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Dou Zhang,1,2,* Xuyi Liu,1,2,* Xiong Li,3,* Xinyi Cai,1,2 Zhenying Diao,1,2 Long Qiu,1,2 Xuelin Chen,1,2 Yuyu Liu,1,2 Jianbo Sun,1 Daxiang Cui,1,4 Qiaoyuan Ye,5 Ting Yin1,2 1Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China; 2Dongguan Biomedical Nano Engineering Technology Research Center, Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China; 3Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, 519000, People’s Republic of China; 4School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China; 5Department of Dermatology and Venereology, Second Clinical Medical College of Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiaoyuan Ye, Department of Dermatology and Venereology, Second Clinical Medical College of Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China, Email 13650248189@163.com Ting Yin, Research Center of Nano Technology and Application Engineering, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, 523808, People’s Republic of China, Email wsyt132@163.comPurpose: Melanoma is a highly aggressive and dangerous malignant skin tumor and there is an urgent need to develop effective therapeutic approaches against melanoma. The main objective of this study was to construct a multifunctional nanomedicine (GNR@PEG-Qu) to investigate its therapeutic effect on melanoma from the oxidative stress pathway.Methods: First, the nanomedicine GNR@PEG-Qu was synthesized and characterized, and its photothermal and antioxidant properties were confirmed. In addition, in vivo imaging capabilities were observed. Finally, the tumor inhibitory effects of GNR@PEG-Qu in vivo and in vitro as well as its biosafety were observed.Results: GNR@PEG-Qu shows good photothermal and anti-oxidation properties. Following exposure to 1064 nm laser irradiation in the second near-infrared II (NIR-II) window, GNR@PEG-Qu shows anti-tumor ability through low-temperature photothermal therapy (PTT) adjuvant drug chemotherapy. GNR@PEG-Qu makes full use of the antioxidant capacity of quercetin, reduces ROS levels in melanoma, alleviates oxidative stress state, and achieves “oxidative stress avoidance” at the tumor site. Quercetin can also downregulate the expression of the heat shock protein Hsp70, which will improve the thermal sensitivity of the tumor site and enhance the efficacy of low-temperature PTT.Conclusion: GNR@PEG-Qu nanoagent exhibits synergistic treatment and high tumor inhibition effects, which is a promising strategy developed to achieve oxidative stress avoidance and synergistic therapy of melanoma using quercetin (Qu)-coated gold nanorod (GNR@PEG).Keywords: melanoma, gold nanorods, quercetin, chemo-photothermal therapy, oxidative stress

Mengli Li,1,&ast; Tongtong Yin,1,&ast; Jiaying Qi,1 Minhao Shi,1 Fangfang Wang,1 Zhiyu Mao,1 Hui Zhang,1,2 Li Wang1 1School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Vocational Health College, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Wang; Hui Zhang, Email li-wang-1@suda.edu.cn; zhanghuichange@sina.comObjective: To explore the cut-off values and health evaluations of upper arm circumference (AC) and calf circumference (CC) on sarcopenia in Chinese community-dwelling older people.Methods: In this cross-sectional study, AC, CC, handgrip strength, muscle mass and gait speed were measured in 1537 Chinese community-dwelling older people in Sub-study 1. Correlation analysis, receiver operator characteristic curve (ROC curve) analysis, and consistency analysis were used for determination of AC and CC cut-off values for sarcopenia diagnosis (sarcopenia-AC and CC). Thereafter, 269 participants accepted additional assessments on physical function, body composition and muscle strength in Sub-study 2. T-test or Mann-Whitney U-test was used to explore the differential effects of sarcopenia-AC and CC on health indicators between sarcopenic and non-sarcopenic participants.Results: In Sub-study 1, the Area Under ROC (AUC) of AC and CC for sarcopenia screening were greater than 0.700 (P< 0.05). The cut-off values, sensitivity and specificity of AC and CC on sarcopenia in males were 25.9 cm (86.0%, 83.6%) and 33.7 cm (90.7%, 81.4%) whereas in females were 26.5 cm (70.8%, 69.7%) and 33.0 cm (86.5%, 69.4%), respectively. In Sub-study 2, the participants with sarcopenia-AC or sarcopenia-CC showed lower muscle strength and lower fat and muscle mass than the ones without (P< 0.05). Additionally, males instead of females with sarcopenia-AC or sarcopenia-CC showed worse performance in time-up and go test and 6-Minute Walk Test (P< 0.05). However, the 30-second chair stand test was not different between participants with and without sarcopenia-AC or sarcopenia-CC in both sexes.Conclusion: We found accurate and Chinese population targeted cut-off values of AC and CC on sarcopenia diagnosis (25.9 cm and 33.7 cm in males; 26.5 cm and 33.0 cm in females) and a good evaluation effect of AC and CC on fat and muscle mass, muscle strength and physical functions in males, not females.Keywords: sarcopenia, upper arm circumference, calf circumference, health assessment

Hongmei Sun,1,2 Chao Lv,2,3 Xiaoxue Zhang,1,2 Xuan Sun,1,3,4 Siyu Chen,1,3,4 Ke Li,3,4 Yazhuo Hu,2,3 Yuxin Feng,1,2 Tong Yin,2,3 Jianjun Jia2,3 1Medical School, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Institute of Geriatrics, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Geriatric Neurology, the Second Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jianjun Jia; Tong Yin, Institute of Geriatrics, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, Haidian District, 100853, People’s Republic of China, Email jiajianjun301@126.com; yintong301@163.comBackground: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer’s disease continuum (ADC).Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.Material and Methods: According to 2018 National Institute on Aging and Alzheimer’s Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ– patients using a logistic regression analysis.Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64– 28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28– 4.95).Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.Keywords: Alzheimer’s disease, pharmacogenomics, variant, gene, donepezil

Yun Sun,1,&ast; Tongtong Yin,2,&ast; Mengli Li,2,3 Fangfang Wang,2 Jiaying Qi,2 Hui Zhang,2,4 Li Wang,2 Jiehua Zhao,5 Yu Zhang5 1Department of Oncology, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3School of Nursing, Hong Kong Polytechnic University, Hongkong, People’s Republic of China; 4School of Nursing, Vocational Health College, Suzhou, Jiangsu, People’s Republic of China; 5Department of Nursing, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Zhang; Jiehua Zhao, Email zhangyu-sz1985@outlook.com; hannah.zhao@benqmedicalcenter.comPurpose: This study aimed to establish equations for estimating muscle mass through anthropometric parameters or together with physical function parameters in the community-dwelling older adults, providing a simple way of muscle mass assessment.Methods: In this cross-sectional descriptive study, a total of 1537 older adults were recruited from the community and accepted the measurements of height, weight, upper arm and calf circumferences, grip strength, and walking speed. Body composition including appendicular skeletal muscle mass (ASM) was measured using bioelectrical impedance analysis (BIA). Participants were randomly divided into the development or validation group. Stepwise multiple linear regression was applied to develop equations in the development group. Thereafter, Pearson correlation coefficients, Bland-Altman plots, paired t-test, intraclass correlation coefficient (ICC) and paired-samples t-tests were used to assess the validity of the equations.Results: All parameters were significantly correlated with ASM (r = 0.195~0.795, P < 0.001) except for the age in the validation group (P = 0.746). The most optimal anthropometric equation was: [adjusted R2 = 0.911, standard error of the estimate (SEE) = 1.311, P < 0.001]. Comparatively speaking, this equation showed high correlation coefficient (r = 0.951, P < 0.001) and ICC (ICC = 0.950, P < 0.001). No significant differences were found between BIA-measured ASM and the estimated ASM. The Bland-Altman plot showed that the mean difference between the estimated ASM and BIA-measured ASM was 0 kg and the limits of agreement of ASM was − 2.70~2.60 kg. Furthermore, inclusion of physical function did not significantly improve the adjusted R2 and SEE.Conclusion: The anthropometric equation offers a practical alternative simple and dependable method for estimating ASM in community-dwelling older adults.Keywords: appendicular muscle mass, anthropometry, physical function, estimation equation, older adults

Chao Gao,1,&ast; Yan Liu,2,&ast; Ting-Lin Zhang,3,&ast; Yi Luo,2,4,&ast; Jie Gao,3,&ast; Jian-Jian Chu,1 Bao-Feng Gong,1 Xiao-Han Chen,1 Tong Yin,1 Jian Zhang,2 You Yin1 1Department of Neurology, Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Shanghai, People’s Republic of China; 2Department of Clinical Pharmacy, Shanghai Jiao Tong University of Medicine, Shanghai, People’s Republic of China; 3Changhai Clinical Research Unit, Shanghai Changhai Hospital of Naval Medical University, Shanghai, People’s Republic of China; 4New Drug Discovery and Development, Biotheus Inc., Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: You Yin; Jian Zhang, Tel +86-21-81885463 ; +86- 21-25077150, Email yinyou179@163.com; zhangjian@xinhuamed.com.cnAbstract: Current therapies for Alzheimer’s disease used in the clinic predominantly focus on reducing symptoms with limited capability to control disease progression; thus, novel drugs are urgently needed. While nanoparticles (liposomes, high-density lipoprotein-based nanoparticles) constructed with synthetic biomembranes have shown great potential in AD therapy due to their excellent biocompatibility, multifunctionality and ability to penetrate the BBB, nanoparticles derived from natural biomembranes (extracellular vesicles, cell membrane-based nanoparticles) display inherent biocompatibility, stability, homing ability and ability to penetrate the BBB, which may present a safer and more effective treatment for AD. In this paper, we reviewed the synthetic and natural biomembrane-derived nanoparticles that are used in AD therapy. The challenges associated with the clinical translation of biomembrane-derived nanoparticles and future perspectives are also discussed. Keywords: Alzheimer’s disease, nanoparticles, blood‒brain barrier, liposomes, bionanotechnology, neurodegenerative diseases

Tao Yin,1,&ast; Yan Lu,2,&ast; Wei Xiong,3,&ast; Chengdong Yu,4 Delu Yin,5 Huijing He6 1Department of Technology, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 2Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Gynecology Endocrine & Reproductive Center, National Clinical Research Center for Obstetric & Gynecologic Diseases Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Growth and Development, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 5Department of Child Health Care, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 6Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huijing He, Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, 5 Dongdansantiao, Dongcheng District, Beijing, 100005, People’s Republic of China, Tel +8615010086743, Email huijing_he@ibms.pumc.edu.cn Delu Yin, Department of Child Health Care, Capital Institute of Pediatrics, 2 Yabao Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +8613810349722, Email deluyin@126.comPurpose: To understand the physical and mental health status of primary healthcare providers (PHPs) including physicians, nurses and other staff and the workplace risk factors for depression, anxiety and intention-to-leave.Patients and Methods: In December 2021, a national cross-sectional survey was conducted from 62 urban communities in China, and all PHPs were invited to complete a standardized questionnaire. Information on demographic, health-related lifestyle, cardiovascular risk factors and physical health status, occupational stress and intention-to-leave was collected. Depression and anxiety were assessed using the Zung Self-Rating Anxiety/Depression Scale (SAS/SDS).Results: A total of 4901 PHPs were included. 67.0% males currently drank alcohol vs 25.3% in females; 36.0% males currently smoked cigarettes vs 1.4% in females. Notably, more than half males were overweight or obese, but this proportion was 24.2% in females. The prevalence of chronic diseases, including hypertension, diabetes, dyslipidemia, non-alcoholic fatty liver disease, gout, and disease clustering were higher in males than in females. The prevalence of depression and anxiety were high, 50% had depression, of whom 15.6% had moderate/severe depression. Over 15% participants had varied levels of anxiety, and approximately 4% had moderate/severe anxiety. PHPs who aged 18– 29 (OR: 1.31, 95% CI: 1.05– 1.64), were males (OR: 1.34, 95% CI: 1.14– 1.57), with lower professional title (comparing with staff with senior title, the ORs of the intermedium, junior and none were 1.83, 2.18 and 2.49, respectively), took charge in nursing (OR: 1.41, 95% CI: 1.20– 1.65), with higher perceived stress level (OR: 1.82, 95% CI: 1.41– 2.34), and suffering from severe fatigue (OR: 2.55, 95% CI: 1.99– 3.27) were more likely to have depression. Likewise, PHPs who were younger, with intermedium professional title, had higher perceived pressure level, and higher fatigue levels were more likely to have anxiety.Conclusion: The mental health of PHPs is worrisome, with a high burden of chronic diseases and occupational risk factors. Younger PHPs, nurses, and those with higher levels of work pressure and fatigue are more vulnerable to psychological problems. The high prevalence of intention-to-leave calls for strategies that relieve the workplace stress and enhance the human resource capability.Keywords: depression, anxiety, stress, intention-to-leave, COVID-19, primary healthcare

Xinxin Zhu,1,* Shiyun Huang,1,* Yuxuan Tang,1,* Zhonglan Wu,2,* Yue Sun,1 Huiyan Ren,1 Hongmei Lu,1 Tingting Yin,1 Qing Zuo,1,* Zhiping Ge,1,* Ziyan Jiang1,* 1Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyan Jiang, Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-13512534017, Email zyjiangchm@163.comBackground: Grade III meconium stained amniotic fluid (MSAF) is a common obstetric disease, and has the greatest impact on poor maternal and neonatal outcomes.Question or Hypothesis or Aim: There is no consensus on treatment, especially on the timing of delivery.Methods: We collected the medical records of 345 women who gave birth with grade III MSAF and analyzed the difference in baseline characteristics and maternal and neonatal outcomes relative to different labor stage, observation times in the first stage of labor, and the presence or absence of abnormal fetal heart rate (FHR) or thick amniotic fluid.Findings: Higher rate of cesarean section was observed when grade III MSAF was found in active labor. Intervention occurred at an observation time of 90– 120 min, but there were no significant differences in maternal or neonatal outcomes shown when the observation time was greater than 3 or 4 hours. However, a higher rate of admission to the neonatal intensive care unit was demonstrated in cases with grade III MSAF with abnormal FHR either in the first or second stage of labor or in cases with thick MSAF in the second stage of labor.Discussion: Higher rate of composite adverse neonatal outcomes was found when secondary MSAF (a transition from clear AF to MSAF) was diagnosed > 3 h before delivery.Conclusion: In the first stage of labor, an observation time of greater than 4 hours might be possible after grade III MSAF is found if the labor has progressed and is without abnormal FHR.Keywords: MSAF, grade III MSAF, observation time, abnormal FHR, thick AF

Dong Xu,1 Xu Zhu,2 Junyu Huo,2 Xupin Xie,1 Changpin Huang,1 Xin Fang,1 Ting Yin3 1Department of Vascular Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Cardiology, Jiangsu Province Hospital and Nanjing Medical University, First Affiliated Hospital, Nanjing, Jiangsu, People’s Republic of China; 3Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ting Yin, Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13777879077, Fax +86 56005600, Email ameliyt@163.com Xin Fang, Department of Vascular, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13867478324, Fax +86 56005600, Email fangxin324@hotmail.comPurpose: Peripheral arterial disease (PAD) presenting with underlying hypertension (HTN) poses a higher risk of bilateral lower limb amputation than PAD patients without HTN. While the role of HTN management of PAD patients has received limited attention. We analyzed the clinical characteristics of PAD in adults with HTN and explored risk factors for PAD to construct a nomogram for evaluating critical limb ischemia (CLI) and lesion severity.Methods Patients and Methods: Between January 2014 and December 2019, we retrospectively evaluated 1886 patients with peripheral artery disease with coexisting HTN. Patients were randomly divided into training (n = 1320, 70%) and validation cohorts (n = 566, 30%), and according to the subjective experience of PAD [Fontaine classification (I–II vs III–IV)], patients were further classified into intermittent claudication (IC) and CLI groups. LASSO regression and multivariate Cox proportional hazard analyses were used to construct a nomogram using variables defined in the training cohort, which was validated in the validation cohort. The evaluation of the predictive discriminative, accuracy and clinical application are further analyzed.Results: In the training cohort, optimal independent factors included age, male sex, body mass index, diabetes mellitus, heart rate, triglyceride, and uric acid (AM-BDHTU), which were included in the nomogram predicting the CLI risk (all P < 0.05). The C-index values for CLI risk in PAD with HTN patients were 0.729 (95% CI: 0.704– 0.807) and 0.728 (95% CI: 0.652– 0.744) in the training and validation sets, respectively. Calibration curves indicated good consistency between predicted and actual outcomes. DCA confirmed the clinical utility of the diagnostic model.Conclusion: The AM-BDHTU nomogram, constructed and validated using simple to obtain clinical variables, when combined with the Fontaine classification, effectively predicts the risk of CLI among PAD patients with HTN.Keywords: peripheral arterial disease, hypertension, vascular-related complications, LASSO regression, nomogram, predictive diagnosis

Li Li,1 Rongjin Sun,1 Joseph Zenga,2 Heather Himburg,3 Lu Wang,1 Shengnan Duan,1 Jingwen Liu,1 Dinh Bui,1 Zuoxu Xie,1 Ting Du,4 Lijun Xie,1 Taijun Yin,1 Stu Wong,2 Song Gao,4 Ming Hu1 1Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Ming Hu, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA, Email mhu@uh.edu Song Gao, Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA, Email Song.Gao@tsu.eduObjective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11– 17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.Graphical Abstract: Keywords: cyclooxygenase-1, cyclooxygenase-2, turnover number, inflammation, absolute quantification, liquid chromatography with tandem mass spectrometry

Xu Zhu,1,&ast; Ting Yin,1,&ast; Ting Zhang,1 Qingqing Zhu,1 Xinyi Lu,1 Luyang Wang,1 Shengen Liao,1 Wenming Yao,1 Yanli Zhou,1 Haifeng Zhang,1,2 Xinli Li1 1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of China; 2Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinli Li, Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of China, Email xinli3267@njmu.edu.cnObjective: This study aimed to analyze immune-related genes and immune cell components in the peripheral blood of patients with acute myocardial infarction (AMI).Methods: Six datasets were obtained from the GEO repository comprising 88 healthy samples and 215 AMI samples. We performed the weighted gene co-expression analysis (WGCNA) and five machine learning (ML) methods to identify immune-related genes and construct diagnostic models. CIBERSORT algorithm was adopted for the assessment of the degree of immune infiltration. Finally, RT-PCR, immunofluorescence double and immunohistochemistry were conducted to analyze the expression level of the identification of featured immune-related genes and localization relationship in heart tissue of AMI mouse model.Results: A total of 496 immune-related DEGs were obtained between AMI and normal samples. WGCNA finally determined the co-expression modules that showed the most significantly positively associated with AMI (r=0.41; P< 0.001). Among the five ML models, XGBoost had the highest AUC (0.849) and accuracy (0.812) to discriminate patients with AMI from normal in the validation sets. Furthermore, we found that the proportion of chemokine receptor (CCR), macrophages, neutrophils, and Treg cells in the AMI groups was significantly higher than that in the normal groups. In vitro RT-PCR verification revealed that SOCS3, MMP9, and AQP9 expression increased significantly in the AMI mouse model. Among the 22 immune cells, AQP9, MMP9, and SOCS3 displayed the strongest positive correlation with neutrophils. In MI-mice, MPO stained strongly along the lateral cardiomyocytes, whereas it was weaker in sham mice. Combined immunofluorescence was observed in same parts of the cytoplasm of cardiomyocytes in myocardial infarction area, indicating co-localization of MPO with MMP9 and SOCS3 in these areas, respectively.Conclusion: Immune-related genes and immune cells are intimately related to AMI. Constructing different ML models based on these biomarkers could be a valuable approach to diagnosing AMI in clinical practice.Keywords: acute myocardial infarction, immune-related genes, immune infiltration, machine learning, diagnostic model

Ting Yin,1 Shi Shi,1 Xu Zhu,1 Iokfai Cheang,1 Xinyi Lu,1 Rongrong Gao,1 Haifeng Zhang,1,2 Wenming Yao,1 Yanli Zhou,1 Xinli Li1 1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of China; 2Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaCorrespondence: Xinli Li; Yanli Zhou, Tel +86 136 1157 3111 ; +86 137 7787 9077, Email xinli3267@njmu.edu.cn; zhyl88@qq.comPurpose: The current study aimed to develop a convenient and accurate prognostic dynamic nomogram model for the risk of all-cause death in acute heart failure (AHF) patients that incorporates clinical characteristics including N-terminal pro-brain natriuretic peptide (NT-pro BNP) and growth stimulation expresses gene 2 protein (ST2).Patients and Methods: We prospectively studied 537 consecutive AHF patients and derived a clinical prediction model. The least absolute shrinkage and selection operator regression model combined with clinical characteristics were used for dimensional reduction and feature selection. Multivariate Cox proportional hazard analysis and “Dynnom” package were used to build the dynamic nomogram for prediction of 1-,2-,and 5-year overall survival for AHF. With bootstrap validation, the time-dependent concordance index (C-index) and calibration curves were used to assess predictive discrimination and accuracy. The contributions of NT-pro BNP and ST2 to the nomogram were evaluated using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), while decision curve analysis (DCA) was used to assess clinical value.Results: Patients were randomly divided into derivation (74.9%, n=402) and validation (25.1%, n=135) cohorts. Optimal independent prognostic factors for 1-,2-, and 5-year all-cause mortality were BS-ACMR (B: NT-pro BNP; S: ST2; A: age; C: complete right bundle branch block; M: mean arterial pressure; and R: red cell distribution width > 14.5%); these were incorporated into the dynamic nomogram (https://bs-acmr-nom.shinyapps.io/dynnomapp/) with bootstrap validation. The C-indexes in the derivation (0.793) and validation (0.782) cohorts were consistent with comparable performance parameters. The calibration curve showed good agreement between the nomogram-predicted and actual survival. Adding NT-pro BNP and ST2 provided a significant net benefit and improved performance over other less adequate schemes in terms of DCA of survival probability compared to those neglecting either of these two factors.Conclusion: The study constructed a dynamic BS-ACMR nomogram, which is a convenient, practical and effective clinical decision-making tool for providing accurate prognosis in AHF patients.Keywords: acute heart failure, all-cause mortality, dynamic nomogram, prediction model, internal validation

Tingting Yin,1,&ast; Yuhui Zhao,1,&ast; Ying Yang,1 Huaxiu Xu,1 Dongxiang Zheng,2 Jun Lyu,3 Guanglei Fu4 1School of Nursing, Jinan University, Guangzhou, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Clinical Research Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 4Infectious Disease Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun LyuClinical Research Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaTel +86 13922274169Email lyujun2020@jnu.edu.cnGuanglei FuInfectious Disease Department, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaTel +86 18922217029Email 1623805741@qq.comBackground: The objective of this study was to establish a nomogram for predicting the overall survival (OS) of patients with acral lentiginous melanoma (ALM).Materials and Methods: The study sample was selected from 1785 patients diagnosed with ALM from 2004 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database, and R software was used to divide patients into the training cohort and validation cohort at a ratio of 7: 3. Stepwise selection method in the Cox regression model was used in the training cohort to select predictive variables to construct the nomogram, and model validation parameters were used in the validation cohort to evaluate the performance of the nomogram.Results: The nomogram showed that age at diagnosis had the greatest impact on OS in patients with ALM, followed by AJCC stage, surgical treatment, SEER stage, sex, race, and marital status. The index of concordance, area under the receiver operating characteristic curve, calibration plots, net reclassification improvement, integrated discrimination improvement, and decision curve analysis demonstrate the good performance of this nomogram.Conclusion: The prognostic value of the nomogram is superior to that of the AJCC staging system alone, and it helps clinicians to better predict 3-, 5-, and 8-year OS in patients with ALM.Keywords: acral lentiginous melanoma, nomogram, overall survival, SEER

Faxuan Wang,1,2,&ast; Binxia Wang,3,&ast; Xiyuan Chen,1,2 Wanlu Liu,1,2 Guoqi Wang,1,2 Xiaoxia Li,1,2 Xiuying Liu,1,2 Nan Li,1,2 Jiaxing Zhang,1,2 Ting Yin,1,2 Jinyun Jing,1,2 Xiaoyu Chang,4 Yanan Jin,5 Yuhong Zhang,1,2 Yi Zhao1 1School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Key Laboratory of Environmental Factors and Chronic Disease Control, Yinchuan, Ningxia, People’s Republic of China; 3Second People’s Hospital of Gansu Province, Lanzhou, Gansu, People’s Republic of China; 4Editorial Department of the Journal of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 5Centers for Disease Control and Prevention in Ningxia, Yinchuan, Ningxia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi ZhaoSchool of Public Health and Management, Ningxia Medical University Tel +86 139 9501 1690Fax +86 951-6980144Email zhaoyi751114@hotmail.comBackground: Recently, the association between lifestyle-related diseases and free amino acids in the blood plasma—especially branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs)—has been highlighted. However, few studies have been carried out on 24-hour urine samples. Therefore, we aimed to explore the relationships between 24-hour urinary BCAAs and AAAs excretion rate and blood pressure (BP) in elderly patients with hypertension.Methods and Results: Each of the 322 elderly patients with hypertension completed an in-person questionnaire interview, underwent a physical examination, and provided a 24-hour urine specimen. We measured their BCAAs and AAAs excretion rate, and used multiple linear regression analysis with variable selection to construct models describing the relationships between their BCAAs and AAAs excretion rate and BP. After adjusted for age, gender, height, and weight, valine was inversely associated with both systolic blood pressure (SBP) (β: − 0.232, 95% CI: − 0.16, − 0.006) and diastolic blood pressure (DBP) (β: − 0.144, 95% CI: − 0.089, − 0.005). These findings were invariant even following adjustment for urine volume and drugs history, and Ile was positively associated with DBP (β: 0.170, 95% CI: 0.001, 0.066).Conclusion: The data revealed that the excretion rate of 24-hour urinary BCAAs was closely related to BP in elderly hypertension patients, and these findings will provide new insights into the association between BACC metabolism and BP.Keywords: hypertension, branched-chain amino acid, aromatic amino acid, association

Ting Yin,1 Iokfai Cheang,1 Xu Zhu,1 Shengen Liao,1 Haifeng Zhang,2 Xinli Li1 1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of China; 2Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaCorrespondence: Haifeng ZhangDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, People’s Republic of ChinaEmail haifeng_zhang@163.comShengen LiaoDepartment of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People’s Republic of ChinaEmail shengenliao@163.comPurpose: The optimal blood pressure (BP) targets in terms of mortality risk after stroke remain unclear. This study aimed to assess the relationship between BP and mortality in stroke survivors.Patients and Methods: We included 1696 participants with self-reported history of stroke aged 18 years and older from the National Health and Nutrition Examination Survey (NHANES) 1999– 2014 and NHANES III with public-use linked mortality files from 2015. Baseline systolic BP (SBP) and diastolic BP (DBP) levels were obtained by taking the average of 3 measures. Cox proportional hazard models and restricted cubic splines were conducted to explore the relationship between BP and all-cause mortality.Results: During a median follow-up period of 5.6 years, 888 deaths occurred. After fully adjusting for confounding factors, SBP displayed a J-curve relationship (nadir 135 mm Hg), while DBP exhibited a reverse J-curve relationship (nadir 73 mm Hg) with the risk of all-cause mortality. However, the J-curve or reverse J-curve pattern between blood pressure and mortality appeared to be limited to individuals with an age > 65 years, identifying a nadir of SBP/DBP of 142/73 mm Hg. The risk of mortality followed a linear relationship for SBP and DBP in stroke survivors aged ≤ 65 years, with risks increasing with higher SBP and lower DBP.Conclusion: In this cross-sectional study that used national survey data, these data suggest a strong J-curve or reverse J-curve relationship between blood pressure and risk of all-cause mortality, whereas the pattern appears to be limited to individuals with an age > 65 years, with a nadir at 142/73 mmHg. However, missing data on stroke type and stroke treatment limits the generalizability. Future prospective studies are needed to determine preferential blood pressure target in patients after stroke.Keywords: blood pressure, J-curve, stroke, age, mortality

Ting Yin,1,2,* Jia-Xing Zhang,1,* Fa-Xuan Wang,1,2 Jian-Hua Zhao,3 Yu Zhao,1,2 Lan Liu,1,2 Xiu-Ying Liu,1,2 Yu-Hong Zhang,1,2 Yi Zhao1,2 1School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 3Ningxia Center for Disease Control and Prevention, Yinchuan, Ningxia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Hong Zhang; Yi ZhaoDepartment of Epidemiology and Health Statistics, School of Public Health and Management, Ningxia Medical University, 1160, South Shengli Street, Yinchuan, Ningxia Hui Autonomous Region, People’s Republic of ChinaTel +86 0951-6980144Fax +86 0951-6980144Email zhabour@163.com; zhaoyi751114@hotmail.comObjective: Sarcopenic obesity is associated with several negative health outcomes. However, there are only a few studies on the relationship between SO and metabolic diseases such as diabetes, hypertension, and abnormal lipid metabolism in Chinese adults. The aim of this work was to evaluate the association between SO and hypertension, diabetes, and abnormal lipid metabolism in Chinese adults, and explore the prediction of SO using relevant anthropometric indicators.Materials and Methods: All participants underwent a questionnaire interview for the collection of demographic data. Thereafter, they underwent physical examination for the measurement of anthropometric variables, which was performed using bioelectrical impedance analysis. Biochemical measurements were determined according to standard laboratory procedures used for the evaluation of blood parameters.Results: We included 14,926 patients aged 35– 74 years old. The mean age of the participants was 56.75 ± 9.76 years old, and 39.80% of them were male. The mean body mass index (BMI) was 24.94 ± 3.40 kg/m2, and the overall prevalence of SO was 65.1%. The results showed that shorter people; people with faster heart rate; heavier weight; lower waist circumference (WC), BMI, triglyceride level, total cholesterol, and low-density lipoprotein cholesterol levels; and higher high-density lipoprotein cholesterol level are at risk for SO.Conclusion: The prevalence of SO is high (65.1%) in Chinese adults aged 35– 74 years old. The occurrence of SO is related to hypertension, diabetes, and abnormal lipid metabolism. BMI, WC, and waist-hip ratio may be predictive indicators of SO. The incidence of SO may be reduced by timely intervention and health education for persons at risk of the condition.Keywords: sarcopenic obesity, hypertension, diabetes mellitus, abnormal lipid metabolism

Wei Xu,1,2 Honglan Wang,3 Lihui Dong,3 Pan Zhang,3 Yan Mu,2 Xueyan Cui,2 Jianping Zhou,3 Meirong Huo,3 Tingjie Yin31Department of Pharmacy, Shandong Provincial Qian Foshan Hospital, Shandong University, Jinan 250014, People’s Republic of China; 2Qianfoshan Hospital, The First Hospital Affiliation with Shandong First Medical University, Jinan 250012, People’s Republic of China; 3State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of ChinaIntroduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA).Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments.Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.Keywords: gambogic acid, nanoparticles, redox-sensitive, intracellular drug delivery, tumor

Chunze Zhang,1,2,* Tingting Yin,3,* Ran Tao,4,* Bo Xiao,5,* Jing Chen,4 Zixuan Li,5 Xueyuan Miao,3 Qing Peng,3 Liu Sun,3 Weihua Zhang,1 Junxu Ren,4 Zhao Zhang,1 Ying Zhang,1 Xichuan Li,6 Wei Zhang51Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, People’s Republic of China; 2State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, People’s Republic of China; 3Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 4Department of Histology and Embryology, School of Basic Medical Sciences, Hebei North University, Zhangjiakou, Hebei, People’s Republic of China; 5School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People’s Republic of China; 6Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, People’s Republic of China *These authors contributed equally to this work Purpose: Y-box binding protein 1 (YBX1) is a multifunctional protein linked to tumor progression and its elevated expression is an indicator of poor prognosis in various cancers. This meta-analysis aimed to investigate the prognostic value and clinical significance of YBX1 in malignant cancer.Methods: Relevant articles published through September 12, 2018 were identified from a comprehensive electronic and manual search in PubMed, Web of Science and Embase databases. The combined odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to estimate the relationship among clinicopathological characteristics, overall survival and disease-free-survival of patients with solid tumor and YBX1 expression.Results: The study included 27 studies and 5,996 patients. Our analysis revealed significant association between increased YBX1 expression and tumor differentiation status, tumor size and lymph node metastasis; moreover, the pooled HR values demonstrated that high nuclear YBX1 expression was significantly associated with worse overall survival (HR=2.14; 95% CI: 1.72–2.67, P

Yu Song,1,2 Han Cai,1 Tingjie Yin,1 Meirong Huo,1 Ping Ma,3 Jianping Zhou,1 Wenfang Lai2 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 3Formulation Development, Tolmar Inc, Fort Collins, CO, USA Background: Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment.Methods: The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model.Results: This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 µg mL-1. Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol®, PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX.Conclusion: The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy. Keywords: tumor targeting, nanoparticles, redox-sensitive

Dan Zou,1 Wei Wang,1 Daoxi Lei,1 Ying Yin,1 Peng Ren,1 Jinju Chen,2 Tieying Yin,1 Bochu Wang,1 Guixue Wang,1 Yazhou Wang1 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People’s Republic of China; 2School of Mechanical and System Engineering, Newcastle University, Newcastle Upon Tyne, UK Abstract: For the treatment of glioma and other central nervous system diseases, one of the biggest challenges is that most therapeutic drugs cannot be delivered to the brain tumor tissue due to the blood–brain barrier (BBB). The goal of this study was to construct a nanodelivery vehicle system with capabilities to overcome the BBB for central nervous system administration. Doxorubicin as a model drug encapsulated in ganglioside GM1 micelles was able to achieve up to 9.33% loading efficiency and 97.05% encapsulation efficiency by orthogonal experimental design. The in vitro study demonstrated a slow and sustainable drug release in physiological conditions. In the cellular uptake studies, mixed micelles could effectively transport into both human umbilical vein endothelial cells and C6 cells. Furthermore, biodistribution imaging of mice showed that the DiR/GM1 mixed micelles were accumulated sustainably and distributed centrally in the brain. Experiments on zebrafish confirmed that drug-loaded GM1 micelles can overcome the BBB and enter the brain. Among all the treatment groups, the median survival time of C6-bearing rats after administering DOX/GM1 micelles was significantly prolonged. In conclusion, the ganglioside nanomicelles developed in this work can not only penetrate BBB effectively but also repair nerves and kill tumor cells at the same time. Keywords: blood–brain barrier, GM1, nanovesicles, doxorubicin, glioma, zebrafish

HaiTao Liu, Tao Yin, Wenjun Yan, Rui Si, Bo Wang, Mai Chen, Fei Li, Qiong Wang, Ling Tao Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China Abstract: Hypoxia-induced pulmonary hypertension, which is characterized by vascular remodeling of blood vessels, is an important complication in COPD. In this study, we found that the expression of miR-214 was differentially expressed by screening 13 candidate miRNAs in pulmonary artery smooth muscle cells (PASMCs). Additionally, using luciferase assay in PASMCs, we found that phosphatase-and-tensin homolog (PTEN) was a target of miR-214. Furthermore, the expression of PTEN was found to be substantially downregulated in PASMCs from COPD patients with pulmonary hypertension (PH) compared with normal controls by using real-time polymerase chain reaction (PCR), immunohistochemistry, and Western blot. In addition, we transfected PASMCs with miR-214 mimics, using real-time PCR and Western blotting, to confirm the miRNA/mRNA relationship. Furthermore, the introduction of miR-214 significantly promoted the proliferation of PASMCs by suppressing apoptosis of the cells, which was mediated by the downregulation of PTEN. Exposure to hypoxia significantly increased the expression of miR-214 and decreased the expression of PTEN in PASMCs, and its proliferation was significantly promoted. Such effects could be significantly attenuated by the introduction of miR-214 inhibitors, which significantly downregulated miR-214 expression and upregulated the expression of PTEN. In conclusion, hypoxia-induced upregulation of miR-214 was found to promote PH development by targeting PTEN in PASMCs, and miR-214 could be a promising diagnostic tool and novel therapeutic target in the management of hypoxia-induced PH in COPD. Keywords: hypoxia, pulmonary hypertension, miR-214, PTEN

Hongjun Kang,1 Zhi Mao,1 Yan Zhao,1 Ting Yin,2 Qing Song,1 Liang Pan,1 Xin Hu,1 Jie Hu,1 Feihu Zhou1 1Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, 2Department of Critical Care Medicine, The Centre Hospital of BaoTou, BaoTou, People’s Republic of China Background: Ethyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal-ligation-and-puncture-induced septic mice. Methods: The animals were treated intraperitoneally with 0.2 mL of Ringer’s lactate solution or an equivalent volume of Ringer’s lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers. Results: Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP. Conclusion: The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis. Keywords: sepsis, ethyl pyruvate, energy metabolism, inflammation, reactive oxygen species

Tinghui Yin1*, Ping Wang1*, Rongqin Zheng1, Bowen Zheng1, Du Cheng2, Xinling Zhang1, Xintao Shuai21Department of Medical Ultrasonic, Third Affiliated Hospital, 2PCFM Laboratory of the Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China*These authors contributed equally to this workAbstract: The fabrication and initial applications of nanobubbles (NBs) have shown promising results in recent years. A small particle size is a basic requirement for ultrasound contrast-enhanced agents that penetrate tumor blood vessel pores to allow for targeted imaging and therapy. However, the nanoscale size of the particles used has the disadvantage of weakening the imaging ability of clinical diagnostic ultrasound. In this work, we fabricated a lipid NBs contrast-enhanced ultrasound agent and evaluated its passive targeting ability in vivo. The results showed that the NBs were small (436.8 ± 5.7 nm), and in vitro ultrasound imaging suggested that the ultrasonic imaging ability is comparable to that of microbubbles (MBs). In vivo experiments confirmed the ability of NBs to passively target tumor tissues. The NBs remained in the tumor area for a longer period because they exhibited enhanced permeability and retention. Direct evidence was obtained by direct observation of red fluorescence-dyed NBs in tumor tissue using confocal laser scanning microscopy. We have demonstrated the ability to fabricate NBs that can be used for the in vivo contrast-enhanced imaging of tumor tissue and that have potential for drug/gene delivery.Keywords: phospholipids, ultrasound, contrast agent, tumor-targeted

Mycorrhizal symbioses the union of roots and soil fungi are universal in terrestrial ecosystems and may have been fundamental to land colonization by plants 1, 2. Boreal, temperate and montane forests all depend on ectomycorrhizae1. Identification of the primary factors that regulate symbiotic development and metabolic activity will therefore open the door to understanding the role of ectomycorrhizae in plant development and physiology, allowing the full ecological significance of this symbiosis to be explored. Here we report the genome sequence of the ectomycorrhizal basidiomycete Laccaria bicolor (Fig. 1) and highlight gene sets involved in rhizosphere colonization and symbiosis. This 65-megabase genome assembly contains 20,000 predicted protein-encoding genes and a very large number of transposons and repeated sequences. We detected unexpected genomic features, most notably a battery of effector-type small secreted proteins (SSPs) with unknown function, several of which are only expressed in symbiotic tissues. The most highly expressed SSP accumulates in the proliferating hyphae colonizing the host root. The ectomycorrhizae-specific SSPs probably have a decisive role in the establishment of the symbiosis. The unexpected observation that the genome of L. bicolor lacks carbohydrate-active enzymes involved in degradation of plant cell walls, but maintains the ability to degrade non-plant cell wall polysaccharides, reveals the dual saprotrophic and biotrophic lifestyle of the mycorrhizal fungus that enables it to grow within both soil and living plant roots. The predicted gene inventory of the L. bicolor genome, therefore, points to previously unknown mechanisms of symbiosis operating in biotrophic mycorrhizal fungi. The availability of this genome provides an unparalleled opportunity to develop a deeper understanding of the processes by which symbionts interact with plants within their ecosystem to perform vital functions in the carbon and nitrogen cycles that are fundamental to sustainable plant productivity.