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Hongyan Tan, Bin Zhang, Xiawei Kang, Lvyao Wang, Xiao Qiu, Xiangyu Hu Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400011, People’s Republic of ChinaCorrespondence: Xiangyu Hu, Email 369930758@qq.comPurpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris.Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects.Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α.Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.Keywords: pityriasis rubra pilaris, JAK inhibitors, tofacitinib, secukinumab, ustekinumab

Xin Qiu,1,2,* Shuang Shen,1,* Donghong Lu,2 Nizhen Jiang,3 Yifei Feng,3 Jindu Li,1 Chenglei Yang,1 Bangde Xiang1,4,5 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 4Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, People’s Republic of China; 5Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bangde Xiang; Chenglei Yang, Email xiangbangde@gxmu.edu.cn; chenglei2017yang@163.comBackground: Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its poor prognosis and high recurrence rates post-surgery. This study examines the predictive efficacy of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the post-hepatectomy prognosis of patients with HCC.Methods: A cohort comprising 1654 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital from 2013 to 2019 was enrolled. Patients were stratified into two groups according to the median ALI level, and then subjected to propensity score matching (PSM) in a 1:1 ratio. Kaplan-Meier survival curves, the traditional Cox proportional hazards (CPH) model, and machine learning (ML) models were employed to analyze and evaluate ALI’s prognostic significance. Furthermore, ALI’s prognostic value in digestive system tumors was validated via analysis of the National Health and Nutrition Examination Survey (NHANES) database.Results: After applying PSM, a final cohort of 1284 patients, categorized into high and low ALI groups, revealed a significantly reduced survival time in the low ALI cohort. Univariate and multivariate Cox analyses identified ALI, BCLC stage, CK19, Hepatitis B virus (HBV) DNA, lymph node metastasis, and microvascular invasion (MVI) as independent predictors of prognosis. Both traditional CPH and ML models incorporating ALI demonstrated excellent predictive accuracy, validated through calibration curves, time-dependent ROC curves, and decision curve analysis. Furthermore, the prognostic value of ALI in digestive tumors was confirmed in the NHANES database.Conclusion: The ALI exhibits potential as a prognostic predictor in patients with HCC following hepatectomy, providing valuable insights into postoperative survival.Keywords: advanced lung cancer inflammatory index, ALI, hepatocellular carcinoma, HCC, prognosis, Cox regression, machine learning, ML

Min Jiang,1,* Hui Zhang,2,* Wenjun Lu,3 Xuedan Qiu,1 Chenyao Lin,1 Rongqing Zhao,1 Qingcao Li,1 Qiaoping Wu1 1Clinical Laboratory, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China; 2Clinical Laboratory, Ninghai County Chengguan Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 3Intensive Care Units, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingcao Li; Qiaoping Wu, The Affiliated LiHuiLi Hospital of Ningbo University, 1111 Jiangnan Road, Ningbo, Zhejiang Province, 315040, People’s Republic of China, Tel +86-574-55835786, Fax +86-574-55835781, Email lqc_lab@163.com; lhlyywqp@163.comBackground: Klebsiella pneumoniae (KP) is a common nosocomial pathogen. Capsules are an important component of KP’s virulence, among which the K1, K2, K5, K20, K54, and K57 serotypes are predominant and exhibit varying degrees of virulence.Methods: The capsule and virulence genes of 150 carbapenem-resistant Klebsiella pneumoniae (CRKP) and 213 carbapenem-sensitive Klebsiella pneumoniae (CSKP) isolates were examined by polymerase chain reaction (PCR). The isolates were tested for hypermucoviscosity by string tests. Phylogenetic relationships between KP isolates were analyzed using multilocus sequence typing (MLST) and a Galleria mellonella infection model confirmed the differences in virulence.Results: A total of 111 of 363 isolates of KP were detected, the highest detected serotypes were K1, K5, and K2, and CSKP was detected more frequently than CRKP. There was a greater prevalence of K1 and K2 serotypes in CSKP, while in CRKP, K5 serotypes were more prevalent. K1 isolates had the highest detection rates for hypermucoviscosity Klebsiella pneumoniae (hmKP) and hypervirulent Klebsiella pneumoniae (hvKP), and carried the most virulence genes. K54 isolates had the lowest detection rate of hmKP while K5 isolates had the lowest detection rate of hvKP and carried the fewest virulence genes. MLST results for serotypes K1, K20, and K57 showed significant homogeneity, while those for serotypes K2, K5, and K54 showed diversity. The Galleria mellonella infection model showed that the K1 serotype was the most virulent and the K54 serotype was the weakest.Conclusion: CSKP isolates were detected more frequently than CRKP isolates for capsular serotype detection. K1 isolates had the most virulence gene and strongest virulence, K5 isolates carried the fewest virulence genes, and K54 isolates had the weakest virulence. Furthermore, significant homogeneity was observed among K1, K20, and K57 isolates.Keywords: Klebsiella pneumoniae, capsular serotypes, virulence, MLST

Yongxiong Huang,1,2,* Xianshuai Qiu,3,* Jinlian Liu,4 Jiangtao Wan,5 Cheng Yu,1 Chun Liu,1 Yang Duan,1 Chong Chen,2 Jingxing Dai,6 Jun Ouyang,6 Ming Liu,3 Shaoxiong Min,1,5 Sujun Qiu1 1Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Spine Surgery, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, 510000, People’s Republic of China; 3Department of Orthopedics and Sports Medicine Center, Heyou Hospital, Foshan, 528333, People’s Republic of China; 4Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 5Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Medical Biomechanics & National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sujun Qiu, Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China, Email qiusjspine@126.com Shaoxiong Min, Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China, Email msxbear24@163.comBackground: Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). The mechanism of IDD development and progression is not fully understood. Peripheral biomarkers are increasingly vital non-radioactive methods in early detection and diagnosis for IDD. Nevertheless, less attention has been paid to the role of mitophagy genes in the progress of IDD. This study aimed to identify the mitophagy disease-causing genes in the process of IDD and mitophagy diagnostic biomarkers for IDD.Methods: Mitophagy-related differentially expressed genes (MRDEGs) related to IDD were investigated by analyzing the microarray datasets of IDD cases from GEO, PathCards and Molecular Signatures Databases. We used R software, WGCNA, PPI, mRNA-miRNA, mRNA-TF, GO, KEGG, GSEA, GSVA and Cytoscape to analyze and visualize the data. We further used ssGSEA for immunoinfiltration analysis to obtain different immune cell infiltration. LASSO model was developed to screen for genes that met the diagnostic gene model requirements. Finally, qRT-PCR, Western blotting and HE were used to verify hub genes and their expression from clinical IDD samples.Results: We identified 14 MRDEGs and 12 hub genes. GO, KEGG, GSEA and GSVA analyses demonstrated that hub genes were critical for the development of IDD. LASSO diagnostic model consisted of six hub genes, among which SQSTM1, ATG7 and OPTN were significantly different between the two IDD disease subtypes. At the same time, SQSTM1 also had a high correlation with immune characteristic subtypes. The results of qRT-PCR and Western blotting also indicated that these genes were significantly differentially expressed in nucleus pulposus cells (NPCs) of the IDD group.Conclusion: We explored an association between MRDEGs-associated signature in IDD and validated that hub genes like SQSTM1 might serve as biomarkers for diagnostic and therapeutic targets for IDD. Meanwhile, this study can provide new insights into the functional characteristics and mechanism of mitophagy in the development of IDD. Keywords: intervertebral disc degeneration, mitophagy-related differentially expressed genes, immune infiltration, diagnostic model, SQSTM1, nucleus pulposus cells

Yuanfeng Wang,1,* Xu Qiu,1,* Jiao Liu,1,* Xuanyi Liu,1 Jialu Pan,2 Jiayi Cai,2 Xiaodong Liu,1,3 Shugen Qu1,3 1College of Public Health and Management, Zhejiang Provincial Key Laboratory of Watershed Science and Health, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3South Zhejiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou, People’s Republic of China*These authors contributed equally to this work.These authors contributed equally to this workCorrespondence: Xiaodong Liu; Shugen Qu, Email forget45@wmu.edu.cn; shugenju@wmu.edu.cnIntroduction: Sepsis is a worldwide epidemic, with high morbidity and mortality. Cuproptosis is a form of cell death that is associated with a wide range of diseases. This study aimed to explore genes associated with cuproptosis in sepsis, construct predictive models and screen for potential targets.Methods: The LASSO algorithm and SVM-RFE model has been analysed the expression of cuproptosis-related genes in sepsis and immune infiltration characteristics and identified the marker genes under a diagnostic model. Gene-drug networks, mRNA-miRNA networks and PPI networks were constructed to screen for potential biological targets. The expression of marker genes was validated based on the GSE57065 dataset. Consensus clustering method was used to classify sepsis samples.Results: We found 381 genes associated with the development of sepsis and discovered significantly differentially expressed cuproptosis-related genes of 16 cell types in sepsis and immune infiltration with CD8/CD4 T cells being lower. NFE2L2, NLRP3, SLC31A1, DLD, DLAT, PDHB, MTF1, CDKN2A and DLST were identified as marker genes by the LASSO algorithm and the SVM-RFE model. AUC > 0.9 was constructed for PDHB and MTF1 alone respectively. The validation group data for PDHB (P=0.00099) and MTF1 (P=7.2e-14) were statistically significant. Consistent clustering analysis confirmed two subtypes. The C1 subtype may be more relevant to cellular metabolism and the C2 subtype has some relevance to immune molecules.The results of animal experiments showed that the gene expression was consistent with the bioinformatics analysis.Discussion: Our study systematically explored the relationship between sepsis and cuproptosis and constructed a diagnostic model. And, several cuproptosis-related genes may interfere with the progression of sepsis through immune cell infiltration.Keywords: machine learning, cuproptosis, immune infiltration, sepsis, diagnostic model

Xun Qiu,1,2,* Libin Dong,1,2,* Kai Wang,1,2 Xinyang Zhong,1,2 Hanzhi Xu,1,2 Shengjun Xu,2 Haijun Guo,2 Xuyong Wei,1,2 Wei Chen,2,3 Xiao Xu1,2 1Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China; 2Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China; 3Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Chen; Xiao Xu, Email jackweichen@zju.edu.cn; zjxu@zju.edu.cnBackground: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence indicates that hypoxia and lactate metabolism play critical roles in tumor progression and therapeutic efficacy. This study aimed to construct a hypoxia- and lactate metabolism-related prognostic model (HLPM) to evaluate survival and treatment responses for HCC patients and develop a nomogram integrated with HLPM and clinical characteristics for prognosis prediction in HCC.Methods: Expression profile and clinical data of HCC were obtained from TCGA and ICGC databases. The univariate, LASSO and stepwise multivariate Cox analyses were used to identify the hypoxia- and lactate metabolism-related biomarkers, whose expression levels were then validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Kaplan–Meier survival curves were utilized to assess the prognostic values of biomarkers or models. Analyses of ImmuCellAI, TIDE and drug sensitivity were conducted to evaluate the therapeutic responses of patients. Furthermore, the nomogram integrated with hypoxic and lactate metabolic characteristics was established through univariate and multivariate Cox analyses. ROC curves, C-index, and calibration curves were depicted to evaluate the performance of the nomogram.Results: Five hypoxia- and lactate metabolism-related biomarkers (KIF20A, IRAK1, ADM, PPARGC1A and EPO) were used to construct HLPM. The expression of five prognostic biomarkers was validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Analyses of ImmuCellAI, TIDE and drug sensitivity implied that patients with low-risk score were more sensitive to immunotherapy and major chemotherapeutic agents. The nomogram that contained age, histological grade and risk score of HLPM was developed and exhibited a better capacity in prognosis prediction than HLPM only.Conclusion: A novel nomogram integrated with hypoxic and lactate metabolic characteristics was developed and validated for prognosis prediction in HCC, providing insight into personalized decision-making in clinical management.Keywords: hepatocellular carcinoma, nomogram, prognosis, lactate metabolism, hypoxia, immunotherapy

Rehua Wang,1,2,* Yongjun Lin,3,* Mao Chen,4 Wei Wang,5 Yongli Chen,6 Xiaoxia Qiu,7 Xing Miao1,2 1Department of Cardiology, Fujian Provincial Hospital, Fuzhou, 350001, People’s Republic of China; 2Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 3Department of General Medicine, the First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 4Department of Scientific Research, Fujian Provincial Hospital, Fuzhou, 350001, People’s Republic of China; 5Department of Psychiatry, Fuzhou Neuro-Psychiatric Hospital Affiliated to Fujian Medical University, Fuzhou, 350008, People’s Republic of China; 6Department of Cardiology, Fujian Provincial Hospital South Branch, Fuzhou, 350028, People’s Republic of China; 7Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xing Miao, Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, No. 134 East Street, Gulou District, Fuzhou, 350001, People’s Republic of China, Tel +86 13763810443, Email miaoxingph@outlook.comPurpose: Temperature changes unfavorably impact on cardiovascular disease. However, the association between temperature changes and coronary artery disease (CAD) is not well documented. This study aimed to explore the association between daily mean temperature and daily CAD hospital admissions on the southeast coast of China (Fuzhou City).Methods: A total of 1883 CAD patients who underwent percutaneous coronary intervention between 2017 and 2019 were obtained. The severity of CAD was evaluated by the Gensini score. Distributed lag non-linear model (DLNM) combined with a quasi-Poisson regression model was used to examine the delayed effect between daily mean temperature and daily CAD hospital admissions. Stratified analyses were performed by Gensini score and severity of lesions. The relative risk (RR) with a 95% confidence interval (CI) was used to assess the relationship.Results: Extreme cold (8°C) (RR=0.49, 95% CI: 0.25– 0.99) and moderate cold (10°C) (RR=0.56, 95% CI: 0.31– 0.99) daily mean temperature with a lag of 0– 20 days were correlated with lower risk of daily CAD hospital admissions. Moderate heat (30°C) (RR=1.80, 95% CI: 1.01– 3.20) and extreme heat (32°C) (RR=2.02, 95% CI: 1.01– 4.04) daily mean temperature with a lag of 0– 20 days related to a higher risk of daily CAD hospital admissions. Similar results were observed for daily mean temperature with a lag of 0– 25 days. Stratified analysis showed the lagged effect of daily mean temperature (lag 0, 0– 5, 0– 15, 0– 20, and 0– 25 days) on the daily CAD hospital admissions was observed only in patients with a Gensini score ≤ 39 (tertile 1).Conclusion: Cold temperatures may have a protective effect on daily CAD hospital admissions in the Fuzhou area, whereas hot temperatures can have an adverse effect.Keywords: temperature, coronary artery disease, gensini score, daily admissions, lag effect

Guimei Fan,1 Mo Yi,2 Xiangmin Qiu,1 Jinfang Zhao1 1Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2School of Nursing, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Jinfang Zhao, Shandong Provincial Hospital Affiliated to Shandong First Medical University, #324 Jingwuweiqi Road, Huaiyin District, Jinan City, Shandong Province, 250021, People’s Republic of China, Email zjfcqt@qq.comPurpose: This study aims to explore the complicated decision-making dilemma and challenges confronted by parents of children suffering from severe asthma within the Pediatric Intensive Care Unit (PICU) when participating in the development of their children’s discharge care plans.Patients and Methods: Employing a phenomenological methodology, a purposive sampling was performed to engage with 17 parents who participated in in-depth and semi-structured interviews between October 2022 and February 2023. The transcripts of these interviews were transcribed into textual data, which was then subjected to Colaizzi’s seven-step analysis for meticulous coding and comprehensive thematic elucidation.Results: The comprehensive analysis of the factors involved in the intricate decision-making dilemmas faced by parents of children with severe asthma during the process of crafting discharge care plans in the PICU revealed five themes and eight sub-themes: 1) Complexity of asthma-related information; 2) Insufficient provision of comprehensive decision-making support; 3) Encountering negative emotions and wavering confidence; 4) Navigating realistic constraints impacting both parents and HCPs; 5) Balancing the advantages and disadvantages of various plans.Conclusion: Parents of children with severe asthma in the PICU encounter intricate and multifaceted decision-making dilemmas while engaging in the formulation of discharge care plans. These complexities significantly dampen their decision-making enthusiasm and introduce potential risks to the children’s prognosis and recovery. In the future, it is imperative to leverage the guidance provided by healthcare professionals (HCPs) in the decision-making process, develop tailored decision support tools specifically designed for the formulation of discharge care plans for children with severe asthma in the PICU.Keywords: severe asthma, parents, discharge care plan, decision-making dilemma, phenomenological study

Xiaohua Wang,&ast; Liyan Yuan,&ast; Xiaoyu Qiu, Bin Yang, Mao-Qiang Man Dermatology Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mao-Qiang Man; Bin Yang, Dermatology Hospital, Southern Medical University, No. 2 Lujing Road, Guangzhou, 510095, People’s Republic of China, Tel +86-20-87255286, Email mqman@hotmail.com; yangbin1@smu.edu.cnObjective: To determine whether COVID-19 infection and psoriasis impact each other.Methods: WeChat app was used to carry out a questionnaire survey in individuals aged 18 years and over.Results: A total of 3581 individuals, including 2515 individuals without psoriasis and 1066 psoriatic patients completed the survey. The rate of COVID-19 infection was significantly higher in psoriatic patients than in those without psoriasis (89.59% vs 77.93%, p < 0.0001). Moreover, the rate of relapse and/or worsening of psoriasis was higher in psoriatic patients with COVID-19 infection than in that without COVID-19 infection (75.29% vs 47.75%, p < 0.0001).Conclusion: COVID-19 infection and psoriasis negatively impact each other.Keywords: COVID-19, psoriasis, infection

Xiaoqin Qiu,1 Yuechou Nong2 1Department of Nursing, The Guangxi Hospital of the First Affiliated Hospital of Sun Yat-sen University, Nanning, Guangxi, 530021, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Guangxi Academy of Medical Sciences, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Yuechou Nong, Email yuechou_gx@163.com

Xiangnan Qiu,1 Changchen Jiang,1 Shenghua Jing,1 Aomei Li,1 Xiangdong Sun,1 Zetian Shen2 1Department of Radiation Oncology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, People’s Republic of China; 2Department of Radiation Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210031, People’s Republic of ChinaCorrespondence: Zetian Shen; Xiangdong Sun, Email sztflk@163.com; sxdflk@163.comPurpose: The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution.Methods: A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery.Results: The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable.Conclusion: In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.Keywords: rectal cancer, preoperative chemoradiotherapy, overall survival, disease control

Yuting Liu,1,&ast; Jie Tang,1,&ast; Xiaolan Qiu,1,&ast; Lucy A Teng,2 Mukesh K Sriwastva,2 Xuedong Han,1 Zhi Li,1 Minmin Liu,1 Shuangyue Liu,1 Dongzhu Da,1 Zhi Li,1 Linlin Zhen,1 Yi Ren1 1Department of Breast and Thyroid Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, USA&ast;These authors contributed equally to this workCorrespondence: Yi Ren; Linlin Zhen, Department of Breast and Thyroid Surgery, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China, Email only_renyi@163.com; simu1027@sina.comBackground: Recent therapeutic approaches have improved survival rate for women with breast cancer, but the survival rate for metastatic breast cancer is still low. Exosomes released by various cells are involved in all steps of breast cancer development.Methods: We established the multimodal imaging report expression in breast cancer cells with lentivirus vectors pGluc and pBirA to investigate the secreted exosomes. Comparative microRNA (miRNA) analysis was performed with miRNA qPCR array in mice with breast cancer lung metastasis. The co-immunoprecipitation and chromatin immunoprecipitation assays were used to identify the mechanism of miRNA sorting to exosomes. The potential therapeutic strategy using an anti-sorting antibody was used to investigate breast cancer lung metastasis.Results: We identified 26 high- and 32 low-expression level miRNAs in exosomes from metastasis compared to those from primary tumors and normal tissues. The tumor suppressors, including miR-200c and let-7a, were reduced in tumor tissues and metastasis but increased in the respective exosomes compared to normal tissues. Furthermore, the Ras-related protein (Rab1A) facilitated miR-200c sorting to exosomes circumventing the influence of tumor suppressor miR-200c on tumor cells, while the metastatic exosome cargo miR-200c inhibited F4/80+ macrophage immune response. Administration of anti-Rab1A antibody significantly repressed the trafficking of miR-200c to exosomes and breast cancer lung metastasis.Conclusion: Our study has identified a novel molecular mechanism for breast cancer lung metastasis mediated by exosome cargo miRNAs and provided a new therapeutic strategy for cancer immunotherapy.Graphical Abstract: Keywords: extracellular vehicles, exosomes, breast cancer lung metastasis, miR-200c, Rab1A, miRNA sorting

Xiaonan Meng,1,2,&ast; Jie Sun,3,&ast; Qi Liu,4,&ast; Yueping Huang,5 Xianwen Qiu,6 David Jung Seto,7,8 Ying Li,3 Liping Wang,2 Chunying Li,2 Sen Gao,9 Haikuo Yu,10 Jiping Zhao,1 Baixiao Zhao1 1Department of Acupuncture and Moxibustion, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Acupuncture and Moxibustion, Beijing Huguosi TCM Hospital, Affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Integrated Chinese and Western Medicine Rehabilitation, Beijing Xiaotangshan Hospital, Beijing, People’s Republic of China; 4Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 5School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 6Department of Acupuncture and Moxibustion, Beijing Shichahai Community Healthcare Center, Beijing, People’s Republic of China; 7Division of Integrative Medicine, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; 8Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 9Department of Rehabilitation, Beijing Huguosi TCM Hospital, affiliated with Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 10Rehabilitation Department, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiping Zhao; Baixiao Zhao, Email zjp7883@sina.com; baixiao100@vip.sina.comBackground: Post-stroke shoulder-hand syndrome (PS-SHS), a common neurological comorbidity after stroke episodes, poses a grave threat on patients’ functional recovery. Preliminary trials have demonstrated that the acupuncture and moxibustion treatment, including a dermal acupuncture tapping method known as plum blossom needling (PBN) can improve pain and motor dysfunctions in patients with PS-SHS. However, there are few reports describing simultaneous moxibustion treatment in combination with PBN. Hence, a novel plum blossom needle device with mild moxibustion (PBNMM) was developed to evaluate its potential efficacy and safety in patients with stage 1 PS-SHS.Materials and Methods: This multicenter, sham-controlled, randomized controlled trial (RCT) will recruit 102 eligible patients with stage 1 PS-SHS from three clinical centers, randomly allocated in a ratio of 1:1:1 to the PBNMM group, PBNMM with no moxa smoke (PBNMM-NMS) group and sham control group. Patients in each group will receive a 30-minute treatment once per day for 4 weeks, with 5 consecutive sessions per week, for a total of 20 sessions. The primary outcome measure will be defined as the decreased scores from baseline in the visual analog scale (VAS) assessment at week 4. Secondary outcome measures will include scores on the Fugl-Meyer Assessment of the Upper Extremity Scale (FMA-UE), the Modified Barthel Index (MBI), and the somatosensory evoked potential (SEP) records. All outcomes will be evaluated at baseline and weeks 4, 5, 6 and 10, and the intention-to-treat analysis will be applied.Conclusion: This study aims to provide robust evidence for the efficacy and safety of the PBNMM for PS-SHS treatment, as well as the specific impact of moxibustion smoke itself in dealing with PS-SHS.Clinical Trial Registration: Chinese Clinical Trial Registry No. ChiCTR2200062441. Registered on 7 August 2022.Keywords: plum blossom needling, mild moxibustion, novel device, post-stroke shoulder-hand syndrome, protocol, randomized controlled trial

Wang H, Zhou C, Su Y, Gou K, Geng X, Qiu X. Drug Des Devel Ther. 2021;15:4865–4873. The authors have informed the journal that ripretinib was used in this study, not erdafitinib as indicated in parts of the paper. Namely, on page 4865, Abstract, Results section; page 4868, Animal Experiments and Pharmacokinetics Study sections; page 4872, Pharmacokinetics Effects and Conclusions sections. The authors have also advised on page 4867, Materials and Methods, Chemicals Materials section, third line from the bottom, the text “Itraconazole” should read “voriconazole”. The authors apologize for any confusion this may have caused.

Qi He, Feihong Ji, Xinghao Fu, Zehao Li, Xinguang Qiu Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Xinguang Qiu, Email qxg0914@126.comIntroduction: Currently, there is no consensus on the specific effect of Extrathyroidal Extension (ETE) on prognosis. The purpose of our study was to study the relationship between different states of ETE and its disease-free survival rate and to determine the basic standard of Micro ETE (tumor extends through capsule only) in risk stratification.Material and Methods: We conducted a retrospective and single-center study that included the clinical data of all papillary thyroid carcinoma (PTC) patients with ETE in our hospital from 2013 to 2017 and followed them up after rigorous screening. According to ETE state, it is divided into four groups: Microscopic, Micro, Minimal, Macro. Kaplan–Meier method was used to calculate disease-free survival (DFS). Log-rank test was used to compare the differences between the groups and to polt the survival curves. P< 0.05 was considered statistically significant. Micro ETE was included in different risk stratification subgroups and their DFS was compared.Results: A total of 436 patients were included: Microscopic group N=50 (11.47%), Micro group N=74 (16.97%), Minimal group N=135 (30.96%), and Macro group N=177 (40.60%). The frequency of ETE was in strap muscles N=191, trachea N=114, laryngeal recurrent nerve N=92, and capsule N=74, etc. The 5-year DFS rate in Micro group was 95.3%, higher than that in Macro group (P< 0.05). The 5-year DFS rate of Micro ETE was 90.0% in the intermediate-risk group and 84.9% in the high-risk group when Micro ETE was included in different risk stratification subgroups.Conclusion: Micro ETE deserves more attention, has a batter prognosis than Macro ETE, and may have little effect on recurrence. It seems more appropriate to treat Micro ETE as the intermediate-risk group in risk stratification.Keywords: extrathyroidal extension, risk stratification, papillary thyroid carcinoma, prognosis

Ting Li1,2 &ast;, Shaowei Niu3 &ast;, Xiang Qiu4 &ast;, Zhaohua Zhai,2 Lin Yang,2 Li Chen,2 Xiao Ming Zhang1,2 1The First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China; 2Medical Imaging Key Laboratory of Sichuan Province, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 3Department of Infection, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 4Department of Radiology, Integrated TCM & Western Medicine Hospital Affiliated to Chengdu University of TCM, Chengdu First People’s Hospital, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao Ming Zhang, Medical Imaging Key Laboratory of Sichuan Province, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, No. 234 Fujiang Road, Nanchong, People’s Republic of China, Tel/Fax +86 08172242635, Email zhangxm@nsmc.edu.cnPurpose: To investigate cerebral blood flow (CBF) characteristics in individuals with generalized tonic‒clonic seizures (GTCS) during the interictal phase using voxel-based analysis of 3D pseudocontinuous arterial spin labeling (PCASL).Patients and Methods: Patients with GTCS (GTCS group) (during the interictal period) and healthy volunteers (control group) underwent head MR imaging with a 3.0T MR scanner with a 3D PCASL sequence. CBF was compared between the two groups. Spearman correlations of CBF in regions of interest (ROIs) in GTCS patients with the duration of disease and age of onset were analyzed and corrected using the false discovery rate (FDR).Results: Twenty patients with GTCS (GTCS group) and twenty healthy volunteers (control group) were recruited for this study. On 3D PCASL, (1) GTCS patients had lower CBF in the brainstem, right cerebellum, right inferior temporal gyrus, parahippocampal gyrus, superior frontal gyrus, middle frontal gyrus, triangular part of inferior frontal gyrus, left temporal pole of superior temporal gyrus and thalamus and had higher CBF in the bilateral superior parietal gyri, precuneus, precentral gyri, postcentral gyri, and left dorsolateral superior frontal gyrus than controls. (2) The CBF of the right temporal pole of the middle temporal gyrus was negatively correlated with the duration of disease (PFDRcorrected< 0.05), with a correlation coefficient r of − 0.7333 and a PFDRcorrected value of 0.04.Conclusion: Voxel-based analysis of 3D PCASL imaging can be used to sensitively detect brain perfusion differences in GTCS patients. The decrease in CBF in the right temporal pole of the middle temporal gyrus may be associated with disease onset. These findings may offer new perspectives on the pathogenesis of GTCS and the underlying pathophysiological changes associated with perfusion.Keywords: arterial spin labeling imaging, generalized tonic‒clonic epilepsy, magnetic resonance imaging, voxel-based analysis, perfusion

Xiaowei Qiu,1 Sipei Zheng,2 Jun Yang,3 Guocan Yu,3,&ast; Yiming Ye4,&ast; 1Department of Radiology, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2The Second School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Clinical Medical Examination Laboratory Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guocan Yu, Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, No. 208 East Huancheng Road, Hangzhou, People’s Republic of China, Email dabaitwo@163.com Yiming Ye, Clinical Medical Examination Laboratory Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, No. 208 East Huancheng Road, Hangzhou, People’s Republic of China, Email 178822130@qq.comObjective: To evaluate the rapid diagnostic accuracy of Mycobacterium tuberculosis RNA (TB-RNA) for pulmonary tuberculosis (PTB) in a large patient sample and to evaluate the difference in TB-RNA diagnostic accuracy in various respiratory specimens.Methods: Patient medical records were retrospectively reviewed to determine the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of the acid-fast bacillus (AFB) smear and TB-RNA to evaluate their diagnostic accuracy against final clinical diagnosis.Results: Of the 2336 patients ultimately included, 1123 provided 1 sputum specimen each and 1213 provided 1 bronchoalveolar lavage fluid (BALF) specimen each. The overall sensitivity, specificity, PPV, NPV, and AUC of the AFB smear were 36.2%, 86.4%, 90.6%, 27.3%, and 0.61, respectively. The overall sensitivity, specificity, PPV, NPV, and AUC of TB-RNA for the rapid detection of PTB were 57.4%, 99.4%, 99.7%, 39.3%, and 0.78, respectively. When sputum and BALF specimens were used for AFB smear testing, the sensitivity, specificity, PPV, NPV, and AUC of the AFB smear were 44.5%, 81.5%, 87.5%, 33.5%, and 0.63; and 29.2%, 92.7%, 94.8%, 22.5%, and 0.61, respectively. The sensitivity, specificity, PPV, NPV, and AUC of TB-RNA for the rapid detection of PTB using sputum were 49.6%, 99.3%, 99.5%, 40.4%, and 0.74, respectively; whereas those of TB-RNA determined using BALF were 63.9%, 99.5%, 99.8%, 38.0%, and 0.82, respectively.Conclusion: The diagnostic accuracy of TB-RNA for PTB was moderate and considerably better than that of the AFB smear. The diagnostic accuracy of TB-RNA for various respiratory specimens differed; the diagnostic accuracy of TB-RNA for BALF specimens was substantially better than that for sputum samples, and BALF specimens were more suitable for TB-RNA.Keywords: tuberculosis RNA, pulmonary tuberculosis, bronchoalveolar lavage fluid, sputum, accuracy

Jeffrey Bonenfant,1,2,&ast; Jiang Li,3,&ast; Luqman Nasouf,1 Joseph Miller,3 Tammy Lowe,1 Lukasz Jaroszewski,3 Xinru Qiu,3 Suman Thapamagar,1,2 Aarti Mittal,1,2 Adam Godzik,3 Walter Klein,1,2,&ast; Meera G Nair3,&ast; 1Department of Medicine, Division of Pulmonary and Critical Care Medicine, Riverside University Health System Medical Center, Moreno Valley, CA, USA; 2Division of Pulmonary, Critical Care, Hyperbaric, Allergy and Sleep Medicine, School of Medicine, Loma Linda University, Loma Linda, CA, USA; 3Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, USA&ast;These authors contributed equally to this workCorrespondence: Meera G Nair, Division of Biomedical Sciences, School of Medicine, University of California Riverside, 3135 Multidisciplinary Research Building 1, 900 University Avenue, Riverside, CA, CA92521, USA, Tel +951-827-7734, Email meera.nair@medsch.ucr.eduBackground: Sepsis mortality has remained unchanged for greater than a decade, and early recognition continues to be the most important factor in mortality outcome. Plasma resistin concentration is increased in sepsis, but its mechanism and clinical relevance is unclear. As one function, resistin interacts with toll-like receptor 4 in competition with lipopolysaccharide, a main component of the gram-negative bacterial cell wall. It is not known if the type of infection leading to sepsis influences resistin production. The objective of this study was to investigate whether 1) early plasma resistin concentration can predict mortality, 2) elevated plasma resistin concentration is associated with clinical disease severity scores, such as SOFA, mSOFA and APACHE II, and 3) plasma resistin concentrations differ between gram negative versus other etiologies of sepsis.Methods: This was an exploratory study in the framework of a prospective observational design. Peripheral venous blood samples were obtained from subjects admitted to the intensive care unit at clinical recognition of sepsis (0 hour) and at 6 and 24 hours. Vasopressor utilization was not a requirement for inclusion. Plasma was analyzed for resistin concentration by ELISA. Cytokine concentrations including IL-6, IL-8, and IL-10 were determined by cytokine bead array. Cytokine data were evaluated against publicly available sepsis RNA expression datasets to compare protein versus RNA expression levels in predicting clinical disease state. Clinical data were collected from electronic health records for clinical severity index calculations and context for interpretation of resistin and cytokine concentrations. Subjects were followed up to 60 days, or until death, whichever came first. Statistical analysis was completed with R package and SPSS software.Results: Resistin levels were elevated in subjects admitted to the intensive care unit with sepsis. Four-hundred subjects were screened with 45 subjects included in the final analysis. Thirteen of 45 patients were non-survivors. Mortality within 60 days correlated with significantly higher resistin concentrations than in survivors. A resistin concentration of > 126 ng/mL at clinical recognition of sepsis and > 197 ng/mL within the first 24 hours were associated with mortality within 60 days with an area under the curve of 0.82 and 0.88, respectively. Most subjects with resistin concentration greater than these threshold values were deceased prior to 30 days. Resistin concentrations correlated with SOFA, mSOFA, and APACHE II scores in addition to having association with increases in inflammatory and sepsis biomarkers. These associations were validated with analysis of RNA expression datasets.Conclusion: Plasma resistin concentrations of > 126 ng/mL at clinical recognition of sepsis and > 197 ng/mL within the first 24 hours of clinical sepsis recognition are associated with all-cause mortality. Resistin concentration within this timeframe also has comparable mortality association to well-validated clinical severity indices of SOFA, mSOFA, and APACHE II scores.Keywords: resistin, gram-negative, sepsis, mortality

Yan Lan, Chensheng Pan, Xiuli Qiu, Jinfeng Miao, Wenzhe Sun, Guo Li, Xin Zhao, Zhou Zhu, Suiqiang Zhu Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Zhou Zhu; Suiqiang Zhu, Tel +86-18171081029 ; +86-13035101141, Email zhouzhu@hust.edu.cn; zhusuiqiang@163.comPurpose: Previous studies have shown that persistent post-stroke depression (PSD) was associated with unfavorable prognosis. The aim of this multicenter prospective study was to investigate the predictors associated with persistent PSD, develop a nomogram and validate its clinical usefulness by decision curve analysis (DCA).Patients and Methods: A total of 875 acute ischemic stroke patients from four hospitals were consecutively recruited and completed 1-year follow-ups. Sociodemographic indicators, vascular risk factors, clinical information, serum biochemical indicators and cytokines were collected on admission. The functional outcome was assessed at 1 year after stroke. Persistent depression was defined as having a presentation of depression at each follow-up points and the depressive symptoms occurring persistently since the diagnosis of depression.Results: There were 513 patients who experienced PSD during the 1-year follow-up, the cumulative incidence of PSD within 1 year was 58.6%. Persistent PSD was recorded in 289 patients, of which 59 (20.4%) result in unfavorable outcomes. The risk factors of persistent PSD in 1 year after stroke were the Hamilton Depression Scale-17 items (HAMD-17) score at admission, serum direct bilirubin and free serum thyroxine (FT4) level and activated partial thromboplastin time (APTT). Nomogram conducted based on these factors has a C-index (± standard deviation) of 0.655 ± 0.039, and the DCA demonstrated that the nomogram had a favorable clinical utility.Conclusion: We found that persistent depression after stroke in the first-year time course after stroke was associated with HAMD-17 score at admission, lower serum direct bilirubin and FT4 level, and APTT. A nomogram was developed with advisable clinical usefulness in our study.Keywords: persistent post-stroke depression, nomogram, decision curve analysis

Yanyan Wang,1 He Wang,2 Wenzhe Sun,1 Jinfeng Miao,1 Wenwen Liang,1 Xiuli Qiu,1 Yan Lan,1 Chensheng Pan,1 Guo Li,1 Xin Zhao,1 Zhou Zhu,1 Suiqiang Zhu1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Medical Affairs, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of ChinaCorrespondence: Zhou Zhu; Suiqiang Zhu, Tel +86 18171081029 ; +86 13035101141, Fax +86 27-83663337, Email zhouzhu@hust.edu.cn; zhusuiqiang@163.comBackground: Post-stroke depression (PSD) is the most common neuropsychiatric complication after stroke, seriously affecting the quality of survivors’ life. As one of the important causes of PSD, neuroendocrine mechanism has been widely studied in recent years. The main objective of this study was to investigate the relationship between adrenocorticotropic hormone (ACTH) on admission and PSD at 3 months.Methods: This is a hospital-based prospective cohort study, which was conducted at three independent hospitals (Tongji Hospital, Wuhan First Hospital and Wuhan Central Hospital) between August 2018 and June 2019. A total of 768 ischemic stroke patients were finally eligible for analysis and categorized into equal tertiles according to the distribution of ACTH and the number of patients. The χ2-test, Mann–Whitney U-test and Kruskal–Wallis test were used to check for statistical significance. And restricted cubic spline (RCS) regression model was used to explore the non-linear relationship between continuous ACTH levels and PSD at 3 months.Results: The optimal cut-off points of ACTH were as follows: (T1) 0.32– 20.55 pg/mL, (T2) 20.56– 39.79 pg/mL, (T3) 39.80– 143.40 pg/mL. A total of 305 patients (39.7%) were diagnosed as PSD at 3 months follow-up. Significant differences were found between the PSD and non-PSD groups in ACTH concentration (P = 0.001). After adjustment for all conventional confounders, the odds ratios of PSD were 1.735 (95% CI = 1.176– 2.560, P = 0.005) for the highest tertile of ACTH and 1.496 (95% CI = 1.019– 2.194, P = 0.040) for the middle tertile of ACTH, as compared with the lowest tertile. In multiple-adjusted RCS regression, continuous ACTH showed saturation effect relation with PSD risk after 31.02 pg/mL (P for nonlinear = 0.0143).Conclusion: Higher ACTH level on admission is a significant and independent biomarker to predict the development of PSD at 3 months follow-up. Besides, saturation effect was revealed even if the underlying mechanism is unclear. For stroke patients, doctors should pay attention to the baseline ACTH for screening high-risk PSD in clinical practice.Keywords: neuroendocrinology, HPA axis, adrenocorticotropic hormone, post-stroke depression, restricted cubic spline, saturation effect

Siqi Gao,&ast; Yifeng Yu,&ast; Zheng Wang, Yifan Wu, Xingan Qiu, Chao Jian, Aixi Yu Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Chao Jian, Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China, Tel +86-27-6781-3120 ; +86-27-6781-3120, Email yuaixi@whu.edu.cn; chaojian@whu.edu.cnPurpose: Currently, skin avulsion–injury reconstruction is mainly based on subjective evaluation of traditional clinical signs. It frequently results in unnecessary tissue loss and incomplete debridement-related infection. This pilot study aimed to develop a novel near-infrared (NIR) II fluorescence imaging method to assess avulsed skin–perfusion status and thus predict its outcome early.Methods: Skin avulsion–injury models were established by avulsing 10× 4 cm pedicled flaps on porcine hindlimbs. A clinically available improved NIR-&Igr;/II multispectral imaging system was applied for NIR imaging using indocyanine green (ICG) fluorescence. Continuous NIR-wavelength filters and dynamic imaging were used to investigate optimal imaging conditions and time window. NIR-&Igr;/II imaging was synchronously conducted for quality comparison of the two methods. Visual inspection and histological studies were used for assessing the final outcome of avulsed skin.Results: NIR-II fluorescence imaging with a 1,100 nm filter obtained satisfactory performance and reached maximum fluorescence intensity at 1 minute after ICG injection. NIR-II imaging clearly visualized the microvascular network in vascularized avulsed skin and revealed “dark areas” in nonvascularized avulsed skin in a real-time fashion. NIR-II fluorescence imaging demonstrated higher resolution than NIR-I imaging, as indicated by ae higher signal-to-background ratio (2.11) and lower full width at half maximum (6.50614). The dark area of avulsed skin on imaging finally developed to necroses that were confirmed by histology.Conclusion: NIR-II real-time fluorescence imaging clearly maps the microvascular network and shows the perfusion status of avulsed skin at higher resolution than traditional NIR-I imaging, and thus precisely predicts the outcome of avulsed skin early.Keywords: ICG, near-infrared fluorescence imaging, skin avulsion-injury, swine model

Chen Wang,1,&ast; Chunyan Peng,2,&ast; Leping Ning,3,&ast; Xueping Qiu,1 Kaisong Wu,4 Na Yang,1 Bingyu Jin,1 Yue Zhao,1 Fang Zheng1 1Center for Gene Diagnosis, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Laboratory Medicine, Taihe hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China; 3Department of Laboratory Medicine, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 4Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Zheng, Center for Gene Diagnosis & Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, People’s Republic of China, Tel +86-27-67813233, Fax +86 27 67813497, Email zhengfang@whu.edu.cnPurpose: SARS-CoV-2 is extremely infectious, and the incidence of nosocomial infection is conceivably high. We aimed to develop and validate a nomogram to assist monitoring nosocomial SARS-CoV-2 infection in hospitalized patients.Patients and Methods: There were 437 COVID-19 hospitalized cases and 420 negative inpatients enrolled from two hospitals in Hubei province, China. We compared the demographic and clinical characteristics of participants between the two groups. Then, LASSO regression and logistic regression were applied to build a nomogram for SARS-CoV-2 infection prediction in the development cohort. Our nomogram was assessed by area under the curve (AUC), calibration curve, decision curve (DCA) and clinical impact curve analysis (CICA).Results: After LASSO regression filtration, eleven laboratory indicators were correlated with SARS-CoV-2 infection. Then, we integrated these features and constructed a nomogram, which showed a high AUC 0.863 (95% CI: 0.834– 0.892) in the development cohort with a sensitivity of 80.41% and specificity of 77.38% and 0.813 (95% CI: 0.760– 0.866) in validation cohort with a sensitivity of 82.98% and specificity of 70.43%. The calibration plot displayed that the predicted outcomes were in good concordance with the actual observations. DCA and CICA further showed a larger clinical net benefit.Conclusion: We constructed and validated a nomogram that integrated eleven laboratory indexes to assist monitoring of nosocomial SARS-CoV-2 infection in hospitalized patients. Our nomogram is remarkably informative for clinical practice, which will be helpful for preventing SARS-CoV-2 further transmission in hospital and avoiding nosocomial infection.Graphical Abstract: Keywords: COVID-19, nomogram, nosocomial SARS-CoV-2 infection, machine learning

Jia-Xin Cai,1– 3,&ast; Ji-Hua Liu,1– 3,&ast; Jun-Yong Wu,1– 3 Yong-Jiang Li,1– 3 Xiao-Han Qiu,1– 3 Wen-Jie Xu,1– 3 Ping Xu,1,2 Da-Xiong Xiang1– 3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drug, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Xu; Da-Xiong Xiang, Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China, Email xuping1109@csu.edu.cn; xiangdaxiong@csu.edu.cnPurpose: In order to prepare a biomimetic nano-carrier which has inflammatory chemotaxis, homologous targeting and reduce immune clearance, for targeted chemotherapy of osteosarcoma, we fabricated the paclitaxel-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles coated with 143B-RAW hybrid membrane (PTX-PLGA@[143B-RAW] NPs) and evaluate its anti-cancer efficacy in vitro and vivo.Methods: PTX-PLGA@[143B-RAW] NPs were prepared by the ultrasonic method and were characterized by size, zeta potential, polymer dispersion index (PDI), Coomassie bright blue staining, transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC). Cellular uptake, cell viability assay, flow cytometry and chemotactic effect of PTX-PLGA@[143B-RAW] NPs were evaluated in vitro. Biodistribution, anti-cancer therapeutic efficacy and safety of PTX-PLGA@[143B-RAW] NPs were evaluated in 143B osteosarcoma xenograft mice.Results: The hybrid membrane successfully coated onto the surface of PLGA nanoparticles. PTX-PLGA@[143B-RAW] NPs had a drug loading capacity of 4.24 ± 0.02% and showed targeting ability to osteosarcoma. PTX-PLGA@[143B-RAW] NPs showed high cellular uptake and improved anti-cancer efficacy against 143B cells. More importantly, PTX-PLGA@[143B-RAW] NPs treatment suppressed tumor growth in tumor-bearing mice with minimal damage to normal tissues.Conclusion: PTX-PLGA@[143B-RAW] NPs could be used for targeted drug delivery and osteosarcoma therapy.Keywords: biomimetic nano-drug delivery system, osteosarcoma, paclitaxel, targeted therapy

Xiangyuan Qiu,1 Xinying Li,1 Yuanliang Yan,2 Yuan Cai,3 Qiuju Liang,2 Bi Peng,3 Zhijie Xu,3– 5 Muzhang Xiao,6 Fada Xia,1 Jinwu Peng3,4 1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 4Department of Pathology, Xiangya Changde Hospital, Changde, 415000, Hunan, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 6Department of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaCorrespondence: Muzhang XiaoDepartment of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xmzsir@sina.comFada XiaDepartment of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xiafada@csu.edu.cnBackground: N6-methyladenosine (m6A) is most common internal RNA modification in eukaryotic cells. Existing evidence shows that m6A is closely related to pathogenesis and progression in breast cancer (BRCA). Therefore, it is critical to investigate the key role of m6A target genes in BRCA.Methods: M6A target genes in BRCA are acquired using RMVar online database. The differentially expressed genes (DEGs) from three microarray datasets (GSE5764, GSE22358, GSE9014) is processed by GEO2R. Oncomine, GEPIA, UALCAN and TNMplot were applied to validate the expression of DST. Survival analyses were performed via DRUGSURV and Kaplan–Meier Plotter database. Univariable survival and multivariate Cox analysis were completed to assess the prognostic value of DST and receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of DST. We also investigated the correlation between DST and cancer immune infiltration via using CIBERSORT, TIMER and TISIDB.Results: DST and COL11A1 were significantly expressed in both DEGs and m6A target genes set. COL11A1 show no significance on the patients’ survival. However, high expression of DST was related to the favorable prognosis. Multivariate analysis revealed that the DST dysregulation is an independent prognostic factor and ROC indicated that the great diagnostic value of DST with AUC of 0.948. Subsequently, immunological analyses showed that DST was significantly associated with various immune infiltration cells, including NK cells, T helper cells and Mast cells. Furthermore, DST was also related with multiple immune checkpoints and chemokines, including LAG3, LMTK3 CD24, CXCL12, KDR and CX3CR1. These results indicated the potential roles of DST in the development of BRCA via altering the immune response.Conclusion: DST can influence the development and progression of BRCA by altering the immune microenvironment.Keywords: breast cancer, DST, N6-methyladenosine, immune microenvironment, immune infiltration

Guo Li,1 Jinfeng Miao,1 Chensheng Pan,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Yanyan Wang,1 Zhou Zhu,1 Suiqiang Zhu,1 Lifei Lian1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of ChinaCorrespondence: Lifei Lian Tel +86-151 7150 7263Email 47009189@qq.comPurpose: Post-stroke depression (PSD) is one of the most common and severe psychological sequelae after stroke, negatively affecting the patient’s functional outcome and quality of life. Rapidly measurable biomarkers to predict PSD are pivotal for the optimized care and allocation of healthcare resources. Lactic dehydrogenase (LDH) levels are increased in patients with central nervous system (CNS) disorders such as cerebral infarction and hypoxic–ischemic encephalopathy, which may be related to the occurrence of PSD in acute ischemic stroke (AIS) patients. This study aimed to investigate whether LDH levels on admission are associated with PSD at discharge.Patients and Methods: A multicenter prospective cohort study was conducted, including all consecutive AIS patients within 7 days after symptom onset from May 2018 to October 2019. According to the distribution of LDH and the number of patients, patients were divided into equal tertiles. PSD was evaluated by DSM-V criteria and the 17-item Hamilton Rating Scale for Depression (HRSD-17) at discharge.Results: A total of 518 AIS patients were included. The optimal cut-off points of LDH were: lowest tertile (T1) 102– 159/L, middle tertile (T2) 160– 189 U/L, and upper tertile (T3) 190– 520 U/L. A total of 249 patients (48.07%) were diagnosed with PSD at discharge. After adjusting for potential confounding factors, the odds ratio of T3 PSD was 1.698 (95% CI, 1.070– 2.694, P=0.025), compared with T1.Conclusion: In summary, LDH serum levels on admission are associated with PSD at discharge. Clinicians should pay more attention to the baseline LDH level in screening for PSD at discharge.Keywords: post-stroke depression, lactic dehydrogenase, screen, cohort study

Xingan Qiu,&ast; Yifan Wu,&ast; Dong Zhang, Hao Zhang, Aixi Yu, Zonghuan Li Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Zonghuan LiDepartment of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of ChinaTel +86-27-67813120; +86-134 76041532Email yuaixi@whu.edu.cn; lizonghuan@whu.edu.cnBackground: Negative-pressure wound therapy (NPWT) is an effective way to promote wound healing. However, its mechanisms have not been investigated thoroughly. Growing evidence suggests that oxidative stress and Raftlin levels play important roles in wound healing. However, whether NPWT promotes wound healing through this mechanism remains unclear.Purpose: Our study focuses on the different levels of oxidative stress and antioxidant response between wounds treated by NPWT and routine dressing change. The objective of this study was to measure the differences in Raftlin levels between the two groups, which is a new biomarker related to wound healing.Methods: We divided 48 male Sprague-Dawley rats with identical full-thickness skin defects into two groups. At specific times (0, 3, 5, 7, 9, 11, and 13 days after surgery), wound tissue samples were obtained for immunohistochemistry and biochemical analysis. The expression of Raftlin and levels of oxidative stress, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured by biochemical analysis. Wound-healing times were also compared.Results: In the NPWT group, MDA levels were significantly decreased on days 3, 5, and 7. Furthermore, the expressions of SOD and CAT were significantly reduced on days 3 and 5. Our data also revealed that Raftlin was significantly upregulated across the whole period of wound healing. Moreover, wound healing in the NPWT group was significantly more rapid (16 days on average) than in the control group (24 days on average). On day 13 post surgery, the wound-healing percentage in the NPWT group was 91%, while that in the control group was 48%.Conclusion: NPWT may promote wound healing by upregulating Raftlin and inhibiting oxidative stress levels.Keywords: SOD, CAT, MDA, Raftlin, negative-pressure wound therapy

Hui-jun Wang,1 Chun-yan Zhou,1 Yan-ding Su,1 Kai-feng Gou,1 Xiao-nan Geng,1 Xiang-jun Qiu1,2 1Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China; 2Functional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuFunctional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied.Methods: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→ 416.85 and 499.1→ 482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated.Results: Ripretinib had a good linear relationship in the range of 1– 1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h.Conclusion: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.Keywords: itraconazole, voriconazole, ripretinib, UPLC-MS/MS, pharmacokinetics, beagle dog

Zeyu Zhang,1 Xiangyuan Qiu,1 Yuanliang Yan,2 Qiujiu Liang,2 Yuan Cai,3 Bi Peng,3 Zhijie Xu,3,4 Fada Xia1 1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Zhijie XuDepartment of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaEmail xzj1322007@csu.edu.cnFada XiaDepartment of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaEmail xiafada@csu.edu.cnBackground: Ferroptosis is the latest-discovered, iron-dependent form of regulated cell death. It has been increasingly recognized that ferroptosis-related genes participate in oncogenesis and development of cancers, including breast cancer (BRCA). Thus, It is important to explore the biofunctions of ferroptosis-related genes in BRCA.Methods: Transcriptome microarray datasets (GSE22358, GSE9014 and GSE8977, GSE2990 and GSE2034) and TCGA-BRCA were retrieved for analyses. And a variety of computational tools were used to identify the roles and associated biological functions in BRCA.Results: Two ferroptosis-related genes (AKR1C1 and AKR1C3) were significantly expressed in GSE22358, GSE9014 and GSE8977. Higher expression of AKR1C1 was related with favorable prognosis. TCGA-BRCA further confirmed the expression of AKR1C1 and the prognostic value of AKR1C1. Co-expression analyses showed the most enriched GO term and KEGG pathways were termination of DNA-templated transcription and Fanconi anemia pathway. Subsequently, immunological analyses showed AKR1C1 was significantly associated with various immune infiltration cells; among these, dendritic cells, neutrophils, macrophages were the top three infiltrating cells. Furthermore, AKR1C1 was also associated with multiple immunostimulatory molecules and chemokines, including PD-1, PD-L1, CTLA4, B7-H3, VSIR, IL-6, BTLA, CXCL2, and CCR7. These results indicated the potential roles of AKR1C1 in the immune reaction during the pathogenesis of breast cancer.Conclusion: This study firstly demonstrated that ferroptosis-related gene, AKR1C1, could be associated with immune microenvironment, thereby influencing the development and prognosis of patient with breast cancer.Keywords: breast cancer, AKR1C1, ferroptosis, immune microenvironment, immune infiltration

Jialing Wu,&ast; Kaiyun You,&ast; Xingsheng Qiu,&ast; Ting Shen, Juanjuan Song, Changlong Chen, Yanhui Jiang, Yimin Liu Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yimin Liu; Yanhui JiangDepartment of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Yuexiu District, Guangzhou City, Guangdong Province, People’s Republic of ChinaTel +86 18922182513Email liuyimin@mail.sysu.edu.cn; jiangyh26@mail.sysu.edu.cnPurpose: Local failure after endoscopic laryngeal surgery (ELS) for early glottic cancer mounts a challenge to researchers to investigate risk factors of recurrence. The present study was therefore designed to explore the prognostic factors in patients who underwent ELS for early glottic cancer.Patients and Methods: We reviewed 328 patients with T1-2N0 glottic cancer who were treated with either ELS or open surgery between 2007 and 2018 at our institution. Survival, univariate and multivariate analyses were performed in different groups (ELS vs open surgery; < 65 vs ≥ 65 years).Results: Age was discovered to be the independent prognostic factor of DFS for patients treated with ELS (HR = 3.673, p = 0.003), but not for patients who underwent open surgery. Survival analysis performed on young patients (< 65 years) showed that survival outcomes between different surgery modalities were significantly different (ELS vs open surgery: five-year DFS: 72.5 vs 84.7%, p = 0.034). Univariate and multivariate analyses further confirmed the finding, whereas these results did not appear in old patients (≥ 65 years).Conclusion: Young patients (< 65 years) treated with ELS had less favorable oncologic outcomes than those treated with open surgery. Young patients (< 65 years) are advised to consider open surgery over ELS.Keywords: early glottic cancer, age, recurrence, prognostic factor, surgery

Zhenwei Wang,1,2 Zhihong Dai,1,&ast; Bingwei Wang,2 Yuren Gao,1 Xiang Gao,1 Liang Wang,1 Sihai Zhou,1 Liqin Yang,1 Xiaofu Qiu,2,3,&ast; Zhiyu Liu1 1Department of Urinary Surgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiyu Liu Tel +86 15541190788Email lzydoct@163.comPurpose: Prostate cancer is the second leading cause of cancer death in men worldwide. Olaparib is clinically approved for the treatment prostate cancer, but cytotoxicity and off-target effects including DNA damage limit its clinical applications. In the current study, new strategies to improve the therapeutic efficacy of olaparib for the treatment of prostate cancer were investigated.Methods: Two prostate cancer cell lines were exposed to the c-MET inhibitor PHA665752 and/or the PARP inhibitor olaparib. Cell counting kit-8, colony formation assays, and transwell assays were conducted to evaluate the cytotoxicity of olaparib alone or in combination with PHA665752 in prostate cancer cell lines. Western blotting, immunofluorescence staining, and the comet assay were used to assess the effects of PHA665752 on olaparib-induced DNA damage.Results: Combined inhibition of c-MET and PARP resulted in effective and synergistic blocking of the growth of prostate cancer cell lines. Invasion and migration were significantly suppressed when the agents were combined. Mechanistically, dual blocking of PARP and c-MET in prostate cancer cell lines was associated with an impaired DNA damage response. Interestingly, immunofluorescence staining analysis of RAD51 protein indicated that the c-MET inhibitor PHA665752 significantly impaired homologous repair via downregulated translocation of RAD51 into the nucleus in prostate cancer cells.Conclusion: The combination of the c-MET inhibitor PHA665752 and the PARP inhibitor olaparib may be a promising therapeutic strategy in patients with prostate cancer.Keywords: combination therapy, PARP inhibitor, PHA665752, prostate cancer

Guo Li,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Jinfeng Miao,1 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Zhou Zhu,1,&ast; Suiqiang Zhu1,&ast; 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhou Zhu Tel +86-18171081029Email zhouzhu@hust.edu.cnSuiqiang Zhu Tel +86-13035101141Email zhusuiqiang@163.comPurpose: The early detection of major post-stroke depression (PSD) is essential to optimize patient care. A major PSD prediction tool needs to be developed and validated for early screening of major PSD patients.Patients and Methods: A total of 639 acute ischemic stroke (AIS) patients from three hospitals were consecutively recruited and completed a 3-month follow-up. Sociodemographic, clinical and laboratory test data were collected on admission. With major depression criteria being met in the DSM-V, 17-item Hamilton Rating Scale For Depression (HRSD) score ≥ 17 at 3 months after stroke onset was regarded as the primary endpoint. Multiple imputation was used to substitute the missing values and multivariable logistic regression model was fitted to determine associated factors with a bootstrap backward selection process. The nomogram was constructed based on the regression coefficients of the associated factors. Performance of the nomogram was assessed by discrimination (C-statistics) and calibration curve.Results: A total of 7.04% (45/639) of patients were diagnosed with major PSD at 3 months. The final logistic regression model included age, baseline NIHSS and mRS scores, educational level, calcium–phosphorus product, history of hypertension and atrial fibrillation. The model had acceptable discrimination, based on a C-statistic of 0.81 (95% CI, 0.791– 0.829), with 71.1% sensitivity and 78.6% specificity. We also transformed the model to a nomogram, an easy-to-use clinical tool which could be used to facilitate the early screening of major PSD patients at 3 months.Conclusion: We identified several associated factors of major PSD at 3 months and constructed a convenient nomogram to guide follow-up and aid accurate prognostic assessment.Keywords: major post-stroke depression, nomogram, calcium–phosphorus product, C-statistic

Chen-jian Zhou,1 Hui-jun Wang,2 Chun-yan Zhou,2 Chao-fan Li,2 Ming-Jia Zhu,2 Xiang-jun Qiu2 1Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, 325027, People’s Republic of China; 2School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A method for the determination of selinexor by UPLC-MS/MS was established to study the effect of posaconazole on the pharmacokinetics of selinexor in rats.Methods: The experiment rats were divided into group A (0.5% CMC-Na) and group B (posaconazole, 20 mg/kg), 6 rats in each group. 30 minutes after administration of 0.5% CMC-Na or posaconazole, all the rats were given selinexor (8 mg/kg), and plasma samples were collected. The plasma samples underwent acetonitrile protein precipitation, and were separated by UPLC on an Acquity UPLC BEH C18 column with gradient elution. Acetonitrile and 0.1% formic acid were used as the mobile phases. The analyte detection was used a Xevo TQ-S triple quadrupole tandem mass spectrometer and multiple reaction monitoring (MRM) for analyte monitoring. We use acetonitrile for protein precipitation.Results: Selinexor had good linearity (1.0– 1000 ng/mL, r2= 0.996 2), and the accuracy and precision, recovery rate and matrix effects(ME) were also met the FDA approval guidelines. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 60.33%, 48.28% and 48.27%, and Tmax increased by 53.92%, CLz/F reduced by 32.08%.Conclusion: This bioanalysis method had been applied to the study of drug interactions in rats. It was found that posaconazole significantly increased the concentration of selinexor in rats. Therefore, when selinexor and posaconazole are combined, we should pay attention to the possible drug–drug interactions to reduce adverse reactions.Keywords: UPLC-MS/MS, selinexor, posaconazole, pharmacokinetics, DDIs, rats

Arun Venkataraman,1 Yuchuan Zhuang,2 Jennifer Marsella,3 Madalina E Tivarus,4,5 Xing Qiu,6 Lu Wang,6 Jianhui Zhong,1,4 Giovanni Schifitto3,4 1Department of Physics and Astronomy, University of Rochester, Rochester, NY, USA; 2Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA; 3Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA; 4Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, USA; 5Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA; 6Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USACorrespondence: Arun Venkataraman Email Arun_Venkataraman@urmc.rochester.eduObjective: To examine resting-state functional MRI (rs-fMRI) networks related to sleep in the context of HIV infection.Methods: rs-fMRI data were collected in 40 HIV-infected (HIV+) individuals at baseline (treatment-naive), 12 week (post-treatment) and one year timepoints. A group of 50 age-matched HIV-negative (HIV-) individuals were also imaged at baseline and one year timepoints. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was administered at all timepoints. Using group independent component analysis (ICA), maps of functional networks were generated from fMRI data; from these, sleep-related networks were selected. A generalized linear model (GLM) was used to analyze if these networks were significantly associated with the PSQI score, and if this relationship was influenced by HIV status/treatment or timepoint.Results: HIV+ individuals had significantly lower PSQI score after treatment (p=0.022). Networks extracted from group ICA analysis included the anterior and posterior default mode network (DMN), central executive network (CEN), bilateral frontoparietal networks (FPNs), and the anterior cingulate cortex salience network (ACC SN). We found the posterior DMN, right FPN, and ACC SN GLMs showed significantly higher goodness-of-fit after incorporating PSQI data (p = 0.0204, 0.044, 0.044, respectively). Furthermore, the correlation between ACC SN and posterior DMN connectivity was significantly decreased in the HIV+ cohort.Conclusion: Functional networks such as the DMN, FPN, CEN, and ACC SN are altered in poor sleep, as measured by the PSQI score. Furthermore, the relationship between these networks and PSQI is different in the HIV+ and HIV- populations.Keywords: HIV, fMRI, sleep quality, functional connectivity

Fen Li,1,2 Sheng Chen,2 Xinwen Qiu,2 Jing Wu,1 Min Tan,1 Min Wang1 1Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Endocrinology and Metabolism, Liuyang People’s Hospital, Changsha, People’s Republic of ChinaCorrespondence: Min WangDepartment of Endocrinology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaTel +86-135-0731-5620Email 19650877@qq.comObjective: To analyze the association between serum uric acid (SUA) and metabolic state in obese inpatients and preliminarily explore potential mechanisms of hyperuricemia in obesity.Methods: A total of 153 obese inpatients were selected and assigned based on SUA level to the normal uric acid (NC group) or high uric acid (HUA) group. Patients’ sex, age, height, weight, blood pressure, BMI, and prevalence of metabolic syndrome were collected and recorded. SUA, FPG, FIns, HOMA-IR, HOMA-IS, HbA1c, TGs, TC, LDL-C, and HDL-C levels were tested. Pearson correlation analysis was performed to analyze the correlation between SUA and related metabolic indicators. Logistic regression was performed to analyze independent risk factors of hyperuricemia in obesity.Results: In the HUA group, the patients were predominantly males, and BMI, DBP, TGs, FPG, FIns, HOMA-IR, HOMA-IS, and metabolic syndrome were higher than those in the NC group (P< 0.05), while HDL-C was lower than that in the NC group (P< 0.05). There were no significant differences between the groups in TC or LDL-C. Pearson correlation analysis showed that in obese patients, SUA was positively correlated with BMI, FIns, HOMA-IR, HOMA-IS, TGs, andmetabolic syndrome and negatively correlated with age and HDL-C. Logistic regression showed that BMI, hyperinsulinemia, and insulin resistance were independent risk factors of hyperuricemia.Conclusion: Development of hyperuricemia in obese populations might be correlated with hyperinsulinemia or insulin resistance.Keywords: obesity, hyperuricemia, insulin resistance

Wenyi Lv,1 Jin Feng,1 Li Chen,1 Shuai Liu,1,2 Xiaoguang Qiu1,2 1Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of China; 2Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, People’s Republic of ChinaCorrespondence: Xiaoguang Qiu; Shuai LiuBeijing Neurosurgical Institute, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel/Fax +86 1059975266; +86 1059975580Email qiuxiaoguang@bjtth.org; s.liu@bjtth.orgPurpose: Basal ganglia intracranial germ cell tumors (iGCTs) can specifically destroy the basal ganglia network, leading to several cognitive, learning, behavioral, and social impairments. This study aimed to investigate the behavior and social disorders of patients with basal ganglia iGCTs.Patients and Methods: We recruited 30 newly diagnosed iGCTs patients (and their parents) for the current study. The Child Behavior Checklist/6– 18 was used to evaluate emotional and behavioral problems. The Conner’s Parent Rating Scales was used to assess symptoms of hyperactivity/impulsivity and conduct problems. The health-related quality of life (HRQoL) was assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale. Performance status was assessed using the Lansky play-performance scale and Karnofsky performance scale. The effects of basal ganglia lesions on these scores were examined.Results: Patients with basal ganglia iGCTs (n = 10) had more behavioral problems (attention problems, aggressive behavior, learning problems, hyperactivity index), social function impairment, anxiety/depression, and poorer HRQoL compared to patients with non-basal ganglia iGCTs (n = 20). There was no significant difference in the Lansky play-performance/Karnofsky performance scale scores.Conclusion: This study demonstrates the effects of basal ganglia lesions on behavioral and emotional outcomes, social functions, and HRQoL of patients with iGCTs. The results may help to understand the function of basal ganglia and provide evidence for the benefit of early psychological intervention to improve the treatment for this rare disease.Keywords: intracranial germ cell tumors, pediatrics, The Child Behaviour Checklist, The Conner’s Parent Rating Scales, health-related quality of life

Xuan Qiu, Manjiang Li, Liqun Wu, Yang Xin, Siyu Mu, Tianxiang Li, Kangjian Song Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of ChinaCorrespondence: Liqun WuLiver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Laoshan District, Qingdao, Shandong 266003, People’s Republic of ChinaTel +86 15315328331Email wulq5810@126.comObjective: To investigate the effects of fatigue on the survival of patients with advanced hepatocellular carcinoma treated with sorafenib.Patients and Methods: A retrospective analysis of 182 cases of patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2017, showed clinical and pathological data and follow-up results. The clinical and pathological data as well as follow-up results of 182 patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2018, were retrospectively analyzed. All patients were treated for at least 3 months. Patients were divided into three groups: fatigue grade I (n=74), fatigue grade II (n=62), and fatigue grade III (n=46), according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 5.0. Survival analysis between groups was performed by the Kaplan–Meier method (Log rank test), continuous variables were analyzed by t-test, and categorical variables were analyzed by chi-square test.Results: The overall survival (OS) of patients who were relieved of fatigue was 33.0± 9.3 months, whereas the OS of patients who were not relieved of fatigue was 15.0± 1.8 months (P< 0.000). Furthermore, the time to progress (TTP) of patients who were relieved of fatigue by resting was 20.3 ± 10.9 months compared to a TTP of 7.7 ± 1.0 months in patients who were not relieved of fatigue (P< 0.000).Conclusion: Patients, especially the elderly and infirm, were more susceptible to toxicity.Keywords: hepatocellular carcinoma, sorafenib, fatigue, survival

Shuang-long Li, Yi Zhang, Qian-shi Cheng, Jun-zhe Xin, Ze-qin Dong, Xiang-jun Qiu School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaTel +86 13698882699Fax +86 379-64830346Email lyxiangjun@126.comObjective: An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of selinexor was established to investigate the effects of isavuconazole, itraconazole and fluconazole on the pharmacokinetics of selinexor in rats, respectively.Methods: Twenty-four healthy male rats were randomly divided into four groups: group A, normal saline; group B, isavuconazole (20 mg/kg); group C, itraconazole (20 mg/kg); and group D, fluconazole (20 mg/kg). After 30 min of oral administration of normal saline, isavuconazole, itraconazole, and fluconazole, all the rats were given selinexor (8 mg/kg). The plasma concentration of selinexor was estimated by UPLC-MS/MS, and the pharmacokinetic parameters of selinexor were calculated by Drug and Statistics (DAS) 2.0 software.Results: Under these experimental conditions, the method showed good linearity and stability. Intraday and interday accuracy and sample recovery were acceptable. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 59.05%, 31.69%, and 31.45%; the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group C increased by 56.14%, 25.34%, and 25.08%; the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group D increased by 43.44%, 29.16%, and 31.96%, respectively. The Tmax of the experimental groups were extended, and CLz/F was also significantly reduced.Conclusion: These results indicated that isavuconazole, itraconazole, and fluconazole have significant inhibitory effects on selinexor pharmacokinetics and increased selinexor plasma exposure in rats. Therefore, when these drugs were used in combination, clinicians should pay attention to the changes in treatment effects and the occurrence of adverse reactions caused by the drug-drug interactions.Keywords: isavuconazole, itraconazole, fluconazole, selinexor, UPLC-MS/MS, pharmacokinetics, drug-drug interactions

Wei Zhou,1,2 Shuang-long Li,3 Ti Zhao,3 Le Li,3 Wen-bin Xing,3 Xiang-jun Qiu,3 Wei Zhang1 1The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Nanyang City Central Hospital, Nanyang 473009, People’s Republic of China; 3School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Wei ZhangThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaEmail zhangw571012@126.comXiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaEmail lyxiangjun@126.comObjective: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles.Materials and Methods: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 μg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 μg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg.Results: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements.Conclusion: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.Keywords: dexmedetomidine, dezocine, midazolam, 1-hydroxymidazolam, pharmacokinetics, drug–drug interactions

Shuli Liu,1 Jinping Wang,1 Xue Luo,1 Xiaoman Li,2 Yuan Miao,1 Liang Wang,1 Qingchang Li,1 Xueshan Qiu,1 En-Hua Wang1 1Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; 2Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Liang WangDepartment of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital, China Medical University, Shenyang 110001, People’s Republic of ChinaTel/ Fax +86 24 23261638Email cmuwangliang@qq.comAbstract: Low-grade fetal lung adenocarcinoma (L-FLAC) is an exceptionally rare pulmonary tumor, presenting with unclear histological and molecular features. In particular, the potential driver genes of L-FLAC remain elusive. To date, only five reports have documented genetic aberrations in L-FLAC. In the current study, we describe an unusual case of L-FLAC coexisting with adenocarcinoma in situ (AIS) of the lung, harboring different genetic mutations. A 39-year-old non-smoker female patient was referred to our hospital with the chief complaint of dyspnea for 20 days. Chest computed tomography (CT) revealed a 2.5× 1.5× 1.5 cm nodule in the right middle lobe, with no mediastinal lymph node enlargement or distant metastases. Thoracoscopic surgery was performed to remove the nodules. Histopathological analysis of the tissue sections, based on findings from immunohistochemical staining, confirmed a diagnosis of L-FLAC coexisting with AIS of the lung. Next-generation sequencing revealed L-FLAC-based mutations in DICER1 and CTNNB1, and AIS harboring KRAS mutations. Currently, the patient remains recurrence-free 17 months after the initial diagnosis. This report presents the first case demonstrating the coexistence of L-FLAC and AIS in the same pulmonary nodule, harboring different genetic mutations. Based on the literature review, this is the second reported case of L-FLAC bearing DICER1 mutations.Keywords: low-grade fetal adenocarcinoma, CTNNB1, DICER1, KRAS, NGS

Miao-sheng Chen, Cui-hong Lin, Ling-yan Huang, Xiao-ming Qiu Department of Pathology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan, People’s Republic of ChinaCorrespondence: Xiao-ming Qiu Tel +86-5972205108Email abcrtom@163.comPurpose: Our objective was to investigate the effect of circSMARCC1 on the developmental and biological behavior of colorectal cancer (CRC).Materials and Methods: The expression of circSAMRCC1 and miR-140-3p in CRC tissues and cell lines (SW620, HCT116, HT29 and SW480) and a normal cell line (NCM460) was detected using qRT-PCR. The expression levels of circSMARCC1 and its linear subtype were detected. Fluorescence in situ hybridization was performed for the evaluation of the localization of circSAMRCC1 and miR-140-3p in the SW620 cell line. The effects of circSAMRCC1 and miR-140-3p on cell proliferation were investigated using CCK8 and colony formation assays, respectively. The effects of circSAMRCC1 and miR-140-3p on cell migration and invasion were determined using Transwell assay. The binding relationship between circSMARCC1 and miR-140-3p was further assessed by bioinformatics, ChIRP analysis and double luciferase reporter assay.Results: The expression of circSAMRCC1 in the CRC tissues and four cell lines is significantly increased, and circSMARCC1 and miR-140-3p are negatively correlated with expression level in the tissue. The downregulation of circSMARCC1 decreased CRC cell viability and suppressed metastasis in vitro and Inhibition of protein (MMP-2, MMP-9, VEGF) expression. miR-140-3p is downregulated in CRC tissues; miR-140-3p mimics inhibited SW620 cell viability, migration and invasion, and miR-140-3p inhibitors reversed the the effect of circSMARCC1 downregulation on cell proliferation, migration and invasion in CRC cells.Conclusion: circSMARCC1 competitively combined with miR-140-3p and functioned through a circSMARCC1/miR-140-3p/MMPs axis as a CRC carcinogen, demonstrating its potential as a biomarker for CRC treatment.Keywords: circSAMRCC1, colorectal cancer, miR-140-3p, cell proliferation, MMP pathway

You-Yi Huang, Hai-Xing Jiang, Qiu-Yue Shi, Xin Qiu, Xi Wei, Xiang-Lian Zhang, Shan-Yu Qin Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Shan-Yu QinDepartment of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of ChinaTel +86 13977110511Email qsy0511@163.comPurpose: Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer.Materials and Methods: CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins.Results: In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway.Conclusion: miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.Keywords: miR-145, Th9 cells, PI3K/Akt, HIF-1α, hepatoma malignant ascites

Shuang-long Li, Yong-liang Zhu, Chun-yang Zhu, Shao-bin Li, Zi-heng Li, Xiang-jun Qiu Medical College of Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuMedical College of Henan University of Science and Technology 471023, People’s Republic of ChinaTel +86 13698882699 Fax + 86 379-64830346 Email lyxiangjun@126.comAbstract: A method for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagle plasma by UPLC-MS/MS was developed and validated. After the plasma was extracted by acetonitrile precipitation, the analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using acetonitrile-formic acid as the mobile phase in gradient mode. The analytes were monitored by multiple reaction monitoring (MRM) in electrospray negative ion mode. The mass transfer pairs were m/z 368.97→ 119.01 for parecoxib, m/z 312.89→ 118.02 for valdecoxib, and m/z 379.98→ 316.02 for celecoxib (internal standard, IS). The correlation coefficients of parecoxib and valdecoxib ranged from 5 to 4000 ng/mL were greater than 0.9998. The recovery of parecoxib and valdecoxib was greater than 82.54%. The inter- and intra-day precision RSD values were 1.36∼ 3.65% and 2.28∼ 5.91%, respectively. The accuracy of RE values were − 1.38%∼ 1.96%. Finally, the matrix effect (ME) and stability were also within acceptable criteria. This method had been successfully applied to the pharmacokinetics of parecoxib and valdecoxib in beagle plasma after injection of parecoxib (1.33 mg/kg, intramuscular injection).Keywords: parecoxib, valdecoxib, UPLC-MS/MS, pharmacokinetics

Xin Duan, Guangcheng Guo, Xinhong Pei, Xinxing Wang, Lin Li, Youyi Xiong, Xinguang Qiu Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Xinguang QiuDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, Henan 450000, People’s Republic of ChinaTel +86 371-67967247Email xfcl6782619qiang@163.comBackground: Baicalin is a natural compound from the roots of Scutellaria lateriflora Georgi, which plays anti-cancer role in multiple cancers. However, the exact role and potential underlying mechanism of baicalin in breast cancer (BC) remain poorly understood.Methods: Thirty BC patients were recruited in this study. MCF-10A, MCF-7 and MDA-MB-231 cells were used to investigate the anti-cancer role of baicalin in vitro. Cell viability, migration, invasion and apoptosis were measured by MTT, trans-well and flow cytometry, respectively. The expression levels of microRNA-338-3p (miR-338-3p) and microrchidia family CW-type zinc-finger 4 (MORC4) were measured by quantitative real-time polymerase chain reaction or Western blot. The interaction between miR-338-3p and MORC4 was explored by luciferase reporter assay and RNA immunoprecipitation.Results: We found that Baicalin treatment inhibited cell viability, migration and invasion but promoted apoptosis of BC cells. The expression of miR-338-3p was decreased in BC tissues and cells and miR-338-3p overexpression suppressed cell viability, migration and invasion but induced apoptosis. MiR-338-3p expression was reversed by baicalin exposure and inhibition of miR-338-3p attenuated the role of baicalin in viability, apoptosis, migration and invasion. MORC4 mRNA level was increased in BC tissues and cells, which was decreased by baicalin exposure. MORC4 was a target of miR-338-3p and its overexpression alleviated the effect of miR-338-3p on cell viability, apoptosis, migration and invasion.Conclusion: In conclusion, baicalin suppressed cell viability, migration and invasion but promoted apoptosis in BC cells by regulating miR-338-3p and MORC4, indicating the promising pharmacological value of baicalin in BC treatment.Keywords: breast cancer, baicalin, miR-338-3p, MORC4

Zhihong Chai,1,* Yufei Yang,2,3,* ZhongYi Gu,4,* Xianli Cai,1 Wenwei Ye,1 Lin Kong,1 Xiaoxiao Qiu,1 Lingxiao Ying,1 Ziliang Wang,2,3 Linyou Wang1 1Department of Gynecology and Department of Radiology, Taizhou Municipal Hospital Affiliated to Taizhou University School of Medicine, Taizhou 318000, People’s Republic of China; 2Department of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, Shanghai 200092, People’s Republic of China; 3Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Department of Nephrology, Children’s Hospital of Fudan University, Shanghai 201102, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziliang WangDepartment of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaEmail huf_zlwang@126.comLinyou WangDepartment of Radiology, Taizhou Municipal Hospital, 381 East Zhongshan Road, Taizhou 318000, People’s Republic of ChinaEmail wanglinyou2007@163.comPurpose: Capsid protein L2 is the minor capsid protein of human papillomavirus 16 (HPV16). Although L2-based vaccines were developed, the therapeutic effect of recombinant viral capsid protein L2 (rVL2) was still to be illustrated.Methods: We used glucose uptake and lactate production assay to verify the inhibitory effect of rVL2 on the glucose metabolism in cervical cancer cells. Secondly, we performed gene-chip assay, RT-PCR, and Western blot to determine the role of ITGB7/C/EBPβ signaling pathway in rVL2-mediated glucose metabolism in vitro. Finally, we used an animal model to verify the function of rVL2 in cervical cancer.Results: We found that rVL2 reduced glucose uptake and lactate production levels in cervical cancer cells, which caused the inhibition of cell proliferation. rVL2 decreased the expression levels of key metabolic enzymes, including GLUT1, LDHA, and ALDOA, to affect cell metabolism in cervical cancer cells by inhibiting ITGB7/C/EBPβ signaling pathway in vitro and in vivo.Conclusion: These results demonstrated the vital role of rVL2 in the glycolysis-induced cell growth and proliferation via suppressing ITGB7/C/EBPβ signaling axis.Keywords: recombinant viral capsid protein L2, rVL2, C/EBPβ, glucose metabolism, cervical cancer

Yong-liang Zhu, Shuang-long Li, Ke-li Chen, Kun-peng Ma, De-qian Wu, Xiang-jun Qiu Medical College of Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuMedical College of Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaEmail lyxiangjun@126.comObjective: To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Methods: Six beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0.Results: The Cmax of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC(0-∞) of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV Cmax of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC(0-∞) were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV Cmax of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC(0-∞) were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the Cmax and AUC(0-∞) of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of Cmax and AUC(0-∞) of ODV and NDV indicated a rise in plasma exposure.Conclusion: Danzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.Keywords: beagle, UPLC-MS/MS, Danzhi Xiaoyao pills, venlafaxine, ODV, NDV, drug–drug interaction

Lili Cao,*,1,2 Xiaofang Che,*,1,2 Xueshan Qiu,3 Zhi Li1,2 Bowen Yang1,2 Shuo Wang1,2 Kezuo Hou1,2 Yibo Fan1,2 Xiujuan Qu1,2 Yunpeng Liu1,21Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 3Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110001, People’s Republic of China*These authors contributed equally to this workBackground: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC.Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients.Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P

Zhen Wang,1,* Chong Zheng,2,* Siyuan Wen,1 Junfei Wang,1 Zitao Zhang,1 Xusheng Qiu,1 Yixin Chen11Department of Orthopedics, Drum Tower Hospital Clinical College of Nanjing University, Nanjing, People’s Republic of China; 2Department of Orthopedics, Changzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Changzhou, People’s Republic of China*These authors contributed equally to this workPurpose: Infected nonunion after open reduction internal fixation (ORIF) is a serious complication. The aim of this study was to evaluate the usefulness of serum D-dimer for preoperative diagnosis of infected nonunion.Patients and methods: Patients undergoing debridement and external fixation for infected nonunion (n=32) and replacement of internal fixation due to aseptic failure (n=34) were enrolled and compared in this retrospective study. The optimum cutoff value of D-dimer for identification of infected nonunion was determined by calculating the Youden J statistic. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of four preoperative laboratory parameters—serum D-dimer level, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)—for diagnosis of infected nonunion were compared.Results: Serum D-dimer level was significantly higher in patients with infected nonunion than in patients with aseptic nonunion: 2.62 mg/mL (range, 0.13–11.90 mg/mL) vs 0.35 mg/mL (range, 0.07–6.46 mg/mL; p1.70 mg/mL) were 75.0% (95% CI: 56.25–87.87) and 91.2% (95% CI: 75.19–97.69).Conclusions: Serum D-dimer level may be useful for preoperative prediction of infected nonunion in patients after ORIF.Keywords: fracture-related infection, laboratory test, preoperative prediction, nonunion

Xia Qiu, Jiangnan Dong, Zheng Zhao, Jun Li, Xiaoyan CaiDepartment of General Surgery, Pudong New Area Gongli Hospital Affiliated to Naval Military Medical University, Shanghai 200135, People’s Republic of ChinaObjective: To elucidate how lncRNA 00668 (LINC00668) influences the development of breast cancer (BC).Materials and methods: Genome-wide expression profile of BC and paracancerous tissues were downloaded from The Cancer Genome Atlas (TCGA) and BC tissues and paracancerous tissues enrolled from our hospital for analyzing the expression level of LINC00668 and its correlation with prognosis. GSEA was conducted to analyze the potential functions of LINC00668. By transfection of sh-LINC00668 in BC cells, proliferation, apoptosis, cell cycle and colony formation of BC cells were accessed. Western blot was conducted to detect protein expressions of Ki-67, CDK4, Bcl-2, p21 and genes in AKT/mTOR pathways after LINC00668 knockdown in BC cells. Finally, tumor-bearing nude mice were administrated with BC cells. We compared the proliferative rate in mice with different administrations. Immunohistochemistry was carried out to access expression levels of Ki-67, CDK4, Bcl-2 and P21 in mice.Results: Both TCGA data and BC tissues harvested from our hospital indicated the higher expression of LINC00668 in BC tissues. LINC00668 expression was negatively correlated to prognosis of BC patients. GSEA pointed out that LINC00668 is enriched in regulations of cell cycle and apoptosis. By transfection of sh-LINC00668 in MDA-MB-231 and MDA-MB-436 cells, the proliferative and colony formation abilities of BC cells decreased. Besides, LINC00668 knockdown in BC cells induced apoptosis and arrested cell cycle. LINC00668 knockdown downregulated Ki-67, CDK4 and Bcl-2, but upregulated p21. The AKT/mTOR pathway was inhibited after LINC00668 silenced. In vivo experiments demonstrated the decreased proliferative rate in tumor-bearing mice administrated with sh-LINC00668 transfected BC cells. Consistently, immunohistochemical results showed lower positive expressions of Ki-67, CDK4 and Bcl-2, but higher positive expression of p21 in sh-LINC00668 group.Conclusion: LINC00668 is highly expressed in BC tissues and can promote the progression of BC by inhibiting apoptosis and accelerating cell cycle progression.Keywords: LINC00668, breast cancer, apoptosis, cell cycle

Kai-yun You,1,* Hai-hua Peng,2,* Yan-hui Jiang,1,* Zhuo-fei Bi,1 Xing-sheng Qiu11Department of Radiation Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University; 2Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510075, People’s Republic of China*These authors contributed equally to this workBackground: Whether concurrent chemotherapy could bring about better oncological outcomes in elderly patients receiving definitive radiotherapy is still unknown. So, the purpose of this study was to find out whether it is essential for elderly patients to undergo concurrent chemotherapy.Methods: We performed a retrospective study of 246 elderly cervical cancer patients who were treated with definitive radiotherapy or chemo-radiation between August 2004 and August 2015. All patients were divided into two groups according to whether they were receiving concurrent chemotherapy or not. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups. Recurrence patterns were also analyzed. Multivariate analysis was performed to explore clinical factors significantly associated with DFS, local recurrence-free survival, and distant metastasis-free survival (DMFS).Results: The 5-year OS in the radiotherapy and chemo-radiation groups were 72.89% and 82.25%, respectively. A significant difference was found between the two groups (P=0.016). The 5-year DFS in the radiotherapy and chemo-radiaton groups were 58.19% and 75.52%, respectively, also with a significant difference between the two groups (P=0.028). Further subgroup analysis showed that in patients with negative lymph nodes, there were no differences in both OS and DFS between patients who did and did not receive concurrent chemotherapy. However, in patients with positive lymph nodes, patients who received concurrent chemotherapy acquired better OS and DFS than those who did not. Multivariable analysis showed that concurrent chemotherapy was an independent predictor of DFS and DMFS.Conclusion: Concurrent chemotherapy could improve oncological outcomes in elderly cervical cancer patients with positive lymph nodes, but not in those with negative lymph nodes.Keywords: cervical cancer, chemotherapy, radiotherapy

Qianmeng Lin,1,2,* Saili Xie,1,* Xiangjun Qiu,3 Jingjing Chen,1 Ren-Ai Xu11The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 3Medical College of Henan University of Science and Technology, Luoyang 471003, People’s Republic of China*These authors contributed equally to this work Background: In clinical practice, common problem polypharmacy could result in the increased risks of drug–drug interactions (DDIs). Co-administered imatinib (IMA) and voriconazole (VOR) as one treatment protocol in cancer patients with fungal infections are common.Purpose: The aim of the present study was to assess the potential DDIs associated with the concurrent use of IMA and VOR in rat liver microsomes (RLMs) and in rats.Methods and results: The concentration levels of IMA, VOR, and their metabolites N-desmethyl IMA (CGP74588) and N-oxide voriconazole (N-oxide VOR) were determined by ultra performance liquid chromatography-tandem mass spectrometry. In vitro study of RLMs, VOR inhibited the IMA metabolism with the half-maximal inhibitory concentration (IC50) of 105.20 μM, while IC50 for IMA against VOR was 61.30 μM. After co-administered IMA and VOR in rats, the Cmax of IMA was increased significantly, while the AUC0→t, AUC0→∞, and Cmax of CGP74588 were decreased significantly. In addition, similar results were also found that the main pharmacokinetic parameters (AUC0→t, AUC0→∞, MRT0→∞, Tmax, and Cmax) of VOR were increased significantly, while the AUC0→t, AUC0→∞, and Cmax of N-oxide VOR were decreased significantly. Incorporation of all the results indicated that both drugs had a inhibitory effect on each other’s metabolism in vitro and in vivo.Conclusion: Thus, it is of great value to monitor the concomitant use of IMA and VOR in the clinic to reduce the risks of unexpected clinical outcomes.Keywords: drug–drug interaction, imatinib, voriconazole, rat liver microsome, metabolism