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Qiying Zeng,1,&ast; Wenjun Xue,2,&ast; Zhicheng Wei,1 Hangdong Shen,1 Huajun Xu,1 Huaming Zhu,1 Jian Guan,1 Hongliang Yi,1 Yunhai Feng,2 Xinyi Li,1 Haibo Ye1 1Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Sleep Disordered Breathing, Otorhinolaryngology Institute of Shanghai Jiao Tong University, Shanghai, 200233, People’s Republic of China; 2Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Eighth People’s Hospital Affiliated to Jiangsu University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinyi Li; Haibo Ye, Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Sleep Disordered Breathing, Otorhinolaryngology Institute of Shanghai JiaoTong University, Shanghai, 200233, People’s Republic of China, Tel/Fax +86-2164834143, Email lixinyilixinyi123@163.com; yehaibo_2012@163.comBackground: Sleep-disordered breathing is more prevalent in individuals with allergic rhinitis (AR) than in those without AR. In addition to increased risk for sleep-disordered breathing, AR is associated with greater severity of obstructive sleep apnea (OSA) symptoms. The aim of this research study was to evaluate the association of multiple single nucleotide polymorphism (SNP) variations in AR with sleep- and breathing-related parameters in men with OSA.Methods: Men who had complained of snoring were consecutively enrolled in the Shanghai Sleep Health Study of Shanghai Sixth People’s Hospital from 2007 to 2018. After rigorous screening, 5322 men were included in the analysis. Anthropometric, fasting biochemical, and polysomnographic parameters, along with 27 AR-associated SNPs were analyzed. The associations between AR-related genetic polymorphisms and OSA were determined via linear, binary, and multinomial logistic regression analyses.Results: Rs12509403 had significantly positive associations with most sleep-breathing parameters. While the risk for OSA was increased by rs12509403, it was decreased by rs7717955 [odds ratio (OR) = 1.341, 95% confidence interval [CI] = 1.039– 1.732, P = 0.024; OR = 0.829, 95% CI = 0.715– 0.961, P = 0.013, respectively]. A graded increase in the risk of being in the highest quartile (Q4) vs the reference category (Q1) for sleep breathing indicators, especially REM-AHI and NREM-AHI, was identified by rs12509403 (OR = 1.496, 95% CI = 1.175– 1.904, P = 0.001; OR = 1.471, 95% CI = 1.151– 1.879, P < 0.001, respectively).Conclusion: The association of multiple AR SNPs with OSA-related hypoxia and sleep indices provides a genetic explanation for the higher AR susceptibility of OSA patients. Understanding the AR-related genetic underpinnings of OSA may lead to more personalized treatment approaches.Keywords: allergic rhinitis, obstructive sleep apnea, single nucleotide polymorphism, polysomnography

Mingjie Wang,1,&ast; Wenxiang Xue,2,&ast; Hanghang Yuan,2 Zhicheng Wang,2 Lei Yu1 1Department of Radiotherapy, Second Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, Jilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhicheng Wang; Lei Yu, Tel +86-431-85619443, Email zhicheng@jlu.edu.cn; yul0826@163.comAbstract: Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC’s survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.Keywords: nanoparticle, nano-drug delivery system, cancer-associated fibroblasts, pancreatic cancer, tumor microenvironment

Yuying Zhou,1,&ast; Wu Xue,2,&ast; Xinyu Meng,2,&ast; Adheesh Bhandari,2,3,&ast; Hanqian Zeng,4 Rajan KC,5 Suzita Hirachan,6 Erjie Xia2 1Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Surgery, Breast and Thyroid Unit, Primera Hospital, Kathmandu, Nepal; 4Department of Surgical Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, People’s Republic of China; 5Central Department of Zoology, Tribhuvan University, Kirtipur, Kathmandu, Nepal; 6Department of General Surgery, Breast and Thyroid Unit, Tribhuvan University, Teaching Hospital, Kathmandu, Nepal&ast;These authors contributed equally to this workCorrespondence: Erjie Xia, Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 577 5557 8527, Email erjiexia1@126.com Yuying Zhou, Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou, Zhejiang, People’s Republic of China, Tel +8615757194239, Email yuying_ne@163.comBackground: Breast cancer (BC) is increasingly becoming the primary reason for death in women, which sounded the alarm. Thus, finding a novel management target for BC is imminent.Materials and Methods: The data on gene expression and clinicopathological characteristics were downloaded from The Cancer Genome Atlas (TCGA). The expression of GNPNAT1 in 40 paired breast cancer and adjacent tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Univariate and Multivariate logistic regression methodology was applied to analyze the prognostic factors for lymph node metastasis (LNM). Based on the status of breast cancer-relative receptors, patients were distributed into six groups, and then the Kaplan-Meier survival analysis with a Log rank test was applied to investigate the involvement among the expression of GNPNAT1 and overall survival (OS).Results: We found higher expression of GNPNAT1 was connected with poor survival in breast cancer by COX regulation analysis. GO, KEGG, and GSEA analysis prompted that GNPNAT1 was connected with the defense mechanism of cells, cell proliferation, and division. Immunization infiltration analysis showed that high GNPNAT1 was negatively connected with 16 immunization infiltration cell types and positively connected with four immunization infiltration cell types.Conclusion: As a whole, our results indicated that GNPNAT1 might be a probable biomarker for diagnosis and prognosis in breast cancer.Keywords: GNPNAT1, biomarker, breast cancer, diagnosis, prognosis

Weisheng Xu,1,2,&ast; Wangsheng Xue,1,&ast; Zeyu Zhou,3,&ast; Jiying Wang,1 Hui Qi,1 Shiyu Sun,1 Tong Jin,1 Ping Yao,1 Jian-Yuan Zhao,4 Fuqing Lin1 1Department of Pain Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, 200331, People’s Republic of China; 3School of Life Sciences, Fudan University, Shanghai, 200433, People’s Republic of China; 4Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200090, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuqing Lin, Department of Pain Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email fuqinglin@tongji.edu.cn Jian-Yuan Zhao, Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200090, People’s Republic of China, Email zhaojy@vip.163.comBackground: As one of the most frequent complications of type 2 diabetes mellitus (T2DM), diabetic peripheral neuropathy (DPN) shows a profound impact on 50% of patients with symptoms of neuropathic pain, numbness and other paresthesia. No valid serum biomarkers for the prediction of DPN have been identified in the clinic so far. This study is to investigate the potential serum biomarkers for DPN firstly based on 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomics technique.Methods: Thirty-six patients enrolled in this study were divided into two groups: 18 T2DM patients without DPN (T2DM group) and 18 T2DM patients with DPN (DPN group). Serum metabolites were measured via 1H-NMR spectroscopy. Bioinformatic approaches including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), independent sample t-test, Fisher’s test, Pearson and Spearman correlation analysis, Stepwise multiple linear regression analysis and receiver operating characteristic (ROC) curve analysis were used to identify the potential altered serum biomarkers.Results: A total of 20 metabolites were obtained and further analyzed. Formate was identified as the only potential biomarker that decreased in the DPN group with statistical significance after multiple comparisons (p< 0.05). Formate also displayed a negative relationship with some elevated clinical markers in DPN. ROC curve analysis showed a good discriminative ability for formate in DPN with an area under the curve (AUC) value of 0.981.Conclusion: Formate could be considered a potential serum metabolic biomarker for DPN. The reduced level of formate in DPN may be associated with mitochondrial dysfunction and gut microbiota alteration. Monitoring the level of serum formate would be an important strategy for the early diagnosis of DPN and a supplement of formate may be a promising treatment for DPN in the future.Keywords: diabetic peripheral neuropathy, type 2 diabetes mellitus, 1H-NMR, metabolomics, formate, uric acid

Luying Qiu,1 Yaxuan Wang,2 Yuye Wang,1,3 Fang Liu,1 Shumin Deng,1 Weishuang Xue,1 Yanzhe Wang1 1Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Neurology, China-Japan Friendship Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yanzhe Wang, Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, Liaoning Province, 110001, People’s Republic of China, Tel +86-15040289417, Email yanzhewangcmu@126.comPurpose: The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro. Excessively activated microglia produce pro-inflammatory mediators such as matrix metalloproteinases [MMPs] and their specific inhibitors, tissue inhibitors of metalloproteinases [TIMPs], causing neuronal damage. Ursolic acid (UA) acts as a neuroprotective agent in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model keeping the MMP/TIMP balance with underlying mechanisms unclear. Our study used OGDR model to determine whether and how UA reduces neuronal damage by reversing MMP/TIMP imbalance caused by microglia in I/R injury in vitro.Methods: SH-SY5Y cells were first cultured with 95% N2 and 5% CO2 and then cultivated regularly for OGDR model. Cell viability was tested for a proper UA dose. We established a co-culture system with SH-SY5Y cells and microglia-conditioned medium (MCM) stimulated by lipopolysaccharide (LPS) and interferon-gamma (IFNγ). MMP9 and TIMP1 levels were measured with ELISA assay to confirm the UA effect. We added recombinant MMP9 (rMMP9) and TIMP1 neutralizing antibody (anti-TIMP1) for reconfirmation. Transmission electron microscopy was used to observe cell morphology, and flow cytometry and Annexin V-FITC and PI labeling for apoptotic conditions. We further measured the calcium fluorescence intensity in SH-SY5Y cells.Results: The MCM significantly reduced cell viability of SH-SY5Y cells after OGDR (p

Duanduan Cong,1 Wenyuan Qi,1 Xiaohui Liu,1 Xiaoyu Xu,1 Lingyun Dong,2 Wei Xue,1,&ast; Kexin Li1,&ast; 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing, People’s Republic of China; 2Beijing Yeedozencom Healthcare Science & Technology Co., Ltd, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Xue; Kexin Li, Clinical Trial Centre (The North Building B4), Beijing Hospital, No. 1 Dahua Road, Dongdan, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +861085133632, Email roserebel@126.com; Kexinli6202@163.comPurpose: To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer S.p.A) in healthy Chinese participants.Patients and Methods: In this open, randomized, single-dose, three-way, crossover study, 18 healthy participants randomly received 100 mg EcSr tablets pre-prandially (a.c.), EcSr tablets post-prandially (p.c.), or Ec tablets a.c. in each period. The concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma were determined by the LC-MS/MS method, and the pharmacokinetic parameters were calculated using WinNonlin (version 8.1).Results: The essential PK parameters under the three treatment conditions (ie Ec a.c., EcSr a.c. and EcSr p.c.) were as follows: Cmax, ASA: 758.38± 455.34, 222.77± 98.04 and 194.54± 61.19 ng, Tmax, ASA: 6.75(2,16), 4.5(2,11) and 8.25(5,11) h, T1/2, ASA: 0.43± 0.08, 1.44± 0.59 and 4.32± 10.04 h, AUC0-t, ASA: 1008.88± 452.27, 918.04± 238.40 and 845.55± 183.25 h·ng/mL; Cmax, SA: 6409.38± 2098.52, 2863.53± 679.73 and 2913.75± 853.27ng/mL, Tmax, SA: 7.25(2,24), 10(3.5– 14) and 10(7,14) h, T1/2, SA: 2.21± 0.46, 2.69± 0.72 and 3.51± 2.06h, AUC0–t, SA: 29,131.41± 9376.23, 27,243.97± 7465.16, 27,240.25± 7444.67 h·ng/mL. When taking EcSr aspirin tablets, the 90% confidence intervals of the geometric mean ratios (pre-prandial/post-prandial) of AUC0-t, ASA and AUC0–∞, ASA, Cmax, SA, AUC0-t, SA and AUC0–∞, SA were within the range of 80.00%– 125.00%.Conclusion: EcSr aspirin tablets showed less inter-individual variation in release and absorption than Ec aspirin tablets, which was well reflected by comparing essential PK parameters. Furthermore, meals had no significant effect on the pharmacokinetics of EcSr aspirin tablets.Keywords: acetylsalicylic acid, salicylic acid, enteric-coated sustained-release, pharmacokinetics

Wenyuan Qi,1,2 Yue Liu,1,2 Wei Xue,1,2 Kexin Li,1,2 J Christopher Gorski,3 Mark Liu,3 Tieliang Yan,3 Duc Tung Nguyen,4 Rajesh Kumar Ramalingam5 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Assessment of Clinical Drugs Risk and Individual Application Key Laboratory, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Global Clinical Pharmacology, Mylan Pharmacetical Inc. (Now Viatris), Morgantown, WV, USA; 4Global Clinical Sciences, MEDA Pharma GmbH & Co. KG (A Viatris Company), Bad-Homburg, Germany; 5Global Medical Affairs, Mylan Pharmaceuticals Private Limited (Now Viatris), Bengaluru, IndiaCorrespondence: Kexin Li, Clinical Trial Centre, Beijing Hospital, No. 1 Dahua Road, Dongdan Dongcheng District, Beijing, People’s Republic of China, Email kexinli6202@163.comObjective: Two studies (Study I and Study II) were conducted in healthy Chinese volunteers to confirm that there was no pharmacokinetic drug interaction between AZE and FLU in MP-AzeFlu. The secondary objective was to evaluate the pharmacokinetic parameters of MP-AzeFlu compared with the commercially available mono-components.Methods: Both studies were a randomized, open-label, three-period, six-sequence, single-dose cross-over trial (William’s design) conducted at Beijing Hospital (Beijing, China) in September and October of 2019 in 30 healthy adult male and female volunteers. The natural log transformed parameters: AUC0-tlast, AUC0-∞ and Cmax were analyzed.Results: The comparison of PK parameters between MP-AzeFlu and Aze (commercially available) showed that the LS mean ratios (90% CI) values for, AUC0–tlast, AUC 0–∞ and Cmax were 100.29% (94.31– 106.66%), 100.76% (94.60– 107.32%) and 93.14% (81.47– 106.48%). The comparison of PK parameters between MP-AzeFlu and Flu (commercially available) for the bioavailability evaluation showed that the LS mean ratios (90% CI) values for, AUC0–tlast, AUC 0–∞ and Cmax were 83.48% (69.81– 99.82%), 100.19% (87.34– 114.94%) and 81.91% (68.50– 97.95%).Conclusion: The study results confirm that neither the FLU or the AZE component in the combination product (MP-AzeFlu), nor the existing qualitative and quantitative differences in the formulation between the currently marketed AZE and FLU mono-product, display significant potential to impact the systemic exposure of AZE or FLU in Chinese subjects.Keywords: MP-AzeFlu, azelastine, fluticasone, allergic rhinitis, pharmacokinetics

Lei Guo,1,&ast; Xiangzhao Xu,2,&ast; Rui Qin,1 Yongqiang Shi,1 Wei Xue,3 Ling He,3 Shuqin Ma,3 Yi Chen1 1Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Department of Anesthesiology, The People’s Hospital of Nanchuan, Chongqing, People’s Republic of China; 3Department of Obstetrics, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Chen, Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, 804S Shengli Street, Yinchuan, Ningxia, 750004, People’s Republic of China, Tel +86-951-6743252, Email czzyxgp@163.comBackground: Norepinephrine and phenylephrine are widely used for obstetric anesthesia. Our central objective was to determine the ED (effective dose) 90 and potency ratio of prophylactic norepinephrine and phenylephrine boluses for preventing postspinal anesthesia hypotension during cesarean section.Methods: Patients scheduled for elective cesarean section (n = 80) were randomly allocated to receive prophylactic norepinephrine (NE) or phenylephrine (PE) boluses immediately after induction of spinal anesthesia. An initial dose of NE (3 μg) and PE (37.5 μg) was given to the first patient, and an up-and-down sequential allocation method was used to determine the next dose level according to the responses (the effectiveness for preventing postspinal anesthesia hypotension [defined as SBP < 80% of baseline value]). Primary outcomes were ED90 and the potency ratio of prophylactic norepinephrine and phenylephrine boluses. Secondary outcomes were the incidence of postspinal anesthesia hypotension, severe postspinal anesthesia hypotension, nausea, vomiting, bradycardia, hypertension, umbilical artery blood gas values, and Apgar scores.Results: The ED90 values for prophylactic norepinephrine and phenylephrine boluses were 8.0 μg (95% CI 7.1– 11.0 μg) and 90.9 μg (95% CI 82.0– 123.9 μg), respectively. The estimated relative potency ratio was 11.4:1. The incidence of bradycardia was lower in the NE group (2.5% vs 20%, P = 0.034). Other outcomes were comparable between the two groups.Conclusion: An 8-μg prophylactic bolus of norepinephrine and a 90-μg prophylactic bolus of phenylephrine can effectively prevent postspinal anesthesia hypotension in patients during cesarean section.Keywords: cesarean section, norepinephrine, phenylephrine, postspinal anesthesia hypotension

Hanqing Yu,&ast; Wen Xue,&ast; Hanjie Yu, Hongchen Gu, Ling Qin, Ai Peng Center for Nephrology and Clinical Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ai Peng; Ling Qin, Center for Nephrology and Clinical Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email pengai@tongji.edu.cn; qinling@tongji.edu.cnPurpose: This study aimed to explore the accuracy for joint application of inflammatory cytokines in diagnosis of gout flare by comparison with peripheral blood cells.Methods: We collected the clinical data of 96 acute gout patients and 144 remission gout patients, and compared the levels of peripheral blood cells, inflammatory cytokines and blood biochemistry indexes between acute and remission gout. We respectively assessed the area under curves (AUCs) for single and multiple inflammatory cytokines including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and single and multiple peripheral blood cells including platelet (PLT), white blood cell (WBC), percentages of neutrophils (N%), lymphocytes (L%), eosinophils (E%), basophils (B%) in diagnosis of acute gout by receiver operating characteristic (ROC) curve analysis.Results: By contrast with remission gout, the levels of PLT, WBC, N%, CRP, IL-1β, IL-6 and TNF-α increased, and the levels of L%, E% and B% decreased in acute gout. The AUCs of PLT, WBC, N%, L%, E% and B% in diagnosis of acute gout were respectively 0.591, 0.601, 0.581, 0.567, 0.608 and 0.635, while the AUC for joint application of these peripheral blood cells was 0.674. Moreover, the AUCs of CRP, IL-1β, IL-6 and TNF-α in diagnosis of acute gout were respectively 0.814, 0.683, 0.622 and 0.746, while the AUC for joint application of these inflammatory cytokines was 0.883, reflecting significantly higher levels than peripheral blood cells.Conclusion: The joint application of multiple inflammatory cytokines can better distinguish acute gout from remission gout compared with peripheral blood cells.Keywords: acute gout, diagnosis, multiple inflammatory cytokines

Hongyang Qian,1,&ast; Yiqiu Wang,1,&ast; Zehua Ma,1,&ast; Lei Qian,1 Xiaoguang Shao,1 Di Jin,1 Ming Cao,1 Shupeng Liu,2 Haige Chen,1 Jiahua Pan,1 Wei Xue1 1Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China; 2Shanghai Institute for Advanced Communication and Data Science, Key Laboratory of Specialty Fiber Optics and Optical Access Networks, School of Communication and Information Engineering, Shanghai University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Xue; Jiahua Pan, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 1630 Dongfang Road, Shanghai, 200127, People’s Republic of China, Tel +86 21 6838 3375, Email xuewei@renji.com; panjiahua@renji.comObjective: To explore the value of surface-enhanced Raman spectroscopy analysis of pretreated plasma samples in prediction of bladder cancer (BCa) recurrence after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).Patients and Methods: SERS was used to analyze plasma samples collected before biopsy and treatment in BCa patients undergoing NAC and RC. The value of clinicopathological parameters and distinctive SERS peaks in the prediction of disease recurrence were analyzed in Cox regression proportional hazard analysis and Log rank test. Principal component analysis and linear discriminant analysis (PCA-LDA) were employed to process spectral data and construct diagnostic algorithms.Results: A total of 88 patients with 440 plasma SERS spectra were collected. The SRES spectra from recurrent patients were compared with patients who remained recurrence free. The SERS demonstrated higher levels of circulating free nucleic acid components in recurrent population, which is represented by significantly higher intensities at SERS peaks of 725 cm− 1, 1328 cm− 1 and 1455 cm− 1. The SERS also detected significantly lower levels of tryptophan shown as lower significantly intensities at the 1558 cm− 1, which is proved to be an independent predictor of BCa recurrence. The addition of SERS peaks of 1558 cm− 1 to classic clinicopathological predictors including pathological tumor stage, lymph node metastasis and pathological downstaging can significantly enhance the power of the predictive model from 0.66 to 0.76 in the area under curve (AUC) of receiver operating characteristic (ROC) curves. Meanwhile, the PCA-LDA diagnostic model based on SERS spectra reveals a high accuracy of 85.2% in prediction of disease recurrence and the AUC of 0.92 in the ROC curve. When validated in the leave-one-out cross-validation method, the accuracy of the model remained 84.1%.Conclusion: We show that SERS analysis of plasma before NAC treatment can accurately classify patients with different risks of disease recurrence after surgery and improve the power of clinicopathological predictive models, thus refining clinical decision-making.Keywords: Raman spectroscopy, bladder cancer, cancer recurrence, neoadjuvant chemotherapy, radical cystectomy

Xin Song,1,2 Qingtao Zhao,1 Hua Zhang,1 Wenfei Xue,1 Zhifei Xin,1 Jianhua Xie,1,2 Xiaopeng Zhang1 1Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 2North China University of Science and Technology, Tangshan, People’s Republic of ChinaCorrespondence: Xiaopeng Zhang, Hebei General Hospital, No. 348, Heping Western Road, Xinhua District, Shijiazhuang, 050000, People’s Republic of China, Tel +8613722865878, Email 13722865878@163.comPurpose: This study aimed to develop and validate a preoperative CT-based nomogram combined with clinical and radiological features for distinguishing invasive from non-invasive pulmonary adenocarcinoma.Patients and Methods: A total of 167 patients with solitary pulmonary nodules and pathologically confirmed adenocarcinoma treated between January 2020 and December 2020 at Hebei General Hospital were retrospectively assessed. To evaluate the probability of invasive pulmonary adenocarcinoma, we developed three models, the multivariate logistic regression model, the stepwise logistic regression model, and the cross-validation model. The Akaike information criterion (AIC) was used to compare the relative strength of different models, and the area under the curve (AUC) was used to quantify the predictive accuracy. The best performing model was presented as a nomogram, calibrated and evaluated for clinical utility.Results: The stepwise logistic regression model revealed highest and mean attenuations of non-enhanced CT images, and lobulation and vacuole presence were predictive factors of invasive pulmonary adenocarcinoma. This model (AIC = 67.528) with the lowest AIC value compared with that of the multivariate logistic regression model (AIC = 69.301) or the cross-validation model (AIC = 81.216) was identified as the best model, and its AUC value (0.9967; 95% CI, 0.9887– 1) was higher than those of the other two models. The calibration curve showed optimal agreement in invasive pulmonary adenocarcinoma probability as predicted by the nomogram and the actual value.Conclusion: We developed and validated a nomogram that could estimate the preoperative probability of invasive pulmonary adenocarcinoma in patients with solitary pulmonary nodules, which may be useful in clinical decision-making associated with personalized surgical intervention and therapeutic regimen selection.Keywords: solitary pulmonary nodule, nomogram, invasive pulmonary adenocarcinoma, lung cancer

Qishun Geng,1,2,&ast; Qian Wei,2,&ast; Zhibo Shen,2,&ast; Yuanyuan Zheng,2 Longhao Wang,2 Wenhua Xue,2 Lifeng Li,2 Jie Zhao1,2 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Engineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie ZhaoDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaEmail zhaojie@zzu.edu.cnLifeng LiEngineering Laboratory for Digital Telemedicine Service, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaEmail lilifeng0317@163.comBackground: The 5-methylcytosine (m5C) is one of the important forms of RNA post modification, and its regulatory mechanism in tumors has received increasing attention. However, its potential role in colorectal cancer remains unclear.Materials and Methods: Here, we systematically investigated the genetic variation and prognostic value of the 14 m5c RNA methylation regulators in colon cancer. The prognostic risk score was constructed using three m5C regulators, which was verified in the GSE17536 (N=177), GSE41258 (N=248) and GSE38832 (N=122) datasets.Results: The risk score developed from the three-m5C signature represents an independent prognostic factor, which can accurately predict the prognosis of patients with colon cancer in multiple datasets. The cytokine–cytokine receptor interaction and chemokine signaling pathway were significantly enriched in the low-risk score group. Further analysis showed that the three-m5C signature was related to tumor immune microenvironment (TIME), affecting the abundance of tumor-infiltrating immune cells. Especially, patients with low risk score had higher immune score than those with high risk score. In addition, gene set enrichment analysis (GSEA) confirmed that all three regulatory factors are associated with the MAPK/p38 signaling pathway.Conclusion: In conclusion, our study illustrates that the three-m5C signature may be involved in the regulation of colon cancer immune microenvironment in synergy with the MAPK signaling pathway. Therefore, further studying the three-m5C signature regulatory mechanisms might provide promising targets for improving the responsiveness of colon cancer to immunotherapy.Keywords: 5-methylcytosine, the three-m5C signature, colon cancer, prognostic, tumor immune microenvironment

Wenfei Xue1 1, Xiaopeng Zhang2 2, Zhancong Niu3 3, Zhifei Xin2 2, Hua Zhang2 2, Qingtao Zhao1 12 2, Jie He2 2, Zhonghui Hu2 2, Guochen Duan1 1 1Study Office of Thoracic Surgery, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, 050000, People’s Republic of China; 3Department of Infectious Diseases, Hebei General Hospital, Shijiazhuang, 050000, People’s Republic of ChinaCorrespondence: Guochen DuanStudy Office of Thoracic Surgery, Hebei Medical University, No. 361, Zhongshan East Road, Changan District, Shijiazhuang, 050017, People’s Republic of ChinaTel +86 13513380703Email duanguoc@126.comBackground: The object of the study was to elucidate the relationship between the neutrophil–lymphocyte ratio (NLR) and the growth of pulmonary ground-glass opacity (GGO) in stage IA lung adenocarcinoma.Methods: All patients with GGO following surgical procedures were enrolled, with the time of follow-up and the variation tendency of GGO recorded. Meanwhile, laboratory parameters, age, gender, smoking history, histology, tumor size, and stage were recorded. Logistic regression was used to evaluate the value of NLR and the cutoff value was calculated by SPSS 22.0.Results: In the whole cohort, 30 cases of growing GGO and 43 cases of stable GGO undergoing surgical procedures were diagnosed as lung adenocarcinoma. There was significant statistical difference between the two groups. Multivariable analysis showed that NLR could predict the GGOs with growth (odds ratio 5.198, 95% confidence interval (95%CI: 1.583– 14.581, P=0.002). Receiver operating characteristics analysis for NLR showed the optimal cutoff value of 2.38, with a sensitivity of 60.0% and specificity of 81.4%.Conclusion: Our study demonstrated that the NLR appeared to have value as a promising clinical predictor of GGOs with growth. Further studies are needed to confirm this conclusion.Keywords: neutrophil–lymphocyte ratio, ground-glass opacity, early lung adenocarcinoma

Jiaofeng Huang,1,&ast; Wenjuan Xue,2,&ast; Mingfang Wang,1 Yinlian Wu,1 Medha Singh,3 Yueyong Zhu,1,4 Rahul Kumar,5 Su Lin1 1Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, People’s Republic of China; 2Department of Traditional Chinese Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, People’s Republic of China; 3Department of General Medicine, Tan Tock Seng Hospital, Singapore; 4Fujian Key Laboratory of Precison Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Department of Gastroenterology and Hepatology, Duke-NUS Academic Medical Centre, Changi General Hospital, Singapore&ast;These authors contributed equally to this workCorrespondence: Su LinDepartment of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, No. 20, Chazhong Road, Taijiang District, Fuzhou, Fujian, 350005, People’s Republic of ChinaTel +86 591-87981657Fax +86 591-87982526Email sumer5129@fjmu.edu.cnIntroduction: Metabolic associated fatty liver disease (MAFLD) is a novel concept for fatty liver disease. Different from non-alcoholic fatty liver disease (NAFLD), the diagnosis of MAFLD requires the presence of metabolic risks. This study aimed to characterize patients with liver steatosis but without metabolic risks (non-MR-steatosis) which may not be diagnosed by MAFLD criteria.Methods: Consecutive patients who underwent biopsy were included in this study. The clinic-pathological characteristics of non-MR-steatosis, NAFLD and MAFLD were compared.Results: A total of 1217 cases were included. There were 426 (35.00%) cases with MAFLD, 585 (48.07%) with NAFLD and 168 (13.80%) with non-MR-steatosis. The majority of the cases were infected with HBV (93.26%). The age and metabolic profiles were highest in MAFLD and lowest in non-MR-steatosis. The body mass index (BMI) level was also lowest in non-MR-steatosis (20.78 ± 1.54 kg/m2). The ALT and AST levels of the non-MR-steatosis group were not statistically different from those of MAFLD or NAFLD groups (p > 0.05). Histologically, there was no significant difference in the degrees of inflammation and fibrosis among the three groups. The severity of steatosis in non-MR-steatosis group was lower than MAFLD or NAFLD groups (p < 0.05). These results were consistent in both HBV and non-HBV subgroups.Conclusion: MAFLD criteria may overlook some steatotic patients without metabolic risks, who may also have steatohepatitis and significant fibrosis.Keywords: metabolic associated fatty liver disease, nonalcoholic fatty liver disease, metabolic risks, lean NAFLD, biopsy

Yue Liu,1,* Chenguang Yang,2,* Wenyuan Qi,1 Zuowei Pei,2 Wei Xue,1 Huolan Zhu,2 Min Dong,2 Ying Guo,2 Duanduan Cong,1 Fang Wang2 1Clinical Trial Center, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing Hospital, Beijing, People’s Republic of China; 2Internal Medicine-Cardiovascular Department, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Wang Email bjh_wangfang@163.comAbstract: Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on Cmax and AUC0-∞.Keywords: anticoagulants, dabigatran, genetics, pharmacogenetics, CES1, ABCB1

Ting Wei, Ye Jia, Wei Xue, Ming Ma, Wenhui Wu College of Food Science and Engineering, Shanghai Ocean University, Shanghai, 201306, People’s Republic of ChinaCorrespondence: Ming Ma; Wenhui WuCollege of Food Science and Engineering, Shanghai Ocean University, No. 999, Huchenghuan Road, Nanhui New City, Shanghai, 201306, People’s Republic of ChinaTel +86-21-61900296Email mma@shou.edu.cn; whwu@shou.edu.cnPurpose: Due to the adverse effects of antidiabetic drugs, nowadays, nutraceuticals have been of much interest to investigators. Therefore, the present study aimed to explore the potential effects of enteral nutritional (EN) formulas on the gut microbiota and metabolic regulation of type 2 diabetes mellitus (T2DM) mice and compare the differences between whey protein and soy protein.Methods: EN formulas made of whey protein or soy protein were administered for five weeks and then mice tissue samples were obtained to examine the metabolic parameters and histopathology of the pancreas, liver, jejunum and colon. 16S rRNA V3-V4 region gene sequencing was used to analyze the changes in the gut microbiota.Results: After the five-week intervention, the alpha diversity had recovered slightly, and the soy protein group (SPG) achieved a better effect than the whey protein group (LPG). The overall composition of gut microbiota was regulated. The abundance of Bacteroidetes and TM7 had raised significantly and the abundance of Firmicutes and Deferribacteres had declined after treatment, with no significant difference between the LPG and SPG. The types of beneficial bacteria were increased at the genus and species level. The level of hexokinase (HK) and pyruvate kinase (PK) had significantly recovered and inhibited the level of α-glucosidase. In addition, the EN formulas treatment reduced the levels of inflammatory factor (TNF-α) in liver and muscle. The level of glucose transporter type 2 (GLUT-2) levels in the liver and intestine also significantly increased. Moreover, the metabolism regulation of the SPG was better than that of the LPG. The EN formulas treatment improved the pancreas, liver, jejunum and colon histology.Conclusion: The EN formulas regulated the overall structure of the gut microbiota and improved the metabolic level in streptozotocin/high-fat diet (STZ/HFD) diabetic mice. Therefore, EN formula may potentially become an effective nutritional adjunctive therapy for T2DM.Keywords: type 2 diabetes mellitus, gut microbiota, enteral nutritional formula, soy protein, whey protein, 16S rRNA gene sequencing

Panpan Xie,1 Wei Xue,1 Wenyuan Qi,1 Yang Li,1 Lei Yang,1 Zhaojun Yang,2 Aixin Shi1 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science; Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing, 100730, People’s Republic of China; 2Research and Development Department, Xin Chen Taifei Medical Technology Co. LTD, Tianjin, 300221, People’s Republic of ChinaCorrespondence: Aixin Shi No. 1 Dahua Road, Dongcheng District, Beijing, People’s Republic of ChinaEmail aixins0302@126.comBackground: Ibuprofenamine hydrochloride spray is novel transdermal nonsteroidal anti-inflammatory drugs (NSAIDs), under clinical development for the treatment of Rheumatoid Arthritis and Osteoarthritis as a novel transdermal drug.Methods: A single and multiple ascending dose study investigated the safety, tolerability and pharmacokinetics of ibuprofenamine hydrochloride in healthy Chinese subjects. A total of 34 subjects (single-dose study: 34 subjects and multiple-dose study: 20 subjects) were involved in the trial. In the single-dose study, subjects were assigned to one of the four groups received 35, 70, 140, 280 mg. In the 70 mg and 140 mg treatment groups, subjects received one dose on the first day and twice a day from day 6 to 12. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts.Results: After a single dose, both ibuprofenamine and ibuprofen plasma exposure showed a more than dose-proportional increase across a dose range of 35– 280 mg. After multiple dosing, both ibuprofenamine and ibuprofen steady-state exposure increased obviously more than dose-proportional manner across the evaluated dose range (twice a day for 7 days) resulted in obvious accumulation. Single or multiple doses of ibuprofenamine hydrochloride were generally well tolerated and no obvious skin irritation was observed.Conclusion: Ibuprofenamine hydrochloride exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for Rheumatoid Arthritis and Osteoarthritis.Keywords: ibuprofenamine hydrochloride spray, tolerability, safety, pharmacokinetics

Zhonghui Hu,1,2,* Wenbo Wu,1,3,* Xiaopeng Zhang,1 Ping Li,4,* Hua Zhang,1 Huien Wang,1 Wenfei Xue,1 Zhiguo Chen,5 Qingtao Zhao,1 Guochen Duan1,5 1Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 2Graduate School, Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Graduate School, Hebei North University, Zhangjiakou, People’s Republic of China; 4Department of Thoracic Surgery, Zigong First People’s Hospital, Zigong, People’s Republic of China; 5Department of Thoracic Surgery, Hebei Children’s Hospital, Shijiazhuang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guochen DuanHebei Children’s Hospital, No. 133 Jianhua South Street, Yuhua District, Shijiazhuang, 050000, People’s Republic of ChinaTel +86 311 13380703Email duanguoc@126.comQingtao ZhaoHebei General Hospital, No. 384 Heping West Road, Xinhua District, Shijiazhuang, 050000, People’s Republic of ChinaTel +86 311 85988756Email tao11182004@163.comPurpose: Advanced lung cancer inflammation index (ALI) has been shown to predict overall survival (OS) in advanced non small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and operable NSCLC. However, there were no studies of the correlation between ALI and operable SCLC. Therefore, this study is aimed to explore the relationship between ALI and the prognosis of operable SCLC.Patients and Methods: A total of 48 patients with SCLC who underwent surgery at Hebei General Hospital and Zigong First People’s Hospital were screened between 2016 and 2020. ALI was calculated as follows: body mass index (BMI, kg/m2)×serum albumin (ALB, g/dL)/neutrophil to lymphocyte ratio (NLR). Receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value of ALI. Patients were divided into two groups according to the cutoff point of ALI: low ALI group with ALI< 48.2 and high ALI group with ALI≥ 48.2. Kaplan-Meier and Cox regression analysis were performed to assess the potential prognostic factors associated with OS.Results: The optimal cutoff value of ALI was determined as 48.2. The low ALI group displayed more adverse clinical characteristics and poorer survival rates. Multivariate analysis revealed that ALI and Charlson comorbidity index (CCI) were significantly correlated with OS.Conclusion: Low ALI was correlated with poor prognosis in patients with SCLC who underwent surgery. Preoperative ALI might serve as a potential prognostic marker for patients with operable SCLC.Keywords: ALI, SCLC, surgery, prognosis

Wei Xue,1 Juhua Mao,2 Qingjie Chen,1 Weide Ling,1 Yuqi Sun3 1Department of Pharmacy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, People’s Republic of China; 2Center for Drug Control, Lishui Institute for Quality Inspection and Testing, Lishui, Zhejiang 323000, People’s Republic of China; 3Department of Anesthesiology, Guangzhou 12th People’s Hospital, Guangzhou, Guangdong 510620, People’s Republic of ChinaCorrespondence: Yuqi SunGuangzhou 12th People’s Hospital, No. 1 Tianqiang Road, Tianhe District, Guangzhou, Guangdong 510620, People’s Republic of ChinaEmail yuqisunhh@163.comBackground: Diabetic nephropathy (DN) is the leading cause of impaired renal function. The purpose of this study was to investigate the effects of Mogroside IIIE (MG IIIE), a cucurbitane-type compound isolated from Siraitia grosvenorii, in high glucose (HG)-induced podocytes and the possible mechanisms.Methods: MPC-5 cells were cultured under normal glucose or HG conditions. After treatment with MG IIIE, cell viability was examined using a cell counting kit-8 assay. The contents of inflammatory factors and oxidative stress-related markers were determined using the corresponding kits. Additionally, apoptosis of MPC-5 cells was determined using flow cytometry assay and the levels of apoptosis-associated proteins were evaluated by Western blot analysis. Moreover, the expression of proteins in AMPK/SIRT1 signaling was tested and the compound C, an AMPK inhibitor, was used to study whether the effects of MG IIIE on HG-induced MPC-5 cells were mediated by activation of the AMPK/SIRT1 signaling pathway.Results: MG IIIE elevated the cell viability of HG-induced MPC-5 cells, reduced the concentrations of inflammatory cytokines and decreased the levels of oxidative stress-related markers. What’s more, the apoptosis of podocytes induced by HG was inhibited after MG IIIE intervention, accompanied by the upregulated expression of Bcl-2 and downregulated expression of Bax, cleaved caspase-3 and cleaved caspase-9. It was also found that MG IIIE could activate the AMPK/SIRT1 signaling, but compound C inhibited this pathway and reversed the inhibitory effects of MG IIIE on inflammation, oxidative stress and apoptosis in HG-stimulated podocytes.Conclusion: MG IIIE can alleviate HG-induced inflammation and oxidative stress of podocytes by the activation of AMPK-SIRT1 signaling.Keywords: podocytes, inflammation, oxidative stress, apoptosis, AMPK

Chenyu Yang,1,2,* Yixiu Wang,3 Weijie Xue,4 Yuwei Xie,3 Qian Dong,1,2,* Chengzhan Zhu2,3,* 1Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 2Shandong Provincial Key Laboratory of Digital Medicine and Computer-Assisted Surgery, Qingdao 266003, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 4Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian DongDepartment of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of ChinaEmail dong_qdu1963@163.comChengzhan ZhuDepartment of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of ChinaEmail zhu_405@163.comPurpose: Autophagy plays an important role in the occurrence and development of hepatocellular carcinoma (HCC). We aimed to develop an autophagy-related genes signature predicting the prognosis of HCC and to depict a competing endogenous RNA (ceRNA) network.Methods: Differentially expressed autophagy-related genes (DE-ATGs), miRNAs and lncRNAs and clinical data of HCC patients were extracted from TCGA. The GO and KEGG analysis were performed to investigate the gene function. Univariate and multivariate Cox regression analysis were used to identify a prognostic signature with the DE-ATGs. And a nomogram, adapted to the clinical characteristics, was established. Then, we established a ceRNA network related to autophagy genes.Results: We screened out 27 differentially expressed genes which were enriched in GO and KEGG pathways related to autophagy and cancers. In univariate and multivariate Cox regression analysis, BIRC5, HSPB8, and SQSTM1 were screened out to establish a prognostic risk score model (AUC=0.749, p< 0.01). Kaplan–Meier survival analysis showed that the overall survival of high-risk patients was significantly worse. Furthermore, the signature was validated in the other two independent databases. The nomogram, including the autophagy-related risk signature, gender, stage and TNM, was constructed and validated (C-index=0.736). Finally, the ceRNA network was established based on DE-ATGs, differentially expressed miRNAs and lncRNAs.Conclusion: We constructed a reliable prognostic model of HCC with autophagy-related genes and depicted a ceRNA network of DE-ATGs in HCC which provides a basis for the study of post-transcriptional modification and regulation of autophagy-related genes in HCC.Keywords: competing endogenous RNA, ceRNA, autophagy-related genes, hepatocellular carcinoma, HCC, TCGA

Background and purpose: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area. Materials and Methods: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. Results: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. Conclusion: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence. Keywords: Health economic evaluation, Cost-utility analysis, Proton beam therapy, Quality evaluation

Yanyan Jia, Meijuan Li, Yuan Cao, Wenlong Feng, Xueru Li, Wenhua Xue, Huirong Shi Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaCorrespondence: Yanyan JiaDepartment of Gynecology and Obstetrics, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road, Zhengzhou 450052, People’s Republic of ChinaEmail jiayy2019@163.comBackground: Ovarian cancer has been a salient public health concern in the world. It is necessary to develop novel antitumor drugs to treat ovarian cancer.Purpose: This study investigated the synthesis, antiproliferation ability, antitumor mechanisms in vitro and in vivo of a novel benzenesulfonamide derivative.Methods: The novel benzenesulfonamide-1,2,3-triazole hybrid 7c was synthesized from 4-fluorobenzenesulfonyl chloride, prop-2-yn-1-amine and 1-(azidomethyl)-3-phenoxybenzene. The structure of this benzenesulfonamide-1,2,3-triazole hybrid 7c was confirmed by 13C NMR, and 1H NMR. Compound 7c was evaluated for its antitumor effects in vitro and in vivo against ovarian cancer OVCAR-8 cells.Results: We discovered that the benzenesulfonamide hybrid 7c potently inhibited cell proliferation against ovarian cancer. Especially, it inhibited cell proliferation with an IC 50 value of 0.54μM against OVCAR-8 cells. It could inhibit migration and invasion against OVCAR-8 cells in a concentration-dependent and time-dependent manner. In addition, compound 7c affected the Wnt/β-catenin/GSK3β pathway against ovarian cancer OVCAR-8 cells. In vivo study suggested that compound 7c inhibited tumor growth remarkably without obvious toxicity.Conclusion: In conclusion, benzenesulfonamide hybrid 7c could be a lead compound for further antitumor drug discovery to treat ovarian cancer.Keywords: benzenesulfonamide, proliferation, migration, invasion, in vivo

Miao Wei,1 Lina Guo,1 Yiru Zhu,1 Yvru Guo,2 Suyuan Yv,1 Genoosha Namassevayam,1 Wenhua Xue,3 Jieyao Li,4 Lifeng Li,4 Zhibo Shen,4 Junlin Yv,4 Zijia Zhu,3 Wenbin Wang,3 Yanjin Liu,5 Jie Zhao,3 Fu Chen6 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 5Department of Nursing, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 6Department of Medical Administration, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Yanjin LiuDepartment of Nursing, The First Affiliated Hospital of Zhengzhou University, PO Box 450052, Zhengzhou, Henan Province, People’s Republic of ChinaEmail liu-yanjin@126.comJie ZhaoDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, PO Box 450052, Zhengzhou, Henan Province, People’s Republic of ChinaEmail zhaojie2016@126.comPurpose: This study aims to explore the mediating role of sense of coherence in the relationship of type C personality and depression among newly diagnosed breast cancer patients.Methods: A descriptive and correlational survey was conducted in 600 breast cancer patients aged ≥18 years from September 2018 to March 2019 in Zhengzhou, China. The demographic questionnaire, Cancer Behavior Scale, Sense of Coherence Scale and Hamilton Depression Scale were included in this study. Data analysis was performed by correlation analysis, multiple linear regression analysis, and structural equation modeling.Results: The valid questionnaires were 575 (effective response rate: 95.8%). The score of sense of coherence was negatively correlated with type C personality and depression (r = −0.41, P < 0.01; r = −0.58, P < 0.01); the score of type C personality and depression were positively correlated (r = 0.51, P < 0.01). The results of multiple linear regression analysis revealed that the effect of type C personality on depression was partly mediated by sense of coherence, which was confirmed by structural equation modeling. The mediation effect accounts for 45.2% (0.269/0.594) of the total effect.Conclusion: The results of this study revealed that sense of coherence as a partial mediating role is essential for reducing the influence of type C personality on depression. Early and targeted psychological interventions on sense of coherence are needed to alleviate the symptom of depression in newly diagnosed breast cancer patients.Keywords: breast cancer, sense of coherence, type C personality, depression, mediation effect

Background: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting: Antenatal clinics in the UK and elsewhere in Europe. Participants: Women with twin pregnancy at

Yuzhu Ma,1,* Daolu Yuwen,2,* Jingwei Chen,1 Bingfeng Zheng,1 Jian Gao,1 Minmin Fan,1 Wenwen Xue,1 Yixuan Wang,1 Wuhao Li,1 Yongqian Shu,3 Qiang Xu,1 Yan Shen1 1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People’s Republic of China; 2Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China; 3Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiang Xu; Yan ShenState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, People’s Republic of ChinaTel/Fax +86 25 8968 7620Email molpharm@163.com; shenyan@nju.edu.cnIntroduction: Exosomes are important mediators of intercellular communication. Previously, we characterized circulating exosomal miR-425-3p as a non-invasive prognostic marker for predicting clinical response to platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC).Methods: Circulating exosomal miR-425-3p was validated by qRT-PCR in paired serum samples from NSCLC patients during the course of platinum-based chemotherapy. Cell coculture was performed to examine the effects of exosomal miR-425-3p on the sensitivity of recipient A549 cells to cisplatin. Using bioinformatics, ChIP and luciferase reporter assays, the transcription factor essential for miR-425-3p expression was identified. Autophagic activity in the recipient cells was determined by Western blot and fluorescence microscopy.Results: Higher levels of exosomal miR-425-3p were found in serum samples from the patients in tolerance versus those at baseline. An upward trend in the expression of circulating exosomal miR-425-3p was revealed during chemotherapy. Furthermore, the expression of exosomal miR-425-3p could be induced by cisplatin in NSCLC cells. Exosomes isolated from either cisplatin-treated or cisplatin-resistant NSCLC cells conferred chemoresistance to sensitive A549 cells in a miR-425-3p-dependent manner. Cisplatin-induced c-Myc was found to directly bind the miR-425-3p promoter and transactivated its expression. Exosomal miR-425-3p facilitated autophagic activation in the recipient cells by targeting AKT1, eventually leading to chemoresistance.Discussion: Our results suggest that apart from a prognostic marker of treatment response, exosomal miR-425-3p might be a potential dynamic biomarker to tailor cisplatin resistance in NSCLC patients during the treatment and represent a promising therapeutic target for therapy-resistant NSCLC.Keywords: exosomes, miR-425-3p, NSCLC, chemoresistance, platinum-based chemotherapy, autophagy

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Weiguang Xue,1 Adam Lloyd,1 Edel Falla,1 Claudia Roeder,2 Rudiger Papsch,2 Klaus Bühler3,41IQVIA, Real-World Evidence, London, UK; 2Merck KGaA, Frankfurt, Germany; 3Centre for Gynecology Endocrinology & Reproductive Medicine Kinderwunsch-Zentrum Stuttgart, Stuttgart, Germany; 4Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, GermanyBackground and objectives: Demand for assisted reproduction technology (ART) in Germany is high, with 100,844 treatment cycles during 2016. Many ART procedures involve ovarian stimulation with follicle stimulating hormone (FSH). Recently, biosimilar FSH products have become available. The objective of this study was to evaluate the cost-effectiveness of the recombinant FSH Gonal-f®, (Originator) in comparison to biosimilar follitropin alfa, Bemfola®, (Biosimilar 1) and Ovaleap®, (Biosimilar 2), from a German payer perspective in terms of cost per live birth.Methods: A decision tree model was developed, based on one cycle of assisted reproduction, to compare the original product to biosimilars. Clinical inputs, including live birth rates and adverse event rates were obtained from published randomized trials. Cost inputs were obtained from publicly available German sources. Clinical inputs, model structure and methodology were based on previous publications and validated by a clinical expert.Results: Results indicated that the live birth rate is higher for the Originator compared to Biosimilar 1 (40.7% vs 32.1% respectively), and Biosimilar 2 (32.2% vs 26.8%). The average cost per live birth for women treated with the Originator was estimated to be lower than those who were treated with biosimilars: Originator vs Biosimilar 1 (€10,510 vs €12,192), Originator vs Biosimilar 2 (€12,590 vs €13,606). The analysis also found that the Originator is associated with an incremental cost-effectiveness of €4,168 and €7,540 per additional live birth versus Biosimilar 1 and Biosimilar 2 respectively. Sensitivity analysis indicated probabilities of pregnancy, embryo transfer and live birth, were key drivers of model costs. Scenario analysis confirmed the robustness of the model outcomes.Conclusion: This study suggests that treatment with the Originator could result in a lower cost per live birth in comparison to biosimilars. Further analysis using real-world data, when available, is recommended to validate the results of the present study.Keywords: reproductive techniques, follitropin alfa, cost per live birth

Jiahua Pan,1,* Xiaoguang Shao,1,* Yinjie Zhu,1,* Baijun Dong,1 Yanqing Wang,1 Xiaonan Kang,2 Na Chen,3 Zhenyi Chen,3 Shupeng Liu,3 Wei Xue1 1Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 2Department of Biobank, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 3Shanghai Institute for Advanced Communication and Data Science, Key Laboratory of Specialty Fiber Optics and Optical Access Networks, School of Communication and Information Engineering, Shanghai University, Shanghai, People’s Republic of China *These authors contributed equally to this work Objective: The objective of this study was to evaluate the performance of surface-enhanced Raman spectroscopy (SERS) in the prediction of early biochemical recurrence after radical prostatectomy (RP).Patients and methods: We synthesized monodisperse gold nanoparticles as SERS-enhanced substrates and analyzed preoperative plasma samples of patients who underwent RP. The roles of clinical risk model (Cancer of the Prostate Risk Assessment [CAPRA] score) and distinctive SERS spectra on prediction of early biochemical recurrence were evaluated. The principal component analysis and linear discriminant analysis (PCA-LDA) were used to manage the spectral data and develop diagnostic algorithm.Results: A total of 306 preoperative plasma Raman spectra from 102 patients were collected. SERS spectrum from those who developed early biochemical recurrence were compared to those who remained biochemical recurrence-free. The SERS detected more abundant circulating free nucleic acid bases in biochemical recurrence population, presenting significant stronger intensities at SERS spectral bands 725 and 1,328 cm-1. The addition of Raman spectral peak 1,328 cm-1 to CAPRA postsurgical (CAPRA-S) score significantly improved the predictive power of logistic regression model compared to simple CAPRA score (P

BackgroundPreterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.Methods and findingsWe conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.ConclusionsThese results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.Trial registrationISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.

Jing He,1,* Zhen-Jian Zhuo,2,* Anqi Zhang,3,* Jinhong Zhu,4 Rui-Xi Hua,5 Wen-Qiong Xue,1 Shao-Dan Zhang,1 Jiang-Bo Zhang,1 Xi-Zhao Li,1 Wei-Hua Jia1 1State Key Laboratory of Oncology in South China, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; 2Faculty of Medicine, School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China; 3Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 4Molecular Epidemiology Laboratory, Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China; 5Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China *These authors contributed equally to this work Background: Potentially functional polymorphisms can modulate protein activities and host’s DNA repair capacity, thereby influencing cancer susceptibility. The association of the polymorphisms in the nucleotide excision repair core pathway genes and gastric cancer susceptibility remains largely unknown. Methods: Here, we systematically analyzed the associations between nine polymorphisms in four key genes (XPA, ERCC1, ERCC2, and ERCC4) in the nucleotide excision repair pathway and gastric cancer risk in a Chinese population including 1142 patients and 1173 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the risk associations. Results: We observed that ERCC1 rs2298881 CA variant genotype was associated with an increased gastric cancer risk (CA vs. CC: adjusted OR [AOR]=1.33, 95% CI=1.09–1.62; dominant model: AOR=1.32, 95% CI=1.10–1.60). However, ERCC1 rs3212986 AA variant genotype was identified as a protective factor for gastric cancer (AA vs. CC: AOR=0.73, 95% CI=0.54–0.98; recessive model: AOR=0.72, 95% CI=0.54–0.96). Genotype-based mRNA expression analysis further indicated that the rs2298881 A allele was associated with decreased ERCC1 mRNA expression. Conclusion: In all, these results indicated that the ERCC1 polymorphisms may affect the risk of gastric cancer in the Chinese Han population. Keywords: gastric cancer, DNA repair, NER, polymorphism, susceptibility

Xiao Liu,1,* Jingge Qu,2,* Weixiao Xue,1 Liangai He,1 Jun Wang,3 Xuejiao Xi,1 Xiaoxia Liu,1 Yunhong Yin,1 Yiqing Qu1 1Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Rheumatology, Second Hospital of Harbin Medical University, Harbin, People’s Republic of China; 3Department of Respiratory Medicine, Second Hospital of Shandong Traditional Chinese Medicine University, Jinan, People’s Republic of China *These authors contributed equally to this work Objectives: MicroRNAs (miRNAs) play essential roles in the development of COPD. In this study, we aimed to identify and validate potential miRNA biomarkers in frequent and non-frequent exacerbators of COPD patients using bioinformatic analysis.Materials and methods: The candidate miRNA biomarkers in COPD were screened from Gene Expression Omnibus (GEO) dataset and identified using GEO2R online tool. Then, we performed bioinformatic analyses including target prediction, gene ontology (GO), pathway enrichment analysis and construction of protein–protein interaction (PPI) network. Furthermore, the expression of the identified miRNAs in peripheral blood monocular cells (PBMCs) of COPD patients was validated using quantitative real-time polymerase chain reaction (qRT-PCR).Results: MiR-23a, miR-25, miR-145 and miR-224 were identified to be significantly downregulated in COPD patients compared with healthy controls. GO analysis showed the four miRNAs involved in apoptotic, cell differentiation, cell proliferation and innate immune response. Pathway analysis showed that the targets of these miRNAs were associated with p53, TGF-β, Wnt, VEGF and MAPK signal pathway. In healthy controls, the miR-25 and miR-224 levels were significantly decreased in smokers compared with nonsmokers (P

Na Chen,1 Ming Rong,1 Xiaoguang Shao,2 Heng Zhang,1 Shupeng Liu,1,3 Baijun Dong,2 Wei Xue,2 Tingyun Wang,1 Taihao Li,3 Jiahua Pan2 1Key Laboratory of Specialty Fiber Optics and Optical Access Networks, School of Communication and Information Engineering, Shanghai University, 2Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 3Beijing Advanced Innovation Center for Imaging Technology, Capital Normal University, Beijing, People’s Republic of China Abstract: The surface-enhanced Raman spectroscopy (SERS) of blood serum was investigated to differentiate between prostate cancer (PCa) and benign prostatic hyperplasia (BPH) in males with a prostate-specific antigen level of 4–10 ng/mL, so as to reduce unnecessary biopsies. A total of 240 SERS spectra from blood serum were acquired from 40 PCa subjects and 40 BPH subjects who had all received prostate biopsies and were given a pathological diagnosis. Multivariate statistical techniques, including principal component analysis (PCA) and linear discriminant analysis (LDA) diagnostic algorithms, were used to analyze the spectra data of serum from patients in control (CTR), PCa and BPH groups; results offered a sensitivity of 97.5%, a specificity of 100.0%, a precision of 100.0% and an accuracy of 99.2% for CTR; a sensitivity of 90.0%, a specificity of 97.5%, a precision of 94.7% and an accuracy of 98.3% for BPH; a sensitivity of 95.0%, a specificity of 93.8%, a precision of 88.4% and an accuracy of 94.2% for PCa. Similarly, this technique can significantly differentiate low- and high-risk PCa with an accuracy of 92.3%, a specificity of 95% and a sensitivity of 89.5%. The results suggest that analyzing blood serum using SERS combined with PCA–LDA diagnostic algorithms is a promising clinical tool for PCa diagnosis and assessment. Keywords: Ag nanoparticles, linear discriminant analysis, gray zone, principle component analysis, benign prostatic hyperplasia, spectral classification

Heng Liu,1,2 Xiao Chen,1 Wei Xue,1 Chengchao Chu,2 Yu Liu,2 Haipeng Tong,1 Xuesong Du,1 Tian Xie,1 Gang Liu,2 Weiguo Zhang1,3 1Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 2State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 3Chongqing Clinical Research Center for Imaging and Nuclear Medicine, Chongqing, People’s Republic of China Abstract: The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma. Keywords: epidermal growth factor-like domain-1, tissue factor, iron oxide nanoparticles, MRI, glioma

Ruyan Wu,1,* Dandan Zhu,1,* Youchun Xia,2,* Haosen Wang,2 Weiwei Tao,1 Wenda Xue,1 Baomei Xia,1 Li Ren,1 Xin Zhou,1 Guochun Li,3 Gang Chen1 1Center for Translational Systems Biology and Neuroscience, Key Laboratory of Integrative Biomedicine of Brain Diseases, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2The Fourth People’s Hospital of Taizhou, Taizhou, People’s Republic of China; 3School of Basic Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China *These authors contributed equally to this work Introduction: Conventional antidepressants, including fluoxetine, have a major disadvantage in delayed onset of efficacy. Yueju, an herbal medicine used to treat mood disorders was recently found to exhibit rapid antidepressant effects. The present study was conducted to evaluate the role of Yueju in rapidly acting on major depressive disorder (MDD).Methods: Participants were MDD patients with scores of 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20 and without history of antidepressant use. They randomly received daily oral doses of Yueju (23 g/day) plus fluoxetine (20 mg/day) (experimental group) or placebo plus fluoxetine (control group) for 7 days. HDRS-24 was used as the primary outcome measurement at baseline, and on days 1, 3, 5, and 7. Concentrations of serum brain-derived neurotrophic factor (BDNF) were assessed at baseline and on days 1 and 7.Results: In all, 18 participants met the criteria for data analysis. Compared to baseline level, only experimental group showed significant decrease of HDRS-24 score from day 3 to day 7 (P

Stephane A Régnier,1 William Malcolm,2 Jennifer Haig,3 Weiguang Xue41Novartis Pharma AG, Basel, Switzerland; 2Novartis Pharmaceuticals UK Ltd, Frimley Business Park, UK; 3Optum, Burlington, ON, Canada; 4Optum, Uxbridge, UKBackground: Ranibizumab and aflibercept are alternative anti-vascular endothelial growth factor agents approved for the treatment of visual impairment (VI) due to diabetic macular edema (DME).Objective: To estimate, from a UK healthcare perspective, the cost-effectiveness of ranibizumab 0.5 mg pro re nata (PRN) and ranibizumab 0.5 mg treat and extend (T&E) compared with aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8) in the treatment of VI due to DME.Methods: A Markov model previously reviewed by the National Institute for Health and Care Excellence was used to simulate the long-term outcomes and costs of treating DME. Health states were defined by increments of ten letters in best-corrected visual acuity (BCVA), with a 3-month cycle length. Patients could gain (or lose) a maximum of two health states between cycles. A 3-year treatment time frame and a lifetime horizon were used. Future costs and health outcomes were discounted at 3.5% per annum. Patient baseline characteristics and the efficacy of ranibizumab PRN were derived using data from the RESTORE study. The relative efficacies of ranibizumab PRN, ranibizumab T&E, and aflibercept were assessed with a network meta-analysis. Different utilities were assigned based on BCVA and whether the treated eye was the better- or the worse-seeing eye. Sensitivity analyses tested the robustness of the model.Results: Lifetime costs per patient of treating DME were £20,019 for ranibizumab PRN, £22,930 for ranibizumab T&E, and £25,859 for aflibercept 2q8. Ranibizumab was dominant over aflibercept, with an incremental gain of 0.05 quality-adjusted life-years (QALYs) and cost savings of £5,841 (PRN) and £2,930 (T&E) compared with aflibercept. Ranibizumab PRN and ranibizumab T&E had 79% and 67% probability, respectively, of being cost-effective relative to aflibercept at a willingness-to-pay threshold of £20,000/QALY. When assuming the higher end of PRN injection frequency (15.9 over 3 years), the cost savings associated with ranibizumab were £3,969.Conclusion: From a UK healthcare perspective, ranibizumab provides greater health gains with lower overall costs than aflibercept in patients with VI due to DME.Keywords: Markov model, cost-utility, health states, macula, retina