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Longbing Ren,1,2 Yan Gao,3 Yuting Jiang,3 Gege Wang,1,2 Qi Li,1,2 Yijun Gu,1,2 Han Yu,1,2 Jue Li,1,2 Lijuan Zhang1,2 1Shanghai East Hospital, Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, Tongji University, Shanghai, 200120, People’s Republic of China; 2Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai 200092, People’s Republic of China; 3Community Health Service Center of Anting Town Affiliated to Tongji University School of Medicine, Tongji University, Shanghai, 201805, People’s Republic of ChinaCorrespondence: Jue Li; Lijuan Zhang Email jueli@tongji.edu.cn; zhangxiaoyi@tongji.edu.cnBackground and Aim: Any single discrete blood pressure (BP) measurement is not enough to estimate adverse cardiovascular events. We aim to comprehensively investigate the association between BP indicators and stroke.Methods: An observational cohort study was conducted among 2888 Shanghai community-aged residents from 2014 to 2018, and a nested case-control study was designed to identify the association between BP indicators and stroke. In total 415 cases of stroke detected during the study period were selected as the case group and 415 non-stroke subjects, matched with factors of age and gender, were randomly selected from the cohort as control group.Results: Multivariate logistic regression analysis revealed that systolic blood pressure (SBP) (adjusted odds ratio [AOR] 1.02, 95% confidence interval [CI] 1.02– 1.03), pulse pressure (PP) (AOR 1.03, 95% CI 1.02– 1.04), mean arterial pressure (MAP) (AOR1.02, 95% CI 1.01– 1.04) and pulse pressure index (PPI) (AOR 25.68, 95% CI 3.19– 206.90) increased the risk of stroke, respectively. After fitting both BP indicators and covariates, isolated abnormal SBP (AOR 2.55, 95% CI 1.74– 3.72) or PP ≥ 50 mmHg (AOR 1.66, 95% CI 1.08– 2.56) independently increased risk of stroke.Conclusion: Besides SBP, PP and multiple factors, assessment should be taken into account comprehensively for stroke prevention and management.Keywords: blood pressure; BP, stroke, nested case-control study, primary care

Hang Zhao,1 Yong Tang,1 Chong Zheng,2 Luping Ren,1,* Guangyao Song1,* 1Endocrinology Department, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Pediatric Orthopaedics, Shijiazhuang the Third Hospital, Shijiazhuang, Hebei, 050011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Luping Ren; Guangyao Song 348, Heping West Road, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaTel +8631185988975; +8631185988556Email renluping1122@163.com; sguangyao2@163.comPurpose: This study aimed to examine whether 25-hydroxyvitamin D (25OHD) levels (an indicator of vitamin D status) are independently associated with insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM).Patients and Methods: This was a cross-sectional study. Participants with T2DM were recruited from the Department of Endocrinology in Hebei General Hospital according to inclusion and exclusion criteria. Data on basic characteristics and blood parameters were collected. We used the IR index (20/[fasting C-peptide × fasting plasma glucose]) to evaluate IR. Potential confounding factors were selected from comparisons among different IR index groups of quartiles and were adjusted in different models.Results: We included 172 subjects (121 men and 51 women) whose mean age was 53.2± 10.6 years. Body mass index (BMI), DM course, insulin use, glycated hemoglobin (HbA1c), fasting blood glucose, fasting C-peptide, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), and albumin were differed among different IR-index groups (all P value < 0.05). In models 1 and 2, no or some confounding factors were adjusted for, and we found that there was no relationship between 25OHD and the IR index. In model 3, when all confounding factors (DM course, insulin use, BMI, HbA1c, TG, HDL-C, ApoA1, albumin and other bone turnover markers) were adjusted for, the IR index was increased by 5.6% when 25OHD levels increased by 1 ng/mL (odds ratio: 1.056; 95% confidence interval: 1.009, 1.105).Conclusion: Vitamin D is independently associated with IR in patients with T2DM.Keywords: diabetes mellitus, type 2, vitamin D, insulin resistance

Jia Yu,1,* Hongyan Sun,2,* Jinhua Zhu,3,* Xintong Wei,1 Hongfei Shi,2 Bin Shen,3 Liyun Ren,1 Yan He,1 Rongyan Zhang,3 Mingzhi Zhang,1 Hao Peng1,4 1Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, People’s Republic of China; 2Center for Disease Prevention and Control of Tianning District, Changzhou, People’s Republic of China; 3Center for Disease Prevention and Control of Wujiang District, Suzhou, People’s Republic of China; 4Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao PengDepartment of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou, 215123, People’s Republic of ChinaTel +86 512 6588 0078Fax +86 512 6588 0052Email penghao@suda.edu.cnObjective: The relationship between obesity and hyperuricemia has been demonstrated by many studies. However, whether or to what extent metabolic condition influents the association between obesity and hyperuricemia was not clear. Here, we aimed to examine the association between obese-metabolic phenotype and hyperuricemia in a large sample of Chinese adults.Methods: According to BMI and metabolic syndrome, obese-metabolic phenotype was defined as metabolically unhealthy obesity (MUO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO) and metabolically healthy non-obesity (MHNO)in the Tianning cohort (N=5072). We conducted a cross-sectional analysis between obese-metabolic phenotype and hyperuricemia, followed by a Mendelian Randomization analysis using GWAS summary data to confirm the causality between uric acid and BMI.Results: The average level of serum UA showed 41.87-higher μmol/L in participants with MHO (β=41.87, P< 0.001) and 63.18-higher μmol/L in participants with MUO (β=63.18, P< 0.001), compared to those with MHNO. Compared to participants with MHNO, those with MUO had the highest likelihood to have hyperuricemia (OR=4.56, P< 0.001), followed by those with MHO (OR=3.32, P< 0.001). Mendelian randomization analysis indicated that uric acid was more likely to be a consequence of BMI (β=0.059, P=6.54× 10− 154).Conclusion: MUO, in comparison with MHO, was significantly associated with hyperuricemia in Chinese adults.Keywords: metabolic syndrome, obesity, serum uric acid, hyperuricemia

Siming Li,1,* Wentao Xu,1,* Minjun Liao,1,2,* Yuanping Zhou,2 Jun Weng,1 Liying Ren,1 Junxiong Yu,1,3 Weijia Liao,1 Zhaoquan Huang1,4 1Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 2Department of Infectious Diseases, Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China; 3Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 4Department of Pathology, Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijia LiaoLaboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of ChinaEmail liaoweijia288@163.comZhaoquan HuangDepartment of Pathology, Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of ChinaEmail 191990449@qq.comBackground: Currently, there is still a lack of effective biomarkers for the recurrence monitoring and survival prognosis assessment of hepatocellular carcinoma (HCC) patients with alpha-fetoprotein (AFP)-negative (≤ 20 ng/mL) after radical resection.Methods: The clinicopathological data of 606 patients (303 in the AFP-negative group and 303 in the AFP-positive group) who underwent radical resection of HCC were analyzed retrospectively.Results: The gamma-glutamyl transpeptidase to lymphocyte count ratio (GLR) of patients in the AFP-negative group was lower than that in the AFP-positive group (p < 0.001). The GLR level of the early-recurrence group was higher than that of the non-early-recurrence group (p =0.003). GLR had fair accuracy in predicting the early-recurrence of HCC patients [c-index=0.654 (95% CI=0.606– 0.702); AUC=0.681 (95% CI=0.625– 0.733)]. Univariate analysis showed that patients with tumor size < 5 cm, no microvascular invasion, single tumor, no metastasis, BCLC stage 0–A, no recurrence, and GLR ≤ 45.0 had longer disease-free survival (DFS) and overall survival (OS) among AFP-negative HCC patients. In addition, multivariate Cox proportional hazards regression analysis showed that tumor size < 5 cm (p =0.003), no recurrence (p < 0.001), and GLR < 45.0 (p < 0.001) were independent predictors of longer OS.Conclusion: GLR may be a potential indicator for early recurrence monitoring and prognosis evaluation in HCC patients with AFP-negative after radical resection.Keywords: hepatocellular carcinoma, AFP-negative, GLR, prognosis, early-recurrence

Ke Wei,1 Jie Luo,1 Jun Cao,1 Lihua Peng,1 Li Ren,1 Fan Zhang2 1Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Department of Anesthesiology, Jianyang People’s Hospital, Jianyang, Sichuan 641400, People’s Republic of ChinaCorrespondence: Ke WeiDepartment of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, 1# Youyi Road, Yuzhong District, Chongqing, People’s Republic of ChinaTel +86 23 89011069Fax +86 23 89011062Email wk202448@hospital-cqmu.comIntroduction: Endoplasmic reticulum (ER) stress seems to mediate the obesity-induced susceptibility to acute lung injury (ALI). The present study was designed to evaluate the role of ER stress in adiponectin (APN)-induced lung protection in an obese rat model treated with lipopolysaccharide (LPS).Methods: Four-week-old male Sprague-Dawley rats fed either a normal chow diet or a high-fat diet for 12 weeks were randomly assigned to one of the following groups: lean rats, diet-induced obesity rats, lean rats with ALI, obese rats with ALI, obese rats pretreated with 4-phenylbutyric acid (4-PBA) before ALI or obese rats pretreated with APN before ALI. At 24 h after instillation of LPS into the lungs, cell counts in the bronchoalveolar lavage fluid (BALF) were determined. Lung tissues were separated to assess the degree of inflammation, pulmonary oedema, epithelial apoptosis and the expression of ER stress marker proteins.Results: The 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) expression in the lung tissues of obese rats was upregulated before ALI, as well as the elevated apoptosis in epithelial cells. During ALI, the expression of ER stress marker proteins was similarly increased in both lean and obese rats, while significant downregulation of Mitofusin 2 (MFN2) was detected in obese epithelial cells. The lung tissues of obese rats showed higher concentrations of tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6) and IL-10, enhanced neutrophil counts and elevated wet/dry weight ratios. APN and 4-PBA decreased the degree of ER stress and suppressed LPS-induced lung inflammation, pulmonary oedema and epithelial apoptosis.Conclusion: APN may exert protective effects against the exacerbated lung injuries in obese rats by attenuating ER stress, which operates as a key molecular pathway in the progression of ALI.Keywords: adiponectin, endoplasmic reticulum stress, obesity, lung injury

Hang Zhao,1 Yunfeng Zhen,1 Zijing Wang,1 Licui Qi,2 Yong Li,3 Luping Ren,1,* Shuchun Chen1,* 1Endocrinology Department, Hebei General Hospital, Shijiazhuang, Hebei 050051, People’s Republic of China; 2Graduate School of Hebei North University, Zhangjiakou, Hebei 07500, People’s Republic of China; 3Graduate School of North China University of Science and Technology, Caofeidian New Town, Tangshan, Hebei 063210, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuchun ChenEndocrinology Department, Hebei General Hospital, 348, Heping West Road, Shijiazhuang, Hebei 050051, People’s Republic of ChinaEmail guang6701@sina.comLuping RenEndocrinology Department, Hebei General Hospital, 348, Heping West Road, Shijiazhuang, Hebei 050051, People’s Republic of ChinaEmail renluping1122@163.comPurpose: The aims of this study were to determine the relationship between 25-hydroxyvitamin D [25(OH) D] and glycated hemoglobin (HbA1c) levels in male and female patients with type 2 diabetes mellitus (T2DM).Patients and Methods: The participants were adults diagnosed with T2DM recruited from Hebei General Hospital. Patient information and information regarding blood indicators were collected. The subjects were divided into no vitamin D deficiency group [25(OH) D > 20 ng/mL] and vitamin D deficiency group [25(OH) D < 20 ng/mL], and these groups were then further subdivided into male-only or female-only subgroups. And then, the subjects were divided into male group and female group in different 25(OH) D levels.Results: HbA1c levels in the vitamin D deficiency group were significantly higher than those in the no vitamin D deficiency group for all subjects. The same was true for female patients but not for male patients. There was no difference in HbA1c levels between male and female patients with T2DM, regardless of 25(OH) D deficiency. A negative correlation existed between 25(OH) D and HbA1c in all subjects, as well as in the male-only and female-only subgroups. Vitamin D deficiency was associated with high HbA1c levels before and after adjusting for confounding factors in all participants and in the female-only subgroup, but not in the male-only subgroup.Conclusion: This study confirmed that vitamin D deficiency was related with high HbA1c levels in patients with T2DM, and this relationship differs between female and male patients.Keywords: diabetes mellitus, type 2, 25-hydroxyvitamin D, glycated hemoglobin

Qinghui Zhao1 12 23 3,* Hongming Tang1 12 23 3,* Lishu Ren4 4, Jie Wei4 4 1School of Life Sciences and Technology, Tongji University, Shanghai 200092, People’s Republic of China; 2Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, People’s Republic of China; 3Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200123, People’s Republic of China; 4Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinghui Zhao Tel +86-21-38804518Email qinghui_zhao@126.comPurpose: A bioactive and degradable scaffold of ternary composite with good biocompatibility and osteogenesis was developed for bone tissue repair.Materials and Methods: Polybutylene succinate (PS:50 wt%), magnesium phosphate (MP:40 wt%) and wheat protein (WP:10 wt%) composite (PMWC) scaffold was fabricated, and the biological performances of PMWC were evaluated both in vitro and vivo in this study.Results: PMWC scaffold possessed not only interconnected macropores (400 μm to 600 μm) but also micropores (10 μm ∼ 20 μm) on the walls of macropores. Incorporation of MP into composite improved the apatite mineralization (bioactivity) of PMWC scaffold in simulated body fluid (SBF), and addition of WP into composite further enhanced the degradability of PMWC in PBS compared with the scaffold of PS (50 wt%)/MP (50 wt%) composite (PMC) and PS alone. In addition, the PMWC scaffold containing MP and WP significantly promoted the proliferation and differentiation of mouse pre-osteoblastic cell line (MC3T3-E1) cells. Moreover, the images from synchrotron radiation microcomputed tomography (SRmCT) and histological sections of the in vivo implantation suggested that the PMWC scaffold containing MP and WP prominently improved the new bone formation and ingrowth compared with PMC and PS. Furthermore, the immunohistochemical analysis further confirmed that the PMWC scaffold obviously promoted osteogenesis and vascularization in vivo compared with PMC and PS.Conclusion: This study demonstrated that the biocompatible PMWC scaffold with improved bioactivity and degradability significantly promoted the osteogenesis and vascularization in vivo, which would have a great potential to be applied for bone tissue repair.Keywords: polybutylene succinate, composite scaffold, cytocompatibility, osteogenesis, vascularization

Hang Zhao,1 Cuijuan Qi,1 Chong Zheng,2 Kexin Gan,1 Luping Ren,1,* Guangyao Song1,* 1Endocrinology Department, Hebei General Hospital, Hebei 050051, People’s Republic of China; 2Pediatric Orthopaedics, Shijiazhuang the Third Hospital, Hebei 050011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Luping Ren Email renluping1122@163.comPurpose: We aimed to determine the relationship between the levels of glycated hemoglobin (HbA1c) and biomarkers of bone metabolism in patients with type 2 diabetes mellitus (T2DM), and whether HbA1c independently influences any of these biomarkers.Patients and Methods: A cohort study of 240 patients with T2DM was performed. Serum was obtained and used to measure HbA1c, total cholesterol (TC), triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol (LDL-C), very-low-density lipoprotein-cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total protein, albumin, blood urea nitrogen (BUN), creatinine, serum 25-hydroxyvitamin D (25OHD), osteocalcin (OC), β-C-terminal cross-linked telopeptide of type I collagen (β-CTX), procollagen type 1 N-terminal propeptide (P1NP), or parathyroid hormone (PTH) concentrations. The participants were divided into three study groups according to HbA1c level: < 7%, 7– 9% and ≥ 9%. Chi-square testing and one-way analysis of variance were used to compare groups. The relationships between HbA1c and bone metabolism biomarker values were analyzed using linear correlation analysis and multiple linear regression analysis.Results: Age, duration of T2DM, and the concentrations of TC, LDL-C, apolipoprotein B, albumin, and BUN showed significant difference among the < 7%, 7– 9% and ≥ 9% HbA1c groups. Of the bone metabolism biomarkers, there were significant differences in serum 25-hydroxyvitamin D (25OHD) and osteocalcin (OC) among the groups. The correlation coefficients (r) for the relationships of HbA1c with 25OHD and OC were − 0.200 and − 0.183, respectively (P < 0.05). Regardless of adjustment for none, some, or all of the confounding factors (age, sex, and duration of T2DM), the 25OHD and OC concentrations were significantly lower in the HbA1c ≥ 9% group than in the HbA1c < 7% group. HbA1c showed no relationship with β-CTX, PINP, or PTH.Conclusion: T2DM patients with poorer glycemic control had lower concentrations of serum 25OHD and OC, suggesting that HbA1c is an independent risk factor for low 25OHD and OC.Keywords: diabetes mellitus type 2, bone metabolism, glycated hemoglobin

Yunfei Niu,1 Lieping Guo,2 Fangyong Hu,3 Lishu Ren,4 Qirong Zhou,1 Jiangying Ru,3 Jie Wei4 1Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China; 2Department of Oncology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of China; 3Department of Orthopaedics, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225009, People’s Republic of China; 4Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, People’s Republic of ChinaCorrespondence: Yunfei NiuDepartment of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of ChinaEmail nyunfei1219@163.comJiangying RuDepartment of Orthopaedics, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225009, People’s Republic of ChinaTel +86-21-311 61690Fax +86-21-31161016Email rujiangying@163.comPurpose: To improve the surface bio-properties of polyetheretherketone (PEEK)/nano magnesium silicate (n-MS) composite (PC).Materials and Methods: The surface of PC was firstly treated by particle impact (PCP) and subsequently modified by concentrated sulfuric acid (PCPS).Results: PCPS surface exhibited not only macropores with sizes of about 150 μm (fabricated by particle impact) but also micropores with sizes of about 2 μm (created by sulfonation of PEEK) on the macroporous walls, and sulfonic acid (-SO3H) groups were introduced on PCPS surface. In addition, many n-MS nanoparticles were exposed on the microporous walls, which formed micro-nano structures. Moreover, the surface roughness and hydrophilicity of PCPS were obviously enhanced as compared with PC and PCP. Moreover, the apatite mineralization of PCPS in simulated body fluid (SBF) was obviously improved as compared with PC. Furthermore, compared with PC and PCP, PCPS exhibited antibacterial performances due to the presence of -SO3H groups. In addition, the responses (eg, adhesion and proliferation as well as differentiation) of bone marrow mesenchymal stem cell of rat to PCPS were significantly promoted as compared with PC and PCP.Conclusion: PCPS with macro-microporous surface containing -SO3H groups and micro-nano structures exhibited antibacterial activity and induced cell responses, which might possess large potential for bone substitute and repair.Keywords: PEEK based composite, sulfonation, macro-microporous surface, antibacterial performances, cell responses

Hailing Cheng,1,* Ning Wang,1,* Jun Tian,1 Yanyun Li,1 Lu Ren,1 Zhenyu Shi2 1Department of Obstetrics and Gynecology, Huaihe Hospital of Henan University, Kaifeng, Henan, People’s Republic of China; 2Henan Medical School, Henan University, Kaifeng, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenyu ShiHenan Medical School, Henan University, Section 229, North of Jinming Avenue, Kaifeng City, Henan Province, People’s Republic of ChinaTel +86-371-22922953Email xzmkra@163.comBackground: Circular RNAs (circRNAs) are significant molecular targets in various types of human cancers. The functional mechanism of circRNA_0025033 (circ_0025033) in ovarian cancer (OC) was discussed in the current report.Methods: The quantitative real-time polymerase chain reaction (qRT-PCR) was used for determining the circ_0025033 and microRNA-330-5p (miR-330-5p) levels. Cell Counting Kit-8 (CCK-8) and transwell assays were separately exploited to analyze cell viability and migration/invasion. Cell apoptosis was assessed using flow cytometry. The protein levels of epithelial–mesenchymal transition (EMT)-related makers and kallikrein-related peptidase 4 (KLK4) were measured by Western blotting. The target combination was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and RNA pull-down assays. And the effect of circ_0025033 on OC in vivo was explored via xenograft tumor assay.Results: Circ_0025033 was overexpressed in OC tissues and cells. Circ_0025033 knockdown inhibited OC cell viability, migration, invasion and EMT while expedited apoptosis. MiR-330-5p was a target of circ_0025033 and circ_0025033 regulated OC cellular behaviors by sequestering miR-330-5p. Moreover, miR-330-5p targeted KLK4 and circ_0025033 affected the KLK4 expression by sponging miR-330-5p. And miR-330-5p functioned as a tumor inhibitor in OC via targeting KLK4. In vivo, circ_0025033 promoted OC growth by the miR-330-5p/KLK4 axis.Conclusion: This study demonstrated that circ_0025033 contributed to the progression of OC via the miR-330-5p/KLK4 axis and might be a candidate target in the identification and treatment of OC.Keywords: circ_0025033, ovarian cancer, miR-330-5p, KLK4

Weiping Yang,1 Piguo Gong,1 Yifeng Yang,1 Chunyan Yang,2 Baohui Yang,3 Lijun Ren1 1Department of Thyroid Breast Surgery, Qingdao Chengyang People’s Hospital, Qingdao 266109, Shandong, People’s Republic of China; 2Obstetric Breast Health Clinic, Qingdao Haici Medical Center, Qingdao 266033, Shandong, People’s Republic of China; 3Department of Internal Medicine, Qingdao Chengyang Second People’s Hospital, Qingdao 266109, Shandong, People’s Republic of ChinaCorrespondence: Lijun RenDepartment of Thyroid Breast Surgery, Qingdao Chengyang People’s Hospital, No. 600, Changcheng Road, Chengyang District, Qingdao, Shandong, People’s Republic of ChinaEmail eijylo@163.comBackground: Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy.Methods: The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo.Results: Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo.Conclusion: Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.Keywords: breast cancer, paclitaxel, chemoresistance, circ-ABCB10, let-7a-5p, DUSP7

Juying Jin, Su Min, Lihua Peng, Xunsong Du, Dong Zhang, Li Ren Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaCorrespondence: Juying JinDepartment of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing 400016, People’s Republic of ChinaEmail juyingjin@hotmail.comObjective: To compare the prevalence and characteristics of chronic postsurgical pain (CPSP) between laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH) groups 3, 6, and 12 months after surgery, and to assess the impact of pain on the activities of daily living (ADL) of patients.Methods: The demographic characteristics, intraoperative clinical factors, and postoperative pain score were collected prospectively in patients scheduled for elective LH or AH for benign disease at our institution from July 2014 to June 2015. Patients were interviewed by telephone and followed up for pain assessment 3, 6, and 12 months after surgery. The prevalence, intensity, and specific locations of pain, as well as analgesic administration and impact on the ADL, were included in the questionnaire.Results: The results from 406 patients (225 patients in the LH group and 181 patients in the AH group) were obtained. Three months after surgery, the prevalence of CPSP was 20.9% in the LH group and 20.4% in the AH group. At 6 months, the prevalence of pain declined to 11.6% in the LH group and 9.4% in the AH group. At 12 months after surgery, only 13 (5.8%) patients in the LH group and 11 (6.1%) patients in the AH group complained about persistent pain. The prevalence of CPSP, as well as the average numerical rating scale pain scores at rest and during movement, during 12 months after surgery were not significantly different between the groups. CPSP after hysterectomy exhibited a negative impact on the ADL.Conclusion: The prevalence and intensity of CPSP were not significantly different between patients undergoing LH or AH within 12 months after surgery. A tendency towards a reduction in chronic pain over time was documented. Chronic post-hysterectomy pain exhibited a negative impact on the ADL.Keywords: chronic post-surgical pain, laparoscopic hysterectomy, abdominal hysterectomy

Jia Yu,1,* Hongyan Sun,2,* Fei Shang,2,* Haishu Wu,2 Hongfei Shi,2 Liyun Ren,1 Yan He,1 Mingzhi Zhang,1 Hao Peng1 1Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, People’s Republic of China; 2Center for Disease Prevention and Control of Tianning District, Changzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao PengDepartment of Epidemiology, School of Public Health And Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou 215123, People’s Republic of ChinaTel +86 512 6588 0078Fax +86 512 6588 0052Email penghao@suda.edu.cnMingzhi ZhangDepartment of Biostatistics, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou 215123, People’s Republic of ChinaTel +86 512 6588 0079Fax +86 512 6588 0052Email zhangmingzhi@suda.edu.cnAim: Fasting glucose has been associated with vascular aging, but the association between HbA1c and vascular aging has been limitedly studied in Chinese and other ethnic populations. We aimed to examine this association in a large sample of Chinese adults.Methods: In the Tianning Cohort (N=5142), fasting glucose, HbA1c, carotid-femoral pulse wave velocity (cfPWV), and pulse pressure (PP) were measured. Vascular aging was defined as having the highest quartile level of cfPWV or PP. We applied quantile regression models to examine the association between glucose metabolism and vascular aging.Results: The median cfPWV was significantly increased as increasing quintiles of fasting glucose (β=0.14, P

Guo Xia He,1,2,* Ning Li,1,3,* Lei Ren,2,4,* Hong Hua Shen,2 Ning Liao,5 Jian Jun Wen,6 Yi Min Xu,2 Jing Wang,4 Qing Yun Li1,3 1Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China; 2Department of Respiratory Rehabilitation, The Fourth Rehabilitation Hospital of Shanghai (Shanghai Jingan Geriatric Hospital), Shanghai 200042, People’s Republic of China; 3Institute of Respiratory Disease, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China; 4Department of Respiratory Medicine, The Second Affiliated Hospital of Suzhou University, Jiangsu 215004, People’s Republic of China; 5West-Nanjing Road Community Health-care Center of Shanghai, Shanghai 200040, People’s Republic of China; 6Caojiadu Community Health Service of Shanghai, Shanghai 200042, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing Yun LiDepartment of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai 200025, People’s Republic of ChinaTel +86 1 350 173 8686Fax +86 215 764 3271Email liqingyun68@hotmail.comPurpose: Pulmonary rehabilitation (PR) is essential to manage patients with COPD. The aim of this study was to investigate the appropriate intensity of PR exercise training for patients with moderate-to-severe COPD.Patients and methods: A prospective multicenter randomized controlled trial was conducted from January 2014 to October 2018. The subjects were randomly assigned to three groups with different intensities of PR, according to their maximum oxygen uptake percentage determined by cardiopulmonary exercise testing. After 20 weeks of exercise training, the effects of low-, moderate-, and high-intensity exercise interventions on patients were compared to determine the most appropriate PR prescription.Results: For patients with moderate COPD, all the measured parameters were significantly improved in the moderate- and high-intensity PR groups (P0.05).Conclusion: High-intensity PR exercise is helpful for patients with moderate to severe COPD. Moderate COPD patients need to receive intensive PR training; the improvement degrees from PR intervention were higher than those of the severe COPD patients. For patients with severe COPD, high-intensity PR exercise may be more beneficial if patients can tolerate it.Keywords: chronic obstructive pulmonary disease, cardiopulmonary exercise testing, exercise therapy, pulmonary rehabilitation

Mi Jian,1,* Wenju Chang,1,2,* Li Ren,1,2,* Tianyu Liu,1,* Yijiao Chen,1 Ye Wei,1,2 Qi Lin,1,2 Jianmin Xu,1,2 Xinyu Qin1,2 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, People’s Republic of China; 2Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Zhongshan Hospital, Fudan University, Shanghai 200030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinyu Qin; Jianmin XuDepartment of General Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200030, People’s Republic of ChinaTel +86 21 6404 1990 Ext 3449Fax +86 21 6403 8038Email surgeonqinxy@aliyun.com; xujmin@aliyun.comPurpose: To evaluate the role of hepatic steatosis (HS) in patients with synchronous colorectal liver-limited metastases (CLLMs) undergoing conversion therapy.Patients and methods: From March 2013 to March 2017, a total of 406 patients with initially unresectable CLLMs accepted conversion therapy in multidisciplinary team (MDT). Before the implementation of conversion therapy, all patients underwent CT scan to assess the presence of hepatic steatosis and divided into the HS group (n = 124) and the non-HS group (n = 282). After using propensity score matching (PSM) to eliminate the potential confounding bias of the two groups, the conversion hepatectomy rate and long-term oncological survival in two groups were compared.Results: After 1:1 PSM, no significant difference was observed at baseline between patients in the HS group (n = 119) and the non-HS group (n = 119). Patients in the HS group had higher conversion hepatectomy rate from MDT evaluation (31.1% vs 18.5%, P = 0.029) and actual hepatectomy rate (30.2% vs 18.5%, P = 0.030), when compared with patients in the non-HS group, respectively. In addition, the HS group achieved better progression-free survival (PFS, P = 0.047) and overall survival (OS, P = 0.035) than that of the non-HS group. Multivariate logistic analysis confirmed that pretreatment HS was an independent predictor for conversion hepatectomy rate (OR, 2.393; 95% CI, 1.463–4.315, P = 0.001), and multivariate Cox analysis revealed that HS was an independent prognostic factor for PFS (HR, 0.493, 95% CI 0.281–0.866, P = 0.014) and OS (HR, 0.559, 95% CI 0.398–0.785, P = 0.001).Conclusion: For CLLM patients who underwent conversion therapy, hepatic steatosis could be an effective predictor for conversion hepatectomy rate and an independent prognostic factor for PFS and OS.Keywords: colorectal cancer, liver metastases, conversion therapy, hepatic steatosis, objective response rate, survival

Fangwen Zhang,1,2,* Ling Li,1,2,* Lei Zhang,1,2 Xin Li,1,2 Xiaorui Fu,1,2 Xinhua Wang,1,2 Jingjing Wu,1,2 Zhenchang Sun,1,2 Fei Kong,1,2 Liangliang Ren,1,2 Mingzhi Zhang1,21Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People’s Republic of China; 2Department of Oncology, Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan 450052, People’s Republic of ChinaCorrespondence: Ling Li; Mingzhi ZhangDepartment of Oncology, Zhengzhou University First Affiliated Hospital, No. 1 Jianshe East Road , Zhengzhou, Henan 450052, People’s Republic of ChinaEmail lingl510@126.com mingzhi_zhang@126.com*These authors contributed equally to this workObjectives: To compare the efficacy of rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH-R) with traditional rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimens in CD5+ double-hit lymphoma (DHL) and to evaluate prognostic factors.Methods: We retrospectively studied 139 patients with newly diagnosed DHL/THL diffuse large B-cell lymphoma (including 20 cases CD5+ and 119 cases CD5−), 87 cases were MYC/BCL2 DHL, 30 cases were MYC/BCL6 DHL, 22 cases were THL. MYC, BCL2 and BCL6 rearrangements were examined by fluorescence in-situ hybridization. CD5 is detected by immunohistochemistry (IHC).Results: The objective response rate (ORR) difference between CD5+ and CD5− was significant (80.0% vs 63.8%, P=0.003). The median follow-up time was 18 months (range: 4–39 months). Progression-free survival (PFS) of CD5+ group was significantly worse than that of CD5- (28.1% vs 59.0%, P=0.028), while no significant difference was observed in overall survival (OS) (32.1% vs 59.9%, P=0.057). Compared with the two regimens, the 2-year survival rate of DA-EPOCH-R group was significantly superior than that of R-CHOP (63.6% vs 45.4%, P=0.034 for PFS; 67.4% vs 47.8%, P=0.038 for OS). Besides, CD5+ patients receiving DA-EPOCH-R had survival benefits compared with R-CHOP in PFS (85.7% vs 23.0%, P=0.029), but there was no statistical difference in OS (87.7% vs 34.4.0%, P=0.064). However, in DA-EPOCH-R protocol, there was no significant difference between CD5+ DHL (MYC/BCl2 and MYC/BCL6) and triple-hit lymphoma (P=0.776 for PFS; P=0.728 for OS). Multivariate analysis showed that CD5+ treatment regimen and disease stage were independent prognostic factors.Conclusion: Our retrospective study shows that CD5+ has a poorer prognosis than CD5− patients. Based on its improved lifetime and good tolerance on CD5+ patients, which is expected to become the first-line treatment for high-risk DLBCL types based on more clinical research.Keywords: CD5, DA-EPOCH-R, R-CHOP, diffuse large B-cell lymphoma, double-hit, treatment, prognosis

Jia Chen,1,2 Zhaoyang Huang,1,2 Liping Li,1,2 Liankun Ren,1,2 Yuping Wang1,21Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, People’s Republic of China; 2Beijing Key Laboratory of Neuromodulation, Beijing 100053, People’s Republic of ChinaAim: Focal cortical dysplasia (FCD) is a common cause of refractory epilepsy in children and adolescents. Epilepsy surgery is a treatment option for FCD. This study aimed to investigate the relationship between postsurgical outcomes and FCD types according to the International League Against Epilepsy (ILAE) classification and assess prognostic factors in pediatric and adolescent epilepsy surgery.Methods: We retrospectively analyzed 92 children and adolescents with a proven pathological diagnosis of FCD who underwent resective surgery at our epilepsy center between August 2012 and September 2015. The patients were followed up for at least 1 year to evaluate the surgical outcomes, and a multivariable regression analysis was performed to identify risk factors of seizure relapse.Results: After surgery, 53.3% of the patients were completely seizure-free during the entire follow-up period. The FCD types, incomplete resection of the epileptic cortex, and use of intracranial electrode were independent risk factors of seizure recurrence. The patients with FCD type II had relatively favorable surgical outcomes compared to the patients with FCD type I. The difference in the postoperative outcome between patients with FCD types III and I was not significant.Conclusion: There is a significant association between FCD types and surgical outcomes in children and adolescents with epilepsy. These findings provide guidance for the optimization of surgical strategies.Keywords: epilepsy, focal cortical dysplasia, surgery, outcome, children, adolescent

Cheng H, Wang N, Tian J, Li Y, Ren L, Shi Z. Cancer Manag Res. 2020;12:2753–2765. At the authors request, the Editor and Publisher of Cancer Management and Research wish to retract the published article. The authors have informed the journal that no ethical approval was given by the ethics committee of the Institute Review Ethics Committee of Huaihe Hospital of Henan University, despite the article stating such approval had been provided. Given this serious breach of our editorial polices the authors decided to retract the paper. 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

Yihao Mao,1,* Qingyang Feng,1,2,* Peng Zheng,1,* Liangliang Yang,1,* Tianyu Liu,1 Yuqiu Xu,1 Dexiang Zhu,1,2 Wenju Chang,1,2 Meiling Ji,1,2 Li Ren,1,2 Ye Wei,1,2 Guodong He,1,2 Jianmin Xu1,2 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, China; 2Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai 200030, China *These authors contributed equally to this work Purpose: Tumor purity is defined as the proportion of cancer cells in the tumor tissue. The impact of tumor purity on colon cancer (CC) prognosis, genetic profile, and microenvironment has not been thoroughly accessed.Materials and methods: Clinical and transcriptomic data from three public datasets, GSE17536/17537, GSE39582, and TCGA, were retrospectively collected (n=1,248). Tumor purity of each sample was inferred by a computational method based on transcriptomic data. Survival-related analyses were performed on microarray dataset containing GSE17536/17537 and GSE39582 (n=794), whereas TCGA dataset was utilized for subsequent genomic analysis (n=454).Results: Right-sided CC patients showed a significantly lower tumor purity. Low purity CC conferred worse survival, and tumor purity was identified as an independent prognostic factor. Moreover, high tumor purity CC patients benefited more from adjuvant chemotherapy. Subsequent genomic analysis found that the mutation burden was negatively associated with tumor purity, with only APC and KRAS significantly more mutated in high purity CC. However, no somatic copy number alteration event was correlated with tumor purity. Furthermore, immune-related pathways and immunotherapy-associated markers (programmed cell death protein 1 [PD-1], programmed death-ligand 1 [PD-L1], cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Lymphocyte-activation gene 3 [LAG-3] and T-cell immunoglobulin and mucin-domain containing-3 [TIM-3]) were highly enriched in low purity samples. Notably, the relative proportion of M2 macrophages and neutrophils, which indicated worse survival in CC, was negatively associated with tumor purity.Conclusion: Tumor purity exhibited potential value for CC prognostic stratification as well as adjuvant chemotherapy benefit prediction. The relative worse survival in low purity CC may attribute to higher mutation frequency in key pathways and purity-related microenvironmental changing. Keywords: adjuvant chemotherapy, colon cancer, prognosis, tumor microenvironment, tumor purity

Peng Zheng,* Li Ren,* Qingyang Feng,* Dexiang Zhu,* Wenju Chang, Guodong He, Meiling Ji, Mi Jian, Qi Lin, Tuo Yi, Ye Wei, Jianmin Xu Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs). Patients and methods: From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes according to custom panel. Mutations were compared between synchronous and metachronous liver metastases and correlated with clinical characteristics. Results: A total of 161 patients were included: 93 patients with synchronous CLM and 68 patients with metachronous CLM. Patients with metachronous CLM were obviously elder. For pathology of primary tumors, synchronous CLMs were larger in size, poorly differentiated, and more frequently local advanced and lymph node positive. For evaluation of liver metastases, synchronous CLM had more and larger metastatic lesions. The median number of mutations in synchronous CLMs was significantly higher than in metachronous group (22 vs. 18, p

Qibin Chen,1 Li Ren,1 Su Min,1 Xuechao Hao,2 Hengsheng Chen,3 Jie Deng1 1Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 2Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, 3Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of China Background: Accompanied with the effective antidepressant effect, electroconvulsive shock (ECS) can induce cognitive impairment, but the mechanism is unclear. Synaptic plasticity is the fundamental mechanism of learning and memory. This study aimed to investigate the effect of ECS on synaptic plasticity changes in rats with depression-like behavior. Methods: Chronic unpredictable mild stress procedure was conducted to establish a model of depression-like behavior. Rats were randomly divided into the following three groups: control group with healthy rats (group C), rats with depression-like behavior (group D), and rats with depression-like behavior undergoing ECS (group DE). Depression-like behavior and spatial learning and memory function were assessed by sucrose preference test and Morris water test, respectively. Synaptic plasticity changes in long-term potentiation (LTP), long-term depression (LTD), depotentiation, and post-tetanic potentiation (PTP) were tested by electrophysiological experiment. Results: ECS could exert antidepressant effect and also induced spatial learning and memory impairment in rats with depression-like behavior. And, data on electrophysiological experiment showed that ECS induced lower magnitude of LTP, higher magnitude of LTD, higher magnitude of depotentiation, and lower magnitude of PTP. Conclusion: ECS-induced learning and memory impairment may be attributed to postsynaptic mechanism of LTP impairment, LTD and depotentiation enhancement, and presynaptic mechanism of PTP impairment. Keywords: electroconvulsive therapy, learning, memory, synaptic plasticity, electrophysiology

Yamin Yang,1 Yue Hu,2 Henry Du,3 Lei Ren,4 Hongjun Wang5 1Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, China; 2Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA; 3Department of Chemical Engineering and Materials Sciences, Stevens Institute of Technology, Hoboken, NJ, USA; 4Department of Biomaterials, College of Materials, Xiamen University, Xiamen, Fujian, China; 5Department of Biomedical Engineering, Chemistry and Biological Sciences, Stevens Institute of Technology, Hoboken, NJ, USA Introduction: In recognition of the potentials of gold nanoparticles (Au NPs) in enhanced photodynamic therapy (PDT) for cancer, it is desirable to further understand the shape-dependent surface plasmonic resonance (SPR) properties of various gold nanostructures and evaluate their performances in PDT. Materials and methods: Monodispersed colloidal spherical solid Au NPs were synthesized by UV-assisted reduction using chloroauric acid and sodium citrate, and hollow gold nanorings (Au NRs) with similar outer diameter were synthesized based on sacrificial galvanic replacement method. The enhanced electromagnetic (EM) field distribution and their corresponding efficiency in enhancing singlet oxygen (1O2) generation of both gold nanostructures were investigated based on theoretical simulation and experimental measurements. Their shape-dependent SPR response and resulted cell destruction during cellular PDT in combination with 5-aminolevulinic acid (5-ALA) were further studied under different irradiation conditions. Results: With comparable cellular uptake, more elevated formation of 1O2 in 5-ALA-enabled PDT was detected with the presence of Au NRs than that with Au NPs under broadband light irradiation in both cell-free and intracellular conditions. As a result of the unique morphological attributes, exhibiting plasmonic effect of Au NRs was still achievable in the near infrared (NIR) region, which led to an enhanced therapeutic efficacy of PDT under NIR light irradiation. Conclusion: Shape-dependent SPR response of colloidal Au NPs and Au NRs and their respective effects in promoting PDT efficiency were demonstrated in present study. Our innovative colloidal Au NRs with interior region accessible to surrounding photosensitizers would serve as efficient enhancers of PDT potentially for deep tumor treatment. Keywords: gold nanoparticles, colloidal gold nanorings, surface plasmonic resonance, photodynamic therapy

Le Ren, Yue Yu Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients. Keywords: pancreatic ductal adenocarcinoma, miRNA, diagnosis, prognosis, chemoresistance

Gulixian Mahemuti, Hui Zhang, Jing Li, Nueramina Tieliwaerdi, Lili Ren Respiratory Department, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Province, People’s Republic of China Background and objective: Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner’s formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma. We aimed to quantify the usefulness and side effects of theophylline with or without ethylene diamine (aminophylline) in acute asthma, with particular emphasis on patient subgroups, such as children, adults, and concomitant medications.Methods: We searched PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, and the WHO Clinical Trials Registry for randomized, controlled clinical trials. We planned a priori subgroup analyses by time post-medication, concomitant medication, control type, and age.Results: We included 52 study arms from 42 individual trials. Of these, 29 study arms included an active control, such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, and 23 study arms compared theophylline (with or without ethylene diamine) with placebo or no drug. Theophylline significantly reduced heart rate when compared with active control (p=0.01) and overall duration of stay (p=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) (p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. Closer examination of the data revealed that the medications given in addition to theophylline or control significantly changed the effectiveness of theophylline (subgroup difference: p

Lei Wang,1,* Guoyuan Li,1,* Ling Ren,2,* Xiangdong Kong,1 Yugang Wang,1 Xiuguo Han,1 Wenbo Jiang,3 Kerong Dai,1 Ke Yang,2 Yongqiang Hao11Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 2Special Materials and Device Research Department, Institute of Metal Research, Chinese Academy of Sciences, Shenyang, 3Medical 3D Printing Innovation Research Center, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Treatment for fractures requires internal fixation devices, which are mainly produced from stainless steel or titanium alloy without biological functions. Therefore, we developed a novel nano-copper-bearing stainless steel with nano-sized copper-precipitation (317L-Cu SS). Based on previous studies, this work explores the effect of 317L-Cu SS on fracture healing; that is, proliferation, osteogenic differentiation, osteogenesis-related gene expression, and lysyl oxidase activity of human bone mesenchymal stem cells were detected in vitro. Sprague–Dawley rats were used to build an animal fracture model, and fracture healing and callus evolution were investigated by radiology (X-ray and micro-CT), histology (H&E, Masson, and safranin O/fast green staining), and histomorphometry. Further, the Cu2+ content and Runx2 level in the callus were determined, and local mechanical test of the fracture was performed to assess the healing quality. Our results revealed that 317L-Cu SS did not affect the proliferation of human bone mesenchymal stem cells, but promoted osteogenic differentiation and the expression of osteogenesis-related genes. In addition, 317L-Cu SS upregulated the lysyl oxidase activity. The X-ray and micro-CT results showed that the callus evolution efficiency and fracture healing speed were superior for 317L-Cu SS. Histological staining displayed large amounts of fibrous tissues at 3 weeks, and cartilage and new bone at 6 weeks. Further, histomorphometric analysis indicated that the callus possessed higher osteogenic efficiency at 6 weeks, and a high Cu2+ content and increased Runx2 expression were observed in the callus for 317L-Cu SS. Besides, the mechanical strength of the fracture site was much better than that of the control group. Overall, we conclude that 317L-Cu SS possesses the ability to increase Cu2+ content and promote osteogenesis in the callus, which could accelerate the callus evolution process and bone formation to provide faster and better fracture healing. Keywords: nano-sized copper, lysyl oxidase, osteogenesis, fracture healing, callus evolution

Sunkui Ke,1 Tong Zhou,2 Peiyan Yang,3 Yange Wang,2 Peng Zhang,2 Keman Chen,2 Lei Ren,2 Shefang Ye2 1Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, 2Department of Biomaterials, College of Materials, Xiamen University, 3Department of Surgery, First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, People’s Republic of China Abstract: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic receptors have been identified as highly promising antitumor agents preferentially eliminating cancer cells with minimal damage, the emergence of TRAIL resistance in most cancers may contribute to therapeutic failure. Thus, there is an urgent need for new approaches to overcome TRAIL resistance. Gold nanoparticles (AuNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AuNPs on TRAIL sensitivity in cancer cells remain unclear. In this study, we found that AuNPs combined with TRAIL exhibited a greater potency in promoting apoptosis in non-small-cell lung cancer (NSCLC) cells compared with TRAIL alone, suggesting that AuNPs sensitize cancer cells to TRAIL. Further experiments demonstrated that the combination of TRAIL and AuNPs was more effective in causing excessive mitochondrial fragmentation in cancer cells accompanied by a dramatic increase in mitochondrial recruitment of dynamin-related protein 1 (Drp1), mitochondrial dysfunctions, and enhancement of autophagy induction. Small interfering RNA (siRNA) silencing of Drp1 or inhibition of autophagy could effectively alleviate apoptosis in cells exposed to TRAIL combined with AuNPs. In vivo studies revealed that AuNPs augmented TRAIL sensitivity in tumor-bearing mice. Our data indicated that AuNPs potentiate apoptotic response to TRAIL in NSCLC cells through Drp1-dependent mitochondrial fission, and TRAIL combined with AuNPs can be a potential chemotherapeutic strategy for the treatment of NSCLC. Keywords: AuNPs, TRAIL, mitochondrial dynamics, Drp1, autophagy/mitophagy

Lihua Ren,1,2 Jin Zhang,1,2 Yang Zou,1,2 Lianshuang Zhang,1,2 Jialiu Wei,1,2 Zhixiong Shi,1,2 Yanbo Li,1,2 Caixia Guo,2 Zhiwei Sun,1,2 Xianqing Zhou1,21Department of Toxicology and Hygienic Chemistry, School of Public Health, 2Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People’s Republic of ChinaAbstract: The reproductive toxicity of silica nanoparticles (SiNPs) is well known, but the underlying mechanism is still not clear. To investigate the toxic mechanism of SiNPs on spermatogenic cells, 60 C57 male mice were randomly and equally divided into three groups (the control group, the saline control group, and the SiNPs group) with two observed time points (45 days and 75 days). The mice in the SiNPs group were administered with SiNPs 2 mg/kg diluted in normal saline, and the mice of the saline control group were given equivoluminal normal saline by tracheal perfusion every 3 days for 45 days (in total 15 times). The control group mice were bred without treatment. In each group, a half number of the mice were sacrificed on the 45th day after the first dose, and the remaining half were sacrificed on the 75th day. The results showed that SiNPs increased the malformation of sperms and decreased the motility and concentration of sperms in epididymis on the 45th day after the first dose. SiNPs induced oxidative stress in testis and led to apoptosis and necroptosis of the spermatogenic cells. Furthermore, SiNPs increased the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 and RIPK3/MLKL on the 45th day after the first dose. However, compared with the saline control group, the index of sperms and the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3/RIPK3/MLKL showed no significant changes in the SiNPs group on the 75th day after the first dose. These data suggested that SiNPs could induce apoptosis and necroptosis in the spermatogenic cells by activating the RIPK1 pathway resulting from oxidative stress in male mice. SiNPs-induced damage recovered on the 75th day after the first dose, which suggested that SiNPs-induced toxicity is reversible.Keywords: silica nanoparticles, RIPK1 signal pathway, apoptosis, necroptosis, spermatogenic cells, reversible