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Baokun Liu,1,2,&ast; Lujun Shen,3,4,&ast; Wen Liu,5 Zhiyong Zhang,1,2 Jieqiong Lei,1,2 Zhengguo Li,1,2 Qinquan Tan,6 Hengfei Huang,7 Xingdong Wang,1,2 Weijun Fan3,4 1Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center Gansu Hospital, Lanzhou, 730050, People’s Republic of China; 2Department of Minimally Invasive Interventional Therapy, Gansu Provincial Cancer Hospital, Lanzhou, 730050, People’s Republic of China; 3Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 4State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 5Department of Radiotherapy, Lanzhou University Second Hospital, Lanzhou, 730030,People’s Republic of China; 6Department of Oncology, Dongguan People’s Hospital, Dongguan, 523000, People’s Republic of China; 7Department of General Surgery, Chongzuo People’s Hospital, Chongzuo, 523000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingdong Wang; Weijun Fan, Email wxd101027@163.com; fanwj@sysucc.org.cnPurpose: The majority of new diagnoses of hepatocellular carcinoma (HCC) still pertain to unresectable cases. Currently, the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors has become the mainstream treatment. According to multiple clinical guidelines, it is strongly advised to consider local therapy as the primary treatment choice for uHCC. This research was conducted to examine the safety and effectiveness of combining hepatic arterial infusion chemotherapy (HAIC) with TKIs and PD-1 inhibitors for the treatment of uHCC.Methods: Between 2015 and 2020, 208 HCC patients received HAIC alone or HAIC in combination with TKIs and PD-1 inhibitors. The overall survival(OS), and progression-free survival(PFS) and the best treatment response were compared between the two treatment groups. Propensity score matching (PSM)was used to minimize confounding bias.Results: Among the enrolled patients, 116 patients (55.8%) received combination therapy, while 92 patients (44.2%) received HAIC alone. The baseline characteristics were similar between the two groups. After PSM, 82 pairs of well-matched liver cancer patients were selected; the overall response rate in the combination group trended better than that in the HAIC alone group. The hazard ratios (HRs) for OS and PFS of the combination approach compared to the HAIC-alone approach were 0.47 (95% CI, 0.322– 0.687; p< 0.001) and 0.58 (95% CI, 0.397– 0.848; p=0.005), respectively.Conclusion: For uHCC patients, combination therapy can provide better OS and PFS compared to HAIC alone.Keywords: hepatocellular carcinoma, TKIs, PD-1, HAIC, combination therapy

Qiang Tan, Ming Chen, Hongmei Yang, Yao Guo, Xiaoyi Zou Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of ChinaCorrespondence: Qiang Tan, Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of China, Email qhdtanqiang@aliyun.comBackground: Subclinical hypothyroidism (SH) increases the risk of cardiovascular events, however the influence of SH on prognosis of ejection fraction preserved heart failure (HFpEF) is not fully understood.Methods: In this prospective observational study, patients with HFpEF were divided into euthyroidism group (n = 413) and SH group (n = 79). Patients were followed up for at least 30 months to examine the association between SH and cardiovascular events in patients with HFpEF. The primary end point was composite cardiovascular events (cardiovascular death and re-hospitalization). The patients underwent flow-mediated dilation (FMD) measurement by ultrasound in order to value endothelial function.Results: The rate of composite cardiovascular events was higher in SH group than in euthyroidism group (54.49% and 26.36%, respectively; p < 0.001). The higher risk of cardiovascular events in SH group was primarily due to a higher risk of re-hospitalization compared to euthyroidism group (45.56% and 20.58%, respectively; p < 0.001). The rate of cardiovascular death was higher in SH group than in euthyroidism group (13.92% and 5.81%, respectively; p = 0.017). Cox proportional hazards regression showed that SH (hazard ratios [HR] 1.921, 95% confidence interval [CI] 1.139– 3.240), level of TSH (HR 1.025, 95% CI 1.010– 1.054), age (HR 1.017, 95% CI 1.002– 1.034), LVEF (HR 0.975, 95% CI 0.953– 0.996), atrial fibrillation (HR 1.581, 95% CI 1.083– 2.307), eGFR (HR 0.987, 95% CI 0.978– 0.997), and NYHA cardiac function (HR 2.342, 95% CI 1.649– 3.326) were independent predictors of cardiovascular events in patients with HFpEF (all P < 0.05).Conclusion: Subclinical hypothyroidism was associated with increased cardiovascular events and death in patients with HFpEF.Keywords: subclinical hypothyroidism, ejection fraction preserved heart failure, endothelial function, flow-mediated dilation, cardiovascular events

Runmin Zhang, Muzhe Li, Huiyun Li, Xun Ran, Fengtian Jin, Qingshan Tan, Zhiwei Chen Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of ChinaCorrespondence: Zhiwei Chen, Department of Orthopaedics, The First Affiliated Hospital of University of South China, 69| Chuanshan Road, Hengyang, Hunan, People’s Republic of China, Tel +86-13973409923, Email CZW9915@sina.comAbstract: Inflammation is a common feature of many inflammatory diseases and tumors, and plays a decisive role in their development. Exosomes are extracellular vesicles unleashed by assorted types of cells, and it is widely known that exosomes of different immune cell sources play different functions. Exosome production has recently been reported for immune cells comprising macrophages, T cells, B cells, and dendritic cells (DCs). Immune cell-derived exosomes are involved in a variety of inflammatory responses.Herein, we summarize and review the role of macrophages, T cells, B cells, and dendritic cells (DC) in inflammatory diseases, with a focus on the role of immune cell-derived exosomes in osteoarthritis, rheumatoid arthritis, and the inflammatory tumor microenvironment (TME).These findings are expected to be important for developing new treatments for inflammatory diseases and ameliorating tumor-related inflammation. Keywords: inflammatory diseases, immune cell-derived exosomes, osteoarthritis, rheumatoid arthritis, inflammatory tumor microenvironment

Shiqi Wang,1 Chao Xia,2 Qirui Zheng,3 Aiping Wang,4 Qian Tan1 1Department of Burns and Plastic Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China; 2Department of Orthopedics, Air Force Hospital of Eastern Theater Command, Nanjing, People’s Republic of China; 3Software Institute, Nanjing University, Nanjing, People’s Republic of China; 4Department of Endocrinology, Air Force Hospital of Eastern Theater Command, Nanjing, People’s Republic of ChinaCorrespondence: Qian Tan, Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China, Tel +86 25 83106666, Email smmutanqian@sina.com Aiping Wang, Department of Endocrinology, Air Force Hospital of Eastern Theater Command, Nanjing, 210002, People’s Republic of China, Email wap454hospital@163.comBackground: Early detection of hard-to-heal diabetic foot ulcers (DFUs) is vital to prevent a poor prognosis. The purpose of this work was to employ clinical characteristics to create an optimal predictive model of hard-to-heal DFUs (failing to decrease by > 50% at 4 weeks) based on machine learning algorithms.Methods: A total of 362 DFU patients hospitalized in two tertiary hospitals in eastern China were enrolled in this study. The training dataset and validation dataset were split at a ratio of 7:3. Univariate logistic analysis and clinical experience were utilized to screen clinical characteristics as predictive features. The following six machine learning algorithms were used to build prediction models for differentiating hard-to-heal DFUs: support vector machine, the naïve Bayesian (NB) model, k-nearest neighbor, general linear regression, adaptive boosting, and random forest. Five cross-validations were employed to realize the model’s parameters. Accuracy, precision, recall, F1-scores, and AUCs were utilized to compare and evaluate the models’ efficacy. On the basis of the best model identified, the significance of each characteristic was evaluated, and then an online calculator was developed.Results: Independent predictors for model establishment included sex, insulin use, random blood glucose, wound area, diabetic retinopathy, peripheral arterial disease, smoking history, serum albumin, serum creatinine, and C-reactive protein. After evaluation, the NB model was identified as the most generalizable model, with an AUC of 0.864, a recall of 0.907, and an F1-score of 0.744. Random blood glucose, C-reactive protein, and wound area were determined to be the three most important influencing factors. A corresponding online calculator was created (https://predicthardtoheal.azurewebsites.net/).Conclusion: Based on clinical characteristics, machine learning algorithms can achieve acceptable predictions of hard-to-heal DFUs, with the NB model performing the best. Our online calculator can assist doctors in identifying the possibility of hard-to-heal DFUs at the time of admission to reduce the likelihood of a dismal prognosis.Keywords: hard-to-heal, diabetic foot ulcers, machine learning, classification

Qian Tan,1,&ast; Zhengkun Cai,2,&ast; Jia Li,3 Jing Li,1 Hongchun Xiang,1 Bocun Li,1 Guowei Cai1 1Department of Acupuncture, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Public Administration, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guowei CaiDepartment of Acupuncture, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaEmail cgw645@163.comObjective: We aim to explore whether acupuncture inhibits inflammation and bone destruction in rat model monosodium iodoacetate (MIA)-induced knee osteoarthritis (KOA) by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography (PET) and micro-computed tomography (CT) imaging.Methods: KOA was induced in rats by intra-articular injection MIA (2 mg/50 μL) through the right knee of the rats. Forty male Sprague Dawley rats weighing 280 to 340 g (12 weeks old) were randomly divided into four groups including Control group, KOA group, KOA plus manual acupuncture group (KOA+MA), KOA plus sham acupuncture group (KOA+SA). The acupuncture treatment lasted for three weeks (one-day rest after six days of treatment). Paw withdrawal threshold test and open-field test were used to assess mechanical allodynia and locomotor activity respectively for once a week. Hematoxylin and eosin (H&E) staining was used to assess the damage of the cartilage, synovium and infrapatellar fat pad (IFP). 18F-FDG PET was performed to quantify joint inflammation. The influence on the subchondral bone in these rats was confirmed by micro-CT.Results: Mechanical hyperalgesia, joint inflammation, and obvious bone destruction were observed in the KOA group. H&E staining of the knee joint found that manual acupuncture played a protective effect in cartilage, synovium and IFP destruction. However, compared with KOA group, the results in sham acupuncture had no significant difference. After manual acupuncture treatment in KOA rats, inflammation was significantly suppressed shown by 18F-FDG PET imaging. Micro-CT analysis of the knee joint revealed that manual acupuncture protected bone by inhibiting osteophyte development and subchondral bone remodeling.Conclusion: The results of 18F-FDG PET and micro-CT showed that manual acupuncture inhibited inflammation and bone destruction, which provides reliable evidence for the effectiveness of acupuncture in hindering development of KOA, and provides reliable evidence for clinical application of acupuncture.Keywords: osteoarthritis, acupuncture, PET, micro-CT, inflammation, bone destruction

Qi Tan,&ast; Limin Duan,&ast; Qi Huang,&ast; Wenjuan Chen,&ast; Zimo Yang, Jiangbin Chen, Yang Jin Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang JinDepartment of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People’s Republic of ChinaTel +86-135-5436-1146Fax +86-27-85755457Email whuhjy@126.comBackground: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1β has been widely studied. In this study, we focused on the effect of IL-1β on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms.Methods: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1β in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1β. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1β and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1β.Results: Our results showed that IL1β was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1β. In vivo, IL-1β increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1β.Conclusion: IL-1β promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1β links inflammation to glycolysis in LUAD, and targeting IL-1β and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.Keywords: interleukin 1β, glycolysis, lung adenocarcinoma, p38 signaling

Qiaowen Tan,1 Shaoke Li,2 Juan Niu,3 Shien Liu,2 Yaling Li,1 Yujie Lu,1 Zhihong Wang,1 Wanqun Xu,1 Yalin Wei,1 Zongjun Guo1 1Department of Geriatrics, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of China; 2Department of Medical Imaging, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of China; 3Clinical Psychology Department, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of ChinaCorrespondence: Zongjun Guo; Shaoke Li Email guozjj@163.com; lsk224@163.comIntroduction: We studied the regulatory mechanism of the habitual brain network in tobacco dependence to provide a theoretical basis for the regulation and cessation of tobacco dependence.Methods: We used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the Fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) of the habitual brain network in tobacco-dependent subjects and to evaluate the relationship between the FC level and tobacco selection preference behavior. In total, 29 male tobacco-dependent participants and 28 male nonsmoking participants were recruited. rs-fMRI was used to collect blood oxygen level-dependent signals of the participants in the resting and awake states. After rs-fMRI, all subjects completed cigarette/coin selection tasks (task 1 and task 2).Results: Compared with the control group, the tobacco dependence group showed increased fractional amplitude values of fALFF in the left posterior cingulate cortex and right parahippocampus. FC in the tobacco-dependent group was increased in the right inferior temporal gyrus, left middle frontal gyrus, left cingulated gyrus, and bilateral superior frontal gyrus, compared with that in the control group. Moreover, the preference selection behavior was associated with the enhancement of FC about parts of the brain regions in the habitual brain network of the tobacco-dependent participants. Thus, habitual network activity was significantly enhanced in tobacco-dependent participants in the resting state. Moreover, a positive correlation was found between the cigarette selection preference of the smokers and certain brain regions related to the habitual network.Discussion: This suggests that increased activity of the habitual brain network may be essential in the development of tobacco-dependent behavior.Keywords: tobacco dependence, behavioral decision preference, habitual brain network, resting-state functional magnetic resonance imaging, functional connectivity, fractional amplitude of low-frequency fluctuations

Qiang Tan, Ming Chen, Jia Hao, Kun Wei Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of ChinaCorrespondence: Qiang TanDepartment of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, No. 258 of Wenhua Road, Qinhuangdao, Hebei Province, 066000, People’s Republic of ChinaEmail qhdtanqiang@aliyun.comBackground and Objectives: Hyperinsulinemia plays a key role in the development of cardiovascular impairment in patients with metabolic syndrome. The aim of this study was to evaluate the influence of hyperinsulinemia on long-term clinical outcomes of percutaneous coronary intervention (PCI) in patients without diabetes mellitus who have acute myocardial syndrome (ACS).Methods: Between March 2016 and January 2019, we enrolled 468 patients with ACS and without diabetes mellitus who received primary PCI. Patients were divided into a low-insulin group (n = 157), medium-insulin group (n = 154), and high-insulin group (n = 157) according to tertiles of fasting insulin level. The primary endpoint was major adverse cardiac events (MACE; all-cause death, non-fatal myocardial infarction, target vessel revascularization [TVR]) at 24 months. The secondary endpoint was angina hospitalization.Results: Patients in the high-insulin group had an unfavorable prognosis, with a higher rate of MACE (34.39%) than the low-insulin group (22.29%) and medium-insulin group (23.37%) at 24 months (P < 0.05). This difference was mainly driven by the increase in TVR. The high-insulin group also had a higher rate of angina hospitalization than the low-insulin group. Cox proportional hazards regression showed that high-insulin level (hazard ratio [HR] 1.870, 95% confidence interval [CI] 1.202– 2.909), small-vessel lesion (HR 1.713, 95% CI 1.111– 2.642), bifurcation lesion (HR 3.394, 95% CI 2.033– 5.067), SYNTAX score (HR 1.084, 95% CI 1.039– 1.130), and stent length (HR 1.017, 95% CI 1.002– 1.032) increased the incidence of MACE in patients with ACS and without diabetes who underwent PCI.Conclusion: Hyperinsulinemia might be a valid predictor of clinical outcomes in patients with ACS undergoing PCI.Keywords: percutaneous coronary intervention, hyperinsulinemia, acute myocardial syndrome, major adverse cardiac events

Yuling Yu,1,&ast; Yuqing Huang,1,&ast; Lin Liu,2 Xiao-Cong Liu,1 Qiuhong Tan,3 Chaolei Chen,1 Jiayi Huang,3 Yingqing Feng,1 Songtao Tang4 1Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3Guangdong Provincial People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 4Department of Cardiology, Community Health Center of Liaobu Town, Dongguan, 523400, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Songtao TangDepartment of Cardiology, Community Health Center of Liaobu Town, Dongguan, 523400, Guangdong, People’s Republic of ChinaEmail 3038384760@qq.comYingqing FengDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 2nd Zhongshan Road, Yuexiu District, Guangzhou, 510080, People’s Republic of ChinaEmail fengyingqing@gdph.org.cnBackground: Vascular overload index (VOI) is a marker of arterial stiffness and arteriolar resistance, which predicts the increasing risks of cardiovascular and cerebrovascular disease. This study aimed to evaluate the association between VOI and new-onset ischemic stroke in an elderly population with hypertension.Methods: This retrospective cohort study included 3315 hypertensive participants aged 60 years or more. Ischemic stroke was diagnosed according to cranial computed tomography, magnetic resonance imaging of the brain or cerebrovascular angiography. The calculation of VOI was based on systolic and diastolic blood pressure. VOI was divided by quartiles (< 7.88 mmHg, 7.88– 16.10 mmHg, 16.10– 27.14 mmHg, ≥ 27.14 mmHg) and evaluated the association with new-onset ischemic stroke by multivariable Cox regression models.Results: A total of 3315 participants (55.5% female) aged 71.4± 7.20 years were included in the analysis. The median follow-up period was 5.5 years, and 206 participants reached the endpoint, new-onset ischemic stroke. With per standard deviation increment in VOI, the risks of new-onset ischemic stroke increased in non-adjusted model (Hazard ratio [HR], 1.11; 95% confidence interval [CI]: 1.03– 1.22; p = 0.001), adjusted model (HR, 1.11; 95% CI: 1.04– 1.22; p = 0.003) and fully-adjusted model (HR, 1.15; 95% CI: 1.08– 1.26; p< 0.001), respectively. In multivariate fully adjusted model, the risks of ischemic stroke increased in higher quartiles in comparison to the first quartiles (p for trend < 0.001).Conclusion: In an elderly hypertensive population, VOI is significantly associated with the incidence of new-onset ischemic stroke. Elevated VOI is the cardiovascular risk factor and increases the probability of new-onset ischemic stroke.Keywords: vascular overload index, ischemic stroke, hypertension, elderly population, blood vessel

Yongjia Huang,1,* Tingting Wang,2,* Qunyou Tan,3,* Dan He,1,* Mingjun Wu,4,* Jingchuan Fan,4 Jie Yang,1 Cailing Zhong,1 Kailing Li,1 Jingqing Zhang1 1Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People’s Republic of China; 2Biochemistry and Molecular Biology Laboratory, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Thoracic Surgery, Daping Hospital of Army Medical University, PLA, Chongqing, People’s Republic of China; 4Institute of Life Science, Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingqing ZhangMedicine Engineering Research Center, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, People’s Republic of ChinaTel +86 13308300303Email zjqrae01@163.comAbstract: Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.Keywords: smart delivery, stimuli-responsive, mitochondria-targeting, tumor microenvironment, cancer therapy

Pengcheng Liu,1,* Jie Tan,2,* Qiuwen Tan,1 Li Xu,1 Tao He,1 Qing Lv1 1Department of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Orthopaedic Surgery & Orthopaedic Institute, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing LvDepartment of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu 610041, Sichuan, People’s Republic of ChinaEmail lvqingwestchina@163.comBackground: Accurate lymph node (LN) staging has considerably prognostic and therapeutic value in patients with colorectal cancer (CRC). The purpose of this study is to evaluate the feasibility of applying carbon nanoparticles (CNPs) to track LN metastases in CRC.Methods: Two researchers independently screened publications in PubMed, EMBASE, Cochrane and Ovid MEDLINE databases. The keywords were (carbon nanoparticles OR activated carbon nanoparticles) AND (colon cancer OR rectal cancer OR colorectal cancer). Titles and abstracts of the articles were meticulously read to rule out potential publications. Next, full texts of the ultimately obtained eligible publications were retrieved and analyzed in detail.Results: The search produced 268 publications, and 140 abstracts were identified after a bibliographic review. Finally, 20 studies relevant to our subject were obtained; however, only 14 papers met our inclusion criteria and were included for final review. All studies included have compared the control group with carbon nanoparticles group (control group, defined as nontattooed group; and carbon nanoparticles group, defined as administering carbon nanoparticles during surgery) for their efficacy in intraoperative detecting and positioning. After analysis, appreciably less amount of bleeding (3/5 trials), shorter operation time (2/4 trials), and shorter time to detect lesions and dissect LNs (2/2 trials) were revealed in CNPs group compared to control group. Thirteen studies have recorded the numbers of the harvested LNs in both groups; meanwhile, CNPs group shows superiority to control group in LN retrieval as well (11/13 trials), which also could effectively aid in locating and harvesting more LNs with diameter below 5 mm.Conclusion: The tracing technique for CNPs is a safe and useful strategy both in localizing tumor and tracing LNs in CRC surgery. But there is still a need for more randomized controlled trials to further establish its contribution to patient survival.Keywords: carbon nanoparticles, colorectal cancer, lymph nodes, trace, tumor location

Zongqiu Wang,1,* Jiwen Hou,2,* Yu Shi,3 Qiaowen Tan,1 Lin Peng,1 Zhiying Deng,1 Zhihong Wang,1 Zongjun Guo1 1Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Geriatrics, The Affiliated Hospital of Chengdu University, Chengdu, People’s Republic of China; 3Department of Critical Medicine, Weihai Central Hospital, Weihai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zongjun GuoDepartment of Geriatrics, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, People’s Republic of ChinaEmail guozjj@163.comObjective: To explore the effects of different lifestyle choices on mild cognitive impairment (MCI) and to establish a decision tree model to analyse their predictive significance on the incidence of MCI.Methods: Study participants were recruited from geriatric and physical examination centres from October 2015 to October 2019: 330 MCI patients and 295 normal cognitive (NC) patients. Cognitive function was evaluated by the Mini-Mental State Examination Scale (MMSE) and Clinical Dementia Scale (CDR), while the Barthel Index (BI) was used to evaluate life ability. Statistical analysis included the χ2 test, logistic regression, and decision tree. The ROC curve was drawn to evaluate the predictive ability of the decision tree model.Results: Logistic regression analysis showed that low education, living alone, smoking, and a high-fat diet were risk factors for MCI, while young age, tea drinking, afternoon naps, social engagement, and hobbies were protective factors for MCI. Social engagement, a high-fat diet, hobbies, living condition, tea drinking, and smoking entered all nodes of the decision tree model, with social engagement as the root node variable. The importance of predictive variables in the decision tree model showed social engagement, a high-fat diet, tea drinking, hobbies, living condition, and smoking as 33.57%, 27.74%, 22.14%, 11.94%, 4.61%, and 0%, respectively. The area under the ROC curve predicted by the decision tree model was 0.827 (95% CI: 0.795∼ 0.856).Conclusion: The decision tree model has good predictive ability. MCI was closely related to lifestyle; social engagement was the most important factor in predicting the occurrence of MCI.Keywords: lifestyle, behaviours habit, mild cognitive impairment, influencing factors, decision tree model

Libei Zhao, Manqiang Peng, Wenxiang Lin, Qian Tan, Muhammad Ahmad Khan, Ding Lin Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, No. 388, Section 2, Furong Middle Road, Changsha City, Hunan Province 410005, People’s Republic of ChinaTel +86 13787255158Email linding@csu.edu.cnPurpose: To explore the feasibility of cyclophosphamide (CP) via a sub-Tenon micro-perfusion system (SMS) in rabbits, and assess its therapeutic efficacy in severe ocular inflammation.Materials and Methods: Distribution and pharmacokinetics of CP were evaluated in vivo, and the concentrations of CP in plasma, vitreous humor, and retina/choroid were quantitated by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) at different time points. After induction of severe experimental uveitis, rabbits were divided into three groups (n=8 in each): the SMS group, subconjunctival injection (SI) group, and control group. Clinical inflammatory score was assessed in rabbits. Electroretinography and histopathology were performed on post-treatment day 8. Statistical analyses were performed using Mann–Whitney and Kruskal–Wallis tests. P-value less than 0.05 was considered significant.Results: The concentrations of CP in vitreous humor and retina/choroid in the SMS group were significantly higher than that of the SI group at 3, 6, 10, and 24 hours (P< 0.01), while plasmatic CP concentrations were comparable at all time points in the SMS group and SI group (P> 0.05). The SMS group showed significantly less inflammation compared to the control group and SI group. Furthermore, the restoration of retinal structure and function were more obvious in the SMS group compared with conventional SI application.Conclusion: Sub-Tenon micro-perfusion of CP exhibited satisfied therapeutic efficacy in rabbits with severe ocular inflammation and may provide a promising alternative for controlling ocular inflammatory disease and immune-mediated ocular diseases.Keywords: cyclophosphamide, sub-Tenon drug delivery, ocular inflammation, treatment, rabbit

Jinbao Wang,1,* Qingjuan Tan,2,* Weishan Wang,1 Jie Yu3 1General Surgery, Linyi Central Hospital, Linyi, Shandong Province, People’s Republic of China; 2Neonatal Intensive Care Unit, Linyi Central Hospital, Linyi, Shandong Province, People’s Republic of China; 3Department of Anal-Colorectal, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie YuDepartment of Anal-Colorectal, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei Province, People’s Republic of ChinaEmail yujie19797@163.comPurpose: To investigate the potential role of the circMTO1/miR-9-5p/NOX4 axis in liver cancer.Materials and Methods: Human genome-wide circrna microarray V2 was used for analyzing the expression profile of circRNAs in human tissue samples. The TargetScan database was used to predict target genes. Gene overexpression and silencing in hepatoma cell lines were achieved by transfecting the cells with suitable constructs. Quantitative real time PCR and Western blotting were used to analyze gene and protein expression levels. CCK-8 analysis was performed to detect cell proliferation and the transwell assay for analyzing cell migration. Annexin V-FITC/PI staining and immunohistochemistry were respectively used to detect apoptosis and protein expression.Results: CircMTO1 were down-regulated in the liver cancer tissues and cell lines compared to their respective normal controls. TargetScan database screening and dual luciferase assay revealed that circMTO1 was a molecular sponge of miR-9-5p, and NOX4 was the target gene of miR-9-5p. Overexpression of circMTO1 and NOX4 inhibited proliferation and migration of hepatoma cells, while the overexpression of miR-9-5p had the opposite effects. In contrast, overexpression of circMTO1 and NOX4 promoted apoptosis, while that of miR-9-5p decreased the cell apoptosis rates.Conclusion: Overexpression of CircMTO1 acts as tumor suppressor in liver cancer by sponging miR-9-5p, which upregulates NOX4.Keywords: circMTO1, miR-9-5p/NOX4 axis, hepatocellular carcinoma, proliferation, apoptosis

Abstract Background In 2016–2017, Vietnam’s Ministry of Health (MoH) implemented an event-based surveillance (EBS) pilot project in six provinces as part of Global Health Security Agenda (GHSA) efforts. This manuscript describes development and design of tools for monitoring and evaluation (M&E) of EBS in Vietnam. Methods A strategic EBS framework was developed based on the EBS implementation pilot project’s goals and objectives. The main process and outcome components were identified and included input, activities, outputs, and outcome indicators. M&E tools were developed to collect quantitative and qualitative data. The tools included a supervisory checklist, a desk review tool, a key informant interview guide, a focus group discussion guide, a timeliness form, and an online acceptability survey. An evaluation team conducted field visits for assessment of EBS 5–9 months after implementation. Results The quantitative data collected provided evidence on the number and type of events that were being reported, the timeliness of the system, and the event-to-signal ratio. The qualitative and subjective data collected helped to increase understanding of the system’s field utility and acceptance by field staff, reasons for non-compliance with established guidelines, and other factors influencing implementation. Conclusions The use of M&E tools for the EBS pilot project in Vietnam provided data on signals and events reported, timeliness of reporting and response, perceptions and opinions of implementers, and fidelity of EBS implementation. These data were valuable for Vietnam’s MoH to understand the function of the EBS program, and the success and challenges of implementing this project in Vietnam.

Min Yu,1,* Liyao Peng,1,* Ping Liu,1 Mingxia Yang,2 Hong Zhou,1 Yirui Ding,1 Jingjing Wang,3 Wen Huang,1 Qi Tan,1 Yanli Wang,1 Weiping Xie,1 Hui Kong,1 Hong Wang1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou 213003, People’s Republic of China; 3Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Kong; Hong WangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, People’s Republic of ChinaTel +86-25-68136426Fax +86-25-68136269Email konghui@njmu.edu.cn; hongwang@njmu.edu.cnBackground: Endothelial cells dysfunction is one of the hallmark pathogenic features of pulmonary arterial hypertension (PAH). Paeoniflorin (PF) is a monoterpene glycoside with endothelial protection, vasodilation, antifibrotic, anti–inflammatory and antioxidative properties. However, the effects of PF on PAH remain unknown.Methods: Here, we investigated the efficacy of PF in the SU5416/hypoxia (SuHx) rat model of PAH. Human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O2 with or without PF treatment.Results: Hemodynamics analysis showed that prophylactic treatment with PF (300 mg/kg i.g. daily for 21 days) significantly inhibited chronic hypoxia/SU5416-induced elevations of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index in rats. Meanwhile, PF significantly reduced pulmonary vascular remodeling, as well as alleviated collagen deposition in lungs and right ventricles in SuHx rats. Additionally, PF inhibited SuHx–induced down-regulation of endothelial marker (vascular endothelial cadherin) and up-regulation of mesenchymal markers (fibronectin and vimentin) in lung, suggesting that PF could inhibit SuHx–induced endothelial-to-mesenchymal transition (EndMT) in lung. Further in vitro studies confirmed that PF treatment suppressed hypoxia-induced EndMT in HPAECs, which was abolished by the knockdown of bone morphogenetic protein receptor type 2 (BMPR2) in HPAECs.Conclusion: Taken together, our findings suggest that PF ameliorates BMPR2 down-regulation-mediated EndMT and thereafter alleviates SuHx–induced PAH in rats.Keywords: paeoniflorin, pulmonary arterial hypertension, endothelial-to-mesenchymal transition, BMPR2, hypoxia

Wenxiang Lin,1,2 Libei Zhao,1,2 Xuetao Huang,3 Qian Tan,1,2 Manqiang Peng,1,2 Muhammad Ahmad Khan,1,2 Ding Lin1,2 1Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Department of Ophthalmology, Changsha Aier Eye Hospital, Changsha, People’s Republic of China; 3Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaTel +86-13787255158Email linding@csu.edu.cnBackground: The aim of this study was to compare the distribution characteristics and ocular pharmacokinetics of norvancomycin (NVCM) in ocular tissues of the anterior segment between continuous topical ocular instillation and hourly administration of eye drop in rabbits.Methods: Sixty rabbits were randomly divided into two groups: continuous topical ocular instillation drug delivery (CTOIDD) group and eye drop (control) group. In the CTOIDD group, NVCM solution (50 mg/mL) was perfused to the ocular surface using the CTOIDD system at 2 mL/h up to 10 h and the same solution was administered at one drop (50 μL) per hour for 10 h in the control group. Animals (N=6 per time-point per group) were humanely killed at 2, 4, 6, 10, and 24 h to analyze their ocular tissues and plasma. The concentrations of NVCM in the conjunctiva, cornea, aqueous humour, iris, ciliary body and plasma were measured by HPLC with photodiode array detector. The pharmacokinetic parameters were calculated by Kinetica 5.1.Results: The highest concentrations of NVCM for the CTOIDD group and control group were 2105.45± 919.89 μg/g and 97.18± 43.14 μg/g in cornea, 3033.92± 1061.95 μg/g and 806.99± 563.02 μg/g in conjunctiva, 1570.19± 402.87 μg/g and 46.93± 23.46 μg/g in iris, 181.94± 47.11 μg/g and 15.38± 4.00 μg/g in ciliary body, 29.78± 4.90 μg/mL and 3.20± 1.48 μg/mL in aqueous humour, and 26.89± 5.57 μg/mL and 1.90± 1.87 μg/mL in plasma, respectively. The mean NVCM levels significantly increased at all time-points in cornea, iris, and ciliary body (p< 0.05) in the CTOIDD group. The AUC0– 24 values in the CTOIDD group were 27,543.70 μg·h/g in cornea, 32,514.48 μg·h/g in conjunctiva, 8631.05 μg·h/g in iris, 2194.36 μg·h/g in ciliary body and 343.9 μg·h/mL in aqueous humour, which were higher than for the eye drop group in all tissues.Conclusion: Since continuous instillation of NVCM with CTOIDD could reach significantly higher concentrations and was sustained for a longer period compared with hourly administration of eye drop, CTOIDD administered NVCM could be a possible method to treat bacterial keratitis.Keywords: topical drug delivery, ocular tissue, anterior segment, area under the curve, rabbit eye