group were analyzed. The clinical characteristics of MG patients with COVID-19 were described. Multivariable logistic regression analysis was used for discovering independent risk factors of MG exacerbation in the patients with MG and COVID-19.Results: A total of 311 (75.30%) MG patients and 428 (72.91%) control subjects were infected with COVID-19, and 64.31% of MG patients with COVID-19 were women. The median age at the time of interview was 41 (IQR: 28, 54) years old, and median onset age was 36 (IQR: 24, 51), both of which were lower than those in MG patients without COVID-19. MG duration was 24 (IQR: 9, 72) months. About 44.69% of patients were generalized MG (GMG). About 11.90% of MG patients with COVID-19 showed severe COVID-19 symptoms and the duration of symptomatic COVID-19 was 9.57 ± 6.79 days, higher than those in the control group. About 35.69% MG patients with immunosuppressive drugs were infected with COVID-19, which is higher than those in the non-infected MG patients (21.57%). A total of 120 (38.59%) MG patients with COVID-19 had comorbidities. About 21 (20.19%) of the 104 MG patients without vaccination showed severe COVID-19 symptoms. Multivariable logistic regression analysis showed that baseline MG activities of daily living profile (MG-ADL, OR 1.280, 95% CI: 1.010– 1.621, p = 0.041), duration of COVID-19 (OR 1.158, 95% CI: 1.100– 1.220, p < 0.001), GMG (OR 2.331, 95% CI: 1.228, 4.426, p = 0.010), and lack of COVID vaccination (OR 2.075, 95% CI: 1.152, 3.738, p = 0.015) were independent factors of exacerbation in MG patients with COVID-19.Conclusion: MG patients with immunosuppressive drugs, younger onset, longer MG duration, or comorbidities are more susceptible to COVID-19. The baseline MG-ADL, duration of symptomatic COVID-19, GMG, and lack of COVID-19 vaccination are independent risk factors of exacerbation in MG patients with COVID-19.Keywords: myasthenia gravis, COVID-19, exacerbation, vaccination, clinical characteristics

Tianchang Lu,1,&ast; Minyi Wang,1,2,&ast; Nannan Liu,1 Shuqiong Zhang,3 Lei Shi,1 Ling Bao,3 Feng Luo,3 Li Shi,1 Shuyuan Liu,1 Yufeng Yao4 1Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, People’s Republic of China; 2School of Life Science, Yunnan University, Kunming, 650500, People’s Republic of China; 3Department of Clinical Laboratory, The Third People’s Hospital of Kunming, Kunming, 650041, People’s Republic of China; 4Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, 650118, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuyuan Liu, Department of Immunogenetics, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, People’s Republic of China, Tel +86 871 68334483, Email shuyuanliuoo@gmail.com Yufeng Yao, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, 650118, People’s Republic of China, Tel +86 871 68335632, Email leoyyf@gmail.comPurpose: Tuberculosis (TB) is known to result from a complex interaction between the host immune response and Mycobacterium infection. The transporter associated with antigen processing (TAP) plays an important role in the processing and presentation pathways for the Mycobacterium tuberculosis (M. tb) antigen. To investigate the possible association of the TAP1 and TAP2 genes with TB.Patients and Methods: A total of 449 TB patients and 435 control subjects were included in this study, and single nucleotide polymorphisms (SNPs) in the TAP gene, as well as TAP1 and TAP2 alleles, were genotyped.Results: TAP gene association analysis of TB diseases showed that rs41551515-T in the TAP1 gene was significantly associated with susceptibility to TB (P=7.96E-04, OR=4.124, 95% CI: 1.683– 10.102), especially pulmonary TB (PTB, P=6.84E-04, OR=4.350, 95% CI: 1.727– 10.945), and the combination of rs1057141-T-rs1135216-C in the TAP1 gene significantly increased the risk of TB susceptibility (P=5.51E-05, OR=10.899, 95% CI: 2.555– 46.493). Five novel TAP1 alleles were detected in Yunnan Han people, and the allele frequency of TAP1&ast;unknown_3 (rs41555220-rs41549617-rs1057141-rs1135216-rs1057149-rs41551515: C-A-T-C-C-T) was notably increased in all TB patients, including in the PTB and EPTB subgroups, and was significantly associated with the risk of susceptibility to TB. However, no association between the TAP2 gene and TB was found in this study.Conclusion: Host genetic variants of rs41551515-T and the combination rs1057141-T-rs1135216-C, as well as TAP1&ast;unknown_3 may play a critical role in susceptibility to TB disease.Keywords: tuberculosis, association, TAP gene, polymorphism, novel allele

Yalan Yang,1,&ast; Dao Xin,2,&ast; Huike Wang,1,&ast; Lulu Guan,1 Xiangrui Meng,1 Taiying Lu,1 Xiwen Bai,3 Feng Wang1 1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Translational Medicine, Nanchang University Queen Mary School, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Wang, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China, Email zzuwangfeng@zzu.edu.cnPurpose: Neoadjuvant immunochemotherapy (nICT) for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) has attracted widespread attention recently, whose safety and clinical benefit was observed in clinical researches. This study aimed to develop and validate a novel predictor systemic inflammation-tumor markers index (SITI) to predict the pathological complete response (pCR) for resectable LA-ESCC patients receiving nICT.Patients and Methods: A total of 147 LA-ESCC patients who underwent nICT followed by surgery from February 2020 to April 2022 were included in the study. The dynamic change of inflammatory indexes was compared at baseline, after two cycles of nICT and postoperative one month. Least absolute shrinkage and selection operator (LASSO) regression was performed to avoid collinearity and identify key indexes, with SITI constructed. After univariate and multivariate stepwise forward logistic analyses, a nomogram for pCR prediction was developed.Results: 41(27.9%) patients achieved pCR among 147 resectable LA-ESCC patients received nICT. Compared with baseline, most inflammatory indexes were significantly decreased at postoperative one month. 5 key indexes were identified and then a predictive index named SITI was constructed. The result showed that lower SITI and earlier clinical tumor node metastasis (cTNM) stage were more likely to achieve pCR. The nomogram for pCR prediction had excellent discrimination performance (C-index = 0.791).Conclusion: The SITI is an independent predictor for pCR in resectable LA-ESCC patients received nICT. To our knowledge, our nomogram is the first model using systemic inflammation-tumor markers for pCR prediction and may be a promising predictor to effectively differentiate pCR for nICT in LA-ESCC patients.Keywords: esophageal squamous cell carcinoma, neoadjuvant therapy, immunotherapy, pathologic complete response, inflammation, nomogram

Ting Lei,1,2,&ast; Tingting Lu,3,4,&ast; Haichuan Yu,1,2,&ast; Xiaojie Su,1,2 Chuchu Zhang,1,2 Lei Zhu,1,2 Kehu Yang,4,5 Jian Liu1,2 1Department of Clinical Medicine, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 2Department of Critical Care Medicine, the First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 3Institute of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, 730000, People’s Republic of China; 4Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, People’s Republic of China; 5Key Laboratory of Evidence-Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, 730000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Liu, No. 1, Donggang West Road, Chengguan District, Lanzhou, Gansu Province, Tel +86 136 0935 4197, Email medecinliu@sina.com; Kehu Yang, Evidence-Based Medicine Center, Lanzhou University, 199 West Donggang R.D, Lanzhou, 730000, People’s Republic of China, Email kehuyangebm2020@163.comBackground: In recent years, the pleiotropic roles of antioxidants have drawn extensive attention in various diseases. Vitamin C is a well-known antioxidant, and it has been used to treat patients with chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis aim to demonstrate the impact of vitamin C supplementation in patients with COPD.Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), SinoMed, Wanfang, and China Science and Technology Journal Database (cqvip.com) for eligible randomized controlled trials (RCTs) from their respective inception to May 18th, 2021, by using the searching terms of COPD, vitamin C, and RCTs. A meta-analysis was performed to evaluate the effects of vitamin C on lung function, antioxidant levels, and nutritional conditions in COPD patients by using Review Manager (Version 5.4).Results: Ten RCTs including 487 participants were eligible for our study. Meta-analysis results showed that vitamin C supplementation (≥ 400 mg/day) can significantly improve the forced expiratory volume in one second as a percentage (FEV1%) in COPD (SMD:1.08, 95% CI:0.03, 2.12, P=0.04). Moreover, vitamin C supplementation significantly improved the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) (WMD:0.66, 95% CI: 0.26, 1.06, P=0.001), vitamin C level in serum (SMD:0.63, 95% CI: 0.02, 1.24, P=0.04) and glutathione (GSH) level in serum (SMD:2.47, 95% CI: 1.06, 3.89, P=0.0006). While no statistically significant difference was observed in body mass index (BMI), fat-free mass index (FFMI), vitamin E level and superoxide dismutase (SOD) level in serum.Conclusion: Vitamin C supplementation could increase the levels of antioxidation in serum (vitamin C and GSH) and improve lung function (FEV1% and FEV1/FVC), especially in patients treated with vitamin C supplementation greater than 400 mg/day. However, further prospective studies are needed to explore the role of vitamin C in improving nutritional status.Keywords: vitamin C, COPD, RCTs, lung function, meta-analysis

Taoying Lu,1– 3 Jingwen Yan,4 Jianfang Chang,5 Jianxiong Cai,1– 3 Lingjia Yin,1,3,6 Jiamin Yuan,1,7 Li Huang,1,7 Yingshuai Li,8 Minghua Bai,9 Kit-Tai Hau,5 Darong Wu,1– 3 Zhimin Yang1,7 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Program for Outcome Assessment in TCM, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 4The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Education Psychology, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China; 6Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; 7Health Construction Administration Center, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 8National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 9School of Traditional Chinese Medicine/National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Darong Wu; Zhimin Yang, State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120, People’s Republic of China, Tel +86 13808869436 ; +86 13822296363, Email darongwu@gzucm.edu.cn; yangyo@vip.tom.comBackground: Body constitution is a fundamental concept in traditional Chinese medicine (TCM) for clinical diagnosis, treatment of illness, and community-based health promotion. Clinical assessment of patients’ body constitutions, however, has never been easy and consistent, even by well-trained clinicians and TCM practitioners. Therefore, questionnaires such as the popular Constitution in Chinese Medicine Questionnaire (CCMQ) can be an appealing and convenient assessment alternative. The present research borrowed advanced methodologies for questionnaire development in psychology and other social sciences to examine the performance of the CCMQ in terms of (i) the strength of relations of each item with its designated constitution, (ii) the reliabilities of each constitution, and (iii) the overall 9-constitution structure. This research provided empirical evidence to support the use of the CCMQ and proposed directions for refinement in future revisions of the CCMQ or similar measures.Methods: A total of 1571 volunteers from three villages in southern China participated in the CCMQ survey. The item characteristics, reliabilities, interconstitution correlations, and confirmatory factor analysis of the 9-body-constitution structure were examined.Results: The results generally supported the appropriateness of the clinical observations (the questionnaire items) and the CCMQ 9-constitution classification structure. Nevertheless, some relatively weaker items, item pairs with similar meanings, and highly overlapping constitutions were identified for future CCMQ revisions.Conclusion: The CCMQ measured the 9 constitutions efficiently and with reasonably good reliability and construct validity. Given the various challenges to assessing TCM body constitutions even by experienced clinicians, the CCMQ provides an appealing alternative to measure the Chinese body constitutions of healthy participants in large-scale research or community health promotion programs. The present study also demonstrated how advanced methodologies in social sciences can help validate and refine the CCMQ and similar complementary medicine measures.Keywords: Chinese constitution, body constitution, CCMQ, Constitution in Chinese Medicine Questionnaire, reliability, construct validity

Wenting Chen,1 Jinxi Liu,1 Caiyun Zheng,1 Que Bai,1 Qian Gao,1 Yanni Zhang,1 Kai Dong,2 Tingli Lu1 1Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, 710072, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710072, People’s Republic of ChinaCorrespondence: Tingli Lu, Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, 710072, People’s Republic of China, Tel/Fax +86 29 8846 0332, Email lutinglixinxin@nwpu.edu.cn Kai Dong, School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710072, People’s Republic of China, Tel/Fax +86 29-82655139, Email dongkai120@xjtu.edu.cnAbstract: In recent years, chemodynamic therapy (CDT) has received extensive attention as a novel means of cancer treatment. The CDT agents can exert Fenton and Fenton-like reactions in the acidic tumor microenvironment (TME), converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH). However, the pH of TME, as an essential factor in the Fenton reaction, does not catalyze the reaction effectively, hindering its efficiency, which poses a significant challenge for the future clinical application of CDT. Therefore, this paper reviews various strategies to enhance the antitumor properties of nanomaterials by modulating tumor acidity. Ultimately, the performance of CDT can be further improved by inducing strong oxidative stress to produce sufficient ·OH. In this paper, the various acidification pathways and proton pumps with potential acidification functions are mainly discussed, such as catalytic enzymes, exogenous acids, CAIX, MCT, NHE, NBCn1, etc. The problems, opportunities, and challenges of CDT in the cancer field are also discussed, thereby providing new insights for the design of nanomaterials and laying the foundation for their future clinical applications.Graphical Abstract: Keywords: chemodynamic therapy, Fenton/Fenton-like reactions, tumor microenvironment, reactive oxygen specie

Yiping Li,1,&ast; Jia Yang,2,&ast; Wenyu Tao,1 Man Yang,1 Xiaoling Wang,1 Tinglian Lu,1,3 Chuanyin Li,2 Ying Yang,1 Yufeng Yao2 1Department of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming City, Yunnan, People’s Republic of China; 2Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming City, People’s Republic of China; 3School of Clinic Medicine, Dali University, Dali City, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying YangDepartment of Endocrinology, The Affiliated Hospital of Yunnan University & The Second People’s Hospital of Yunnan Province, Kunming, 650021, Yunnan, People’s Republic of ChinaEmail yangying2072@126.comYufeng YaoInstitute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan, 650118, People’s Republic of ChinaEmail leoyyf@gmail.com; yufeng_yao@imbcams.com.cnBackground: Insulin receptor (INSR), insulin receptor substrate (IRS) and glucose transporter 4 (GLUT4) play important roles in the insulin resistance pathway. The microRNA (miRNA or miR) involved in INSR, IRS or GLUT4 could be associated with the development of type 2 diabetes (T2DM).Methods: The aim of this study was to investigate the association of T2DM with 12 single nucleotide polymorphisms (SNPs) in 7 miRNAs (miR-195, miR-126, miR-144, miR-155, miR-21, miR-93 and miR-222) involved in the insulin resistance pathway. A total of 1593 subjects with T2DM and 1656 nondiabetic subjects were genotyped. Then, the associations of these SNPs with the development of T2DM and individual metabolic traits were evaluated, such as fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1C).Results: Our data showed that the C allele of rs1292037 in miR-21 could increase the risk of developing T2DM (P = 0.002, OR = 1.17; 95% CI: 1.06– 1.29). In addition, the T allele of rs13137 in miR-21 could be a risk factor for T2DM (P = 0.003, OR = 1.16; 95% CI: 1.05– 1.28). According to inheritance mode analysis, compared with the T/T-T/C genotype, the C/C genotype of rs1292037 showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13– 1.63). For rs13137, compared with the A/A-A/T genotype, the T/T genotype also showed a risk effect in T2DM in the recessive mode (P = 0.001, OR = 1.35; 95% CI: 1.13– 1.62). Moreover, in the nondiabetic group, compared with the rs78312845 A/G (FPG = 5.177± 0.488mmol/L; HbA1C = 5.147± 0.293%) and A/A genotypes (FPG = 5.155± 0.486mmol/L; HbA1C = 5.136± 0.299%), the G/G genotype (FPG = 4.887± 0.482mmol/L; HbA1C = 4.960± 0.397%) was associated with lower FPG (P = 0.012 and 0.019) and HbA1C (P = 0.008 and 0.011).Conclusion: Our results revealed that rs1292037 and rs13137 in miR-21 were associated with T2DM susceptibility in a Han Chinese population. Moreover, the rs78312845 in miR-195 contributed to the level of FPG and HbA1C in nondiabetic group in the Han Chinese population.Keywords: polymorphisms, T2DM, insulin resistance, Chinese population, microRNA

Tao Lu, Jai Prakash Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The NetherlandsCorrespondence: Jai PrakashEngineered Therapeutics, Department of Biomaterials Science and Technology, University of Twente, Drienerlolaan 5, Enschede, 7500AE, The NetherlandsTel +31 53 4893096Email j.prakash@utwente.nlAbstract: Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.Keywords: pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, tumor stroma, tumor vasculature, drug perfusion, drug penetration

Xing Li,&ast; Hua Shen,&ast; Tinghong Zhou, Xiaoyu Cao, Ying Chen, Yan Liang, Ting Lu, JiaFen He, ZhouLin Dou, ChuaiKai Liu, Yong Tang, Zeixang Zhu Department of Critical Care, Changsha of Traditional Chinese Medicine Hospital, Changsha, 410010, Hunan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zeixang Zhu; Yong TangDepartment of Critical Care, Changsha of Traditional Chinese Medicine Hospital, No. 22, Xingsha Road, Changsha, 410010, Hunan Province, People’s Republic of ChinaEmail Zhuzexiang12@163.com; 407891521@qq.comBackground: Sepsis is the leading cause of death in critically ill patients, and the prevention of which requires precise outcome prediction and early intervention. We evaluated the prognostic prediction value of serum thioredoxin-1 (Trx-1) as an anti-inflammatory factor in patients with sepsis.Methods: As a prospective study, patients with sepsis admitted to the intensive care unit (ICU) of our hospital during 2020 were recruited. Medical history collection, sequential organ failure assessment (ΔSOFA), and laboratory tests were performed within 24 h of admission. Serum levels of Trx-1 and other inflammatory biomarkers were detected with samples dynamically collected before, during, and after septic shock. Patients were categorized as survivors and non-survivors according to survival status on day 28. Correlation between Trx-1 and other sepsis-associated parameters as well as the correlation of Trx-1 and other sepsis-associated parameters with 28-day mortality were evaluated. Prognostic factors were identified by Cox regression analyses.Results: A total of 187 patients were recruited. Serum Trx-1 level was positively correlated with inflammatory factors (interleukin-6, C-reactive protein, procalcitonin) and index of sepsis severity (ΔSOFA score, partial pressure of oxygen/fraction of inspired oxygen), all of which were significantly higher in non-survivors than survivors. While Trx-1 level at different timepoints and its evolution over time significantly differed between survivors and non-survivors, the initial Trx-1 level outperformed the other parameters in predicting 28-day survival. With 38.27 ng/mL as the cutoff value, serum Trx-1 predicted 28-day survival with optimal sensitivity and specificity.Conclusion: Early increases in serum levels of Trx-1 can predict 28-day mortality in sepsis patients in the ICU.Keywords: thioredoxin-1, prognosis, sepsis, mortality

Yiting Huang,1,2 Siyi Yu,2 Georgia Wilson,2 Joel Park,2 Ming Cheng,2 Xuejun Kong,3 Tao Lu,1 Jian Kong2 1School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Martino Imaging Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Tao LuSchool of Life Sciences, Beijing University of Chinese Medicine, No. 11 East Road, North 3rd Ring Road, Beijing, 100029, People’s Republic of ChinaEmail taolu@bucm.edu.cnJian KongDepartment of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 120 2nd Ave, Room 101C, Charlestown, MA, 02129, USAEmail jkong2@mgh.harvard.eduIntroduction: Previous studies have suggested that cerebral projections of the norepinephrine (NE) and dopamine (DA) systems have important etiology and treatment implications for autism spectrum disorder (ASD).Methods: We used functional magnetic resonance imaging to evaluate spontaneous resting state functional connectivity in boys aged 7– 15 years with ASD (n=86) and age-, intelligence quotient-matched typically developing boys (TD, n=118). Specifically, we investigated functional connectivity of the locus coeruleus (LC) and ventral tegmental area (VTA), the main source projection of neurotransmitters NE and DA, respectively.Results: 1) Both the LC and VTA showed reduced connectivity with the postcentral gyrus (PoCG) in boys with ASD, reflecting the potential roles of NE and DA in modulating the function of the somatosensory cortex in boys with ASD. 2) The VTA had increased connectivity with bilateral thalamus in ASD; this alteration was correlated with repetitive and restrictive features. 3) Altered functional connectivity of both the LC and VTA with brain regions such as the angular gyrus (AG), middle temporal gyrus visual area (MT/V5), and occipital face area (OFA) in ASD group.Discussion: Our findings implicate the role of LC-NE and VTA-DA systems from the perspective of functional neuroimaging and may shed light on pharmacological studies targeting NE and DA for the treatment of autism in the future.Keywords: autism spectrum disorder, locus coeruleus, ventral tegmental area, norepinephrine, dopamine, functional connectivity

Que Bai,1,* Kai Han,1,* Kai Dong,1 Caiyun Zheng,1 Yanni Zhang,1 Qianfa Long,2 Tingli Lu1 1School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710072, People’s Republic of China; 2Mini-Invasive Neurosurgery and Translational Medical Center, Xi’an Central Hospital, Xi’an Jiaotong University, Xi’an 710003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qianfa Long; Tingli Lu Tel +86 029-88460332Email lonva@live.cn; lutinglixinxin@nwpu.edu.cnAbstract: Diabetic wound shows delayed and incomplete healing processes, which in turn exposes patients to an environment with a high risk of infection. This article has summarized current developments of nanoparticles/hydrogels and nanotechnology used for promoting the wound healing process in either diabetic animal models or patients with diabetes mellitus. These nanoparticles/hydrogels promote diabetic wound healing by loading bioactive molecules (such as growth factors, genes, proteins/peptides, stem cells/exosomes, etc.) and non-bioactive substances (metal ions, oxygen, nitric oxide, etc.). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favored by researchers. In addition, nanoparticles/hydrogels can be combined with some technology (including PTT, LBL self-assembly technique and 3D-printing technology) to treat diabetic wound repair. By reviewing the recent literatures, we also proposed new strategies for improving multifunctional treatment of diabetic wounds in the future.Keywords: hydrogels, nanoparticles, nanotechnology, diabetic wound healing

Yuansheng Zheng,1,* Yiwei Huang,1,* Guoshu Bi,1,* Zhencong Chen,1 Tao Lu,1 Songtao Xu,1,2 Cheng Zhan,1 Qun Wang1 1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai City, People’s Republic of China; 2Department of Thoracic Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen City, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng Zhan; Qun WangDepartment of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel/Fax +86-21-64041990Email czhan10@fudan.edu.cn; wang.qun@zs-hospital.sh.cnBackground: Most non-small cell lung cancer patients with enlarged mediastinal lymph nodes (LN) in preoperative computer tomography (CT) images are diagnosed with N0 in the pathological examination after surgery. However, these patients seem to have worse survival than those without enlarged mediastinal LN in our clinical practice. This study aimed to investigate whether the size of mediastinal LN is correlated with the prognosis in pathological N0 patients, which could help us to predict the prognoses further.Methods: The retrospective cohort study involved 758 N0 patients with a thin layer CT scan. We have measured the size of mediastinal LN, including long diameter, short diameter, and volume on CT image, and classified patients by X-tile. Next, we explored the risk factors of enlarged LN by univariate and multivariate logistic analysis. Then, we have compared the 5-year cancer-specific survival by Kaplan–Meier and log-rank method. Multivariate Cox analysis was utilized to further survival analysis. Finally, we have constructed the prediction model by nomogram.Results: A total of 150 N0 patients (19.8%) had mediastinal LN enlargement in our study. After multivariate logistic analysis, we found the LN enlargement was significantly correlated with age (p=0.001), pathology (p < 0.001) and tumor recurrence (p < 0.001). The patients with LN enlargement had a worse 5-year cancer-specific survival (75.3% vs 92.8%, p < 0.001) after Kaplan–Meier analysis. Patients with a larger volume had increased risk of tumor-associated death when compared with the normal group (p < 0.001) by multivariate Cox analyses.Conclusion: N0 patients with larger mediastinal LN had a worse 5-year cancer-specific survival and a higher risk of recurrence. The volume of LN was the most valuable prognostic factor in N0 patients.Keywords: mediastinal lymph nodes, enlarged, prognosis, computed tomography

Ainian Chen,1 Lingling Zhong,1 Keju Ju,1 Ting Lu,1 Jia Lv,2 Hua Cao1 1Department of Neurology, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China; 2Department of Neurosurgery, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of ChinaCorrespondence: Hua CaoDepartment of Neurology, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, 01 Huanghe Road West, Huai’an 223300, Jiangsu, People’s Republic of ChinaTel/Fax +86 13861565810Email hacan979@yeah.netBackground: Glioblastoma (GBM) is the most common primary malignant tumor in adult central nervous system and results in disappointing survival outcomes. Although the diagnosis and therapy approach have been developed recently, the prognosis of GBM remains poor. A novel, minimally invasive biomarker for GBM is necessary for early diagnosis or prognosis prediction.Methods: All circRNAs were detected by qRT-PCR in GBM samples including training and validation sets. We used the risk score analysis to assume the diagnosis ability for GBM. The receiver operating characteristic curve was also employed.Results: Among the 14 candidates, circRNA, circNT5E, circFOXO3, circ_0001946, circ_0029426, circ-SHPRH, and circMMP9 were detected with increased levels in the training set. Further investigation in the validation set indicated that circFOXO3, circ_0029426, and circ-SHPRH might be the fingerprints for GBM compared with controls. The risk score analysis revealed that the combination of three circRNAs could distinguish the GBM from healthy control with the area under curve value of 0.980 and 0.906, respectively.Conclusion: The three circRNAs might be novel fingerprints for predicting the occurrence of GBM.Keywords: glioma, circRNA, plasma, biomarker, serum

Qiaojuan Guo, 1–3,* Mengwei Chen, 4,* Hanchuan Xu, 1 Tianzhu Lu, 1 Han Zhou, 1 Yanyan Chen, 1 Jingfeng Zong, 1 Yun Xu, 1 Bijuan Chen, 1 Bingyi Wang, 1 Lili Zhu, 1 Jianji Pan, 1, 2 Shaojun Lin 1, 2 1Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People’s Republic of China; 2Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People’s Republic of China; 3Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Radiation Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China*These authors contributed equally to this workCorrespondence: Shaojun LinDepartment of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou 350014, People’s Republic of ChinaTel +86 591-83638732Fax +86 591-83928767Email linshaojun@yeah.netBackground: In this study, we retrospectively evaluated a series of metastatic nasopharyngeal carcinoma (mNPC) patients who received oral maintenance chemotherapy using S-1/capecitabine after systemic chemotherapy and local radiation therapy, and aimed to explore potential efficient treatment strategies for this subset of patients.Patients and Methods: Thirty-seven patients with mNPC (19 newly diagnosed metastatic patients and 18 metastatic cases after definitive chemoradiotherapy) who received the treatment strategies mentioned above were analyzed.Results: After a median follow-up time of 37 months, the 3-year progression-free survival and overall survival (OS) rates were 47.6% and 87.7%, respectively. The median time to progression was 27.6 months, while the median OS was not reached at time of last follow-up. The most common acute adverse events were hematological and gastrointestinal toxicity, and all were tolerable and curable.Conclusion: Oral maintenance chemotherapy using S-1/capecitabine in mNPC patients after systemic chemotherapy could yield a superb outcome. Further multicenter prospective clinical trials are warranted.Keywords: metastatic nasopharyngeal carcinoma, maintenance chemotherapy, systemic chemotherapy, S-1, capecitabine

Guoshu Bi,* Tao Lu,* Guangyu Yao, Yunyi Bian, Mengnan Zhao, Yiwei Huang, Yi Zhang, Liang Xue, Cheng Zhan, Hong Fan Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Fan; Cheng ZhanZhongshan Hospital, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People’s Republic of ChinaTel +86 139 1689 7139Fax +86 21 6404 1990 Ext 2915Email fan.hong@zs-hospital.sh.cn; czhan10@fudan.edu.cnBackground: Lymph node ratio (LNR), defined as the ratio of the number of positive lymph nodes to the total of all resected nodes, has been reported to be a predictor of survival of patients with several types of cancer. However, the prognostic value of LNR and other factors in patients with resected N2 stage lung squamous cell carcinoma has never been considered.Methods: Data from 1778 patients with resected N2 stage lung squamous cell carcinoma were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of LNR was identified by X-tile. A multivariable Cox model and corresponding nomogram were constructed to predict overall survival (OS) and cancer-specific survival (CSS). Both the cutoff value of LNR and the model were further validated in 146 similar patients treated in Zhongshan Hospital. Heat maps were created to visualize the distribution of LNR and the number of positive lymph nodes with the predicted survival probabilities.Results: The optimal cutoff value for LNR was identified as 0.42. Multivariable analysis showed that age, sex, tumor laterality, type of surgery, T stage, chemotherapy and LNR were independently correlated with OS. Harrell’s C-index of the nomogram (0.64) was significantly higher than the index of the T stage-based model (0.54). Calibration curves showed good agreement between predicted and observed survival probabilities. The robustness of the model was also demonstrated by external validation.Conclusion: LNR less than 0.42 was associated with improved OS and CSS for patients with resected N2 stage lung squamous cell carcinoma.Keywords: lymph node ratio, N2 stage lung squamous cell carcinoma, prognostic model, nomogram, heatmap

Kai Dong,* Qiuya Lei,* Runhao Guo, Xianglong Wu, Yanni Zhang, Ning Cui, Jian-Yu Shi, Tingli LuKey Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workPurpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells.Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells.Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels.Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.Keywords: reactive oxygen species, oxidative stress, cinnamaldehyde, TPGS, nanogels

Jinyi Lang*,1 Chaosu Hu*,2 Taixiang Lu,3 Jianji Pan,4 Tongyu Lin51Department of Radiation Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, People’s Republic of China; 5Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workAbstract: Nasopharyngeal carcinoma (NPC) is a rare type of head and neck cancer, with a higher incidence reported only in Southeast Asia and Northern Africa. Owing to the rarity of NPC occurrence, no internationally accepted consensus or guideline for its diagnosis and treatment is available. Based on the current evidences and practices, the Chinese experts on multidisciplinary diagnosis and treatment of NPC were designated to develop a national consensus for the treatment strategy of NPC. In this consensus, we report the development for improving the treatment efficacy and quality of life of NPC patients in China. The consensus also describes and recommends the role of multidisciplinary management approach in the management of NPC. A multidisciplinary team should include experts from different domains who can cater to the individualized needs of patients with NPC in a much more efficient manner. In addition, the team may also play a key role in developing guiding principles for future research, contributing to the improvement in the management of NPC.Keywords: Asian, Chinese, consensus, nasopharyngeal carcinoma, radiotherapy

Huocong He*,1 Shuo Qie,*,2,3 Qiaojuan Guo,4 Shuyang Chen5,6 Changyan Zou,1 Tianzhu Lu,4 Ying Su,1 Jingfeng Zong,4 Hanchuan Xu,4 Dan He,5 Yun Xu,4 Bijuan Chen,4 Jianji Pan,4 Nianli Sang2,5 Shaojun Lin41Department of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People’s Republic of China; 2Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA 19104, USA; 3Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA; 4Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People’s Republic of China; 5Department of Biology, Drexel University College of Arts & Sciences, Philadelphia, PA 19104, USA; 6Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA*These authors contributed equally to this workBackground: Stanniocalcin 2 (STC2) expression is upregulated under multiple stress conditions including hypoxia, nutrient starvation and radiation. Overexpression of STC2 correlates with tumor progression and poor prognosis.Purpose: We previously demonstrated that overexpression of STC2 in nasopharyngeal carcinomas (NPC) positively correlates with radiation resistance and tumor metastasis, two major clinical obstacles to the improvement of NPC management. However, it remains elusive whether STC2 expression is a critical contributing factor for post-radiation survival and metastasis of NPC cells.Materials and methods: Using the radiation resistant CNE2 cell line as a model, we examined the importance of STC2 expression for post-radiation survival, migration and invasion. Here, we report the establishment of STC2 knockout lines (CNE2-STC2-KO) using the CRISPR/Cas9-based genome editing technique.Results: Compared with the parental line, STC2-KO cells showed similar proliferation and morphology in normal culture conditions, and loss of STC2 did not compromise the cell tumorigenicity in nude mice model. However, STC2-KO lines demonstrated increased sensitivity to X-radiation under either normoxic or hypoxic conditions. Particularly, upon X-radiation, parental CNE2 cells only slightly whereas STC2-KO cells remarkably decreased the migration and invasion ability. Cell cycle analysis revealed that loss of STC2 accumulated cells in G1 and G2/M phases but decreased S-population.Conclusion: These data indicate that the expression of STC2, which can be stimulated by metabolic or therapeutic stresses, is one important factor to promote survival and metastasis of post-radiation NPC cells. Therefore, targeting STC2 or relative downstream pathways may provide novel strategies to overcome radiation resistance and metastasis of NPC.Keywords: metabolic stress, metastasis, migration, nasopharyngeal carcinoma, radiation resistance, stanniocalcin 2

Yan Huang,1–4* Juan Hu,1–4* Ting Lu,1–4 Yi Luo,1–4 Jimin Shi,1–4 Wenjun Wu,1–4 Xiaoyan Han,1–4 Weiyan Zheng,1–4 Jingsong He,1–4 Zhen Cai,1–4 Guoqing Wei,1–4 He Huang,1–4 Jie Sun1–41Bone Marrow Transplantation Center,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China; 2Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China; 3Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China; 4Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China*These authors contributed equally to this workBackground: According to the recent National Comprehensive Cancer Network (NCCN) guidelines, the risk level in acute myeloid leukemia (AML) patients with FLT3-ITD and NPM1 double mutation (AMLFLT3-ITD+/NPM1+,) depends on the allelic ratio of FLT3-ITD. But despite a low or high allelic ratio of FLT3-ITD, AMLFLT3-ITD+/NPM1+, patients belong to the favorable or intermediate risk, for whom allogeneic stem cell transplantation is not obligated. However, some latest studies pointing out that NPM1 and FLT3-ITD double mutation patients showed an inferior prognosis, which have raised concern about the risk categorization and more effective treatment of AMLFLT3-ITD+/NPM1+, patients.Methods: A total of 76 patients were selected for coexisting FLT3 and NPM1 mutations with normal cytogenetics. The prognostic risk factors were analyzed, and treatment strategies including allogeneic stem cell transplantati1on and chemotherapy were compared.Results: In 76 AMLFLT3-ITD+/NPM1+, patients, 36.8% of patients had hyperleukocytosis (HL) and DNMT3A R882 mutation was the most common concomitant gene (23.7%). For 53 patients in the complete remission (CR), 22 had received allogeneic hematopoietic stem cell transplantation (allo-HSCT) on first complete remission (CR1). Patients in transplantation group had better overall survival (OS) and disease-free survival (DFS) than chemotherapy only (P=0.002 and 0.001, respectively). In multivariable Cox model analyses, HL and DNMT3A R882 mutation were independent adverse prognostic factors (all P

Di Chen,1 Tong Lu,2 Junying Tan,1 Kun Zhao,1 Yuli Li,1 Wenjie Zhao,1 Hao Li,1 Qiuyue Wang,1 Yuanyong Wang,2 Liangzhou Wei11Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 2Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of ChinaPurpose: The rapidly rising incidence of esophageal adenocarcinoma (EAC), which is usually diagnosed late with a poor prognosis, has become a growing problem. This study investigated the potential transcription factor (TF)-related molecular mechanisms of EAC by using bioinformatics analysis and qRT-PCR validation.Methods: Expression profile datasets for mRNAs (GSE92396, GSE13898, GSE26886 and GSE1420) and miRNAs (GSE16456) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. Then, a TF-miRNA-mRNA network was constructed based on bioinformatics data from the TRRUST, TRED and miRTarBase database. Furthermore, overall survival analysis for the mRNAs and miRNAs in the TF-miRNA-mRNA network was performed with data from TCGA, and qRT-PCR was used to validate the results.Results: A total of 294 overlapping DEGs were identified in EAC tissues compared to normal tissues, including 181 downregulated and 113 upregulated genes. Then, 16 TFs that could target the DEGs and were related to cancer were predicted based on public databases, and 41 DEGs that could be targeted were identified as key genes. Additionally, 12 DEMs were predicted through miRTarBase to be associated with the key genes, and TP53-(miR-125b)-ID2 and JUN-(miR-30a)-IL1A from the TF-miRNA-mRNA network were identified to potentially play significant roles in EAC. Furthermore, CCL20, IL1A, ABCC3, hsa-miR-23b, and hsa-miR-191, which are involved in the TF-miRNA-mRNA network, were found to be significantly associated with patient survival in EAC. Finally, the expression of a miRNA-mRNA pair (hsa-miR-30a-5p and IL1A) was revealed to be correlated with prognosis.Conclusion: In this study, a TF-miRNA-mRNA network was constructed to analyze the potential molecular mechanisms of EAC. Key genes and miRNAs associated with patient survival were identified, which may reveal promising approaches for EAC diagnosis and therapy.Keywords: esophageal adenocarcinoma, prognosis, differentially expressed genes, microRNA, transcription factor

Ya He,1,2 Zhihai Wang,1 Chuan Liu,1 Zhitao Gong,1 Yanshi Li,1 Tao Lu,1 Guohua Hu1 1Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Department of Otolaryngology Head and Neck Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China Purpose: Several PCDH genes were shown to be downregulated or silenced in carcinomas and act as candidate tumor suppressor genes. However, the functions of PCDH17 in nasopharyngeal carcinoma (NPC) remain unclear. Here, we investigated the PCDH17 promoter methylation status and its impact on the expression and functions of PCDH17 in NPC. Patients and methods: To determine the mRNA levels and promoter methylation status of PCDH17 in NPC cell lines as well as 42 NPC patient specimens, we performed reverse transcription PCR, methylation-specific PCR, and bisulfite genome sequencing. The effects of ectopic PCDH17 expression in NPC cell lines were determined by colony formation, cell proliferation, wound healing, in vitro human umbilical vein endothelial cells tube formation, migration, invasion, cell cycle, and apoptosis assays and an in vivo subcutaneous tumor model. Results: PCDH17 expression was almost absent or significantly reduced in 100% of the NPC cell lines (5/5). However, 5-aza-2′-deoxycytidine and trichostatin A treatment restored PCDH17 expression. Promoter methylation was involved in PCDH17 silencing. Ectopic expression of PCDH17 in silenced NPC cells reduced colony formation, cell migration, angiogenesis, VEGF secretion, and tumorigenicity. Conclusion: PCDH17 plays a tumor suppressor role in NPC. PCDH17 methylation may be a tumor-specific event and can be used as an epigenetic biomarker for NPC. Keywords: nasopharyngeal carcinoma, PCDH17, tumor suppressor gene, methylation, epigenetic inactivation

Tao Lu,* Xiaodong Yang,* Yiwei Huang, Mengnan Zhao, Ming Li, Ke Ma, Jiacheng Yin, Cheng Zhan, Qun WangDepartment of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China*These authors contributed equally to this work Purpose: This study used the Surveillance, Epidemiology, and End Results (SEER) data to investigate the changes in incidence, treatment, and survival of lung cancer from 1973 to 2015.Patients and methods: The clinical and epidemiological data of patients with lung cancer were obtained from the SEER database. Joinpoint regression models were used to estimate the rate changes in lung cancer related to incidence, treatment, and survival.Results: From 1973 to 2015, the average incidence of lung cancer was 59.0/100,000 personyears. The incidence increased initially, reached a peak in 1992, and then gradually decreased. A higher incidence rate was observed in males than in females and in black patients than in other racial groups. Since 1985, adenocarcinoma became the most prevalent histopathological type.The surgical rate for lung cancer was about 25%, and treatment with chemotherapy showed an increasing trend, while the radiotherapy rate was in downward trend. The surgical rate for non-small-cell lung cancer (NSCLC) was higher than that for small cell lung cancer (SCLC), while chemotherapy for SCLC far exceeded that for NSCLC. Treatment with chemotherapy andradiotherapy for advanced stage had higher rate than early stage. The 5-year relative survival rate of lung cancer increased with time, but

Yang Wo, Shicheng Li, Yuanyong Wang, Tong Lu, Yi Qin, Xiao Sun, Wenjie Jiao Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China Purpose: To identify potential risk factors of lymph node metastasis and to verify the prognostic significance of the lymph node ratio (LNR) and the total number of lymph nodes examined (NNE) in tracheobronchial adenoid cystic carcinoma (ACC) patients, using a large population-based database.Patients and methods: From Surveillance, Epidemiology, and End Results database, we identified 263 patients with tracheobronchial ACC in whom complete lymph node data could be obtained. Logistic regression analysis was performed to determine predictive factors of nodal metastasis. X-tile software determined the optimal cut-off points for LNR and NNE. Kaplan–Meier analyses and Cox regression models were adopted for survival analysis.Results: Of 263 patients, 75 (28.5%) had lymph node involvement. Tumors of bronchial origin (P

Hsuan-Han Lee,1 Cheng-Ho Chang,1 Liang-Jen Wang,2 Chih-Ching Wu,3,4 Hsing-Ling Chen,5 Ti Lu,1 Ru-Band Lu6,7 Sheng-Yu Lee1,6,8,9 1Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 2Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 4Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan; 5Department of Nuclear Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 6Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan; 7Institute of Behavioral Medicine Sciences, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan; 8Department of Psychiatry, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 9Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan Introduction: In this study, we aim to determine 1) the differences in cortisol in patients with bipolar II disorder (BD-II) and control subjects and 2) the correlation between cortisol levels and cognitive function in patients with BD-II during a 24-week follow-up period.Methods: We recruited a total of 32 BD-II patients and 30 healthy control subjects. The BD-II patients were assessed for clinical severity and serum cortisol level at baseline and at weeks 8, 16, and 24. The Brief Assessment of Cognition in Affective Disorders (BACA) was adopted to evaluate cognitive function at baseline and endpoint (week 24). Meanwhile, we assessed the controls for serum cortisol level and BACA at baseline.Results: We observed that the BD-II group had a higher serum cortisol level and lower BACA composite scores compared with the healthy controls at baseline. A significant correlation was found between changes in Verbal Fluency, a subset of BACA, and changes in serum cortisol level after the 24-week follow-up, controlling for age, gender, years of education, and clinical severity (P

Lixia Fan,1,* Zhenglei He,1,* Sarah A Head,2 Yinghui Zhou,1 Ting Lu,1 Xulong Feng,1 Xueqing Zhang,1 Meng Zhang,1 Yongjun Dang,3 Xinghong Jiang,4 Minghua Wang1 1Department of Biochemistry and Molecular Biology, Medical College, Soochow University, Suzhou, Jiangsu, China; 2Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA; 3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China; 4Department of Neurobiology, Medical College, Soochow University, Suzhou, China *These authors contributed equally to this work Background/Purpose: Prostate cancer is a major burden on public health and a major cause of morbidity and mortality among men worldwide. Drug combination therapy is known as a powerful tool for the treatment of cancer. The aim of this study is to evaluate the synergistic inhibitory mechanisms of clofoctol and sorafenib in the treatment of prostate cancer. However, the molecular mechanisms of this phenomenon have not been illuminated clearly. In this study, we investigated the anti-tumor effects of clofoctol in combination with sorafenib in vitro and in vivo. Methods: The activity and mechanism of clofoctol in combination with sorafenib were examined in PC-3cells. mRNA and protein expression of key players in the ER stress pathway were detected with RT-PCR and Western blotting. Cell viability was estimated by CCK-8 assay or Alamar blue assay, and apoptosis and cell cycle were monitored and measured by flow cytometry. PC-3 cells were inoculated subcutaneously in male BALB/c nude mice. The therapeutic regimen was initiated when the tumor began showing signs of growth and treatment continued for 5 weeks. Results: Our data indicate that clofototol and sorafenib induce cell death through synergistic induction of endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR). Combination therapy with clofoctol and sorafenib induced an upregulation of markers of all three ER stress pathways: PERK, IRE1 and ATF6. In addition, combination therapy with clofoctol and sorafenib markedly inhibited the growth of prostate cancer xenograft tumors, compared with clofoctol or sorafenib alone. Conclusion: The combination of clofoctol and sorafenib can serve as a novel clinical treatment regimen, potentially enhancing antitumor efficacy in prostate cancer and decreasing the dose and adverse effects of either clofoctol or sorafenib alone. These results lay the foundation for subsequent research on this novel therapeutic regimen in human prostate cancer. Keywords: drug combination, endoplasmic reticulum stress, unfolded protein response, prostate cancer, clofoctol

Jing Jin,1 Yanting Shen,2 Biao Zhang,1 Rong Deng,3 Dianshuai Huang,1 Tianqi Lu,1 Fei Sun,1,* Shuping Xu,2,* Chongyang Liang1,*1Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, People’s Republic of China; 2State Key Lab of Supramolecular Structure and Materials, Jilin University, Changchun 130021, Jilin, People’s Republic of China; 3International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), Jilin University, Changchun 130021, Jilin, People’s Republic of China*These authors contributed equally to this workBackground: Macropinocytosis can occur in various types of cells and displays multiple functions. However, real-time observation and characterization of the structures of macropinocytosis on the surface of the cell membrane is not yet possible.Materials and methods: Here, we establish a real-time live cell surface imaging method using three-dimensional-structured illumination microscopy. Based on this, observation of the dynamic macropinocytosis process and morphological data of internalized structures on the surface of pancreatic cancer cells were achieved during macropinocytosis. Next, different-sized silica nanoparticles (SiO2 NPs) were used as the scale for identifying the size range of internalized substances of macropinocytosis in pancreatic cancer cells.Results and conclusion: Our study not only provides a practical method and more structural data for further investigation of macropinocytosis, but also makes deeper understanding of the cell response toward nanomaterials as well as nanodrugs possible.Keywords: nanomaterials, macropinocytosis, 3D-SIM, internalization

Shicheng Li,1,* Yunpeng Xuan,1,* Bing Gao,2 Xiao Sun,1 Shuncheng Miao,1 Tong Lu,1 Yuanyong Wang,1 Wenjie Jiao1 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China; 2School of Basic Medicine, Qingdao University, Qingdao, China *These authors contributed equally to this work Background: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide. The main obstacle to early diagnosis or monitoring of patients at high risk of poor survival has been the lack of essential predictive biomarkers.Methods: RNA-sequencing was performed on LUAD affected tissue and paired adjacent to noncancerous tissue samples and Gene Expression Omnibus dataset GSE19188 and GSE33532 were used to obtain an intersection of differential expressed genes and construct a protein–protein interaction network to get hub genes. Then corresponding overall survival information of two cohorts of LUAD patients from our hospital and The Cancer Genome Atlas project-LUAD were included in the present study. An analysis of the Kyoto Encyclopedia of Genes and Genomes database and Gene Ontology were carried out to study the signature mechanism.Results: In our study, we identified eight candidate genes (DLGAP5, KIF11, RAD51AP1, CCNB1, AURKA, CDC6, OIP5 and NCAPG) closely related to survival in LUAD. A linear prognostic model of the eight genes was constructed and weighted by the regression coefficient (β) from the multivariate Cox regression analysis of The Cancer Genome Atlas-LUAD cohort to divide patients into low- and high-risk groups. The prognostic ability of the signature was validated in LUAD patients at our hospital. Patients assigned to the high-risk group exhibited poor overall survival compared to patients in the low-risk group. Finally, functional enrichment analysis showed that cell division played a vital role in the development of LUAD.Conclusion: The study identified an mRNA signature including eight genes, which may serve as a potential prognostic marker of LUAD. Keywords: RNA-seq, prognostic, signature, lung adenocarcinoma

He Y, Wang Z, Liu C, et al. Cancer Manag Res. 2019;11:1601–1613. At the request of the authors, the Editor-in-Chief and Publisher of Cancer Management and Research wish toretract the published article. We were notified of some potential issues found in the electrophoresis images presented in Figure 1B and C of the published article. The authors were asked to provide the original, unedited images for these figures as well as the original, unedited images for the Western blots shown in Figures 3B and 5C. The authors responded and explained that the required raw data for the gel electrophoresis and Western blots images had been lost and asked to retract the article to maintain the principle of scientificintegrity. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Zhao Wang,1,2* Yufan Ma,1,3,4* Hayssam Khalil,1 Rutao Wang,1–3 Tingli Lu,1 Wen Zhao,1 Yang Zhang,3 Jamin Chen,1,2 Tao Chen,1–3 1Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 2Shaanxi Liposome Research Center, Xi'an, Shaanxi, 3Xi'an Libang Pharmaceuticals Co, Ltd, Xi'an, 4School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China *These authors contributed equally to this work. Background: Pseudomonas aeruginosa represents a good model of antibiotic resistance. These organisms have an outer membrane with a low level of permeability to drugs that is often combined with multidrug efflux pumps, enzymatic inactivation of the drug, or alteration of its molecular target. The acute and growing problem of antibiotic resistance of bacteria to conventional antibiotics made it imperative to develop new liposome formulations for antibiotics, and investigate the fusion between liposome and bacterium. Methods: In this study, the factors involved in fluid liposome interaction with bacteria have been investigated. We also demonstrated a mechanism of fusion between liposomes (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]/dimyristoylphosphatidylglycerol [DMPG] 9:1, mol/mol) in a fluid state, and intact bacterial cells, by lipid mixing assay. Results: The observed fusion process is shown to be mainly dependent on several key factors. Perturbation of liposome fluidity by addition of cholesterol dramatically decreased the degree of fusion with P. aeruginosa from 44% to 5%. It was observed that fusion between fluid liposomes and bacteria and also the bactericidal activities were strongly dependent upon the properties of the bacteria themselves. The level of fusion detected when fluid liposomes were mixed with Escherichia coli (66%) or P. aeruginosa (44%) seems to be correlated to their outer membrane phosphatidylethanolamine (PE) phospholipids composition (91% and 71%, respectively). Divalent cations increased the degree of fusion in the sequence Fe2+ > Mg2+ > Ca2+ > Ba2+ whereas temperatures lower than the phase transition temperature of DPPC/DMPG (9:1) vesicles decreased their fusion capacity. Acidic as well as basic pHs conferred higher degrees of fusion (54% and 45%, respectively) when compared to neutral pH (35%). Conclusion: Based on the results of this study, a possible mechanism involving cationic bridging between bacterial negatively charged lipopolysaccharide and fluid liposomes DMPG phospholipids was outlined. Furthermore, the fluid liposomal-encapsulated tobramycin was prepared, and the in vitro bactericidal effects were also investigated. Keywords: fusion, lipid-mixing assay, lipid composition