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Meiju Zhou, Xiaona Dai, Fang Yuan Department of Rheumatology and Immunology, Zhejiang Hospital, Hangzhou, People’s Republic of ChinaCorrespondence: Fang Yuan, Department of Rheumatology and Immunology, Zhejiang Hospital, No. 1229 Gudun Road, Hangzhou, 310030, People’s Republic of China, Email yuanfany@126.comObjective: To assess the efficacy of methotrexate (MTX) and hydroxychloroquine (HCQ) in improving fatigue symptoms in patients with primary Sjögren’s syndrome (pSS).Methods: A single-center retrospective study was conducted on pSS patients experiencing fatigue symptoms. All patients received either MTX, HCQ, or a combination of MTX + HCQ for a period of six months. Clinical efficacy was measured using the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), fatigue severity scale (FSS), and visual analog scale (VAS) score. These measures were assessed at baseline and at 1, 2, 3, and 6 months.Results: A total of 86 pSS patients with fatigue symptoms were enrolled (27 received MTX, 29 received HCQ, and 30 received MTX + HCQ). Patients receiving MTX and MTX + HCQ showed significant improvements at 6th month in ESSDAI, ESSPRI, FSS, FACIT-F, and VAS scores (all P < 0.01) compared with baseline. Repeated-measures analysis of variance revealed that patients treated with MTX and MTX + HCQ experienced significant improvements in ESSDAI, FSS, FACIT-F, and VAS scores (all P < 0.01) from baseline to the 6th month. The HCQ group did not show significant improvement in FSS, FACIT-F, and VAS scores (all P > 0.05), although their ESSDAI and ESSPRI scores did improve significantly (all P < 0.01). Patients in the MTX group showed the most improvement in mean changes of ESSDAI score, FSS score, FACIT-F score, and VAS score from baseline to the 6th month. And patients received MTX treatment significantly had more fatigue remission numbers (all P < 0.05).Conclusion: In clinical practice, methotrexate is more effective than hydroxychloroquine in improving fatigue symptoms, as measured by patient-reported fatigue scales (FSS, FACIT-F, and VAS scores) in patients with pSS.Keywords: primary Sjögren’s syndrome, fatigue, methotrexate, hydroxychloroquine

Fuzhen Yuan,1 Zhenhua Huang,1,2 Dingye Yao,1,2 Junsheng Sun1,2 1Department of General Practice, Longgang District Central Hospital of Shenzhen, Shenzhen, 5181116, People’s Republic of China; 2Shenzhen Clinical College of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, 5181116, People’s Republic of ChinaCorrespondence: Junsheng Sun, Department of General Practice, Longgang District Central Hospital of Shenzhen, No. 6082, Longgang Avenue, Longgang District, Shenzhen, Guangdong Province, 518100, People’s Republic of China, Tel +86-15338897372, Email junshengsun@126.comAbstract: Vitamin B12 is essential for various bodily functions, and its deficiency may cause hematological manifestations. We report a case of a previously healthy 65-year-old female who was admitted to our hospital with reduced sense of taste and painful tongue. The serum level of vitamin B12 was decreased. However, her complete blood count did not show any evidence of macrocytosis, instead, her mean corpuscular volume was low. Gene sequencing indicated an β-thalassemia minor and that probably masked the megaloblastic features of vitamin B12 deficiency.Keywords: pernicious anemia, autoimmune gastritis, thalassemia, glossitis

Linqi Li,1 Jing Cao,2 Jiao Qin,2 Xiangxiang Chen,2 Feng Yuan,2 Ping Deng,2,&ast; Hebin Xie1,2,&ast; 1School of Public Health, University of South China, Heng Yang, Hunan, People’s Republic of China; 2The Affiliated Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hebin Xie, The Affiliated Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China, Tel +86 15173132201, Email 2018050642@usc.edu.cnPurpose: To analyze the factors affecting patients’ prognoses based on the community acquired-bloodstream infection patient data from 2017 to 2021.Patients and Methods: The data of 940 patients were retrieved, having at least one positive bilateral blood culture within 48 hours of hospitalization, and grouped into survivor and non-survivor groups. The clinical characteristics, laboratory results, causative pathogen and other indicators were collected and compared, and risk factors were identified by applying Cox proportional hazard regression model to the data.Results: Community acquired-bloodstream infection is most commonly caused by Escherichia coli, Klebsiella species and Staphylococcus hominis. Among the total of 940 selected patients, 52 (5.5%) died during hospitalization. The demographic parameters like age and gender, clinical protocols like maintenance hemodialysis, glucocorticoid use during hospitalization, catheter placement, procaicitonin, total protein, albumin, creatinine, uric acid contents and Sequential Organ Failure Assessment scores were significantly different between the survivor and non-survivor groups. The survival analysis results revealed that age (HR=1.02, 95% CI: 1.00– 1.05, P=0.002), glucocorticoid use during hospitalization (HR=3.69, 95% CI: 1.62– 8.37, P=0.021) and Sequential Organ Failure Assessment score (HR=1.10, 95% CI: 1.03– 1.18, P=0.004) might be the risk factors affecting 30-day mortality in patients with community acquired-bloodstream infection.Conclusion: The identified risk factors may help guide clinical treatment protocol for patients with community acquired-bloodstream infection, providing more effective treatment strategy selection with improved clinical outcomes.Keywords: prognosis, pathogen, clinical characteristics, treatment

Fan Jiang, Lingyi Lu, Sihan Wang, Feng Yuan, Lu Cao, Suling Xu,&ast; Bingjiang Lin&ast; Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang; National Clinical Medical Research Center for Skin and Immune Diseases, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Suling Xu; Bingjiang Lin, Department of Dermatology, The First Affiliated Hospital of Ningbo University, No. 59 Liuting Street, Ningbo, Zhejiang, 315000, People’s Republic of China, Email linbingjiangnb@163.comPurpose: The purpose of this study was to investigate the comprehensive impact of family history of psoriasis, lesion size, disease severity, and the possibility of joint involvement on patients’ quality of life(QoL).Patients and Methods: Data from 5961 patients with psoriasis recruited from 440 hospitals throughout China were analyzed. The effects of family history of psoriasis, Body Surface Area(BSA), Psoriasis Area and Severity Index(PASI), and Psoriasis Epidemiology Screening Tool(PEST) on their Dermatology Life Quality Index(DLQI) were studied using a moderated chained mediated effects test.Results: A total of 912 patients (15.30%) had a family history of psoriasis, and 5071 patients (85.10%) had plaque psoriasis. In patients with plaque psoriasis, the variables of family history, PASI, PEST, and DLQI were positively correlated with each other. Additionally, in patients with other types of psoriasis, PASI was positively correlated with PEST and DLQI. Age was positively correlated with PASI and PEST and negatively correlated with DLQI in patients with plaque psoriasis; their Body Mass Index(BMI) and disease duration were in positive correlation with PASI and PEST. The mediation effect of PASI and PEST between family history and DLQI was remarkable in patients with plaque psoriasis and not in those with other types of psoriasis. BSA moderated the association between family history and PASI in patients with plaque psoriasis.Conclusion: PASI and PEST play a chain mediating role in the relationship between family history and DLQI in patients with plaque psoriasis, and high levels of BSA increase the ability of family history to positively predict PASI in plaque psoriasis, thereby affecting the patient’s QoL.Keywords: plaque psoriasis, PASI, PEST, quality of life, family history

Hong Yang,1 Maogang Chen,2 Ying Hu,1 Mengjiao Xu,1 Yiping Li,1 Lunhao Liu,1 Dan Yuan,1 Fengshun Yuan,1 Ling Li,1 Li Ye,1 Chang Zhou,1 Yan Zhang,1 Shu Liang,1 Ling Su1 1Department of AIDS/STD Control and Prevention, Sichuan Center for Disease Control and Prevention, Chengdu, People’s Republic of China; 2Department of Microbiology, Liangshan Yi Autonomous Prefecture Center for Disease Control and Prevention, Xichang, People’s Republic of ChinaCorrespondence: Shu Liang; Ling Su, Email liangshu523@163.com; sl7512@163.comBackground: Men who have sex with men (MSM) is one main type of high-risk activities facilitating HIV-1 transmission in Sichuan province. Previous works on HIV-1 incidence and prevalence among MSM only concentrated before 2018, the situation after that is unknown. In addition, the distribution of hot-spots related to current HIV-1 epidemic is also rarely known among MSM in Sichuan.Objective: To update trends of HIV-1 prevalence and incidence and to visualize hot-spots of ongoing transmission in Sichuan province during surveillance period among MSM between 2018 and 2022.Methods: Limiting Antigen Avidity assay was performed to detect recent infection within new HIV-1 diagnoses founded during surveillance period among MSM. The HIV-1 prevalence and incidence were calculated according to an extrapolation method proposed by publications and guidelines. Trend tests were performed using χ2 tests with linear-by-linear association. The spatial analysis was conducted with ArcGIS 10.7 to figure hot-spots of HIV-1 recent infections among MSM.Results: Between 2018 and 2022, 16,697 individuals participated in HIV-1 MSM sentinel surveillance program, of which 449 samples (98.25%) were tested with LAg-Avidity EIA, and 230 samples were classified as recent infection. Respectively, the overall prevalence and incidence were 2.74% and 3.69% (95% CI: 3.21, 4.16) and both had significant declining trends (p < 0.001). Luzhou city had a highest HIV-1 incidence (10.74%, 95% CI: 8.39, 13.10) over the study period and was recognized as a hot-spot for recent HIV-1 infection among MSM.Conclusion: During the surveillance period, both HIV-1 prevalence and incidence were declining. However, Luzhou city had an unusually high HIV-1 incidence and became an emerging hot-spot of recent HIV-1 infection among MSM. This finding suggested focused attention, cross-regional intervention strategies, and prevention programs are urgently required to curb the spread of ongoing transmission.Keywords: human immunodeficiency virus type 1, HIV-1 recent infection, incidence, hot-spots, men who have sex with men

Debiao Xiang,1– 3 Lili Zhou,4 Rui Yang,1,4 Fang Yuan,1– 3 Yilin Xu,4 Yuan Yang,1,4 Yong Qiao,1– 3 Xin Li1– 3 1Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan Province, People’s Republic of China; 2Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs, Changsha, Hunan Province, People’s Republic of China; 3The Clinical Application Research Institute of Antibiotics in Changsha, Changsha, Hunan Province, People’s Republic of China; 4College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Xin Li, 176 Laodong West Road, Tianxin District, Changsha, Hunan Province, People’s Republic of China, Tel +86 0731-85171320, Email xin-li@cssdsyy.comAbstract: Currently, cancer remains one of the most significant threats to human health. Treatment of most cancers remains challenging, despite the implementation of diverse therapies in clinical practice. In recent years, research on the mechanism of ferroptosis has presented novel perspectives for cancer treatment. Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions. The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc−. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.Keywords: cancers, ferroptosis, nano-drug delivery system, target

ObjectivesRecurrence and survival in early T-stage oral tongue squamous cell carcinoma (OTSCC) may be impacted by histopathologic risk factors. This study aims to examine which of these factors predict long-term outcomes of T1 and T2 OTSCC.MethodsA retrospective review of T1 and T2 OTSCC patients treated with surgery at a single tertiary care center was conducted. Multivariate regression and Kaplan-Meier survival plots were used to identify predictors of recurrence and compare disease-free survival respectively.Results100 consecutive patients were studied. Of these, 51 were staged pT1, 49 pT2, 69 pN0, 10 pN1, and 21 pN2. Multivariate regression analysis revealed that >4 nodes was the strongest predictor of overall recurrence [odds ratio 1.68 (1.23–2.28), p = 0.001], while >4 nodes [odds ratio 1.14 (1.09–1.85), p = 0.008] and pT2 [odds ratio 1.15 (1.01–1.30), p = 0.033] were predictors of local recurrence (R2 = 0.112). Five-year disease-free survival was not significantly impacted by any risk factors except for the number of positive nodes—86% for ≤4 nodes vs. 20% for >4 nodes (p 4 nodes and pT2 staging—adjuvant therapy should be considered.

Meiju Zhou,1 Ci Lu,2 Fang Yuan1 1Department of Rheumatology and Immunology, Zhejiang Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Rheumatology and Immunology, Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Fang Yuan, Department of Rheumatology and Immunology, Zhejiang Hospital, No. 1299 Gudun Road, Hangzhou, Zhejiang Province, 310012, People’s Republic of China, Tel +86-18072963566, Email yuanfany@126.comObjective: To assess physicians’ knowledge and awareness of chronic pain associated with rheumatoid arthritis (RA) in Rheumatology departments throughout Zhejiang province to improve chronic pain relief in RA patients.Methods: A cross-sectional questionnaire survey was conducted onsite and online among rheumatologists in tertiary and secondary hospitals across Zhejiang province, China. The questionnaire inquired about rheumatoid arthritis-related pain cognition, pain assessment, pain management protocols, and medication choice.Results: Among the 150 questionnaires included, 98 were from tertiary hospitals, and 52 were from secondary hospitals. There was no difference in rheumatologists’ perceptions of chronic pain in RA patients between tertiary and secondary hospitals. About 55.1% of rheumatologists from tertiary hospitals and 44.2% of rheumatologists from secondary hospitals utilized unstandardized pain assessment scales. About 46.9% of rheumatologists in tertiary hospitals and 36.5% of rheumatologists in secondary hospitals favored the numerical rating scale (NRS). About 87.8% of rheumatologists in tertiary hospitals and 71.7% of rheumatologists in secondary hospitals conducted pain assessment within 4 hours of admission. About 66.3% of rheumatologists working in tertiary hospitals and 32.7% of rheumatologists practicing in secondary hospitals believed their hospitals had pain departments. For RA patients who complained of pain for the first time, secondarily, or repeatedly, 48%, 26%, and 36.7% of rheumatologists preferred nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and opioid analgesics, respectively. For RA patients with mild, moderate, or severe pain, 74%, 6%, and 16% of rheumatologists preferred NSAIDs, glucocorticoids, and opioid analgesics, respectively.Conclusion: The assessment and treatment of chronic pain associated with RA are not standardized. For management, more rheumatologists preferred NSAIDs and glucocorticoids.Keywords: rheumatoid arthritis, chronic pain, survey and questionnaire

Hong Yang, Yiping Li, Mengjiao Xu, Ying Hu, Fengshun Yuan, Lunhao Liu, Ling Li, Dan Yuan, Li Ye, Chang Zhou, Yan Zhang, Ling Su, Shu Liang Center for AIDS/STD Control and Prevention, Sichuan Center for Disease Control and Prevention, Chengdu, People’s Republic of ChinaCorrespondence: Shu Liang; Ling Su, Email liangshu523@163.com; sl7512@163.comBackground: Sichuan Province has gradually become a hot-spot for HIV/AIDS. Little is known about the HIV-1 incidence and prevalence among four sub-groups since 2015. Meanwhile, the distributions of hot-spot areas related to recent infection cases that indicate current transmission among the four subgroups are also rare.Objective: The main purpose of this study was to assess the HIV-1 prevalence and incidence and to visualize the distributions of hot-spot areas of current transmission among four subgroups (people who inject drugs, male STD clinic attendees, female sex workers and men who had sex with men) during the surveillance period in Sichuan province between 2016 and 2022.Results: Of the 267,617 individuals, 2158 HIV-positive samples were tested with Lag-Avidity EIA, among which 493 samples were identified as recent infections. Among people who inject drugs (PWID), both HIV-1 prevalence (from 1.41% to 0.34%) and incidence (from 0.03% to 0.140%) showed a significant decreasing trend. Among men who had sex with men (MSM), female sex workers (FSWs), and male STD clinic attendees, HIV-1 prevalence indicated significant decreasing trends, whereas HIV-1 incidence showed no significant changes. Spatial analysis demonstrated the formation of hot-spots and clusters of current transmissions sharing regional differences, mainly concentrated in the southeast, and most of these were consecutive hot-spots.Conclusion: The prevention and control were efficacious and persistent. However, among the other three subgroups, there is a need for a regional cooperative in prevention and control approaches and collaborative research in many aspects.Keywords: human immunodeficiency virus, recent infection, hot spots, people who inject drugs, PWID, male STD clinic attendees, mSTD, female sex workers, FSWs

Xi-Qin Wang,1 Fang Yuan,2 Bao-Rui Yu2 1Department of Internal Medicine, Yuhua Yunfang Integrated Traditional Chinese and Western Medicine Clinic, Shijiazhuang, Hebei, 050023, People’s Republic of China; 2Department of Cardiovascular Medicine, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, 450000, People’s Republic of ChinaCorrespondence: Xi-Qin Wang, Department of Internal Medicine, Yuhua Yunfang Integrated Traditional Chinese and Western Medicine Clinic, NO. 59 Ta’nan Road, Shijiazhuang, Hebei, 050023, People’s Republic of China, Tel +86-13522595882, Email yunfangzhensuo@163.com Fang Yuan, Department of Cardiovascular Medicine, Fuwai Central China Cardiovascular Hospital, NO. 1 Fuwai Avenue, Zhengzhou, Henan, 450000, People’s Republic of China, Tel +86-13653821840, Email xy20050615@163.comBackground: Hypertrophic cardiomyopathy (HCM) is an extremely insidious and lethal disease caused by genetic variation. It has been studied for nearly 70 years since its discovery, but its cause of the disease remains a mystery. This study is aimed to explore the genetic pathogenesis of HCM in order to provide new insight for the diagnosis and treatment of HCM.Methods: Patients with HCM at 4 hospitals from January 1, 2020, to December 31, 2021, were collected. Peripheral blood of these patients was collected for whole exome sequencing. Moreover, data on the HCM transcriptome were analyzed in the GEO database.Results: Totally, 14 patients were enrolled, and 6 single-nucleotide variation (SNV) mutant genes represented by MUC12 were observed. Most of the gene mutations in HCM patients were synonymous and non-synonymous, and the types of base mutations were mainly C > T and G > A. Copy number variants (CNVs) predominantly occurred on chromosome 1 in HCM patients. Furthermore, we found that the only ATP2A2 gene was differentially expressed in 3 groups of transcriptome data in GEO database, and the presence of ATP2A2 mutation in 10 samples was observed in this study.Conclusion: In summary, 7 mutated genes represented by MUC12 and ATP2A2 were found in this study, which may provide novel insights into the pathogenic mechanism of HCM.Keywords: hypertrophic cardiomyopathy, whole exome sequencing, single-nucleotide variation, copy number variants, gene mutation

Fangfang Yuan,1 Weiqiang Xiao,2 Xiaokun Wang,2 Yuewen Fu,1 Xudong Wei1 1Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University& Henan Cancer Hospital, Zhengzhou, People’s Republic of China; 2Department of Laboratory Science, The Affiliated Cancer Hospital of Zhengzhou University& Henan Cancer Hospital, Zhengzhou, People’s Republic of China;Correspondence: Xudong Wei; Yuewen Fu, Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, People’s Republic of China, Tel +86-371-65587218 ; +86-371-65587027, Email xudongwei@zzu.edu.cn; zlyyfuyuewen1480@zzu.edu.cnObjective: To analyze the clinical characteristics and prognostic risk factors of carbapenem-resistant Pseudomonas aeruginosa (CRPA) bloodstream infections in patients with hematologic malignancies.Methods: Medical records and drug susceptibility data of patients with hematologic malignancies complicated by CRPA bloodstream infections admitted to the Cancer Hospital of Zhengzhou University between January 1, 2018, and December 31, 2022, were retrospectively analyzed.Results: A total of 64 patients were included in the study, with a mortality rate of 37.5% (24/64) at 28 days after the occurrence of CRPA bloodstream infection. In Cox regression analysis, an absolute neutrophil count < 0.5× 109/L at discharge (HR 0.039, 95% CI 0.006 ~ 0.258, p=0.001), admission to the intensive care unit (HR 7.546, 95% CI 1.345 ~ 42.338, p= 0.022), and a higher Pitt bacteremia score (HR 0.207, 95% CI 0.046 ~ 0.939, p = 0.041) were independent risk factors associated with 28-day mortality. Survival analysis showed that patients receiving ceftazidime-avibactam-based (HR 0.368, 95% CI 0.107~ 1.268, p = 0.023) or polymyxin B (HR 2.561, 95% CI 0.721 ~ 9.101, p = 0.015) therapy had a higher survival rate.Conclusion: Patients with hematologic neoplasms had high mortality from CRPA bloodstream infections, and admission to the intensive care unit, higher Pitt bacteremia score (PBS) scores, granulocyte deficiency, and granulocyte deficiency at discharge were independently associated with higher mortality. Early anti-infective treatment with ceftazidime-avibactam or polymyxin B may improve the clinical prognosis of patients.Keywords: Pseudomonas aeruginosa, carbapenem resistance, bloodstream infection, hematologic neoplasm, risk factors

Mina Wang,1,2,&ast; Fang Yuan,1,&ast; Xiaobai Xu,1,&ast; Tao Zhang,1 Jing Guo,1 Guiling Wang,1 Linpeng Wang,1 Jingqing Sun,1 Fan Zhang,1 Bin Li1 1Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, People’s Republic of China; 2Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fan Zhang; Bin Li, Email wawndzh@126.com; libin@bjzhongyi.comIntroduction: Post-stroke complex regional pain syndrome (CRPS) is a devastating disease that causes severe physical and emotional consequences. Conventional therapies are limited due to the insufficient benefits and side effects, and fire needling therapy is considered an alternative for post-stroke CRPS of the upper limb.Methods and Analysis: This is a study protocol for a pilot randomised, two-arm, single-centre, clinical trial at Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University. The trial started in March 2023 and is expected to end in December 2024. A total of 60 patients (aged 40– 75 years, male or female) with post-stroke CRPS of the upper limb will be randomly assigned to treatment group (fire needling therapy, 5 sessions per week for 2 weeks) or control group (manual acupuncture, 5 sessions per week for 2 weeks) in a 1:1 ratio using block randomisation and opaque envelopes. Fire needling therapy or manual acupuncture will be performed in ten acupoints. Participants will complete the trial by visiting the research centre at Week 14 for a follow-up assessment. The primary outcome is the response rate. Secondary outcomes include FMA, Barthel Scale/Index (BI), pain threshold (PPT), and muscle elasticity modulus (using shear wave elastography [SWE]). A chi-squared test will be used for response rate. A mixed-effects linear model and a mixed-effects model will be used for FMA, BI, PPT, and SWE, respectively.Discussion: This is the first standardised protocol to compare the effectiveness of fire needling therapy and manual acupuncture. We will use a rigorous methodology to minimise bias and set up supervising committees to ensure the quality of our study, thus providing trustworthy evidence for better understanding of fire needling therapy in treating post-stroke CRPS of the upper limb.Keywords: post-stroke complex regional pain syndrome, upper limb, fire needling therapy, manual acupuncture

Fang Yuan,1,&ast; Feng-Na Zhu,2,&ast; Xiao-Juan Liu,1,&ast; Jun Li,3 Hong-Tao Xu1 1Department of Pediatrics, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China; 2Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Wuhan, 430070, People’s Republic of China; 3Department of Blood Purification, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, 430070, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Li; Hong-Tao Xu, General Hospital of Central Theater Command of the People’s Liberation Army, 627&num;, Wuluo Road, Wuchang District, Wuhan, Hubei Province, 430070, People’s Republic of China, Tel +86-13659846692, Fax +86-27-50773333, Email lijun15261@163.com; xuht5409@163.comBackground: Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is an X-linked dominant genetic disease involving multiple systems. Previous literature has not reported the case of parents with negative genetic test results, and typical early clinical symptoms and auxiliary inspection results were also lacking.Case Report: A female child was found to have broken skin immediately after birth with no family inheritance disease, and the area of the broken skin increased. Immediately afterward, Head magnetic resonance imaging (MRI) showed multiple blood lesions in the brain. Then, the wide-angle digital retinal imaging system suggesting that fundus fluorescein angiography showed fundus vascular loop-like changes. And blood genetic testing showed that exons 4– 10 of the NEMO gene located in Xq28 were deleted. The patient was eventually diagnosed with IP. However, her parents were a non-consanguineous healthy couple, with no specific skin, oral, or perineal diseases. And her parents’ blood genetic testing showed that the parents and sisters of the patient did not have the NEMO gene exon deletion of Xq28.Conclusion: This case demonstrates the process from suspected neonatal IP cases without familial inheritance to diagnosis, which showed the typical early clinical symptoms and auxiliary inspection results. This case showed that the parents of patients with IP do not necessarily have clinical symptoms and positive symptoms of genetic testing results.Keywords: incontinentia pigment, genodermatosis, Bloch-Sulzberger syndrome, skin disease, NEMO gene

Mina Wang,1,2,&ast; Xiaobai Xu,1,&ast; Bingcong Zhao,1 Lu Liu,1 Luopeng Zhao,1 Fan Zhang,1 Xu Ji,1 Fang Yuan,1 Qiuyu Xia,1 Shaosong Wang,1 Wei Tian,1 Linpeng Wang,1 Bin Li1 1Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Li; Xiaobai Xu, Email libin@bjzhongyi.com; xu_xiaobai1990@sina.comPurpose: Knee osteoarthritis (KOA) is regarded as one of the leading musculoskeletal diseases. Although the efficacy is under exploration, fire needling therapy is considered an effective alternative for KOA. This trial aims to investigate the effectiveness of different frequencies of fire needling therapy in attenuating pain and promoting function in KOA patients.Methods: This is a study protocol for a pilot, three-arm, single-center, randomized controlled trial. A total of 90 participants with KOA will be recruited and randomly assigned to the high-frequency fire needling group (3 sessions per week, for 6 weeks), the low-frequency fire needling group (1 session per week, for 6 weeks) or the positive control group (Diclofenac Diethylamine Emulgel, 3 times per day, for 6 weeks) in a 1:1:1 ratio. Participants will accomplish the trial at Week 14 after a follow-up evaluation. The response rate will be set as the primary outcome that the proportion of participants obtaining a minimal clinically important difference, which is identified as ≥ 2 units on the numerical rating scale (NRS) and ≥ 6 units on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score at Week 6 compared with Week 0. Secondary outcomes are NRS, WOMAC, Brief Pain Inventory, Short-Form Health Survey-12, Timed Up and Go Test, and pain threshold.Discussion: This is the first standardized protocol comparing fire needling therapy and positive control drugs. This trial may provide reliable evidence for the effectiveness of fire needling therapy and dose–effect property of it in KOA. Trial registration: The trial has been registered on Chinese Clinical Trial Registry (Registered number: ChiCTR2100043041), registered on 4 February 2021.Keywords: knee osteoarthritis, fire needling therapy, different frequencies, dose–effect property

Juan Wu,1,2 Hongrong Xu,1 Hui Li,1 Lei Ma,3 Juan Chen,3 Fei Yuan,1 Lei Sheng,1 Chao Liu,1 Weili Chen,1 Xuening Li1 1Department of Clinical Pharmacology & Cancer Center, ZhongShan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Pharmacy, Shanghai Children’s Medical Center, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China; 3Haihe Biopharma Co., Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Xuening Li, Department of Clinical Pharmacology & Cancer Center, ZhongShan Hospital, Fudan University, 180 Fenglin Road, Shanghai, People’s Republic of China, 200032, Tel +86 21 3158 7860, Fax +86 21 3158 7866, Email li.xuening@zs-hospital.sh.cnObjective: This study aimed to investigate the effect of food on the pharmacokinetics and safety profiles of SCC244, a novel oral c-Met inhibitor in healthy Chinese male subjects.Methods: It was a randomized, open-label, and 3-period crossover design, single-dose phase I clinical trial. A total of 18 healthy male subjects were enrolled. These subjects received a single oral 300 mg dose of SCC244 with a 14-day washout between each period. Blood samples were collected at the designated time points and determined using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated by noncompartmental methods. Tolerability was assessed by physical examination, vital sign measurements, 12-lead ECG, clinical laboratory tests, and adverse events (AEs) monitoring throughout the study.Results: Eighteen eligible subjects were enrolled in the study. The ratios (90% CI) of Cmax values for SCC244 in high-fat and low-fat meal states to that observed in fasted state were 194.8% (174.3– 217.7%) and 194.6% (174.1– 217.5%), respectively. The ratios of AUC0-t and AUC0-inf in the high-fat meal state versus the fasted state were 237.4% (208.7– 270.0%) and 235.9% (207.5– 268.3%), respectively. The ratios of AUC0-t and AUC0-inf in the low-fat meal state versus the fasted state were 219.2% (192.7– 249.3%) and 218.3% (192.0– 248.3%), respectively. Median Tmax values and mean t1/2 were similar in all groups. The most common AEs were headache, blood fibrinogen decreased, head discomfort, dizziness, and protein urine presence. All AEs were Common Terminology Criteria for Adverse Events (CTCAE) grade 1 (except 1 case of grade 2) and have resolved by the end of the study.Conclusion: The bioavailability of the tablet formulation of SCC244 was significantly increased when administered with high- and low-fat meals. However, the meals did not affect the median Tmax and t1/2. Safety under different fed conditions was comparable to fasted conditions in this study.Keywords: SCC244, c-Met inhibitor, food effect, pharmacokinetics, safety

Xiuzhen Zhang,&ast; Ying Zhang,&ast; Limei Luo, Ying Le, Ying Li, Fengyi Yuan, Yan Wu, Ping Xu Department of Endocrinology and Metabolism, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Xu, Department of Endocrinology and Metabolism, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China, Email xu.ping@szhospital.comObjective: In this pilot-study, the effects of a multispecies probiotic supplement on glycaemic control and metabolic parameters in adults with type 1 diabetes (T1DM) were explored.Material and Methods: A total of 50 T1DM patients were enrolled and randomly placed into a group receiving capsules containing multi-probiotic strains (Bifidobacterium longum, Lactobacterium bulagricumi, Streptococcus thermophilus) and insulin (probiotics group, n = 27) or a group receiving a placebo and insulin (placebo group, n = 23). All patients underwent continuous glucose monitoring at baseline and 12 weeks after intervention. The primary outcomes were determined by comparing factors such as changes in fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) between the groups.Results: Probiotic supplementation significantly reduced FBG (− 1.0 ± 4.7 vs 1.8 ± 4.7 mmol/L, p = 0.048), 30 min postprandial glucose (− 0.5 ± 4.6 vs 1.9 ± 3.3 mmol/L, p = 0.0495), and low-density lipoprotein cholesterol (− 0.07 ± 0.45 vs 0.32 ± 0.78 mmol/L, p = 0.0413), compared with the placebo. Although not statistically significant, probiotic supplementation also lowered HbA1c levels by 0.49% (− 5.33 mmol/mol, p = 0.310). Besides, no significant difference was observed in the continuous glucose monitoring (CGM) parameters between the two groups. Further subgroup analysis revealed a significant reduction in mean sensor glucose (MSG; − 0.75 (− 2.11, 0.48) mmol/L vs 1.51 (− 0.37, 2.74) mmol/L, p = 0.010) and time above range (TAR; − 5.47 (− 20.1, 3.04)% vs 18.9 (− 1.11, 35.6)%, p = 0.006), as well as an greater improvement in the time in range (TIR; 9.32 (− 4.84, 16.6)% vs − 19.9 (− 31.4, 0.69)%, p = 0.005) in male patients than female patients in the probiotics group.Conclusion: Multispecies probiotics exerted beneficial effects on fasting and postprandial glucose and lipid profiles in adult T1DM patients, especially for male patients and those with higher baseline FBG levels.Keywords: continuous glucose monitoring, glycaemic variability, lipid profile, probiotics, type 1 diabetes mellitus

Hong Yang, Yiping Li, Fang He, Fengshun Yuan, Lunhao Liu, Ling Li, Dan Yuan, Li Ye, Chang Zhou, Yan Zhang, Ling Su, Shu Liang Center for AIDS/STD Control and Prevention, Sichuan Center for Disease Control and Prevention, Chengdu, People’s Republic of ChinaCorrespondence: Shu Liang; Ling Su, Email liangshu523@163.com; sl7512@163.comBackground: Sichuan Province is severely affected by the HIV epidemic in China. Little is known about the characteristics of recent infections among new HIV diagnoses, which is critical to prevention strategies, evaluation of the HIV epidemic and health resource allocation. Meanwhile, individuals at primary stages of infection are related to the hot-spot areas of ongoing transmission in new HIV diagnoses, which is also rarely known.Objective: This article aimed to report the proportion of recent infections among new HIV diagnoses, and to reveal demographic characteristics associated with HIV recent infections, and finally, to indicate the hot-spot areas of ongoing transmission in Sichuan province between 2018 and 2020.Methods: Limiting Antigen (LAg)-Avidity assay was performed to detect recent infection within new HIV diagnoses reported in odd months between 2018 and 2020. Results were reclassified according to the data on CD4 cell count, antiretroviral treatment and the existence of an AIDS-defining illness. Logistic regression was used to determine characteristics associated with HIV recent infections. The spatial analysis was conducted with ArcGIS 10.7 to figure hot-spot areas of HIV recent infections.Results: 42,089 newly diagnosed HIV-1 cases were tested using the LAg-Avidity EIA. In total, 5848 (13.89%) of those were classified as HIV recent infections. Female, age between 18– 25 years and men who had sex with men were related to higher proportion of HIV recent infections. Logistic regression revealed that MSM aged between 18– 25 years were more likely to be classified as recent infection. Spatial analysis demonstrated significant clustering in Chengdu, Yibin, Luzhou city between 2018 and 2020. Hot spots were mainly clustered in the center of Sichuan in 2018, but gradually spread to southwest and northwest between 2019 and 2020.Conclusion: Enhanced preventive measures among relevant risk groups and areas where the potential HIV-1 transmission is ongoing is urgently needed to curb further spread.Keywords: human immunodeficiency virus, HIV, HIV recent infection, Sichuan, hot spots

Ming Shao,1,2,&ast; Fangting Yuan,1,2,&ast; Jingwen Liu,1,2 Hesheng Luo1,2 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Hubei Key Laboratory of Digestive Diseases, Wuhan, 430060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hesheng Luo, Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China, Email whdxxhnklhs@whu.edu.cnPurpose: Ulcerative colitis (UC) patients have disturbances in the microbiota-gut-brain axis, and mast cells are important components of this axis. The mast cell-specific receptor Mrgprb2 has effects on host defense against bacterial infection and neurogenic inflammation, which may help mast cells act on the axis. This study analyzed how Mrgprb2 participates in the pathogenesis of UC by affecting the microbiota-gut-brain axis.Materials and Methods: Mrgprb2 knockout (b2KO) mice and wild-type (WT) mice were fed 2% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, which was then replaced with normal water for 14 days. This cycle was repeated three times. Feces were collected on Days 21, 42, and 63 for intestinal microbiota analysis, and mice were euthanized on Day 64. Hypothalamus, amygdala and colon tissues were removed and analyzed.Results: Compared with WT mice, B2KO mice exhibited increased weight loss, colon shortening and colonic pathological damage after colitis induction. Analysis of the intestinal microbiota showed that b2KO mice with colitis had a significant decrease in the abundance and diversity, as well as an increase in Allobaculum and a decrease in norank_f__Muribaculaceae and Ileibacterium. In colon tissues, the expression of mucin 2 (MUC2) and junctional adhesion molecule A (JAM-A) in b2KO mice was reduced, and oxidative stress levels were higher. B2KO mice with colitis had higher corticotropin-releasing hormone (CRH), corticotropin-releasing hormone receptor 1 (CRHR1), neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) mRNA levels in hypothalamus tissues and glucocorticoid receptor mRNA levels in the amygdala.Conclusion: In the microbiota-gut-brain axis, Mrgprb2 was involved in regulating the intestinal microbiota composition, intestinal barrier and oxidative stress levels, and was related to stress regulation, which might help to explain the pathogenesis of UC.Keywords: ulcerative colitis, mast cells, Mrgprb2, microbiota-gut-brain axis

Fu-zhen Yuan,1 Wei Shui,2 Yan-li Xing,2 Yuan-yuan Niu,2 Xin Zhang,2 Chang-ran Zhang2 1Department of General Practice Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of General Medicine, The Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Chang-ran Zhang, Department of General Medicine, The Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, No. 183, Huangpu East Road, Huangpu District, Guangzhou, People’s Republic of China, Tel +86 13711409903, Email zhcr2303@sina.comPurpose: Previous studies have shown that the red cell index (RCI) can be considered as a simple and useful method to evaluate respiratory function. However, at present its association with adverse hospitalization outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not fully understood. Our study aimed to examine the relationship between adverse hospitalization outcomes and RCI among AECOPD patients.Patients and Methods: We performed a retrospective analysis of consecutive patients from January 2015 to October 2021. In this study, RCI was the independent variable, measured at baseline, and adverse hospitalization outcome was the dependent variable. According to the RCI median (RCI=2.221), we divided 377 patients into two roughly equal groups (188 and 189, respectively). Next, the association between RCI and adverse hospitalization outcomes was explored using multivariable logistic regression models. To identify any non-linear relationship, a generalized additive model (GAM) was employed.Results: With a total of 377 patients with AECOPD, we divided them into two roughly equal groups to compare the clinical factors and RCI levels. The patients in the higher RCI group showed poorer outcome incidence (18 [9.57%] vs 31 [16.40%]; p = 0.049). After accounting for potential confounders, the results showed that RCI was positively associated with adverse hospitalization outcomes (odds ratio [OR] = 1.15, 95% CI: 1.01– 1.32). In addition, a non-linear relationship was detected between RCI and adverse hospitalization outcomes, which had an inflection point of 3.2. There were odds ratios and confidence intervals of 0.8 (0.7– 1.0) and 1.3 (1.2– 1.4) on the left and right sides of the inflection point, respectively.Conclusion: The RCI and adverse hospitalization outcomes exhibited a non-linear relationship in the AECOPD patients. RCI is strongly positively correlated with adverse hospitalization outcomes when it was greater than 3.2.Keywords: AECOPD, RCI, worse hospitalization outcomes, non-linearity

Pengfei Liu,1,&ast; Quanhui Chen,1,&ast; Fang Yuan,2 Qingru Zhang,1 Xiaoying Zhang,1 Chan Xue,1 Yuqing Wei,1 Yakun Wang,1 Hanqiao Wang1,2 1Department of Sleep Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Physiology, Hebei Key Laboratory of Neurophysiology, Shijiazhuang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hanqiao Wang, Department of Sleep Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, People’s Republic of China, Tel +86 18533112218, Email wanghanqiao99@126.comPurpose: Mixed events in obstructive sleep apnea (OSA) patients (mixed-OSA) indicate respiratory regulation instability and are essential for OSA pathogenesis and prognosis. It also shows a decreased compliance with continuous positive airway pressure (CPAP). Using predictors to identify mixed-OSA has significant clinical guidance for OSA precise diagnosis and treatment. This study aimed to establish a simple and accessible method for rapid screening of mixed-OSA, thus promoting OSA precise diagnosis.Patients and Methods: A total of 907 patients with suspected OSA were screened, of which 513 OSA patients, including 344 with pure-OSA and 169 with mixed-OSA, were finally included in the study. The clinical characteristics and polysomnography (PSG) parameters of the two OSA groups were compared. Multivariate logistic regression analysis was used to investigate the factors affecting the morbidity of mixed-OSA. The receiver operating characteristic (ROC) curve was used to explore if some convenient PSG parameters can be used to predict mixed-OSA.Results: About 33% of OSA patients were identified as mixed-OSA. Multivariate logistic regression analysis showed that apnea hypopnea index (AHI) and lowest oxygen saturation (LSO2) were independently associated with mixed-OSA after adjusting for age, sex, body mass index (BMI), smoking, drinking, hypertension, and Epworth Sleepiness Score (ESS) (AHI: OR=1.046, 95% CI 1.032– 1.060, P < 0.001; LSO2: OR=0.958, 95% CI 0.936– 0.981, P < 0.001). ROC curve analysis showed that AHI > 47 or LSO2 < 77% indicated mixed-OSA. The sensitivity and specificity of AHI> 47 was 0.952 and 0.652, respectively, and 0.822 and 0.675 for LSO2 < 77%, respectively.Conclusion: Our research found that AHI > 47 or LSO2 < 77% are independently associated with mixed-OSA and can be used to quickly identify the occurrence of mixed-OSA. Therefore, this study can help detect mixed-OSA and precise individual diagnosis of OSA patients.Keywords: mixed events, apnea hypopnea index, lowest saturation, precise individual diagnosis

Meiju Zhou, Fang Yuan Department of Rheumatology and Immunology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Fang YuanDepartment of Rheumatology and Immunology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 1229 Gudun Road, Hangzhou, Zhejiang Province, 310030, People’s Republic of ChinaEmail yuanfany@126.comObjective: To determine the prevalence of hypocomplementemia in primary Sjogren’s syndrome (pSS) patients and compare the clinical characteristics of patients with and without hypocomplementemia.Methods: A retrospective study was conducted in 120 treatment-naive Chinese patients that met the 2012 American College of Rheumatology Classification Criteria for pSS and were followed up for 3 to 24 months. Based on the complement results, patients were divided into four groups: only low C3, only low C4, both low C3 and C4 (double low), normal group. The data on patient demographics, clinical manifestations, laboratory results, disease activity and pharmacologic therapy were collected and compared among the four groups.Results: The prevalence of only low C3, only low C4, both low C3 and C4 in pSS patients was 21.7%, 16.7%, and 10%, respectively. The mean age of the four groups was significantly different. Unlike rampant caries and parotitis, the prevalence of dry eyes and dry mouth differed among the four groups. The proportion of patients with anemia, leukocytopenia, lymphadenopathy, hematological involvement and fatigue was significantly higher in the double low group and lower in the normal complement group. The proportion of patients with increased serum IgG was higher in the only low C4 group than in the other groups. Logistic regression revealed that hypocomplementemia was an independent risk factor for lymphadenopathy and leukopenia. The double low group had a significant history of exposure to glucocorticoids and cyclophosphamide, compared with other groups.Conclusion: Our study found that the clinical characteristics of pSS patients with hypocomplementemia differed from those without hypocomplementemia. Hypocomplementemia in pSS was associated with hematological involvement, hyper-IgG, lymphadenopathy, and fatigue, contributing to more significant exposure to glucocorticoid and cyclophosphamide.Keywords: primary Sjogren’s syndrome, hypocomplementemia, complement C3, complement C4

He Jiang, Feifei Yuan, Zhiying Zhao, Tongchun Xue, Ningling Ge, Zhenggang Ren, Lan Zhang Department of Hepatic Oncology, Zhongshan Hospital, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Lan ZhangDepartment of Hepatic Oncology, Zhongshan Hospital, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel +86-021-64041990Fax +86 021-64038472Email zhang.lan@zs-hospital.sh.cnPurpose: Ribosomal protein metallopanstimulin-1 (MPS-1) is implicated in tumorigenesis. However, to date, the underlying role of MPS-1 in the generation, progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. This study aims to investigate the expression of MPS-1 in HCC and its significance for the prognosis of HCC.Methods: The Oncomine and GEPIA databases were used to analyze the expression pattern of MPS-1 in HCC. Immunohistochemical staining was performed on tissue microarrays containing 169 HCC tissue samples to examine the expression of MPS-1. In addition, univariate and multivariate Cox regression analyses and Kaplan–Meier analysis were used to verify the correlation between clinicopathological factors in HCC patients and its clinical prognostic significance.Results: MPS-1 was more highly expressed in HCC than in normal tissues, and MPS-1 expression was correlated with serum AFP levels (P = 0.003), liver cirrhosis (P = 0.024), tumor embolus (P = 0.009) and tumor recurrence (P < 0.003). MPS-1 was an independent prognostic factor for the overall survival of HCC (HR, 1.92; 95% CI, 1.01– 3.68), and a higher expression of MPS-1 predicted poorer survival. Furthermore, high expression of MPS-1 indicated a poor prognosis in patients with AFP positivity, cirrhosis or HBsAg positivity.Conclusion: These findings demonstrate that MPS-1 is highly expressed in HCC and serves as an independent prognostic marker, highlighting the potential role of MPS-1 as a novel biomarker and therapeutic target for HCC.Keywords: hepatocellular carcinoma, ribosomal protein, MPS-1, biomarker, prognosis

Fuqiang Liu,1– 4 Feng Han,4,5 Xiaoli Liu,4,5 Lina Yang,4,5 Caixia Jiang,4,5 Chen Cui,1– 4 Fang Yuan,1– 4 Xin Zhang,1– 4 Lei Gong,1– 4 Xinguo Hou,1– 4 Yuan Liu,1– 4 Li Chen1– 4 1Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 3Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, 250012, People’s Republic of China; 4Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, Shandong, 250012, People’s Republic of China; 5Department of Endocrinology, Zhangqiu District People’s Hospital, Jinan, 250200, People’s Republic of ChinaCorrespondence: Yuan Liu; Li Chen Email liuyuan198735@163.com; chenli3@medmail.com.cnBackground: To investigate the correlation between serum interleukin-17A (IL-17A) levels and diabetic retinopathy (DR) in elderly individuals with type 2 diabetes mellitus (T2DM).Methods: The study included 194 elderly patients (94 males and 100 females) with T2DM. Digital retinal photography as well as fundus fluorescein angiography was employed to distinguish between nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). In addition, multiple logistic regression analysis was conducted to determine the correlation between serum IL-17A levels and DR status.Results: The average age of the study cohort was 69.14 ± 6.33 years, of which 52.08% were male. The study participants with the highest IL-17A (Q4) levels had higher TC, DBP, and low-density lipoprotein cholesterol (LDL-C) values than those the other groups. Analysis using unadjusted and adjusted linear regression revealed that the effect size of 1.09 for DR in the unadjusted model indicates that IL-17A is associated with an increase of 1.09 in DR (mmol/L) (β 1.09, 95% confidence interval (CI) 1.03, 1.16). Using the minimum-adjusted model (the model 2), as IL-17A increased, DR was higher by 1.11 (β 1.11, 95% CI 1.04, 1.18). With the fully adjusted model (the model 3), for each additional IL-17A increase, DR was higher by 1.15 (β 1.15, 95% CI 1.06, 1.24).Conclusion: Serum IL-17A levels are apparently positively correlated to DR in Chinese elderly individuals with T2DM.Keywords: interleukin-17A, diabetic retinopathy, type 2 diabetes mellitus

Meng Miao,1 Fang Yuan,2 Xiaotian Ma,3 Haiming Yang,1 Xiang Gao,1 Zhengyu Zhu,4 Jianzhong Bi4 1Department of Neurology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, People’s Republic of China; 2Department of Health Care, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, People’s Republic of China; 3Department of Medicine Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, People’s Republic of China; 4Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People’s Republic of ChinaCorrespondence: Zhengyu Zhu; Jianzhong BiDepartment of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People’s Republic of ChinaTel +8617660083488; +8615153178111Email zhuzhengyu_1@hotmail.com; bjz@sdu.edu.cnBackground: Early cognitive impairment after transient ischemic stroke (TIA)/mild ischemic stroke (MIS) is common but easily overlooked. It has been demonstrated that DNA methylation plays a significant role in cognitive impairment and ischemic stroke. Furthermore, it has been reported that the RIN3 gene influences transportation of the amyloid β-protein. However, to our knowledge, there has been no research related to correlations between RIN3 methylation and early-onset cognitive impairment after TIA/MIS. Therefore, this study aimed to investigate this relationship in TIA/MIS patients.Methods: This study include 28 control subjects and 84 patients with TIA/MIS who were evaluated within 7 days of TIA/MIS onset using four single-domain cognitive scales. In addition, DNA methylation of whole blood was tested. RIN3 methylation was compared between TIA/MIS and control groups and between TIA/MIS patients with early cognitive impairment and those without early cognitive impairment. Clinical variables and RIN3 methylation sites with statistical differences were then used to construct a predictive model.Results: Hypomethylation of the RIN3 gene was observed in the whole blood of TIA/MIS patients relative to healthy controls. Furthermore, patients with early cognitive impairment after TIA/MIS had hypomethylation of RIN3 relative to those without early cognitive impairment.Conclusion: RIN3 methylation is strongly associated with TIA/MIS and TIA/MIS with early cognitive impairment. It is possible to influence the disease process by methylation via appropriate lifestyle and clinical interventions, and methylation of RIN3 gene sites may predict the occurrence of TIA/MIS with early cognitive impairment.Keywords: amyloid &Bgr;-protein, cognitive impairment, hypomethylation, ischemic stroke, transportation

Shengyong Zhai,1,* Xiaojing Sun,2,* Longfeng Du,1 Kai Chen,1 Shanshan Zhang,2 Yiran Shi,1 Fei Yuan1 1Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China; 2School of Management and Information, Shandong Transport Vocational College, Weifang City, Shandong Province, 261041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fei YuanDepartment of Oncology Surgery, Weifang People’s Hospital, Weifang Medical College, NO.181, Guangwen Street, Kuiwen District, Weifang City, Shandong Province, 261041, People’s Republic of ChinaTel +86 13696360906Fax +86-536-8675792Email zsy-1985122@163.comPurpose: This study is a retrospective analysis of exploring the efficiency of surgical management on patients with synchronous colorectal liver metastasis (SCLM).Patients and Methods: Nine hundred fifty-three consecutive patients with SCLM from Weifang People’s Hospital of Shandong Province between January 2006 and December 2015 were reviewed. The values of different factors were analyzed, such as different surgical indications of liver metastases, simultaneous or staged resection of primary colorectal cancer and liver metastases, and primary tumor resection (PTR) of asymptomatic patients with unresectable liver metastases.Results: Median survival time (47.3 months) and 5-year survival rate (31%) for patients with resected liver metastases were significantly superior to that of with nonoperative treatment (17.2 months, 4%, P< 0.001); enlarging the standard of liver metastases resection can improve the resection rates (31.0% vs 13.6%, P< 0.001); for patients with resectable liver metastases, the in-hospital cost for simultaneous resection group was lower than that in the staged resection group (36,698 vs 45,134 RMB, P< 0.001); for patients of the asymptomatic primary tumor with unresectable liver metastases, PTR was associated with improved median survival (18.0 vs 15.0 months, P=0.006).Conclusion: For patients with SCLM, liver resection is considered the best treatment; expanding indications of liver resection can improve the resection rates. Simultaneous resection of the primary tumor and liver metastases were indicated in patients with resectable SCLM; PTR was recommended for asymptomatic patients with unresectable hepatic metastases.Keywords: surgical treatment, synchronous colorectal liver metastases, survival analysis, primary tumor resection

Lei Sheng,1,* Wei Cao,2,* Pingping Lin,3 Weili Chen,1 Hongrong Xu,1 Chunjiu Zhong,4 Fei Yuan,1 Hanjing Chen,1 Hui Li,1 Chao Liu,1 Mengjie Yang,1 Xuening Li1 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People’s Republic of China; 3Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Shandong, 266071, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuening LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, 200032, People’s Republic of ChinaTel +86 21 3158 7860Fax +86 21 6443 7963Email li.xuening@zs-hospital.sh.cnPurpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials.Methods: Healthy subjects were sequentially enrolled into one of five SAD (150– 1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4– 9, followed by a single morning dose on day 10.Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.Keywords: Alzheimer’s disease, benfotiamine, thiamine, thiamine diphosphate, pharmacokinetics

HaiXia Ren,1,* FangTing Yuan,1,2,* Wei Tan,1 YiJuan Ding,1 Ping An,1 HeSheng Luo1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China; 2Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: HeSheng Luo Email LHSxhnk@163.comBackground and Aim: EVO is a natural alkaloid that reportedly has potential value in regulating gastrointestinal motility, but this conclusion remains controversial, and the molecular mechanism is unclear. In this study, we aimed to explore the effect of short-chain fatty acids on rat colonic hypermotility induced by water avoidance stress and the underlying mechanism.Methods: We constructed a hypermotile rat model by chronic water avoidance stress, and Western blot was used to detect the protein level of nNOS in colon tissue. The organ bath and multichannel physiological signal acquisition systems were used to examine the spontaneous contractions of smooth muscle strips. The whole‐cell patch‐clamp technique was used to investigate L‐type voltage‐dependent calcium and BKCa channel currents in colonic smooth muscle cells.Results: EVO inhibited the spontaneous contractions of colonic smooth muscle strips in a dose-dependent manner. Moreover, EVO decreased the fecal output induced by chronic water avoidance stress. TTX did not block the inhibitory effect of EVO on spontaneous colon contractions, while L-NNA, a selective nNOS synthase inhibitor, did partially abolish this inhibitory effect. The protein expression of nNOS in the colon tissues of rats administered EVO was significantly increased compared to that in control rats. EVO reversibly inhibited the L-type calcium channel current without changing the steady-state activation or inactivation in colonic smooth muscle cells. EVO significantly inhibited the BKCa current but did not change the shape of the I‐V curves.Conclusion: EVO inhibits gastrointestinal motility by inhibiting L-type calcium and BKCa channels in colonic smooth muscle cells and indirectly interacting with nNOS.Keywords: evodiamine, gastrointestinal motility, nitric oxide, L‐type voltage‐dependent calcium channels, BKCa channel

FangTing Yuan,1,* Wei Tan,1,* HaiXia Ren,1 Lin Yan,1 Ying Wang,1,2 HeSheng Luo1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China; 2Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: HeSheng Luo Email LHSxhnk@163.comPurpose: Short-chain fatty acids (SCFAs) have been reported to play an important role in regulating gastrointestinal motility. The aim of this study is to investigate the possible role of SCFAs in water avoidance stress-induced colonic hypermotility.Methods: A rat IBS model was established by water avoidance stress (WAS). Intestinal motility was assessed by fecal pellets expulsion. The fecal SCFA level was detected using gas chromatography-mass spectrometry (GC-MS). Western blotting was performed to assess the expression of SCFAs receptors. To determine the role of SCFAs in gut dysmotility, the rats of the WAS+SCFAS and SCFAs group were administrated with oral SCFAs. The colonic contractile activity was recorded with a RM6240 multichannel physiological signal system.Key Results: WAS induced gastrointestinal hypermotility and increased defecation in rats. After repeated stress, the fecal SCFAs decreased significantly and the proportion of acetic acid, propionic acid, and butyric acid had changed from Control 2.6:1:1.5 to WAS 2:1:2.3. Protein levels of SCFAs receptors in the colon were promoted by WAS. In addition, oral SCFAs partly inhibited the colonic spontaneous motility both for SCFAs and WAS+SCFAs group in vivo. Meanwhile, we observed acetate had no effect on the contractile amplitudes of muscle strips, but it could slow down contractile frequency in a dose-dependent manner (1– 100 mM). Propionate significantly inhibited the motor activity of colonic strips (1– 30 mM). Butyrate inhibited the contractile amplitude of CM strips in a dose-dependent manner (1– 30 mM), but for LM, it exhibited a stimulating effect at low concentrations of butyrate 1 mM– 10 mM and was suppressed at high concentrations of 30 mM butyrate. Total SCFAs increased the contractile amplitude at low concentration (5– 50 mM) and inhibited it at high concentration (50– 150 mM). All SCFAs slowed down the frequency of colonic activity.Conclusion: The stress-induced colonic hypermotility by WAS could be ameliorated through oral SCFA supplementation. SCFAs may have potential clinical therapeutic use in modulating gut motility.Keywords: gastrointestinal motility, SCFAs, chronic stress, IBS

Zhan Gu,1,* Yan Bi,2,* Fan Yuan,2,* Ruirui Wang,1 Dong Li,3 Jianying Wang,1 Xiaojuan Hu,1 Guang He,2 Lei Zhang,1 Bao-cheng Liu1 1Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 2Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China; 3Zhangjiang Community Health Service Center of Pudong New District, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bao-cheng Liu Email baochliu@shutcm.edu.cnBackground: As fat and obesity play a vital role in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD), this study aims to investigate the association between the fat mass and obesity-associated gene (FTO) and MAFLD.Methods: Six SNPs (rs6499640, rs1421085, rs8050136, rs3751812, rs9939609 and rs9930506) within FTO were genotyped for 741 MAFLD patients (median age, 69.98; interquartile range, 66.55– 75.93) and 825 healthy people (median age, 69.94; interquartile range, 66.39– 75.64). Allele and genotype frequencies, pairwise linkage disequilibrium (LD) and haplotype analysis were calculated.Results: BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, alanine transaminase, glutamyl transpeptidase and the prevalence of diabetes were found to be higher in the MAFLD individuals comparing to the control ones (P < 0.05). For rs1421085, the C allele frequency was remarkably higher in MAFLD after Bonferroni correction (OR [95% CI] =1.353 [1.095– 1.671]; Pcorr =0.030), and a significantly different genotype result was observed in log-additive model (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024). For rs8050136, significantly increased A allele frequency was observed in MAFLD (OR [95% CI] =1.371 [1.109– 1.695]; Pcorr =0.024), and A-allele carriers showed increased MAFLD risk (OR [95% CI] =1.393 [1.103– 1.759]; Pcorr =0.030). For rs3751812, the T allele frequency was remarkably higher in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024), and T-allele carriers demonstrated high MAFLD risk (OR [95% CI] =1.392 [1.103– 1.756]; Pcorr =0.030). For rs9939609, A allele frequency was also remarkably high in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; Pcorr =0.024), and A-allele carriers were more susceptible to MAFLD (OR [95% CI] =[1.103– 1.756]; Pcorr =0.030). A strong LD was found among rs1421085, rs8050136, rs3751812 and rs9939609 (r2 > 0.8), and individuals with C-A-T-A haplotype had an elevated MAFLD risk (P =0.005).Conclusion: The case-control study indicated that C variant of rs1421085, A variant of rs8050136, T variant of rs3751812 and A variant of rs9939609 are associated with elevated MAFLD risk in the older Chinese Han population.Keywords: MAFLD, FTO, polymorphism, genetic association, susceptibility

Jian Guo,1,2,* Fei Yuan,3,* Yixin Yang,1 Yunze Li,1 Fangping Bao,2 Xuejiao Guo,1 Zhiying Feng1 1Department of Pain Medicine, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310003, People’s Republic of China; 2Department of Anesthesiology, The Fourth Affiliated Hospital, Zhejiang University, School of Medicine, Yiwu, Zhejiang 322000, People’s Republic of China; 3Department of Anesthesiology, Shaoxing Second Hospital, Shaoxing, Zhejiang 312000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiying Feng Email fzy1972@zju.edu.cnObjective: To explore the effect of genetic polymorphisms of cytokines on the dosage of sufentanil for patient-controlled intravenous analgesia (PCIA) after radical lung cancer surgery.Methods: A total of 100 patients, aged 18 years and above, with ASA grade Ⅰ-Ⅱ and body mass index (BMI) 18.5 to 30, and who were scheduled for radical lung cancer surgery under total intravenous anaesthesia with PCIA of sufentanil from September 2015 to March 2016, were selected. DNA was collected from peripheral blood samples before surgery, and the iMLDRTM multiple single-nucleotide polymorphism typing kit was used to detect 16 related single-nucleotide polymorphism (SNP) sites of interleukin-1A (IL-1A), interleukin-1β (IL-1β), interleukin-1RN (IL-1RN), interleukin-6 (IL-6), C-X-C motif chemokine ligand 8 (CXCL8), interleukin-10 (IL-10), tumour necrosis factor (TNF), nuclear factor kappa-B1 (NFκB1), REL (REL proto-oncogene, NF-kB subunit), and nuclear factor kappa-B inhibitor alpha (NFκBIA). The general characteristics of patients, surgery and anaesthesia data, postoperative resting VAS pain scores, postoperative opioid dosages of sufentanil for PCIA and opioid-related adverse events were recorded. The effects of the examined genetic polymorphisms of the cytokines on the dosage of sufentanil were analysed.Results: Eight of 100 patients withdrew for various reasons, and, eventually, 92 patients were included. The patients’ resting visual analogue scale (VAS) scores at 24 h, 48 h, and 72 h after surgery were 2.3 ± 1.2, 2.0 ± 0.9, and 1.9 ± 1.0, respectively. The total amounts of sufentanil used were 34.7 ± 10.5 μg, 65.2 ± 13.7 μg, and 94.7 ± 11.6 μg, respectively. We found that the TT genotype of NFκBIA rs696 had higher PCIA sufentanil dosages than the CC genotype and the CT genotype at 48– 72 h postoperation (p=0.023, p=0.025, respectively).Conclusion: The genetic polymorphisms of the cytokine NFκBIA rs696 might affect the dosage of sufentanil for PCIA after radical lung cancer surgery. The specific mechanism needs further study.Keywords: genetic polymorphisms, single-nucleotide polymorphism, SNP, patient-controlled intravenous analgesia, PCIA, nuclear factor kappa-B inhibitor alpha, NFκBIA

Objective: Stapes surgery is technically challenging, yet its methodology is not standardized. We aim to elucidate preferences in stapes surgery among American Otological Society (AOS) otologists and determine if any common practice patterns exist. Study design: Cross-sectional study via emailed questionnaire. Setting: Surgery centers. Subjects and methods: Members of the AOS were an emailed a survey to quantify variables including surgical volume, anesthetic preference, laser use, type of procedure, footplate sealing technique, antibiotic use, and trainee participation. Results: Most otologists (71%) performed 2 to 5 stapes surgeries per month under general anesthesia (69%) with stapedotomy (71%) as the preferred procedure. Most (56%) used the rosette method of laser stapedotomy with manual pick debris removal for footplate fenestration. Either the handheld potassium titanyl phosphate (KTP) laser (40%) or handheld carbon dioxide (CO2) laser (33%) was used. The heat-activated memory hook (51%) was the preferred prosthesis. Footplate sealing method was variable, as was antibiotic use among respondents. Trainee participation was limited, as 42% of otologists allowed residents to place the prosthesis, and fewer allowed residents to crimp the prosthesis, and laser or drill the footplate. Surgeons with higher surgical volume (≥ 6 surgeries per month) demonstrated the following statistically significant correlations: footplate fenestration with laser in a rosette pattern and pick for debris removal (rs = −0.365, P = 0.014) and trainee participation with fellows only (rs = 0.341, P = 0.022). Conclusions: Trends in various surgical decisions showed a lack of consensus in all aspects of stapes surgery.

Meng-Jie Yang, Hong-Rong Xu, Hui Li, Wei-Li Chen, Fei Yuan, Xue-Ning Li Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 31587861Fax +86 21 64437963Email li.xuening@zs-hospital.sh.cnPurpose: Aprepitant is used to prevent nausea and vomiting associated with moderately and highly emetogenic chemotherapy. In this open-label, 2-period study, the safety, tolerability, and pharmacokinetics (PK) of aprepitant (EMEND®) were evaluated in healthy Chinese and Caucasian subjects.Patients and Methods: Twelve Chinese and 12 Caucasian subjects were to receive a 125 mg single-dose of aprepitant during period 1; subsequently, after 15 days washout, only Chinese subjects were to receive the 3-day regimen in period 2. In each period, serial blood samples were collected and analyzed by a validated liquid chromatographic and mass spectrometric method to characterize aprepitant PK across both groups.Results: In both Chinese and Caucasian subjects, there were no serious adverse events. AUC0-∞, Cmax, Tmax, and t1/2 were largely comparable between the two ethnicities. Comparing the result of period 1 in Chinese and Caucasian subjects, the geometric least-squares mean maximum plasma concentrations (Cmax) were 1482 ng/mL and 1435 ng/mL, and the area under the concentration–time curve (AUC0-∞) 34,035 hr·ng/mL and 34,188 hr·ng/mL. In period 2, the geometric mean AUC0– 24 on Day 1 and Day 3 were 19,446 hr·ng/mL and 27,843 hr·ng/mL, and the geometric mean Cmax on Day 1 and Day 3 were 1423 ng/mL and 1757 ng/mL, respectively.Conclusion: Aprepitant is generally safe and well tolerated in healthy Chinese and Caucasian subjects. Aprepitant PK is comparable between Chinese and Caucasian subjects following single-dose administration. The PK following a clinical 3-day regimen on healthy Chinese subjects has been characterized.Keywords: pharmacokinetics, aprepitant, chemotherapy-induced nausea and vomiting, ethnicity, healthy subjects

Chao Liu,1 Hong Lu,2 Fei Yuan,1 Wei-Li Chen,1 Hong-Rong Xu,1 Hui Li,1 Cheng-Pang Hsu,3 Ogo Egbuna,3 Jihua Wu,2 Clapton Dias,3 Bassam Abosaleem,3 Jitesh Rana,3 Maria Laura Monsalvo,3 Xue-Ning Li,1 Zhigang Yu4 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Clinical Pharmacology and Early Development, Amgen China R & D Center, Shanghai, People’s Republic of China; 3Research & Development, Amgen Inc., Thousand Oaks, CA, USA; 4Clinical Development, Amgen China R & D Center, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 6026 7666Email li.xuening@zs-hospital.sh.cnZhigang YuResearch & Development, Amgen Inc., Thousand Oaks, CA 91320, USATel +1 805 447-9384Email zhigangy@amgen.comPurpose: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects.Subjects and methods: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration–time curve from time 0 to time of last quantifiable concentration (AUClast).Results: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 μg/mL and 67.6 (15.2) μg/mL, respectively, and mean (SD) AUClast was 166 (55) day·μg/mL and 1110 (274) day·μg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo).Conclusion: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.Keywords: cardiovascular disease, homozygous familial hypercholesterolemia, PCSK9 inhibitors, monoclonal antibodies, ethnic sensitivity

Fang Yuan,1,* Jinliang Wang,1,* Ruixin Li,1,* Xiao Zhao,1 Yuxuan Zhang,2 Biao Liu,3 Yonghong Lei,4 Yi Hu1 1Department of Oncology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China; 2Princeton International School of Mathematics and Science, Princeton, NJ 08540, USA; 3Department of Biological Analysis, Explore (Beijing) Biotech Co, Ltd, Beijing 100091, People’s Republic of China; 4Department of Plastic Surgery, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghong LeiDepartment of Plastic Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, People’s Republic of ChinaTel +86 10 13161281016Email lyhhlx@126.comYi HuDepartment of Oncology, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, People’s Republic of ChinaTel +86 10 13911031186Email huyi0401@aliyun.comBackground: Yes-associated protein (YAP) is downstream of the Hippo signaling pathway, which regulates several cellular processes. P53 is a key transcriptional regulator that responds to a variety of cellular stresses and regulates key cellular processes such as DNA repair, cell-cycle progression, angiogenesis, and apoptosis. Overexpression of YAP antagonizes P53 activity and targets its expression. However, the mechanism that underlies the post-transcriptional crosstalk between P53 and YAP has not been well dissected.Methods: We performed an integrated analysis and found that SIRT1 is a key candidate that connects YAP and P53 by modulating their acetylation.Results: We found that YAP promotes P53 deacetylation, promotes cell survival by inhibiting P53-induced G0/G1 arrest and apoptosis in A549 cells. Conversely, P53 enhances YAP acetylation, and decreases A549 cell survival by strengthening YAP acetylation-induced G0/G1 arrest and apoptosis both in vitro and in vivo.Conclusion: Our results demonstrate that SIRT1 is responsible for YAP and P53 deacetylation of specific residues, and reveal for the first time, a new regulatory mechanism of P53 and YAP crosstalk by SIRT1-mediated deacetylation, which may be involved in lung tumorigenesis.Keywords: P53, YAP, SIRT1, crosstalk

Bo Shen,1 Aihua Qian,1 Wenji Lao,1 Weiguang Li,1 Xi Chen,1 Benyan Zhang,2 Huafeng Wang,2 Fei Yuan,2 Yunwei Sun11Department of Gastroenterology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China; 2Department of Pathology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of ChinaBackground: Many studies have shown that programmed cell death protein 1 (PD-1) and its ligand, PD-L1, are expressed in advanced gastric cancer. Furthermore, detection of these proteins is associated with infiltrating CD8+ T-cells, indicating that an adaptive immune resistance mechanism occurs in advanced gastric cancer. However, PD-L1 and PD-1 expression in gastric intraepithelial neoplasia and early-stage gastric cancer (EGC) has yet to be elucidated.Patients and methods: Fifty-four resections of low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and EGC were stained by immunohistochemistry for PD-1, PD-L1, and CD8. CD8+ T-cell densities both within tumors and in the tumor-stromal interface were analyzed. Flow cytometry (FACS) was used to analyze the PD-1 expression in tumor tissues and peripheral blood mononuclear cells. Furthermore, the relationship between Helicobacter pylori (Hp) infection and PD-1 and PD-L1 was also evaluated.Results: We demonstrated that PD-L1 expression was significantly increased in HGIN and EGC compared with LGIN, and both PD-1 and PD-L1 showed similar expression patterns, being mainly detected in infiltrating immune cells. FACS also showed that PD-1 was expressed on both CD4+ and CD8+ T-cells. However, no difference was found in CD8+ T-cell infiltration between LGIN and HGIN+EGC, and this was not not found to be associated with PD-L1 or PD-1 expression. However, Hp infection was significantly associated with expression of PD-L1 and PD-1.Conclusions: The PD-1/PD-L1 checkpoint is involved in intraepithelial neoplasia and EGC, but an adaptive immune resistance mechanism does not occur. Expression of PD-1/PD-L1 is also associated with Hp infection, and so Hp infection may be an important initiating factor.Clinical Trial Registration information: This study was approved by the Institutional Review Board of Ruijin Hospital and written informed consent was obtained from all patients.Keywords: PD-L1, PD-1, Helicobacter pylori, LGIN, HGIN

Qianqian Sun,1,2 Fan Yuan,1,2 Decheng Ren,1,2 Gaini Ma,1,2 Fengping Yang,1,3 Xi Wu,1,3 Lin He,1,3 Guang He1,21Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, P.R. China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Institute of Mental Health, Shanghai Jiao Tong University, Shanghai 200030, P.R. China; 3Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. ChinaPurpose: Venlafaxine is one of the commonly prescribed antidepressants for major depressive disorder (MDD). Accumulated evidence revealed the involvement of glutamatergic system in the pathophysiology of MDD and antidepressant treatment. Methods: We recruited 193 MDD patients who have been taking venlafaxine for 6 weeks, and investigated whether single nucleotide polymorphisms (SNPs) in GSK-3β and BDNF were associated with treatment response. Nine SNPs were selected randomly depending on association studies. Efficacy of treatment was determined by 17-item Hamilton Rating Scale. Allele and genotype frequencies were compared between responders and nonresponders.Results: After adjusting the false discovery rate, no significant difference was observed between response and nonresponse groups in allele or genotype distributions after venlafaxine treatment for 6 weeks.Conclusion: Our results indicated that genetic variants in the GSK-3β and BDNF may not be associated with treatment response in MDD patients treated with venlafaxine.Keywords: association, GSK-3β, BDNF, major depressive disorder, venlafaxine

Xiang Fang,1,* Zeping Yu,1,* Yan Xiong,1 Fang Yuan,2 Hongyuan Liu,3 Fan Wu,4 Wenli Zhang,1 Yi Luo,1 Liuhong Song,5 Chongqi Tu,1 Hong Duan1 1Department of Orthopedics, West China School of Medicine/West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Radiology, West China School of Medicine/West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Orthopedics, Sichuan Provincial Fifth People’s Hospital, Chengdu, Sichuan, People’s Republic of China; 4Department of Orthopedics, Fourth People’s Hospital of ZiGong, Sichuan, People’s Republic of China; 5Department of Orthopedics, People’s Hospital of Pengzhou, Sichuan, People’s Republic of China *These authors contributed equally to this work Purpose: We sought to assess the early clinical outcome of 3D-multimodality image (3DMMI)-based virtual surgical planning for resection and reconstruction of malignant giant pelvic tumors.Patients and methods: In this retrospective case-control study, surgery was planned and performed with 3DMMI-based patient-specific instruments (PSI) in 13 patients with giant pelvic malignancy and without 3DMMI-based PSI in the other 13 patients. In the 3DMMI group, 3DMMI was utilized, taking advantages of computed tomography (CT), contrast-enhanced CT angiography (CTA), contrast-enhanced magnetic resonance imaging (MRI), contrast-enhanced magnetic resonance neurography (MRN), which could reveal the whole tumor and all adjacent vital structures. Based on these 3DMMI, virtual surgical planning was conducted and the corresponding PSI was then designed. The median follow-up was 8 (3–24) months. The median age at operation was 37.5 (17–64) years. The mean tumor size in maximum diameter was 13.3 cm. Surgical margins, intraoperative and postoperative complications, duration of surgery, and intra-operative blood loss were analyzed.Results: In the non-3DMMI group, the margins were wide in six patients (6/13), marginal in four (4/13), wide-contaminated in two (2/13), and intralesional in one (1/13). In the 3DMMI group, the margins were wide in 10 patients (10/13), marginal in three (3/13), and there were no wide-contaminated or intralesional margins. The 3DMMI group achieved shorter duration of surgery (P=0.354) and lower intraoperative blood loss (P=0.044) than the non-3DMMI group.Conclusion: The 3DMMI-based technique is advantageous to obtain negative surgical margin and decrease surgical complications related to critical structures injury for malignant giant pelvic tumor. Keywords: surgical planning, 3D-multimodality image, pelvic tumor, patient-specific instruments, surgical margin

Chenfei Zhou,1,* Xiaojing Feng,2,* Fei Yuan,3 Jun Ji,4 Min Shi,1 Yingyan Yu,4 Zhenggang Zhu,1,4 Jun Zhang1 1Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2–) gastric cancer patients.Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2– samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses.Results: The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2– samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P=0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P=0.002) in HER2+ samples were higher than those in HER2– samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2– samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2– samples.Conclusion: Differences in genomic landscape between HER2+ and HER2– gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2– gastric cancer. Keywords: gastric cancer, HER2, whole-genome sequencing, gene mutation, gene amplification

Anan Yu,1,* Jieqiong Lv,1,* Fang Yuan,1 Zihua Xia,1 Kaiyan Fan,1 Gang Chen,1,2 Jialin Ren,1 Cuicui Lin,1 Shijie Wei,1,2 Fan Yang1,2 1Department of Pharmaceutics, 2Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China *These authors contributed equally to this work Purpose: This study aimed to develop a novel methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelle drug delivery system to improve lamotrigine (LTG) distribution in the hippocampus.Methods: LTG-loaded mPEG-PLA/TPGS mixed micelles and LTG-loaded mPEG-PLA micelles were formulated, and their characteristics, particle size, surface morphology, and release behavior in vitro were researched. Then, a microdialysis sampling technique coupled with two validated chromatographic systems was developed for the continuous measurement of the protein-unbound form of LTG in the rat plasma and hippocampus after administering two kinds of micelles and LTG solution intranasally. Results: The drug loading and mean size of LTG-loaded micelles and LTG-loaded mixed micelles prepared with optimal formulation were 36.44%±0.14%, 39.28%±0.26%, 122.9, and 183.5 nm, respectively, with a core–shell structure. The cumulative release rate in vivo of LTG-loaded mixed micelles was 84.21% at 24 hours and showed more sustained release while that of LTG-loaded micelles was 80.61% at 6 hours. The Tmax and area under concentration-time curve from zero to time of last quantifiable concentration of LTG solution, LTG-loaded micelles, and LTG-loaded mixed micelles were 55, 35, and 15 minutes and about 5,384, 16,500, and 25,245 (min·µg)/L in the hippocampus, respectively.Conclusion: The results revealed that LTG-loaded mPEG-PLA/TPGS mixed micelles enhanced the absorption of LTG at the nasal cavity and reduced the efflux of LTG in the brain, suggesting that the function of TPGS inhibited P-glycoprotein and LTG-loaded mPEG-PLA/TPGS mixed micelles had the potential to overcome refractory epilepsy. Keywords: epilepsy, intranasal administration, lamotrigine, P-glycoprotein, blood brain barrier, TPGS

Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK) activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t) and maximum plasma concentration (Cmax). Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively). Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (%) and mean glucose area under effect curve 0–4 hours change from baseline (%) (P

Xian-ye Tang,1,2,* Wei Zheng,1,2,* Min Ding,3 Kai-jin Guo,1,2 Feng Yuan,1 Hu Feng,1 Bin Deng,1 Wei Sun,1 Yang Hou,4 Lu Gao5,6 1Department of Orthopedic, The First Clinical Medical College, Nanjing Medical University, Nanjing, 2Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, 3Department of Emergency Trauma Surgery, East Hospital Affiliated to Tongji University, 4Department of Orthopedic, Changzheng Hospital, Shanghai, 5College of Life Sciences, Northeast Agricultural University, Harbin, Heilongjiang, People’s Republic of China; 6Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA *These authors contributed equally to this work Abstract: Chondrosarcoma is the second most common type of primary bone malignancy in the United States after osteosarcoma. Surgical resections of these tumors are the only effective treatment to chondrosarcoma patients due to their resistance to conventional chemo- and radiotherapy. In this study, miR-125b was found to perform its tumor-suppressor function to inhibit glucose metabolism via the direct targeting of oncogene, ErbB2. We report miR-125b was downregulated in both chondrosarcoma patient samples and cell lines. The total 20 Asian chondrosarcoma patients showed significantly downregulated miR-125b expression compared with normal tissues. Meanwhile, miR-125 was downregulated in chondrosarcoma cells and doxorubicin resistant cells. Overexpression of miR-125 enhanced the sensitivity of both parental and doxorubicin resistant cells to doxorubicin through direct targeting on the ErbB2-mediated upregulation of glycolysis in chondrosarcoma cells. Moreover, restoration of the expression of ErbB2 and glucose metabolic enzymes in miR-125 pretransfected cells recovered the susceptibility to doxorubicin. Our study will provide a novel aspect on the overcoming chemoresistance in human chondrosarcoma cells and may help in the development of therapeutic strategies for the treatments of patients. Keywords: miR-125b, chondrosarcoma, doxorubicin, glucose metabolism, sensitization

In this paper, we briefly introduce the history of the Defense Advanced Research Projects Agency (DARPA) Grand Challenge programs with particular focus on the 2012 Robotics Challenge. As members of team DRC-HUBO, we propose different approaches for the Rough-Terrain task, such as enlarged foot pedals and a transformation into quadruped walking. We also introduce a new gait for humanoid robot locomotion to improve stability performance, called the Ski-Type gait. We analyze the stability performance of this gait and use the stability margin to choose between two candidate step sequences, Crawl-1 and Crawl-2. Next, we perform a force/torque analysis for the redundant closed-chain system in the Ski-Type gait, and determine the joint torques by minimizing the total energy consumption. Based on the stability and force/torque analysis, we design a cane length to support a feasible and stable Crawl-2 gait on the HUBO2 humanoid robot platform. Finally, we compare our experimental results with biped walking to validate the Ski-Type gait. We also present our team performance in the trials of the Robotics Challenge.

Leaf day respiration is one of the most fundamental plant physiological processes and plays a vital role in the plant carbon cycle. However, day respiration is inherently complex and difficult to measure. In this study, the Kok method and the Laisk method were used to measure leaf day respiration for the saplings of one evergreen conifer species (Pinus koraiensis) and two deciduous broadleaved species (Tilia amurensis and Fraxinus mandshurica) in a temperate forest. Results show that discrepancy between the corrected day respiration values estimated by the Kok and Laisk methods was only 4% for the three tree species. On average, day respiration was 55.9% and 52.6% lower compared to night respiration for the three tree species, as measured by the Kok and Laisk method, respectively. Day respiration of the evergreen conifer species estimated by the Kok method was 31.7% lower while that estimated by the Laisk method was 36.8% lower than that of the deciduous broadleaved species. Night respiration of the evergreen conifer trees was 40.7% lower than those of the deciduous broadleaved trees. Day respiration rate is positively correlated with night respiration rate. Notably, day respiration rate decreased with increased photosynthetic photon flux density, and even a small amount of light significantly inhibited leaf day respiration in all three species.

Jinbao Qin,1,* Chen Peng,2,* Binghui Zhao,2,* Kaichuang Ye,1 Fukang Yuan,1 Zhiyou Peng,1 Xinrui Yang,1 Lijia Huang,1 Mier Jiang,1 Qinghua Zhao,3 Guangyu Tang,2 Xinwu Lu1,4 1Department of Vascular Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai JiaoTong University, School of Medicine; 2Department of Radiology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, School of Medicine; 3Department of Orthopaedics, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University; 4Vascular Center of Shanghai JiaoTong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Macrophages are becoming increasingly significant in the progression of atherosclerosis (AS). Molecular imaging of macrophages may improve the detection and characterization of AS. In this study, dendrimer-entrapped gold nanoparticles (Au DENPs) with polyethylene glycol (PEG) and fluorescein isothiocyanate (FI) coatings were designed, tested, and applied as contrast agents for the enhanced computed tomography (CT) imaging of macrophages in atherosclerotic lesions. Cell counting kit-8 assay, fluorescence microscopy, silver staining, and transmission electron microscopy revealed that the FI-functionalized Au DENPs are noncytotoxic at high concentrations (3.0 µM) and can be efficiently taken up by murine macrophages in vitro. These nanoparticles were administered to apolipoprotein E knockout mice as AS models, which demonstrated that the macrophage burden in atherosclerotic areas can be tracked noninvasively and dynamically three-dimensionally in live animals using micro-CT. Our findings suggest that the designed PEGylated gold nanoparticles are promising biocompatible nanoprobes for the CT imaging of macrophages in atherosclerotic lesions and will provide new insights into the pathophysiology of AS and other concerned inflammatory diseases. Keywords: atherosclerosis, CT, in vivo imaging