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Yun Xiang,1,2,* Dini Lin,1,* Qiang Zhou,1 Hongyu Luo,1 Zixin Zhou,1 Shuyi Wu,2 Keyuan Xu,2 Xiaoting Tang,1 Pingping Ma,2 Chunyuan Cai,1 Xinkun Shen1 1Wenzhou Key Laboratory for the Diagnosis and Prevention of Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People’s Hospital), Wenzhou, 325016, People’s Republic of China; 2School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China*These authors contributed equally to this work and share first authorshipCorrespondence: Xinkun Shen; Chunyuan Cai, Wenzhou Key Laboratory for the Diagnosis and Prevention of Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People’s Hospital), Wenzhou, Zhejiang Province, 325016, People’s Republic of China, 108# Wansong Road, Email shenxinkun123@wmu.edu.cn; caichunyuan123@wmu.edu.cnBackground: Large-diameter titanium dioxide nanotubes (TNTs) have shown promise in preserving osteoblast function under oxidative stress (OS) in vitro. However, their ability to enhance osteogenesis in vivo under OS conditions and the underlying mechanisms remain unclear.Purpose: This study aimed to evaluate the osteogenic potential of 110 nm TNTs (TNT110) compared to 30 nm TNTs (TNT30) in an aging rat model exhibiting OS, and to investigate the mechanisms involved.Methods: Surface properties of TNTs were characterized, and in vitro and in vivo experiments were conducted to assess their osteoinductive effects under OS. Transcriptomic, proteomic analyses, and Western blotting were performed to investigate the protective mechanisms of TNT110 on osteoblasts. Protein adsorption studies focused on the roles of fibronectin (FN) and albumin (BSA) in modulating osteoblast behavior on TNT110.Results: In both in vitro and in vivo experiments, TNT110 significantly improved new bone formation and supported osteoblast survival under OS conditions. Subsequent ribonucleic acid sequencing results indicated that TNT110 tended to attenuate inflammatory responses and reactive oxygen species (ROS) expression while promoting endoplasmic reticulum (ER) stress and extracellular matrix receptor interactions, all of which are crucial for osteoblast survival and functionality. Further confirmation indicated that the cellular behavior changes of osteoblasts in the TNT110 group could only occur in the presence of serum. Moreover, proteomic analysis under OS conditions revealed the pivotal roles of FN and BSA in augmenting TNT110’s resistance to OS. Surface pretreatment of TNT110 with FN/BSA alone could beneficially influence the early adhesion, spreading, ER activity, and ROS expression of osteoblasts, a trend not observed with TNT30.Conclusion: TNT110 effectively protects osteoblast function in the OS microenvironment by modulating protein adsorption, with FN and BSA synergistically enhancing osteogenesis. These findings suggest TNT110’s potential for use in implants for elderly patients.Keywords: osteoporosis, oxidative stress, titania nanotube, protein adsorption, osteogenesis

Man Zhang,1,2,* Siman Nie,3,* Ziwei Hai,2 Yixin Du,2 Menghan Jiang,4 Chunfeng Cai2 1Department of Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Wuhan University School of Nursing, Wuhan, Hubei, People’s Republic of China; 3Beijing Tsinghua Changgung Hospital, Beijing, People’s Republic of China; 4Shandong University of Traditional Chinese Medicine College of Health Sciences, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunfeng Cai, Faculty of Wuhan University School of Nursing, Wuhan, Hubei, People’s Republic of China, Email 1660433132@qq.comAim: Chronic disease self-management is critical to disease prognosis and patient quality of life. Several psychological factors influence this process of self-management. In this background, the present study investigated the impact of illness perceptions and coping style on self-management in people with peritoneal dialysis (PD).Methods: The study is a cross-sectional study. From May 2022 to January 2023, a convenience sampling method was used to recruit 246 peritoneal dialysis patients. General information questionnaire, brief illness perception questionnaire, medical coping style modes questionnaire and the self-management scale for peritoneal dialysis patients were used in this study. We used SPSS 24.0 to analyze the data, and the statistical methods included descriptive analysis, single factor analysis, Pearson correlation analysis and multiple linear regression analysis.Results: A total of 246 patients were included in this study (93.89% response rate). Cognitive representations and emotional representations were 30.40, 14.18, respectively. However, illness comprehensibility was 2.87. Illness perceptions were negative significantly correlated with self-management. With regard to coping style, our patients were more likely to adopt avoidance and resignation coping style. Confrontation and avoidance were positively related to self-management, while acceptance-resignation was negatively related.Conclusion: Self-management of peritoneal dialysis patients needs to be improved. Age, female sex, monthly income, illness perceptions and coping style were independently associated with self-management.Impact: These findings suggest that interventions that improve illness perceptions and coping style should be explored to ultimately improve their self-management. For example, patients can be provided with psychological counseling so that they can face the disease correctly, and we should pay attention to the positive role of social support.Keywords: peritoneal dialysis, illness perception, coping style, self-management

Wenbin Zou,1,&ast; Wan Kuang,2,&ast; Chun Cai,1 Yan Qian1 1Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Qian, Tongji Hospital, Tongji Medical College, 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei Province, 430000, People’s Republic of China, Tel +86-27-83665211, Email qianyan@tjh.tjmu.edu.cnBackground & Aims: The objective of this study was to evaluate the prognostic nutritional index (PNI) as a predictor of short-term postoperative complications in esophageal squamous cell carcinoma patients undergoing neoadjuvant immunochemotherapy.Methods: Clinical data were collected from 77 patients undergoing radical esophageal cancer surgery after neoadjuvant immunochemotherapy at Tongji Hospital from January 2022 to January 2023. The receiver operating characteristic curve (ROC) was utilized to establish the optimal cut-off point for the PNI. Subsequently, patients were stratified into low and high PNI groups according to this cut-off point, and comparisons were made between the two groups in terms of clinical data and postoperative complications.Results: Out of the 77 patients included in the study, 31 were categorized in the low PNI group and 46 in the high PNI group, with a defined cutoff point of 47.38. Significant statistical variances were noted in the occurrence rates of general complications (P < 0.001), pulmonary infections (P < 0.001), and anastomotic fistula (P = 0.034) between the two groups. The low PNI group displayed elevated rates of these complications in comparison to the high PNI group.Conclusion: The research findings indicate that preoperative nutritional assessment using the PNI can effectively predict short-term postoperative complications in esophageal squamous cell carcinoma patients who have undergone neoadjuvant therapy. Furthermore, the results suggest that implementing nutritional interventions for patients with moderate-to-severe malnutrition, as indicated by preoperative PNI evaluation, may help reduce the incidence of postoperative complications.Keywords: prognostic nutritional index, neoadjuvant immunochemotherapy, postoperative complications, esophageal squamous cell carcinoma

Chuang Cai,1,&ast; Wentan Zeng,2,&ast; Hongwei Wang,3 Shuqi Ren2 1Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, Zhongshan City, Guangdong Province, People’s Republic of China; 2Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City Hospital of Integration of TCM & Western Medicine, Zhongshan City, Guangdong Province, People’s Republic of China; 3Department of Pediatrics, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, Zhongshan City, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuqi Ren, Department of Laboratory Medicine, Tanzhou People’s Hospital of Zhongshan, Zhongshan City hospital of integration of TCM & western medicine, No. 10 Dexiu road, Zhongshan City, Guangdong Province, People’s Republic of China, Tel +8615521067602, Fax +860760-23639928, Email shuchijen@163.com Chuang Cai, Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan City, Guangdong Province, 528404, People’s Republic of China, Tel +86 18826431030, Fax +86 0760-88823566, Email caich6@foxmail.comPurpose: Hierarchical management is advocated in China to effectively manage chronic obstructive pulmonary disease (COPD) patients and reduce the incidence and mortality of acute exacerbation of COPD (AE-COPD). However, primary and community hospitals often have limited access to advanced equipment and technology. Complete blood count (CBC), which is commonly used in these hospitals, offers the advantages of being cost-effective and easily accessible. This study aims to evaluate the significance of routine blood indicators in aiding of diagnosing AE-COPD.Patients and Methods: In this research, we enrolled a total of 112 patients diagnosed with AE-COPD, 92 patients with stable COPD, and a control group comprising 60 healthy individuals. Clinical characteristics, CBC parameters, and serum CRP levels were collected within two hours. To assess the associations between NLR/PLR/MLR and CRP by Spearman correlation test. The diagnostic accuracy of NLR, PLR and MLR in AE-COPD was assessed using Receiver Operating Characteristic Curve (ROC) and the area under the curve (AUC). Binary Logistic Regression analysis was conducted for the indicators of NLR, PLR and MLR.Results: We found that patients with AE-COPD had significantly higher levels of NLR, PLR and MLR in contrast to patients with stable COPD. Additionally, the study revealed a noteworthy correlation between CRP and NLR (rs=0.5319, P< 0.001), PLR (rs=0.4424, P< 0.001), and MLR (rs=0.4628, P< 0.001). By utilizing specific cut-off values, the amalgamation of NLR, PLR and MLR augmented diagnostic sensitivity. Binary logistic regression analysis demonstrated that heightened NLR and MLR act as risk factors for the progression of AE-COPD.Conclusion: The increasing levels of NLR, PLR and MLR could function as biomarkers, akin to CRP, for diagnosis and assessment of acute exacerbations among COPD patients. Further research is required to validate this concept. Keywords: acute exacerbation of chronic obstructive pulmonary disease, AE-COPD, neutrophil-lymphocyte ratio, NLR, platelet-lymphocyte ratio, PLR, monocyte-lymphocyte ratio, MLR

Jingsong Luo,1,2 Yuxin Chen,2 Yanmin Tao,1 Yaxin Xu,3 Kexin Yu,2 Ranran Liu,2 Yuchen Jiang,2 Cichong Cai,2 Yiyang Mao,2 Jingyi Li,2 Ziyi Yang,2 Tingting Deng1 1School of Nursing, The Chengdu University of Traditional Chinese Medicine, Sichuan, 610000, People’s Republic of China; 2Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China; 3School of Nursing, Tongji University, Shanghai, 200000, People’s Republic of ChinaCorrespondence: Tingting Deng, School of Nursing, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China, Email dengtingting999@163.comBackground: There is substantial evidence from previous studies that abnormalities in sleep parameters associated with depression are demonstrated in almost all stages of sleep architecture. Patients with symptoms of sleep-wake disorders have a much higher risk of developing major depressive disorders (MDD) compared to those without.Objective: The aim of the present study is to establish and compare the performance of different machine learning models based on sleep-wake disorder symptoms data and to select the optimal model to interpret the importance of sleep-wake disorder symptoms to predict MDD occurrence in adolescents.Methods: We derived data for this work from 2020 to 2021 Assessing Nocturnal Sleep/Wake Effects on Risk of Suicide Phase I Study from National Sleep Research Resource. Using demographic and sleep-wake disorder symptoms data as predictors and the occurrence of MDD measured base on the center for epidemiologic studies depression scale as an outcome, the following six machine learning predictive models were developed: eXtreme Gradient Boosting model (XGBoost), Light Gradient Boosting mode, AdaBoost, Gaussian Naïve Bayes, Complement Naïve Bayes, and multilayer perceptron. The models’ performance was assessed using the AUC and other metrics, and the final model’s predictor importance ranking was explained.Results: XGBoost is the optimal predictive model in comprehensive performance with the AUC of 0.804 in the test set. All sleep-wake disorder symptoms were significantly positively correlated with the occurrence of adolescent MDD. The insomnia severity was the most important predictor compared with the other predictors in this study.Conclusion: This machine learning predictive model based on sleep-wake disorder symptoms can help to raise the awareness of risk of symptoms between sleep-wake disorders and MDD in adolescents and improve primary care and prevention.Keywords: adolescent major depressive disorder, sleep-wake disorders symptom, insomnia, obstruct sleep apnea, machine learning prediction model, xgboost

Yang Qian, Chenting Cai, Mengqing Sun, Dan Lv, Yun Zhao The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Dan Lv, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China, Email fylvdan@nbu.edu.cnAbstract: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is the exacerbation of a range of respiratory symptoms during the stable phase of chronic obstructive pulmonary disease (COPD). AECOPD is thus a dangerous stage and key event in the course of COPD, as its deterioration and frequency seriously affects the quality of life of patients and shortens their survival. Acute exacerbations occur and develop due to many factors such as infection, tobacco smoke inhalation, air pollution, comorbidities, airflow limitation, various biomarkers, history of previous deterioration, natural killer cell abnormalities, immunoglobulin G deficiency, genetics, abnormal muscle and nutritional status, negative psychology, and seasonal temperature changes. There is relatively limited research on the impact of the role of standardized management on the alleviation of AECOPD. However, with the establishment of relevant prevention and management systems and the promotion of artificial intelligence technology and Internet medical approaches, long-term effective and standardized management of COPD patients may help to achieve the quality of life and disease prognosis in COPD patients and reduce the risk of AE.Keywords: chronic obstructive pulmonary disease, acute exacerbation, related risk factors

Yu Yu,&ast; Ligang Ding,&ast; Yu Deng,&ast; Hao Huang, Sijing Cheng, Chi Cai, Min Gu, Xuhua Chen, Xiaohui Ning, Hongxia Niu, Wei Hua Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Hua, Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Email drhuaweifw@sina.comBackground: The joint association of atrial fibrillation (AF) and statin therapy with adverse outcomes in heart failure (HF) patients with cardiac resynchronization therapy (CRT) has not been fully investigated so far. The purpose of this study was to explore the independent and joint association of AF and statin therapy with adverse outcomes.Methods: Study patients were divided into four groups according to AF status and statin use: Non-AF/Statin, Non-AF/Non-Statin, AF/Statin, and AF/Non-Statin. Multivariate Cox proportional hazards regression models were used to evaluate the independent and joint association of AF and statin therapy with poor prognosis.Results: Among 685 CRT patients, there were 180 deaths (26.5%) and 198 HF hospitalization (29.6%) during the 14 years of follow-up. AF was associated with a 46% increased risk of all-cause mortality (HR, 1.46; 95% CI, 1.03– 2.07) and a 59% increased risk of HF hospitalization (HR, 1.59; 95% CI, 1.16– 2.20) than those without AF. However, statin therapy failed to improve the prognosis. In the joint analysis, compared with the Non-AF/Statin group, the AF/Non-Statin group suffered a higher risk of all-cause mortality (HR, 1.75; 95% CI, 1.04– 2.93) and HF hospitalization (HR, 1.76; 95% CI, 1.08– 2.86). Furthermore, adding AF to the traditional risk factor model significantly improved the predictive value for death (C-statistic from 0.654 to 0.691) and HF (C-statistic from 0.613 to 0.675).Conclusion: AF was associated with poor prognosis, and statin use failed to improve the prognosis. Further analysis showed that statin therapy is ineffective in improving prognosis and fails to attenuate the adverse effects of AF.Graphical Abstract: Keywords: atrial fibrillation, cardiac resynchronization therapy, joint association, prognosis, statin therapy

Jiali Zhao,1 En Lin,1 Chaonong Cai,1 Manyao Zhang,2 Decheng Li,1 Shanglin Cai,1 Guifang Zeng,1 Zeren Yin,1 Bo Wang,1 Peiping Li,1 Xiaopeng Hong,1 Jiafan Chen,1 Baojia Zou,1 Jian Li1 1Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Anesthesiology, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of ChinaCorrespondence: Jian Li; Baojia Zou, Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Tel +86-756-252-8781, Fax +86-756-252-8166, Email lijian5@mail.sysu.edu.cn; zoubj6@mail.sysu.edu.cnBackground: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1α (HIF-1α) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1α regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1α.Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1α overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of β-actin, HIF-1α, PI3K p110α, p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models.Results: Hypoxia could upregulate HIF-1α to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1α-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss.Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1α mediated resistance via targeting PI3K/AKT/HIF-1α signaling pathway.Keywords: hepatocellular carcinoma, epirubicin, Tanshinone I, HIF-1α, resistance

Wenting Gong,1,&ast; Wen Tang,2,&ast; Lan Luo,3 Furong Zhang,1 Chenyang Cai,1 Jiangyan Zhang,1 Xiaolin Wu,4 Jianping Shang,4 Xiaolan Shu,2 Ting Wang,5 Danna Tu,6 Zhengjiang Jin,7,&ast; Ronghao Zheng4,&ast; 1Department of pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatric Intensive Care Unit, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Child Health, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 5Department of Pediatric Neurology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 6Department of Pediatric Cardiology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 7Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ronghao Zheng, Department of Pediatric Nephrology, Rheumatology, and Immunology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 745 Wu luo Road, Hongshan District, Wuhan, 430070, Hubei Province, People’s Republic of China, Tel +86 02787169267, Email hytwo2001@126.com Zhengjiang Jin, Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, 745 Wu luo Road, Hongshan District, Wuhan, 430070, Hubei Province, People’s Republic of China, Email king199735@126.comPurpose: To explore the trends and correlation between antibiotics consumption and antimicrobial resistance in children in a specialist hospital from 2016– 2021 in China.Patients and Methods: This retrospective study investigated data on the consumption of antibiotics and antimicrobial resistance in children. Antibiotics consumption was expressed as defined daily doses (DDDs)/1000 patient-days based on the Guidelines for Anatomical Therapeutic Chemical. The trends in antibiotics consumption and antimicrobial resistance rates were analyzed by linear regression, while Spearman correlation analysis was employed to evaluate their correlations.Results: An increasing trend in the annual consumption of carbapenems and monobactams was detected (all P< 0.05). A significant upward trend was detected in the annual resistance rates of Enterococcus faecium to ciprofloxacin, Streptococcus pneumonia to ceftriaxone, Acinetobacter baumannii to carbapenems, Enterobacter cloacae to carbapenems, Pseudomonas aeruginosa to ceftazidime, and Escherichia coli to cefepime, while the annual resistance rates of Escherichia coli to carbapenems had a significant downward trend (all P< 0.05). The consumption of cephalosporin/β-lactamase inhibitor (C/BLI) combinations and carbapenems had significant positive correlations with the resistance rates of Acinetobacter baumannii to carbapenems (r=0.763, P< 0.001; r=0.806, P< 0.001), Enterobacter cloacae to carbapenems (r=0.675, P< 0.001; r=0.417, P=0.043), and Pseudomonas aeruginosa to ceftazidime (r=0.625, P=0.001; r=0.753, P< 0.001), respectively. Also, increasing consumption of monobactams was related to the upward resistance rates of Acinetobacter baumannii to carbapenems (r=0.557, P=0.005) and Enterobacter cloacae to carbapenems (r=0.507, P= 0.011).Conclusion: This study demonstrated significant positive associations between antibiotics consumption and specific antimicrobial resistance rates. The current findings pointed out some directions to pursue in controlling the prevalence of certain resistant bacterial strains in children.Keywords: antibiotic consumption, antimicrobial resistance, correlation, children

Huihuang Lin,1,&ast; Huaping Zhang,1,&ast; Dongyong Yang,1,&ast; Xiaoyang Chen,1,&ast; Yunfeng Chen,1,&ast; Duanhong Song,1 Chi Cai,2 Yiming Zeng1 1Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Fujian Medical University, Center of Respiratory Medicine of Fujian Province, Quanzhou, People’s Republic of China; 2Department of Radiology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiming Zeng, Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Fujian Medical University, Center of Respiratory Medicine of Fujian Province, No. 34, Zhongshanbei Road, Licheng District, Quanzhou, People’s Republic of China, Tel +86 13515042402, Fax +86 0595 22770258, Email zeng_yi_ming88@163.comPurpose: Surgical bullectomy is the standard treatment of giant emphysematous bulla (GEB). However, bronchoscopic treatment should be considered as an alternative approach for patients who are unfit for surgical treatment. The study aimed to evaluate the clinical efficacy of endobronchial occlusion for the treatment of GEB using silicone plugs.Methods: This retrospective study recruited four patients with GEB who were unsuitable for surgery. Preoperative planning was performed using high-resolution computed tomography and a virtual bronchoscopic navigation system. Customized silicone plugs were then placed in the target airway via bronchoscopy to cause GEB regression and atelectasis.Results: All procedures were completed successfully in four patients. Three months after the procedures, compared with baseline, increases in the mean forced expiratory volume in 1 s (from 1.20 L/s to 1.33 L/s), forced vital capacity (from 2.63 L to 2.90 L), diffusion lung capacity for carbon monoxide (from 29% to 41% of the predicted value) and 6-minute walking test (from 412 m to 474 m) were observed. Additionally, the mean total lung capacity (from 6.80 L to 6.35 L), residual volume (from 3.97 L to 3.52 L), and St. George’s Respiratory Questionnaire scores (from 67 to 45) were all lower than baseline data.Conclusion: Our preliminary results demonstrated that the endobronchial placement of silicone plugs could be a low-cost, safe, and effective choice for the treatment of GEB in surgically unfit patients.Keywords: giant bulla, bronchoscopy, silicone spigot, endobronchial occlusion

Chunyan Cai, Xing Peng, Yumei Zhang Department of Gynaecology, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, 223300, People’s Republic of ChinaCorrespondence: Chunyan Cai, Department of Gynaecology, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, 223300, People’s Republic of China, Email sisicaii@126.comBackground: Interleukin-6 (IL-6) has been reported to be associated with the prognosis of cancers. As for cervical cancer (CC), previous studies investigated the association between IL-6 expression in CC tumor tissue and CC prognosis; however, no studies assessed the effects of serum IL-6 levels on the survival of CC. This study aimed to explore the effects of serum IL-6 levels on prognosis in patients with CC.Methods: In total, 327 patients with CC and 355 controls were recruited from this hospital from May 2015 to May 2016. Serum IL-6 levels were measured before treatment. The Kaplan–Meier method was utilized to estimate survival rates. The overall survival (OS) and disease-free survival (DFS) were evaluated. The univariate and multivariate Cox regression analyses were used to identify risk factors associated with the prognosis of CC.Results: We found that the serum IL-6 level in the CC group was significantly higher than that in the control group. The diagnostic value of serum IL-6 level in detecting CC patients was moderate, and the specificity and sensitivity were 77.46% and 47.09%, respectively. Data suggested that the serum IL-6 level was significantly linked with the smoking status, FIGO stage, tumor size, treatment methods, and HPV infection. The univariate and multivariate analysis indicated that FIGO stage IIB-IIIC, lymph node metastasis, and high serum IL-6 levels were negatively associated with the OS and DFS in patients with CC.Conclusion: Serum IL-6 has a moderate diagnostic ability for detecting CC and may be a potential CC biomarker. High serum IL-6 level is associated with adverse prognosis in patients with CC and could be a prognosis indicator for CC patients.Keywords: interleukin-6, cervical cancer, prognosis, diagnosis

Xin Gao,1 Xuemei He,1 Hiroyuki Oshima,2 Daisuke Miyatake,2 Yukio Otsuka,2 Kota Kato,3 Chunxiao Cai,4 Tomasz Wojtkowski,5 Nan Song,6 Yuichiro Kaneko,7 Aixin Shi1 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Clinical Pharmacology and Exploratory Development, Astellas Pharma Inc., Tokyo, Japan; 3Analysis & Pharmacokinetics Research Labs., Astellas Pharma Inc., Ibaraki, Japan; 4Development Medical Department, Astellas (China) Investment Co., Ltd, Beijing, People’s Republic of China; 5Data Science Development, Astellas Pharma US, Inc., Northbrook, IL, USA; 6Development Division Biostatistics and Statistical Programming, Astellas (China) Investment Co., Ltd, Beijing, People’s Republic of China; 7Biostatistics Group, Japan-Asia Data Science, Development, Astellas Pharma Inc, Tokyo, JapanCorrespondence: Aixin Shi, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, 100730, People’s Republic of China, Tel +86-10-85133632, Email aixins0302@126.comObjective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses.Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated.Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0– 1.5h and mean t1/2 was 7.4– 13.0h for all doses. In the multiple-dose period, median tmax was 1.5– 2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of > 150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death.Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses.Clinicaltrials.gov Identifier: NCT04143477.Keywords: rheumatoid arthritis, treatment, dose-proportionality, tsDMARDs

Yanyan Wang,1,2,&ast; Chengyong Li,1,2,&ast; Weiyi Wang,1,2 Jiajia Wang,1,2 Jinhui Li,1,2 Shuangjie Qian,1,2 Chao Cai,3 Yuntao Liu1 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of China; 2School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuntao Liu, Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of China, Tel +8657755579362, Email 18267850815@163.com Chao Cai, Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Disease, Hepatology Institute of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of China, Tel +8613506662567, Email 13506662567@163.comObjective: Serum albumin to globulin ratio (AGR) is a marker of inflammatory disease, but its role in inflammatory bowel disease (IBD) remains unknown. The primary purpose of the present research was to explore the relationship between serum AGR and inflammatory bowel disease (IBD).Methods: A total of 179 patients with ulcerative colitis (UC), 210 patients with Crohn’s disease (CD), and non-IBD controls (age- and gender-matched controls who have gastrointestinal (GI) symptoms) were enrolled in the research. Demographic data, endoscopic score, and serum biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, and Ca2+ were included. The Mayo score and the Harvey-Bradshaw Index (HBI) were applied to evaluate the disease activity of UC and CD, respectively.Results: Serum AGR was significantly lower among IBD patients compared with non-IBD controls. There was a negative association between serum AGR and Mayo score in patients with UC (r = − 0.413, p < 0.001), and serum AGR was also associated with HBI score in patients with CD (r = − 0.471, p < 0.001). After adjusting other potential variables, low serum AGR (below-median) was independently associated with Mayo score (β = − 0.196, p = 0.026) and HBI score (β = − 0.162, p = 0.022), respectively. The area under the curve (AUC) for AGR to distinguish UC was 0.701, and the AUC of CD was 0.759. Based on the optimal cut-off value, multivariate logistic regression indicates that low AGR can differentiate UC from non-UC (OR = 2.564, 95% CI = 1.433– 4.587, p = 0.002) and CD from non-CD (OR = 3.732, 95% CI = 1.640– 8.492, p = 0.001).Conclusion: AGR may become a promising candidate to help clinicians differentiate IBD and evaluate IBD disease activity. Inflammation and nutritional status might be the future directions to explore its mechanism.Keywords: inflammatory bowel disease, biomarker, inflammation, malnutrition, activity evaluation

Zihan Wei, Ying Zhang, Sizhen Yang, Chenhui Cai, Jiawen Ye, Hao Qiu, Xu Hu, Yiyun Qu, Xuan Wen, Tongwei Chu Department of Orthopedics, Xinqiao Hospital of Chongqing, Second Affiliated Hospital of Army Medical University, Chongqing, 400037, People’s Republic of ChinaCorrespondence: Tongwei Chu, Department of Orthopedics, Xinqiao Hospital of Chongqing, Second Affiliated Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China, Tel/Fax +8613708388336, Email chtw@sina.comObjective: To compare the cervical sagittal balance parameters and clinical efficacy of three fusion devices after short-segment anterior cervical discectomy and fusion.Patients and Methods: Retrospectively analyzed 516 patients with cervical spondylosis who underwent surgery at our hospital from May 2013 to May 2019. All patients had complete data and were divided into three groups according to the selected fusion cage. Neck and upper limb pain were assessed by the visual analog scale (VAS) score. Neurological function was evaluated by the modified Japanese Orthopedics Society (mJOA) score. Also, the curvature of the cervical spine and the occurrence of dysphagia were observed.Results: There were no significant differences in the general information, thoracic inlet angle, T1 slope, or surgical data among the groups (p> 0.05). There were significant differences in the scores between pre- and postoperatively in the different groups (p< 0.05). There were no significant differences in the C2-C7 Cobb angle or C2-C7 sagittal vertebral axis before the operation among the groups (p> 0.05). There was a significant difference in the correction and loss of correction among the groups postoperatively and on follow-up (p> 0.05). Dysphagia was less likely in the Zero-P VA fusion group than in the other two groups.Conclusion: Different fusion instruments can relieve the symptoms. In the Prodisc-C Vivo group, no significant improvement in cervical sagittal balance was achieved. A good effect on improving sagittal balance was observed in both the Zero-P VA fusion and Skyline anterior cervical titanium plate groups, but a better effect on preventing dysphagia was observed in the Zero-PVA fusion group.Keywords: retrospective analyze, cervical spondylosis, anterior cervical discectomy and fusion, cervical sagittal balance parameters, fusion devices

Jiawen Ye, Sizhen Yang, Zihan Wei, Chenhui Cai, Ying Zhang, Hao Qiu, Tongwei Chu Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Tongwei ChuDepartment of Orthopedics, Xinqiao Hospital, Army Medical University, Shapingba District, Chongqing, People’s Republic of ChinaTel +86 13708388336Email chtw@sina.comPurpose: To explore the incidence and risk factors for adjacent segment disease (ASD) in patients with lumbar degenerative diseases after transforaminal lumbar interbody fusion (TLIF).Patients and Methods: The clinical data of 1258 patients who underwent transforaminal lumbar interbody fusion (TLIF) for lumbar degenerative diseases in our hospital from January 2011 to December 2017 were retrospectively analyzed. Patients were divided into the ASD group and non-ASD (N-ASD) group, and the incidence of ASD was calculated. We compared age, BMI, comorbidities, surgery-related parameters, and imaging parameters before surgery between the two groups and used univariate analysis and logistic regression analysis to explore the risk factors for ASD.Results: Among the 1258 patients who underwent TLIF due to lumbar degenerative diseases, 65 patients developed ASD and received surgical treatment for it, for an incidence of 5.2%. The average onset time of ASD was 68.3± 25.1 (20– 123) months. Univariate analysis showed that BMI, hypertension, preoperative adjacent segment disc degeneration and preoperative adjacent intervertebral disc height were significantly different between the ASD and N-ASD groups (P< 0.05). Incorporating the above indicators into the logistic regression model, the results showed that BMI and preoperative adjacent intervertebral disc degeneration were risk factors for ASD after TLIF.Conclusion: The incidence of ASD after TLIF in patients with lumbar degenerative disease is approximately 5.2%. High BMI and preoperative adjacent segment disc degeneration are risk factors for ASD after TLIF.Keywords: lumbar degenerative disease, transforaminal lumbar interbody fusion, adjacent segment disease, risk factors

Zhiwei Zheng,1,&ast; Cui Yang,2,&ast; Chun Cai,1 Huide Zhu1 1Department of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Department of Obstetrics and Gynecology Shantou Central Hospital, Shantou, 515000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huide ZhuDepartment of Pharmacy, Cancer Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of ChinaTel +86 075488555844-1140Fax +86 0754 88555844Email zhuhuide_2009@163.comBackground: Recent studies have revealed that the presence of systemic inflammation is associated with poor survival for esophageal squamous cell carcinoma. We aimed to investigate prognostic values of preoperative neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in resectable esophageal squamous cell carcinoma.Methods: A cohort of 167 resectable ESCC patients was retrospectively reviewed between January 2017 and September 2020. The best cut-off value of NLR and PLR was selected by plotting the receiver operating characteristic curve. All reviewed patients were divided into high NLR/PLR or low NLR/PLR group to evaluate prognostic factors.Results: Among the 167 patients, 34 (20.36%) were women and 133 (79.64%) were men. The mean age was 62.64 ± 7.91 years, with an age range from 44 to 85 years. All patients were divided into low NLR (< 2.20) or high NLR (≥ 2.20) group (AUC=62.5% with the sensitivity of 61.8% and specificity 60.9%, P=0.025), low PLR (< 110) or high PLR (≥ 110) group (AUC=59.6% with the sensitivity of 82.4% and specificity 35.3%, P=0.083). High NLR and PLR were associated with a larger tumor diameter (P< 0.05), while high NLR was also associated with poor tumor classification (P=0.022). There was a positive correlation between NLR and PLR (r = 0.614, P < 0.001). High NLR and PLR were significantly associated with poor disease-free survival. Multivariate analyses identified NLR as a prognostic factor in resectable ESCC.Conclusion: The NLR and PLR predict disease-free survival in resectable esophageal squamous cell carcinoma.Keywords: neutrophil lymphocyte ratio, platelet lymphocyte ratio, disease-free survival, resectable esophageal squamous cell carcinoma

Yimin Yao, Chang Cai, Fei Sun, Wei Gong Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of ChinaCorrespondence: Wei GongDepartment of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of ChinaTel +86-512- 67780008Email 20184132209@stu.suda.edu.cnPurpose: Biomarkers of the systemic inflammatory response and nutritional-related indicators have been used to assess the host anti-tumor immune response and predict prognosis in esophageal squamous cell carcinoma (ESCC). However, a new indicator system combining platelet-to-lymphocyte ratio (PLR) and albumin-globulin ratio (AGR), AGR-PLR score (APS), has not yet been evaluated for the prognosis prediction among ESCC patients.Methods: A retrospective analysis was performed, including 633 patients with ESCC, comprising 450 in the training cohort and 183 in the validation cohort.Results: In this study, we found that the overall survival time among patients with an APS of 2 was significantly shorter than that among patients with an APS of 1, and the survival time of patients with an APS of 1 was significantly shorter than that of patients with an APS of 0. Multivariate analysis showed that the APS was an independent prognostic factor for patients with ESCC. The APS demonstrated better prognostic accuracy and effectiveness for ESCC patients than either PLR or AGR alone. In addition, a new prediction nomogram was established according to tumor grade, APS, and tumor, node, metastasis (TNM) stage. Compared with the traditional 8th version of TNM staging system, this nomogram demonstrated improved sensitivity and specificity for the prediction of 3- and 5-year survival.Conclusion: APS is a novel independent prognostic indicator for the radical resection of ESCC and a potential biomarker for monitoring the therapeutic response.Keywords: AGR, ESCC, nomogram, prognosis, PLR

Bowen Weng, Xiaoyue Zhang, Wenchao Hong, Chongbing Yan, Xiaohui Gong, Cheng Cai Department of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People’s Republic of ChinaCorrespondence: Cheng CaiDepartment of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People’s Republic of ChinaTel +86 21 52976179Fax +86 21 62790494Email caicheng2004@163.comAbstract: In recent years, there have been an increasing number of infections due to multidrug-resistant organisms in the neonatal intensive care unit. Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a challenge in clinical anti-infection treatment. Herein, we report the case of CRKP sepsis in an extremely low-birth weight infant (ELBWI) who did not respond to meropenem and vancomycin, but was treated successfully after a 10-day antibiotic course with trimethoprim–sulfamethoxazole (TMP-SMZ). Recent research on CRKP-associated sepsis and the application of TMP-SMZ therapy in children and neonates were reviewed to offer a reference for clinical practice.Keywords: carbapenem-resistance, extremely low birth weight infant, Klebsiella pneumoniae, sepsis, trimethoprim–sulfamethoxazole

Jian Zheng,1 Xiaoxi Li,2 Cunwei Cai,3 Chengyu Hong,1 Bin Zhang4 1Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 2Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 3Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of ChinaCorrespondence: Jian ZhengDepartment of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, NO. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of ChinaTel/ Fax +86-24-31916363Email zhengjian_2020@163.comBackground: The roles of microRNA (miR)-32 and miR-548a in non-small cell lung cancer (NSCLC) have been studied. But their influences on NSCLC cells to cisplatin (DDP) resistance remain elusive. This study estimated the mechanisms of miR-32 and miR-548a in NSCLC cells to DDP.Methods: Differentially expressed miRs in DDP-sensitive and resistant tissues were screened out using a GSE56036 chip. Then the predictive efficacies of miR-32 and miR-548a on DDP resistance were analyzed in NSCLC patients. The target mRNAs of miR-548a and miR-32 were predicted. miR-548a and miR-32 were knocked down to assess the influences of miR-32 and miR-548a on NSCLC growth. DDP-resistant cells were constructed and miR-32 and miR-548a expression was detected in resistant cells. After miR-32 and miR-548a knockdown, the IC50 value of DDP was detected. Then, the activation level of Wnt/β-catenin pathway was detected. The roles of miR-32 and miR-548a in NSCLC growth in vivo were detected by tumorigenesis experiment.Results: miR-32 and miR-548a were poorly expressed in DDP-resistant NSCLC. miR-32 and miR-548a mimic enhanced the DDP sensitivity of NSCLC cells. Both miR-32 and miR-548a targeted ROBO1, and overexpression of ROBO1 inhibited the promotion of miR-32 and miR-548a mimic on DDP sensitivity. ROBO1 activated the Wnt/β-catenin pathway, thus enhancing the DDP resistance.Conclusion: miR-32 and miR-548a target ROBO1 and inhibit Wnt/β-catenin activation, thus promoting the drug sensitivity of NSCLC cells to DDP.Keywords: non-small cell lung cancer, miR-32, miR-548a, cisplatin resistance, ROBO1, Wnt/β-catenin pathway

Haitao Li,* Yunlai Zhi,* Chunyan Ma, Qianqian Shen, Fanghu Sun, Chengkuan Cai Department of Urology, Lianyungang Clinical College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fanghu SunDepartment of Urology, Lianyungang Clinical College of Nanjing Medical University/The First People’s Hospital of Lianyungang, No. 6, Zhenghua East Road, Lianyungang, Jiangsu Province 222002, People’s Republic of ChinaTel +86 18961326564Email lyglht123@163.comBackground: Prostate cancer (PCa) is a major contributor to reduce the life quality of males. Circular RNAs were frequently reported to be associated with cancers. In the case of radiotherapy to PCa, the role of circ_0062020 was still inconclusive, which was further explored in this study.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of circ_0062020, miR-615-5p and thyroid hormone receptor interactor 13 (TRIP13) in PCa tissues and cells, as well as in normal tissues and cell. Meanwhile, the proliferation of PCa cells was evaluated by clone formation assay and cell counting kit 8 (CCK8) assay. Moreover, the metastasis of PCa cells was assessed by transwell and wound healing assays. Furthermore, the apoptosis of PCa cells was determined by flow cytometry assay. Besides, dual-luciferase reporter system was applied to verify the correlation between miR-615-5p and circ_0062020 or TRIP13, which was predicted by online tool CircRNA interactome or TargetScan. In addition, the protein expression of TRIP13 was measured by Western blot in PCa tissues and cells and normal tissues and cells. Finally, xenograft tumor assay was performed to further confirming the function of circ_0062020 in PCa in vivo.Results: Circ_0062020 and TRIP13 were upregulated, while miR-615-5p was downregulated in PCa tissues and cells. Circ_0062020 knockdown or miR-615-5p overexpression inhibited the proliferation and metastasis, and promoted apoptosis, which could be reversed by miR-615-5p inhibitor or pc-TRIP13 in ionizing radiation (IR)-treated PCa cells. As expected, circ_0062020 sponged miR-615-5p to regulate TRIP13 expression in PCa cells. Circ_0062020 knockdown also suppressed PCa tumor growth in vivo.Conclusion: Circ_0062020 suppressed the radiosensitivity by miR-615-5p/TRIP13 axis in PCa cells, which might provide insights into the radiotherapy for PCa.Keywords: prostate cancer, circ_0062020, miR-615-5p, TRIP13, radiosensitivity

Omar Abdihamid,1 Changjing Cai,1 Linda Kapesa,2 Shan Zeng1,3,4 1Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China; 2Department of Oncology, Muhimbili National Hospital, Dar-es-Salaam, Tanzania; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China; 4Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of ChinaCorrespondence: Shan ZengDepartment of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of ChinaTel +86-13574846576Email zengshan2000@csu.edu.cnAbstract: Cancer patients are susceptible groups to COVID-19, and risk-adjusted models show that most cancer patients have a 25– 39% mortality risk if infected with COVID-19. The infection rate of SARS-CoV-2 in cancer patients in China was 0.79% (12 of 1524 patients; 95% CI, 0.31.2%). The case fatality rate of COVID-19 in the overall population ranges from 2.3 to 8.0%; among these, the case fatality rate for cancer patients is at 5.6%. In a retrospective cohort study of 28 COVID-19-infected cancer patients, a total of 15 (53.6%) patients had severe outcomes with a mortality rate of 28.6%. In a pooled analysis by Aakash et al, a 2% cancer prevalence was found among admitted patients with COVID-19. In Italy, a report shows that among the 3200 patients who died of SARS-CoV-2, 19.4% were patients with cancer. In New York, 61 (28%) cancer patients succumbed to COVID-19 with a case fatality rate of 37% (20/54) and 25% (41/164) for hematologic and solid malignancies, respectively. Impacts of COVID-19 in cancer care include interruptions of life-saving therapies, distraction effects, and diagnostic overshadowing that involve diverting attention to the pandemic rather than to cancer patients and disruptions of primary palliative care to patients due to forced quarantine. Herein, we review the landscape of COVID-19 in cancer care. We also briefly share our experience and the measures in place to protect cancer patients against COVID-19 in our center.Keywords: SARS-CoV-2, cancer care, high-risk, mortality

Xiaoxian Pan,1,* Caihong Wang,1,* Rong Li,2 Li Su,1,3,4 Mingwei Zhang,1,3,4 Chuanshu Cai,1,3,4 Shiping Liu,1 Weijian Zhang,1,3,4 Jihong Song,2 Jinsheng Hong1,3,4 1Department of Radiotherapy, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2The School of Nursing, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Key Laboratory of Radiation Biology (Fujian Medical University), Fujian Province University, Fuzhou, Fujian, People’s Republic of China; 4Fujian Provincial Key Laboratory of Precision Medicine for Cancer, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinsheng Hong Email 13799375732@163.comPurpose: This study aims to explore the applicability of the Nutrition Risk Screening 2002 (NRS2002) tool in screening nutritional risk and the Patient-Generated Subjective Global Assessment (PG-SGA) in determining nutrition status in nasopharyngeal carcinoma (NPC) patients.Materials and Methods: NRS2002 and PG-SGA were simultaneously applied to evaluate the nutritional status of NPC patients before induction chemotherapy, as well as before and after radiotherapy. The PG-SGA results were considered golden standard in evaluating nutrition status, and the ROC curve value and Youden index were applied to analyze NRS2002 effectiveness in screening nutritional risk.Results: A total of 102 NPC patients were included in this study. Patients with an NRS2002 score < 3 and PG-SGA score ≥ 4 accounted for 5.3% (5/95), 19.6% (18/92) and 94.8% (36/38) at the time before induction chemotherapy, before radiotherapy and at the end of radiotherapy, respectively. The cut-off values of NRS2002 scores all < 2 corresponded to the maximum Youden index at the three procedural times. And the area under curve (AUC) were 0.598 (P = 0.390), 0.665 (P = 0.015) and 0.940 (P = 0.034), respectively. At the end of radiotherapy, NRS2002 scores of < 3 and < 2 were used as cut-off values for nutritional risk screening, respectively. Additionally, the malnutrition-missed detection rates were 36.0% and 12.0% (χ2 = 15.789; P < 0.001).Discussion: NRS2002 nutritional risk screening combined with the PG-SGA nutritional assessment has certain applicability in NPC. NRS2002 score ≥ 2 can be considered as a new cut-off point for nutritional assessment.Keywords: nasopharyngeal carcinoma, nutritional risk screening, nutrition assessment, NRS2002, PG-SGA

Mingshan Xue,1,* Chuanxu Cai,2,* Lili Guan,1,* Yifan Xu,1 Jinsheng Lin,1 Yifeng Zeng,1 Haisheng Hu,1 Rongchang Chen,1 Hongman Wang,3 Luqian Zhou,1 Baoqing Sun1 1Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Laboratory Medicine, Shenzhen Institute of Respiratory Diseases, Shenzhen People’s Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The Fifth Affiliated Hospital of Zunyi Medical University Zhuhai, Zhuhai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Luqian Zhou; Baoqing Sun Email zhlx09@163.com; sunbaoqing@vip.163.comBackground and Objective: Severe chronic obstructive pulmonary disease (COPD) is the terminal stage of the disease characterized by declined lung function, malnutrition, and poor prognosis. Such patients cannot tolerate long-time sports rehabilitation owing to dyspnea and fail to achieve the desired therapeutic effect; therefore, increasing nutritional support will be an important strategy for them. The present study applied metabolomics technology to evaluate the correlation between serum concentrations of polyunsaturated fatty acid (PUFA) metabolites, nutritional status, and lung function in patients with COPD to provide a theoretical basis for accurate nutritional support.Materials and Methods: We enrolled 82 patients with stable severe COPD in our hospital. The general characteristics including height, weight, and lung function were recorded. Metabolomics was used to detect the concentrations of serum metabolites of n-3 and n-6 at baseline and at 24 and 52 weeks after enrollment. The correlations between nutrition level and pulmonary function and clinical indicators were evaluated.Results: The concentrations of n-3 and n-6 increased over time along with the progression of COPD. Body mass index (BMI) and percent of ideal body weight (IBW%) decreased with disease development, and BMI was found to be significantly correlated with FEV1% predicted and FEV1/FVC. Serum levels of n-6 metabolites such as linoleic acid (LA), γ-linoleic acid (GLA), and arachidonic acid (ARA) (all P < 0.01) and the n-3 metabolites such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (all P < 0.05) showed significant correlations with BMI and were closely correlated with FEV1% predicted and FEV1/FVC of lung function (all P< 0.05).Conclusion: This study demonstrates that malnutrition in patients with severe COPD is progressive and is positively correlated with n-3 and n-6 polyunsaturated fatty acids and lung function.Keywords: chronic obstructive pulmonary disease, metabolomics, nutritional level

Xiaoting Zhao,1,2 Mei Jiang,1,2 Ziyu Wang,2 Xiaohong Chen,3 Hongzhen Wang,4 Wentao Yue,1 Chao Cai5,6 1Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou, Beijing, People’s Republic of China; 3Department of Otolaryngology, Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Oncology, Rizhao City Hospital of Traditional Chinese Medicine, Rizhao, Shandong, People’s Republic of China; 5Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China; 6Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou, Beijing, People’s Republic of ChinaCorrespondence: Chao Cai; Wentao Yue Email fangzecai@126.com; yuewt@ccmu.edu.cnBackground: Laryngeal carcinoma is a common cancer among head and neck tumors, accounting for 0.5– 1% new cancer cases or deaths of all tumors throughout the body. Despite improvements in diagnostic and therapy, the prognosis of laryngeal carcinoma patients still remains poor. Thus, it is very important to identify the biomarkers involved in the molecular pathogenesis of laryngeal carcinoma. Cyclin Y (CCNY) is a conserved cell cycle regulator that acts as a growth factor in many cancers. The clinical significance of CCNY in laryngeal carcinoma remains unknown. The function of CCNY in laryngocarcinoma was studied in this paper.Materials and Methods: CCNY knock-out cells were constructed by CRISPR/CAS9 technique. CCNY overexpression cells were also constructed based on CCNY knock-out cells. Cell growth ability was detected by MTS assay, high-content cell analysis, colony formation assays, and anchorage-independent growth assays. The protein levels in laryngocarcinoma cells were determined by Western blot. The role of CCNY in cell cycle progression was evaluated by flow cytometry.Results: CCNY knock-out cells and CCNY up-regulation cell models were obtained successfully. Suppression of CCNY expression inhibited Hep2 cell growth. Cell growth was enhanced by the up-regulation of CCNY. The percentage of cells in G1 phase was altered when CCNY expression was down-regulated or up-regulated. The phosphorylation level of MEK and ERK as well as cyclin E protein level was also regulated by the expression level of CCNY.Conclusion: In laryngocarcinoma cell line Hep2 cells, cell proliferation was controlled by CCNY. The expression of CCNY was involved in the cell cycle progress of Hep2 cells. It indicated that CCNY could promote cell growth by activating MEK/ERK/cyclin E signaling pathway.Keywords: laryngocarcinoma, CCNY, cell cycle, ERK, cyclin E

Zhuofu Wu, 1, 2 Sitong Zhang, 1 Xiaojun Wang, 2 Can Cai, 2 Guang Chen, 1 Li Ma 2 1Key Laboratory of Straw Biology and Utilization, The Ministry of Education, College of Life Science, Jilin Agricultural University, Changchun 130118, People’s Republic of China; 2Department of Physics, Georgia Southern University, Statesboro, GA 30460, USACorrespondence: Guang ChenCollege of Life Science, Jilin Agricultural University, No. 2888 Xincheng Avenue, Changchun 130118, People’s Republic of ChinaTel/Fax +86 431 8453 2942Email guangc61@gmail.com Li MaDepartment of Physics, Georgia Southern University, 65 Georgia Avenue, Math/Physics Building Room 1003, Statesboro, GA 30460, USATel +1 912 478 5950Fax +1 912 478 0471Email lma@GeorgiaSouthern.eduPurpose: Combined superoxide dismutase (SOD)/catalase mimetics have attracted much attention because of their efficacy against reactive oxygen species-associated diseases; however, their application is often limited owing to their poor stability and the absence of favorable grafting sites. To address this, we developed a new class of SOD/catalase mimetics based on hybrid nanoflowers, which exhibit superior stability and possess the desired grafting sites for drugs and endogenous molecules.Methods: In this work, for the first time, we used polynitroxylated human serum albumin (PNA) to mediate the formation of hybrid copper-based nanoflowers. H 2O 2 depletion and O 2 evolution assays were first performed to determine the catalase-like activity of the hybrid nanoflowers. Next, the xanthine oxidase/cytochrome c method was used to assay the SOD-like activity of the nanoflowers. Further characteristics of the nanoflowers were evaluated using scanning electron microscopy (SEM), electron paramagnetic resonance (EPR), and Fourier-transform infrared spectroscopy (FTIR). Operational stability was assessed via the reusability assay.Results: The H 2O 2 depletion and O 2 evolution assays indicated that PNA-incorporated nanoflowers have genuine catalase-like activity. Kinetic analysis revealed that the reactions of the incorporated nanoflowers with H 2O 2 not only obey Michaelis–Menton kinetics, but that the nanoflowers also possess a higher affinity for H 2O 2 than that of native catalase. The FTIR spectra corroborated the presence of PNA in the hybrid nanoflowers, while the EPR spectra confirmed the intermolecular interaction of nitroxides bound to the human serum albumin incorporated into the nanoflowers. The remarkable operational reproducibility of the hybrid nanoflowers in catalase-like and SOD-like reactions was verified across successive batches.Conclusion: Herein, a comparison of Michaelis constants showed that the hybrid nanoflower, a catalase mimetics, outperforms the native catalase. Acting as a “better-than-nature” enzyme mimetics, the hybrid nanoflower with superior stability and desired ligand grafting sites will find widespread utilization in the medical sciences.Keywords: catalase, superoxide dismutase, polynitroxylated human serum albumin, reactive oxygen species, copper-based nanoflowers

Chuanxu Cai,1,2,* Xiqing Bian,3,* Mingshan Xue,1 Xiaoqing Liu,1 Haisheng Hu,1 Jingxian Wang,4 Song Guo Zheng,5 Baoqing Sun,1 Jian-Lin Wu31Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Laboratory Medicine, Shenzhen People’s Hospital, Shenzhen, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macao, People’s Republic of China; 4Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 5Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA*These authors contributed equally to this workBackground and objective: The prevalence of asthma is greater than 20% in patients previously diagnosed with COPD. Patients with asthma–COPD overlap (ACO) are at risk of rapid progression of disease and severe exacerbations. However, in some patients with ACO, a clear distinction from COPD is very difficult by using physiological testing techniques. This study aimed to apply a novel metabolomic approach to identify the metabolites in sera in order to distinguish ACO from COPD.Methods: In the study, blood samples were collected from patients with COPD, ACO, and healthy controls. Cholamine derivatization-ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to investigate serum metabolites of eicosanoids.Results: A clear intergroup separation existed between the patients with ACO and those with COPD, while ACO tends to have higher serum metabolic levels of eicosanoids. A robust Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA) model was found for discriminating between ACO and COPD (R2Y =0.81, Q2=0.79). In addition, there is a significant correlation between some metabolites and clinical indicators, such as hydroxyeicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acids (HPETEs) and FEV1/FVC. The higher values of area under the receiver operating characteristic curves (ROC) of HETEs, which were metabolized from HPETEs through lipoxygenase (LOX), indicated that they should be the potential biomarkers to distinguish ACO from COPD.Conclusion: Eicosanoids can clearly discriminate different biochemical metabolic profiles between ACO and COPD. The results possibly provide a new perspective to identify potential biomarkers of ACO and may be helpful for personalized treatment.Keywords: metabolomics, COPD, asthma–COPD overlap, cholamine derivatization-UHPLC-Q-TOF/MS

Yihang Gong,1,* Baojia Zou,1,* Siqi Peng,2 Peiping Li,1 Genglong Zhu,1 Jiafan Chen,1 Jianxu Chen,1 Xialei Liu,1 Wenying Zhou,3 Lei Ding,1 Yutong Chen,2 Linjuan Zeng,2 Baimeng Zhang,1 Chaonong Cai,1 Jian Li11Department of Hepatobiliary Surgery; 2Department of Oncology; 3Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province 519000, People’s Republic of China*These authors contributed equally to this work Background/aim: Hepatic stellate cells (HSCs) are critical determinants of liver tumor behavior such as vascular invasion, cell proliferation and migration. The apoptosis of HSCs can inhibit tumor growth and contribute to repressing hepatocellular carcinoma (HCC) progression. Our study aims to investigate the impact of nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on HSCs under hypoxic conditions and the association of nuclear GAPDH with HCC patient outcomes and tumor progression.Patients and methods: Following stable cell passage, 0.3% O2 was used to induce hypoxia. Cell proliferation and apoptosis were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays and flow cytometry, respectively. Proteins expression were detected by extracting nuclear and cytoplasmic proteins and performing Western blots. GAPDH nuclear translocation was blocked by the agent deprenyl. Immunohistochemical staining for GAPDH was investigated in 137 HCC tissue samples from our center. An analysis of the clinicopathological features, Kaplan-Meier analysis and Cox proportional hazards regression analysis were applied.Results: MTT assays and flow cytometry analyses showed that the nuclear accumulation of GAPDH led to the apoptotic death of HSCs, while blockade of this process with deprenyl significantly decreased apoptosis. Western blots revealed that deprenyl inhibited the nuclear translocation of GAPDH. An analysis of the immunohistochemical staining of HSCs in HCC tissue samples (137) revealed that nuclear GAPDH expression was significantly positively correlated with HIF-1α expression. Overall survival (OS) and time-to-recurrence (TTR) estimated by Kaplan-Meier analyses showed that patients with high HIF-1α or low nuclear GAPDH levels in HSCs had significantly poorer prognosis compared with patients with low HIF-1α or high nuclear GAPDH expression in HSCs. Moreover, patients with combined high HIF-1α/low nuclear GAPDH expression in HSCs had the worst prognosis. The Cox regression analysis revealed that the combination of nuclear GAPDH/HIF-1α expression in HSCs was an independent prognostic factor for OS and TTR in HCC patients.Conclusions: These findings provide a novel mechanism underlying the involvement of intranuclear GAPDH in hypoxia-induced HSCs apoptosis and a correlation between nuclear GAPDH levels and the clinical prognosis, which may prompt the development of a novel therapeutic strategy for HCC.Keywords: apoptosis, GAPDH, HSC, HCC, hypoxia

Jing Wang,1* Yu Pang,2* Wei Jing,1* Wei Chen,1* Ru Guo,1* Xiqin Han,1 Limin Wu,3 Guangxu Yang,4 Kunyun Yang,5 Cong Chen,6 Lin Jiang,7 Chunkui Cai,8 Zhi Dou,9 Lijuan Diao,10 Hongqiu Pan,11 Jianyun Wang,12 Feifei Du,13 Tao Xu,14 Lixia Wang,15 Renzhong Li,16 Naihui Chu1 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing 101149, P.R. China; 2National Clinical Laboratory on Tuberculosis, Beijing Chest Hospital affiliated to Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing 101149, P.R. China; 3Tuberculosis Prevention Institute, Hangzhou Center for Disease Control and Prevention, Zhejiang 310021, P.R. China; 4Tuberculosis Prevention Institute, Changchun Infectious Disease Hospital, Jilin 130123, P.R. China; 5Department of Tuberculosis Resistance, Hunan Chest Hospital, Hunan 410013, P.R. China; 6Multidrug Resistant Tuberculosis Project Office, Wuhan Pulmonary Hospital, Hubei 430030, P.R. China; 7Department of Internal Medicine, The Fifth People’s Hospital of Ganzhou, Jiangxi 341000, P.R. China; 8Department of Drug-Resistant Tuberculosis, Dalian Tuberculosis Hospital, Liaoning, 116033, P.R. China; 9Department of Tuberculosis, Qiqihar Tuberculosis Prevention and Control Institute, Heilongjiang 161006, P.R. China; 10Department of Tuberculosis, Nanyang Tuberculosis Control Institute, Henan 473000, P.R. China; 11Department of Tuberculosis, The Third People’s Hospital of Zhenjiang, Jiangsu 212000, P.R. China; 12Department of Infection, Lanzhou Pulmonary Hospital, Gansu 730046, P.R. China; 13Department of Respiratory, The Fourth People’s Hospital of Ningxia Hui Autonomous Region, Ningxia 750021, P.R. China; 14Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China; 15National Center for Tuberculosis Control and Prevention, Chinese Center For Disease Control and Prevention, Beijing 102206, P.R. China; 16Department of Tuberculosis Resistance Prevention and Control, Chinese Center for Disease Control and Prevention, Beijing 102206, P.R. China *These authors contributed equally to this work Background: Our aim was to assess whether the use of cycloserine (CS) would bring additional benefit for multidrug-resistant tuberculosis (MDR-TB) patients, and to estimate the incidence and associated risk factors of adverse drug reactions (ADRs) from CS.Patients and methods: In this study, we retrospectively reviewed the clinical outcomes and ADRs of MDR-TB patients treated with CS containing regimens between January 2012 and June 2015 in China.Results: A total of 623 MDR-TB cases enrolled in this study received regimens containing CS. Of these cases, in 411 of the patients 374 (66.0%) were “cured” and 37 (5.9%) “complete treatment” by the end of the study. The elderly, patients with prolonged previous exposure to and history of anti-TB drugs, and pre-existing co-morbidity were more likely to be associated with adverse outcomes of MDR-TB patients (P

Baojia Zou,1,* Xialei Liu,1,* Yihang Gong,1,* Chaonong Cai,1 Peiping Li,1 Shan Xing,2 Bibesh Pokhrel,1 Baimeng Zhang,1 Jian Li1 1Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China; 2Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China *These authors contributed equally to this work Background/Aim: Cancer-associated fibroblasts (CAFs) are important factors in the progression of hepatocellular carcinoma (HCC). But the characterization of these cells remains incomplete. This study aims to identify a panel of markers for CAFs that are associated with HCC progression. Materials and methods: The sequencing data and clinicopathological characteristics of 366 patients were obtained from the Cancer Genome Atlas (TCGA) database (366 HCC tissues and there were 50/366 cases with corresponding normal liver tissues). In vitro validation of the markers was performed by quantitative real-time PCR using the hepatic stellate cell line LX2 induced by the HCC cell line Huh7. The activation of LX2 was confirmed by α-smooth muscle actin and fibroblast activation protein, using quantitative real-time PCR and immunofluorescence staining. In vivo detections of the 12 markers were done in 40 tissue samples (30 HCC and 10 normal). Results: We successfully identified 12 CAF markers from TCGA data: FGF5, CXCL5, IGFL2, MMP1, ADAM32, ADAM18, IGFL1, FGF8, FGF17, FGF19, FGF4, and FGF23. The 12-marker panel was associated with the pathological and clinical progressions of HCC. All 12 markers were upregulated in vitro. In vivo expressions of these markers were paralleled with those in TCGA data. Conclusion: A 12-marker panel of CAFs in HCC is identified, which is associated with both pathological and clinical progressions of cancer. Keywords: hepatocellular carcinoma, cancer-associated fibroblasts, CAFs marker panel, TCGA database analysis, transcriptome profiling

Isis Gayed,1 Vivian Salama,2 Lydia Dawood,1 Steven Canfield,3 David Wan,1 Chunyan Cai,4 Usha Joseph,1 Robert Amato5 1Nuclear Medicine Section, Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, 2Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, 3Division of Urology, Department of Surgery, 4Division of Clinical and Translational Science, Department of Internal Medicine, 5Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA Background: Radium-223 dichloride (Ra-223 Xofigo) has recently been approved as an addition to the host of available therapies in the USA as a treatment option for metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. This study describes our initial experience in patients treated with Ra-223 dichloride. It attempts to optimize patients’ selection for the best outcome from Ra-223 dichloride therapy.Methods: Consecutive patients who were referred for treatment with Ra-223 dichloride were prospectively followed. Patients’ demographics, functional status per the Eastern Cooperative Oncology Group (ECOG) performance score, pain level per the numeric rating score (NRS), prostate-specific antigen (PSA), creatinine, and hematological values were compared at baseline and at the end of therapy. Patients also had a bone scan before starting therapy and at the end of therapy. Patients were divided into the favorable response (FR) group if their pain and/or functional status improved and the unfavorable response (UR) group if they did not improve, deteriorated, or deceased. Bone scan findings before and after Ra-223 dichloride therapy were compared in both the FR and UR groups.Results: Twenty patients were treated with Ra-223 dichloride. Twelve patients had innumerable bone metastases, three patients had super scans, and three patients had two to seven bone lesions. Two patients were lost to follow-up after the first injection. There were eight patients in the FR group and 10 patients in the UR group. Patients with UR had mean ECOG and NRS pain scores of 1.3 and 5.0 versus 0.8 and 4.4 in the FR group. The mean PSA and creatinine levels in the UR group were 445.2 ng/mL and 1.2 mg/dL versus 22.7 ng/mL and 1.1 mg/dL in the FR group. The mean hemoglobin, platelets, and absolute neutrophil values were 11.2 g/dL, 314.9 K/cmm, and 7.3 K/cmm in the UR group versus 11.6 g/dL, 207.0 K/cmm, and 6.2 K/cmm in the FR group. Seven of the eight patients with FR had a bone scan at the end of therapy showing improvement in five patients, a mixed response in one patient, and progression in another patient. Five patients in the UR group completed five or six injections and had bone scans showing flare of bone metastases in three patients, progression in one patient, and improvement in the fifth patient. Three patients in the UR group died after the first or second injections. Two of these patients had baseline super scans and the third one had widespread bone metastases.Conclusion: mCRPC patients with lower PSA levels at baseline and fewer bone lesions are more likely to respond favorably to Ra-223 dichloride therapy. Keywords: Radium-223 dichloride, castrate-resistant bone metastases, prostate cancer, radioactive therapy

Quan Chen,1 Siheng Li,2 Zixiong Feng,1 Meng Wang,3 Chengzhi Cai,2 Jufang Wang,3 Lijuan Zhang1 1School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, People’s Republic of China; 2Department of Chemistry, University of Houston, Houston, TX, USA; 3School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, People’s Republic of China Abstract: We have demonstrated a novel drug delivery system to improve the selectivity of the current chemotherapy by pH-responsive, polymeric micelle carriers. The micelle carriers were prepared by the self-assembly of copolymers containing the polybasic poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) block. The mixed copolymers exhibited a comparatively low critical micelle concentration (CMC; 1.95–5.25 mg/L). The resultant mixed micelles were found to be

Jiankun Yu,1 Jinmin Zhang,1 Haonan Xing,1 Yanping Sun,1 Zhen Yang,1 Tianzhi Yang,2 Cuifang Cai,1 Xiaoyun Zhao,3 Li Yang,1 Pingtian Ding1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China; 2Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, ME, USA; 3Department of Microbiology and Cell Biology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China Abstract: Two different disulfide (SS)-containing poly(amidoamine) (PAA) polymers were constructed using guanidino (Gua)-containing monomers (ie, arginine [Arg] and agmatine [Agm]) and N,N'-cystamine bisacrylamide (CBA) by Michael-addition polymerization. In order to characterize these two Gua-SS-PAA polymers and investigate their potentials as short hairpin RNA (shRNA)-delivery carriers, pSilencer 4.1-CMV FANCF shRNA was chosen as a model plasmid DNA to form complexes with these two polymers. The Gua-SS-PAAs and plasmid DNA complexes were determined with particle sizes less than 90 nm and positive ζ-potentials under 20 mV at nucleic acid:polymer weight ratios lower than 1:24. Bioresponsive release of plasmid DNA was observed from both newly constructed complexes. Significantly lower cytotoxicity was observed for both polymer complexes compared with polyethylenimine and Lipofectamine 2000, two widely used transfection reagents as reference carriers. Arg-CBA showed higher transfection efficiency and gene-silencing efficiency in MCF7 cells than Agm-CBA and the reference carriers. In addition, the cellular uptake of Arg-CBA in MCF7 cells was found to be higher and faster than Agm-CBA and the reference carriers. Similarly, plasmid DNA transport into the nucleus mediated by Arg-CBA was more than that by Agm-CBA and the reference carriers. The study suggested that guanidine and carboxyl introduced into Gua-SS-PAAs polymers resulted in a better nuclear localization effect, which played a key role in the observed enhancement of transfection efficiency and low cytotoxicity. Overall, two newly synthesized Gua-SS-PAAs polymers demonstrated great potential to be used as shRNA carriers for gene-therapy applications. Keywords: short hairpin RNA, gene carrier, bioresponsive, guanidinylated disulfide-containing poly(amido amine), nuclear localization, transfection efficiency, cytotoxicity

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run.

Jiankun Yu,1 Jinmin Zhang,1 Haonan Xing,1 Zhen Yang,1 Cuifang Cai,1 Conglu Zhang,1 Xiaoyun Zhao,1 Minjie Wei,2 Li Yang,1 Pingtian Ding1 1School of Pharmacy, Shenyang Pharmaceutical University, 2School of Pharmacy, China Medical University, Shenyang, People’s Republic of China Abstract: Guanidinylated poly(amido amine)s with multiple disulfide linkages (Gua-SS-PAAs) were designed and constructed as nonviral gene carriers. The main chains of these novel carriers were synthesized based on monomers containing guanidino groups (guanidine hydrochloride and chlorhexidine), which could avoid complicated side-chain-modification reactions while introducing the guanidino groups. The synthesized Gua-SS-PAAs polymers were characterized by 1H nuclear magnetic resonance, molecular weight, and polydispersity. Furthermore, Gua-SS-PAAs polymers were complexed with pDNA, and the properties of the complexes were determined, including entrapment efficiency, particle size, ζ-potential, atomic force microscopy images, stability, DNA complexation ability, reduction sensitivity, cytotoxicity, and transfection efficiency. The new Gua-SS-PAAs carriers exhibited higher transfection efficiency and lower cytotoxicity compared with two widely used gene delivery carriers, polyethylenimine and lipofectamine 2000. Furthermore, the relationship between the side-chain structure and morphological/biological properties was extrapolated, and the results showed that guanidine in the side chain aids in the improvement of transfection efficiency. In addition, the introduction of guanidino group might confer the new carriers with nuclear localization function compared to carriers without it. Keywords: gene carrier, transfection efficiency, cytotoxicity, nuclear localization, guanidine

Yuexia Xie,1,2,* Dejun Liu,3,* Chenlei Cai,1,* Xiaojing Chen,1 Yan Zhou,1 Liangliang Wu,1 Yongwei Sun,3 Huili Dai,1,2 Xianming Kong,1,2 Peifeng Liu1,2 1Central Laboratory, 2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, 3Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: The application of Fe3O4 nanoparticles (NPs) has made great progress in the diagnosis of disease and in the drug delivery system for cancer therapy, but the relative mecha­nisms of potential toxicity induced by Fe3O4 have not kept pace with its development in the application, which has hampered its further clinical application. In this article, we used two kinds of human hepatoma cell lines, SK-Hep-1 and Hep3B, to investigate the cytotoxic effects and the involved mechanisms of small Fe3O4 NPs with different diameters (6 nm, 9 nm, and 14 nm). Results showed that the size of NPs effectively influences the cytotoxicity of hepatoma cells: 6 nm Fe3O4 NPs exhibited negligible cytotoxicity and 9 nm Fe3O4 NPs affected cytotoxicity via cellular mitochondrial dysfunction and by inducing necrosis mediated through the mitochondria-dependent intracellular reactive oxygen species generation. Meanwhile, 14 nm Fe3O4 NPs induced cytotoxicity by impairing the integrity of plasma membrane and promoting massive lactate dehydrogenase leakage. These results explain the detailed mechanism of different diameters of small Fe3O4 NPs-induced cytotoxicity. We anticipate that this study will provide different insights into the cytotoxicity mechanism of Fe3O4 NPs, so as to make them safer to use in clinical application. Keywords: hepatoma cells, nanoparticles, cytotoxicity, mechanism, oxidative stress

Understanding spatial and temporal variation in soil respiration (RS) in different forest ecosystems is crucial to estimate the global carbon balance. Bamboo forest is a special forest type in southern China covering an area of 5.38 million ha, 70% of which are Moso bamboo (Phyllostachys heterocycla (Carr.) Mitford cv. Pubescens) forests. Bamboo forests contribute more than 10% to the whole carbon stock of forest ecosystems in China, and therefore play a critical role in the regional and national carbon balance. However, little information on the seasonal dynamic of RS and the carbon balance of Moso bamboo forests is available. In this study, litter removal and trenching methods were applied to partition RS into root respiration (RR), litter respiration (RL) and soil organic matter derived respiration (RM), and to study their seasonal dynamics and carbon balance in a pure Moso bamboo forest. Monthly RS, its source components and combined monthly environmental factors were measured. RS and its source components showed a significant seasonal variability with higher values from June to August and lower values from December to February driven by soil temperature and moisture (P < 0.001). Annual average RS, RR, RL and RM were 2.37, 0.69, 0.58 and 1.10 μmol m-2 s-1 with Q10 values of 1.25, 1.15, 1.19 and 1.26, respectively. Annual RS was 8.97 t C ha-1, and RR, RL and RM contributed 29%, 22% and 49%, respectively. Annual NEP was 4.72 t C ha-1 y-1, indicating that the Moso bamboo forest studied is a significant carbon sink.

Xiaoping Li,1–3,* Chi Cai,3,* Rong Luo,4 Rongjian Jiang,1 Jie Zeng,1 Yijia Tang,1 Yang Chen,1 Michael Fu,5 Tao He,1 Wei Hua31Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People’s Hospital, Chengdu, Sichuan, 2School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 3Department of Clinical Electrophysiology, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 4Key Laboratory of Thermoregulation and Inflammation of Sichuan Higher Education Institutes, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 5Department of Medicine, Sahlgrenska University Hospital/Östra Hospital, Gothenburg, Sweden*These authors contributed equally to this workObjective: Recent studies have shown that sex and age are associated with outcomes in patients with cardiomyopathy. The purpose of this study was to determine the all-cause mortality of dilated cardiomyopathy (DCM) by age and sex.Methods and results: The patients were divided into non-elderly (age