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Zi-jun He,1,2,* Jin-tao Wei,1,* Hai-mei Jiang,1 Jin-yong Wang,1 Jiong-yao Lai,1 Shu-qing Li,1 Zhi Chen,1 Qing-lu Luo1– 3 1Department of Rehabilitation Medicine, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, People’s Republic of China; 2Dongguan Experimental Centre for Sports Rehabilitation Research, Dongguan, People’s Republic of China; 3Dongguan Key Specialty of Traditional Chinese Medicine (Rehabilitation Department), Dongguan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing-lu Luo; Zhi Chen, Department of Rehabilitation Medicine, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s hospital), Wanjiang District, Dongguan, Guangdong, 510280, People’s Republic of China, Email luo_qinglu@126.com; 13686616688@139.comObjective: To identify distinct developmental trajectories of weight-bearing pain (WBP) and non-weight-bearing pain (NWBP) and examine the trajectory predictors in individuals with or at risk of knee osteoarthritis.Methods: We included 971 participants from the Osteoarthritis Initiative whose baseline magnetic resonance imaging data and 9-year follow-up data on pain were available. We applied group-based trajectory modeling to identify WBP and NWBP trajectories over 9 years. Univariate and multivariate multinomial logistic regression analyses were performed to examine the predictors of identified trajectories.Results: Three distinct WBP trajectories were identified: “no pain” (32.4%), “mild pain” (44.6%), and “moderate pain” (23%). Three distinct NWBP trajectories were identified: “no pain” (50.9%), “mild pain” (33.4%), and “moderate pain” (15.7%). In multivariate analyses, high body mass index, depression, multisite pain, radiographic knee OA, and comorbidities were associated with worse development trajectories for WBP and NWBP. Weak quadriceps strength and bone marrow lesion were only associated with worse WBP trajectories, whereas low education level was only associated with worse NWBP trajectories.Conclusion: The developmental course of pain is heterogeneous in WBP or NWBP. Quadriceps strength and bone marrow leisure may be WBP-specific predictors, whereas education level may be a NWBP-specific predictor. The assessment of knee pain should be more accurate, which may help select appropriate therapeutic targets.Keywords: knee osteoarthritis, pain, weight-bearing, trajectories, predictors

Yuan Xu, Jing-Yan Wang, Yang Zou, Xue-Wei Ma, Tian Meng College of Health Industry, Sichuan Tourism University, Chengdu, Sichuan, 610100, People’s Republic of ChinaCorrespondence: Yuan Xu, Email 230973159@qq.comAbstract: Inflammatory cytokines, interleukin-36 (IL-36), IL-37, IL-38 belong to IL-1 family. The IL-36 subfamily obtains pro- and anti-inflammatory effects on various immune responses. Cytokine IL-37, has anti-inflammatory functions in immunity, and the recently identified IL-38 negatively associated with disease pathogenesis. To date, expression of IL-36, IL-37, IL-38 is reported dysregulated in osteoarthritis (OA) and rheumatoid arthritis (RA), and may be disease markers for arthritis-related diseases. Interestingly, expression of IL-38 was different either in OA patients or animal models, and expression of IL-36Ra in synovium was different in OA and RA patients. Moreover, functional studies have demonstrated significant role of these cytokines in OA and RA progress. These processes were related to immune cells and non-immune cells, where the cytokines IL-36, IL-37, IL-38 may regulate downstream signalings in the cells, and then involve in OA, RA development. In this review, we comprehensively discuss recent advancements in cytokines and the development of OA, RA. We hope that targeting these cytokines will become a potential treatment option for OA and RA in the future.Keywords: IL-36, IL-37, IL-38, osteoarthritis, rheumatoid arthritis

Yu Chen Xu,1,&ast; Qiu Qin Wang,1,&ast; Meng Yuan Chen,1 Yu Jie Gao,1 Jia Yi Wang,1 Hao Tian Ge,1 Heng Weng,1 Ju Ping Chen,2 Gui Hua Xu1 1School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gui Hua Xu, School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Email 7115@njucm.edu.cn Ju Ping Chen, Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China, Email 1523515573@qq.comPurpose: Pain is a common yet undertreated symptom of Parkinson’s disease (PD). This study investigated the effect of Gua Sha therapy on pain in patients with PD.Patients and Methods: A total of 56 PD patients with pain were randomized into either the experimental group (n=28), receiving 12 sessions of Gua Sha therapy, or the control group (n=28) without additional treatment. Participants underwent assessment at baseline, after the twelfth invention, and at the 2-month follow-up timepoints. The primary outcome was KPPS and VAS. Secondary outcomes included UPDRS I–III, PDSS-2, HADS, PDQ-39, and blood biomarkers (5-HT, IL-8, IL-10).Results: The experimental group reported a significant improvement in pain severity, motor functions, affective disorder, and sleep quality (P < 0.05). Furthermore, increasing trends in both 5-HT and IL-10, as well as decreasing trends in IL-8 were observed. No serious adverse events occurred.Conclusion: The preliminary findings suggest that Gua Sha therapy may be effective and safe for alleviating pain and improving other disease-related symptoms in PD patients.Keywords: Parkinson’s disease, pain, Gua Sha therapy, randomized controlled trial

Zhi Hui Gu, Jia Yi Wang, Chen Xin Yang, Hui Wu Department of Social Medicine, China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Hui Wu, Department of Social Medicine, School of Health Management, China Medical University, Shenyang North New District, No. 77 Puhe Road, Shenyang, Liaoning, 110122, People’s Republic of China, Email hwu@cmu.edu.cnBackground: Gynecological cancer generally refers to malignant tumors in gynecology, commonly including cervical cancer, endometrial cancer, and ovarian cancer. Patients with gynecological cancer often suffer from sleep disorders after clinical treatment. Except for serious sleep disorders, female characteristics, family roles, and feudal beliefs make their self-stigma at a medium to high level, leading to huge pressure. This study aims to identify potential categories of sleep disorders, and analyze the relationship between self-stigma, perceived stress, and sleep disorders.Methods: A cross-sectional study was conducted in 2021– 2022. Two hundred and two patients’ data were collected from ShengJing Hospital Affiliated to China Medical University in Liaoning, Shenyang by using paper questionnaires for face-to-face surveys. The survey tools included the Pittsburgh Sleep Quality Index (PSQI), the Perceived Stress Scale (PSS), and the Social Impact Scale (SIS). Potential profile analysis (LPA), multiple logistic regression analysis, and structural equation modeling (SEM) were performed by Mplus 8.3, SPSS 26.0, and Amos 24.0 statistical tools, respectively.Results: Three latent patterns of sleep disorders were found: “Good Sleep group (42.5%)”, “Sleep Deficiency group (32.4%)”, and “Sleep Disturbance group (25.1%)”. Patients with high perceived stress were more likely to report a moderate (OR=1.142, 95% CI: 1.061– 1.230) or high (OR=1.455, 95% CI: 1.291– 1.640) level of sleep disorders. Self-stigma did not have a direct effect on sleep disorders (0.055, P> 0.05), but it could have indirect effect on sleep disorders through perceived stress (0.172, P< 0.01).Conclusion: The perceptions of sleep disorders among gynecological cancer patients varies and exhibits individual differences. Gynecological cancer patients who feels alienated or discriminated may cause high pressure. This internal pressure can exacerbate sleep disorders.Keywords: sleep disorders, self-stigma, perceived stress, latent profile analysis, mediating effect, gynecological cancer

Ya-Jun Yang,1,&ast; Yu-Mei Feng,1,&ast; Tong-Xuan Wang,1 Jing-Yun Wang,2 Qian-Yun Pang,1 Hong-Liang Liu1 1Department of Anesthesiology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2School of Medicine, Chongqing University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong-Liang Liu; Qian-Yun Pang, Department of Anesthesiology, Chongqing University Cancer Hospital, No. 181, Hanyu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel +86 13883686721, Email liuhl75@163.comBackground: Noradrenaline (NA) is commonly used intraoperatively to prevent fluid overload and maintain hemodynamic stability. Clinical studies provided inconsistent results concerning the effect of NA on postoperative outcomes. As aging is accompanied with various diseases and has the high possibility of the risk for postoperative complications, we hypothesized that intraoperative NA infusion in older adult patients undergoing major non-cardiac surgeries might potentially exert adverse outcomes.Methods: In this retrospective propensity score-matched cohort study, older adult patients undergoing major non-cardiac surgeries were selected, 1837 receiving NA infusion during surgery, and 1072 not receiving NA. The propensity score matching was conducted with a 1:1 ratio and 1072 patients were included in each group. The primary outcomes were postoperative in-hospital mortality and complications.Results: Intraoperative NA administration reduced postoperative urinary tract infection (OR:0.124, 95% CI:0.016– 0.995), and had no effect on other postoperative complications and mortality, it reduced intraoperative crystalloid infusion (OR:0.999, 95% CI:0.999– 0.999), blood loss (OR: 0.998, 95% CI: 0.998– 0.999), transfusion (OR:0.327, 95% CI: 0.218– 0.490), but increased intraoperative lactate production (OR:1.354, 95% CI:1.051– 1.744), and hospital stay (OR:1.019, 95% CI:1.008– 1.029).Conclusion: Intraoperative noradrenaline administration reduces postoperative urinary tract infection, and does not increase other postoperative complications and mortality, and can be safely used in older adult patients undergoing major non-cardiac surgeries.Keywords: noradrenaline, outcome, older adult, non-cardiac surgery

Wen-Yu Zhai,1,2,&ast; Fang-Fang Duan,3,&ast; Yao-Bin Lin,1,2,&ast; Yong-Bin Lin,1,2 Ze-Rui Zhao,1,2 Jun-Ye Wang,1,2 Bing-Yu Rao,1,2 Lie Zheng,4 Hao Long1,2 1Department of Thoracic Surgery, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Lung Cancer Research Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 3Department of Medical oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 4Medical Imaging Division, Department of Medical Imaging and Interventional Radiology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Long, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, and Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China, Email longhao@sysucc.org.cn Lie Zheng, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, and Medical Imaging Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China, Email zhenglie@sysucc.org.cnBackground: We aimed to investigate the predictive value of a systematic serum inflammation index, pan-immune-inflammatory value (PIV), in pathological complete response (pCR) of patients treated with neoadjuvant immunotherapy to further promote ideal patients’ selection.Methods: The clinicopathological and baseline laboratory information of 128 NSCLC patients receiving neoadjuvant immunochemotherapy between October 2019 and April 2022 were retrospectively reviewed. We performed least absolute shrinkage and selection operator (LASSO) algorithm to screen candidate serum biomarkers for predicting pCR, which further entered the multivariate logistic regression model to determine final biomarkers. Accordingly, a diagnostic model for predicting individual pCR was established. Kaplan–Meier method was utilized to estimate curves of disease-free survival (DFS), and the Log rank test was analyzed to compare DFS differences between patients with and without pCR.Results: Patients with NSCLC heterogeneously responded to neoadjuvant immunotherapy, and those with pCR had a significant longer DFS than patients without pCR. Through LASSO and the multivariate logistic regression model, PIV was identified as a predictor for predicting pCR of patients. Subsequently, a diagnostic model integrating with PIV, differentiated degree and histological type was constructed to predict pCR, which presented a satisfactory predictive power (AUC, 0.736), significant agreement between actual and our nomogram-predicted pathological response.Conclusion: Baseline PIV was an independent predictor of pCR for NSCLC patients receiving neoadjuvant immunochemotherapy. A significantly longer DFS was achieved in patients with pCR rather than those without pCR; thus, the PIV-based diagnostic model might serve as a practical tool to identify ideal patients for neoadjuvant immunotherapeutic guidance.Keywords: non-small-cell lung cancer, pan-immune-inflammatory value, neoadjuvant immunochemotherapy, pathological complete response, survival benefits

Jie-Yu Wang,1,2 Xiao-Qing Lv,2 Jing-Mei Wu,2 Wang-Qin Tang,2 Gui-Ying Luo,1 Chun-Mei Liang,1 Dan-Ni Wang,3 Jing-Fang Hong,2 Yun-Xia Cao1,4,5 1Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2School of Nursing, Anhui Medical University, Hefei, People’s Republic of China; 3Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, People’s Republic of China; 4NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, People’s Republic of China; 5Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, People’s Republic of ChinaCorrespondence: Jing-Fang Hong; Yun-Xia Cao, Email 13739273006@163.com; hongjingfang@ahmu.edu.cn; caoyunxia6@126.comPurpose: Infertility has adverse effects on the quality of life (QoL) of infertile couples. Previous studies found important associations between sexual function, self-esteem and QoL, but mainly focused on one individual’s approach rather than both partners. This study adopted a dyadic approach to evaluate the relationship between sexual function and QoL in couples with infertility through mediation and improving self-esteem.Patients and Methods: Between October 2020 and January 2021, 428 couples with infertility (n=856) undergoing in-vitro fertilization (IVF) at a tertiary hospital in Hefei, China, were registered for the current descriptive cross-sectional research. The dyads’ sociodemographic and clinical features, as well as their sexual function, self-esteem, and QoL were evaluated. The Fertility quality of life scale (FertiQoL), Rosenberg Self-Esteem Scale (RSES), Female Sexual Function Index (FSFI), and International Index of Erectile Function-15 (IIEF-15) were used to evaluate the participants. The Actor-Partner Interdependence Mediation Model (APIMeM) was utilized to examine data from the dyadic relationships.Results: According to the APIMeM analysis, sexual function of individuals with infertility was directly and indirectly connected with their QoL, mediated through their self-esteem. The women’s sexual function was found to be positively associated with their partner’s QoL, with the women’s self-esteem acting as a complete mediator. The men’s sexual function was found to be positively associated with partner’s QoL, with the men’s self-esteem acting as a complete mediator.Conclusion: The findings suggest that boosting participants’ self-esteem can help them and their partners have a better QoL. Also, therapies aimed at improving and sustaining self-esteem of couples with infertility could help mitigate the negative influence of low sexual function on their QoL.Keywords: in-vitro fertilization, dyad, quality of life, self-esteem, sexual function

Ching-Chun Li,1 Tsung-Kun Chang,1,2 Yen-Cheng Chen,1,3 Hsiang-Lin Tsai,1,2 Ching-Wen Huang,1,2 Wei-Chih Su,1,3 Cheng-Jen Ma,1,3 Tzu-Chieh Yin,1,4,5 Po-Jung Chen,1 Jaw-Yuan Wang1– 3,6– 8 1Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 6Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Department of Surgery, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, TaiwanCorrespondence: Jaw-Yuan Wang, Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung, 807, Taiwan, Tel +886-7-3122805, Email cy614112@ms14.hinet.net; jawyuanwang@gmail.comBackground: The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)-only, liver metastasis (LiM)-only, and lung metastasis (LuM)-only CRC.Methods: Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1– 41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.Results: Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.Conclusion: Our study revealed that in patients with PC-only mCRC treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC.Keywords: prognosis, metastatic colorectal cancer, peritoneal carcinomatosis-only, UGT1A1, irinotecan dose escalation

Jian-Yao Wang,1,&ast; Jing Lao,2,&ast; Yu Luo,3 Jing-Jie Guo,2 Hao Cheng,2 Hong-Yan Zhang,2 Jun Yao,4 Xiao-Peng Ma,1 Bin Wang1 1Department of General Surgery, Shenzhen Children’s Hospital, Shenzhen, 518026, Guangdong Province, People’s Republic of China; 2Shenzhen Children’s Hospital of China Medical University, Shenzhen, 518026, Guangdong Province, People’s Republic of China; 3Zhuhai Campus of Zunyi Medical University, Zhuhai, 519090, Guangdong Province, People’s Republic of China; 4Department of Gastroenterology, Jinan University of Medical Sciences, Shenzhen Municipal People’s Hospital, Shenzhen, 518020, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Peng Ma; Bin Wang Tel +86-075583008073Email 1345012907@qq.com; szwb1967@126.comPurpose: This study aimed to identify novel methylation-regulated genes as diagnostic biomarkers and therapeutic targets for hepatoblastoma (HB).Materials and Methods: The DNA methylation data of 19 HB tumor samples and 10 normal liver samples from the GSE78732 dataset and gene expression profiling data of 53 HB tumor samples and 14 normal liver samples from the GSE131329 dataset and 31 HB tumor samples and 32 normal liver samples from the GSE133039 dataset were downloaded form the Gene Expression Omnibus database. Next, differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were identified. Venn diagrams were used to identify methylation-regulated genes. The VarElect online tool was selected to identify key methylation-regulated genes, and a protein–protein interaction (PPI) network was constructed to show the interactions among key methylation-regulated genes and DEGs. Finally, Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to investigate the potential regulatory mechanisms of key methylation-regulated genes.Results: A total of 457 DMGs and 1597 DEGs were identified between the HB and normal liver samples. After DMGs and DEGs overlapping, 22 hypomethylated and upregulated genes and 19 hypermethylated and downregulated genes in HB were screened. Survival analysis revealed that 13 methylation-regulated genes were associated with the prognosis of liver cancer. Moreover, SPP1, UHRF1, and HEY1 were selected as the key DNA methylation-regulated genes. The PPI network revealed that all of them could affect TP53, while both UHRF1 and HEY1 could influence BMP4. Enrichment analysis suggested that the DEGs were involved in TP53-related pathways, including the cell cycle and p53 signaling pathway. Finally, SPP1, UHRF1, and HEY1 were hypomethylated and upregulated in the HB samples compared with those in the normal liver samples.Conclusion: SPP1, UHRE1, and HEY1 may play important roles in HB and be used as biomarkers for its diagnosis and treatment.Keywords: DNA methylation, gene, hepatoblastoma, biomarker, tumor

Jun-Yan Wang, Fan Zhang, Lei Hong, Su-Ju Wei Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of ChinaCorrespondence: Su-Ju WeiDepartment of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of ChinaTel +86 311-86095672Email wei11071@126.comBackground: Non-small-cell lung carcinoma (NSCLC) is the most common type of lung cancer. Circular RNA_0000429 (circ_0000429) is an identified circular RNA (circRNA) that is correlated with cancer progression. However, the role of circ_0000429 in NSCLC remains unknown. In the present study, we aimed to investigate the function of circ_0000429 in NSCLC and the underlying mechanism.Methods: The expression patterns of circ_0000429 were determined using qRT-PCR in NSCLC samples and cell lines. The subcellular distribution of circ_0000429 in NSCLC cells was analyzed by fluorescence in situ hybridization (FISH). Cell proliferation was examined utilizing the CCK-8 assay. Cell migration and invasion were evaluated using the transwell assay. We used the bioinformatics software TargetScan and miRanda to predict circRNA–miRNA and miRNA–mRNA interactions.Results: Our results showed that circ_0000429 expressions were significantly upregulated in NSCLC tissues and cell lines. Knockdown of circ_0000429 significantly inhibited the cell proliferation, migration, and invasion of NSCLC cells in vitro. Furthermore, we demonstrated that circ_0000429 acted as a sponge to absorb microRNA-1197 (miR-1197) and promoted MADD expression.Conclusion: Collectively, our results demonstrated that circ_0000429 exhibited a carcinogenic role by sponging miR-1197 and regulating CMADD expression in NSCLC. These findings provided evidence for understanding the role of circ_0000429 in NSCLC tumorigenesis.Keywords: circRNA_0000429, miRNA-1197, MADD, NSCLC

Elber Yuksel Aydin, 1, 2 Andrea Schneider, 1, 3 Dragana Protic, 1, 4 Jun Yi Wang, 1, 5 Veronica Martínez-Cerdeño, 1, 6 Flora Tassone, 1, 7 Hiu-Tung Tang, 7 Susan Perlman, 8 Randi J Hagerman 1, 3 1Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA, USA; 2Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; 3Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, USA; 4Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, Belgrade, Serbia; 5Center for Mind and Brain, University of California Davis School of Medicine, Sacramento, CA, USA; 6Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine, University of California Davis School of Medicine and Shriners Hospital, Sacramento, CA, USA; 7Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA, USA; 8Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, CA, USACorrespondence: Randi J HagermanMIND Institute UCDMC, 2825 50th Street, Sacramento, CA 95817, USAEmail rjhagerman@ucdavis.eduAbstract: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that usually begins in the early 60s and affects carriers of premutation expansion (55– 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Additional disorders can co-occur with FXTAS including Alzheimer’s disease (AD). Here we discuss a case report of a male with 67 CGG repeats in FMR1 who had mild late-onset FXTAS symptoms followed by neurocognitive disorder symptoms consistent with AD. The patient has developed tremor and ataxia that are the two characteristic symptoms of FXTAS. In addition, he shows rapid cognitive decline, brain atrophy most substantial in the medial temporal lobe, and decreased metabolism in the brain regions that are the characteristic findings of AD. The purpose of this study is to describe a patient profile with both diseases and review the details of an overlap between these two diseases.Keywords: FXTAS, Alzheimer’s disease, cognitive decline, neurocognitive disorder, premutation, neurogenetics

Dong-Ping Li,1,* Ying-Ling Chen,1,* Hong-Yue Jiang,1,* Yun Chen,1 Xiao-Qing Zeng,1 Li-Li Xu,1 Yang Ye,2 Chang-Qiang Ke,2 Ge Lin,3 Ji-Yao Wang,1,4 Hong Gao1,41Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2State Key Laboratory of Drug Research & Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, People’s Republic of China; 3School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR; 4Evidance-based Medicine Center of Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this work Purpose: To investigate the mitochondria-related mechanism of Gynura segetum (GS)-induced apoptosis and the protective effect of phosphocreatine (PCr), a mitochondrial respiration regulator.Methods: First, the mechanism was explored in human hepatocyte cell line. The mitochondrial oxidative stress was determined by fluorescence assay. The level of sirtuin 3 (SIRT3), acetylated superoxide dismutase 2 (Ac-SOD2), SOD2, and apoptosis were detected by Western blotting. Mito-TEMPO and cell lines of viral vector-mediated overexpression of SIRT3 and SIRT3H248Y, were used to further verify the mechanism of GS-induced apoptosis. GS-induced liver injury mice models were built by GS through intragastric administration and interfered by PCr through intraperitoneal injection. A total of 30 C57BL/6J mice were assigned to 5 groups and treated with either saline, PCr (100 mg/kg), GS (30 g/kg), or PCr (50 or 100 mg/kg)+GS (30 g/kg). Liver hematoxylin and eosin (HE) staining, immunohistochemical analysis, and blood biochemical evaluation were performed.Results: GS induced hepatocyte apoptosis and elevated levels of mitochondrial ROS in L-02 cells. The expression of SIRT3 was decreased. Downregulation of SIRT3 was associated with increased levels of Ac-SOD2, which is the inactivated enzymatic form of SOD2. Conversely, when overexpressing SIRT3 in GS-treated cells, SOD2 activity was restored, and mitochondrial ROS levels and hepatocyte apoptosis declined. Upon administration of PCr to GS-treated cells, they exhibited a significant upregulation of SIRT3 and were protected against apoptosis. In animal experiments, serum ALT level and mitochondrial ROS of the mice treated with GS and 50 mg/kg PCr were significantly attenuated compared with only GS treated. The changes in SIRT3 expression were also consistent with the in vitro results. In addition, immunohistochemical analysis of the mouse liver showed that Ac-SOD2 was decreased in the PCr and GS co-treated group compared with GS treated group.Conclusion: GS caused liver injury by dysregulating mitochondrial ROS generation via a SIRT3-SOD2 pathway. PCr is a potential agent to treat GS-induced liver injury by mitochondrial protection.Keywords: Gynura segetum, apoptosis, mitochondrial, ROS, SIRT3, phosphocreatine

Juan-Yi Wang,1 Tao Wu,2 Wu Ma,1 Shuo Li,1 Wen-Jiang Jing,1 Jun Ma,1 Dong-Mei Chen,1 Xiao-Jie Guo,1 Ke-Jun Nan3 1Department of Oncology, 3201 Affiliated Hospital of Medical College of Xi’an Jiaotong University, Hanzhong, Shaanxi, People’s Republic of China; 2Department of Gynecologic Cancer, Shaanxi Province Tumor Hospital, Xi’an, Shaanxi, People’s Republic of China; 3Department of Medical Oncology, The First Affiliated Hospital, College of Medicine of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China Background and aim: Gastric cancer (GC) is a fatal malignancy with high rate of recurrence and metastasis. Here, we investigated the correlations between the expression of autophagic protein LC3B and 2 epithelial–mesenchymal transition-related proteins (E-cadherin and Vimentin) and the clinicopathological factors and prognosis of patients with GC.Materials and methods: The expression of LC3B, E-cadherin, and Vimentin in GC samples (110 cases) and paracarcinoma tissues (40 cases) was analyzed using the Oncomine databases and further detected by immunohistochemistry. The correlations among these markers expression and clinicopathological features in GC were analyzed. The patients were followed for survival analysis.Results: Compared to the nontumor tissues, the expression of LC3B and Vimentin proteins were significantly elevated in GC tissues, but the E-cadherin expression was decreased (all p

Yueh Lan Huang,1 Chih-Cheng Lai,2 Ya-Hui Wang,3 Cheng-Yi Wang,1 Jen-Yu Wang,1 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 2Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan Background: There is conflicting information regarding the effects of selective and nonselective beta-blocker treatment in patients with COPD.Participants and methods: This nested case–control study used the Taiwan National Health Insurance Research Database. We included COPD patients who used inhalation steroid and beta-blockers between 1998 and 2010. From this cohort, there were 16,067 patients with severe exacerbations included in the analysis and 55,970 controls matched on age, sex, COPD diagnosis year, and beta-blockers treatment duration by risk set sampling.Results: For the selective beta-blocker users, the current users had a lower risk of severe exacerbations than the nonusers (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85–0.96). In contrast, for the nonselective beta-blocker users, the current users had a higher risk of severe acute exacerbations than the nonusers (OR, 1.21; 95% CI, 1.14–1.27). A higher risk of severe exacerbation during increasing mean daily dose or within about the initial 300 days was found in nonselective beta-blockers, but not in selective beta-blockers. One selective beta-blocker, betaxolol, had a significantly lower risk of severe exacerbations (OR, 0.75; 95% CI, 0.60–0.95). Two nonselective beta-blockers (labetalol and propranolol) were associated with a significantly higher risk of exacerbations (OR, 1.49; 95% CI, 1.32–1.67 for labetalol; OR, 1.16; 95% CI, 1.10–1.23 for propranolol).Conclusion: Selective beta-blockers can be cautiously prescribed for patients with COPD and cardiovascular disease (CVD), however, nonselective beta-blockers should not be prescribed for patients with COPD. Betaxolol may be the preferred choice of suitable selective beta-blocker for patients with COPD, however, labetalol and propranolol should be avoided for patients with COPD. Keywords: beta-blocker, COPD, selective, nonselective

Ligen Shi,1,2 Jingyi Wang,1 Shenbin Xu,2 Yunrong Lu1 1Department of Psychiatry, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 2Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: Vilazodone is a new molecule approved for major depressive disorder (MDD). This report focuses on the efficacy and tolerability of vilazodone for MDD. MEDLINE, EMBASE, and Cochrane Library were searched. A total of 1,930 patients from four trials were included. A significant improvement in the Montgomery–Asberg Depression Rating Scale (MADRS) total score was seen as early as week 2 (P

Zhiwei Lu,* Yusheng Cheng,* Xiongwen Tu, Liang Chen, Hu Chen, Jian Yang, Jinyan Wang, Liqin Zhang Department of Respiratory Medicine, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study was to appraise the effect of community-acquired pneumonia (CAP) on inhospital mortality in critically ill acute exacerbation of COPD (AECOPD) patients admitted to a respiratory intensive care unit.Patients and methods: A retrospective observational study was performed. Consecutive critically ill AECOPD patients receiving treatment in a respiratory intensive care unit were reviewed from September 1, 2012, to August 31, 2015. Categorical variables were analyzed using chi-square tests, and continuous variables were analyzed by Mann–Whitney U-test. Kaplan–Meier analysis was used to assess the association of CAP with survival of critically ill AECOPD patients for univariate analysis. Cox’s proportional hazards regression model was performed to identify risk factors for multivariate analysis.Results: A total of 80 consecutive eligible individuals were reviewed. These included 38 patients with CAP and 42 patients without CAP. Patients with CAP had a higher inhospital rate of mortality than patients without CAP (42% vs 33.3%, P

Shu-Chuan Ho,1,2 Jiun-Yi Wang,3,4 Han-Pin Kuo,5 Chien-Da Huang,5 Kang-Yun Lee,2,6 Hsiao-Chi Chuang,1,2 Po-Hao Feng,2,6 Tzu-Tao Chen,2,* Min-Fang Hsu7,* 1School of Respiratory Therapy, College of Medicine, 2Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 3Department of Healthcare Administration, Asia University, Wufeng, 4Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 5Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 6Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 7Department of Nursing, Yuanpei University of Medical Technology, Hsinchu City, Taiwan *These authors contributed equally to this work Background: Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of death in the world. Patients with COPD experience airflow obstruction, weight loss, skeletal muscle dysfunction, and comorbidities. Anthropometric indicators are risk factors for mortality in geriatric assessment. Purpose: This study examined and compared the associations of anthropometric indicators, such as low body mass index (BMI), low mid-arm circumference (MAC), and low calf circumference (CC), with the prediction of a 3-year follow-up mortality risk in patients with COPD. Methods: We recruited nonhospitalized patients with COPD without acute conditions from a general hospital in Taiwan. The BMI, MAC, and CC of all patients were measured, and they were followed for 3 years through telephone interviews and chart reviews. The Kaplan–Meier survival curves stratified by BMI, MAC, and CC were analyzed. Variables univariately associated with survival were entered into a multivariate Cox regression model. The Bayesian information criterion was used to compare the predictive ability of the three anthropometric indicators to predict mortality rate. Results: In total, 104 patients were included (mean ± standard deviation age, 74.2±6.9 years; forced expiratory volume in 1 second [%], 58.4±20.4 predicted; males, 94.2%); 22 patients (21.2%) died during the 36-month follow-up. During this long-term follow-up, the three anthropometric indicators could predict mortality risk in patients with COPD (low BMI [

Jun-Ying Wang,1 Jie Chen,1 Jiang Yang,2 Hao Wang,1 Xiu Shen,1 Yuan-Ming Sun,1 Meili Guo,3 Xiao-Dong Zhang4 1Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 2Environment, Energy and Natural Resources Center, Department of Environmental Science and Engineering, Fudan University, Shanghai, 3Department of Physics, School of Science, Tianjin Chengjian University, 4Department of Physics, School of Science, Tianjin University, Tianjin, People’s Republic of China Abstract: Gold nanoclusters (Au NCs) have exhibited great advantages in medical diagnostics and therapies due to their efficient renal clearance and high tumor uptake. The in vivo effects of the surface chemistry of Au NCs are important for the development of both nanobiological interfaces and potential clinical contrast reagents, but these properties are yet to be fully investigated. In this study, we prepared glutathione-protected Au NCs of a similar hydrodynamic size but with three different surface charges: positive, negative, and neutral. Their in vivo biodistribution, excretion, and toxicity were investigated over a 90-day period, and tumor uptake and potential application to radiation therapy were also evaluated. The results showed that the surface charge greatly influenced pharmacokinetics, particularly renal excretion and accumulation in kidney, liver, spleen, and testis. Negatively charged Au NCs displayed lower excretion and increased tumor uptake, indicating a potential for NC-based therapeutics, whereas positively charged clusters caused transient side effects on the peripheral blood system. Keywords: gold clusters, in vivo toxicity, long-term, cancer therapy

Wei Zhu,1,* Yan Wu,2,* Yi-Fang Meng,1 Jin-Yu Wang,1 Ming Xu,1 Jian-Jun Tao,1 Jiong Lu1 1Department of Ophthalmology, Changshu No 2 People’s Hospital, Changshu, 2Department of Ophthalmology, The First People’s Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Age-related macular degeneration (AMD) is now one of the leading causes of blindness in the elderly population. The antioxidative effects of curcumin on aging retinal pigment epithelial (RPE) cells are still unclear. We conducted an in vitro study to investigate the effects of curcumin on aging RPE cells. A pulsed H2O2 exposure aging model was adopted. Aging RPE cells were treated with curcumin 20 µM, 40 µM, and 80 µM. Apoptosis of RPE cells was analyzed by flow cytometry. The intracellular reactive oxygen species concentration was detected using a specific probe and apoptosis-associated proteins were detected by Western blot. Expression of oxidative biomarkers, including superoxide dismutase, maleic dialdehyde, and glutathione, was detected commercially available assay kits. Compared with normal cells, lower cell viability, higher apoptosis rates, and more severe oxidation status were identified in the aging RPE cell model. Curcumin improved cell viability and decreased apoptosis and oxidative stress. Further, curcumin had a significant influence on expression of apoptosis-associated proteins and oxidative stress biomarkers. In conclusion, treatment with curcumin was able to regulate proliferation, oxidative stress, and apoptosis in aging RPE cells. Accordingly, application of curcumin may be a novel strategy to protect against age-related change in AMD. Keywords: curcumin, retinal pigment epithelium, apoptosis, age-related macular degeneration

Shu-Chuan Ho,1,* Min-Fang Hsu,2,3,* Han-Pin Kuo,4 Jiun-Yi Wang,2 Li-Fei Chen,4 Kang-Yun Lee,5,6 Hsiao-Chi Chuang11School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, 2Department of Healthcare Administration, Asia University, Wufeng, Taichung, 3Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, 4Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, 5Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, 6Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workBackground: Exercise intolerance is a major issue affecting many people with COPD. Six-minute walking distance (6MWD) is a widely used indicator of exercise capacity in patients with COPD. The process is strenuous and time-consuming, especially for patients who have muscle wasting. Anthropometric indicators that reflect body lean mass, such as body mass index (BMI), mid-arm circumference (MAC), and calf circumference (CC), may have value in predicting exercise intolerance.Purpose: This study attempted to determine the abilities of simple anthropometric indicators including BMI, MAC, and CC in reflecting the exercise intolerance of COPD patients.Methods: We recruited 136 nonhospitalized ambulatory COPD patients without acute conditions from a general hospital in Taiwan. Each subject’s BMI, MAC, and CC were measured, and they were examined with pulmonary function tests and a 6-minute walk test.Results: Among the three anthropometric indicators examined, CC showed the strongest correlation with the 6MWD, followed by MAC and BMI. CC was also strongly associated with functional capacity, followed by MAC, according to the receiver operating characteristic curves. CC and MAC, but not BMI, were significantly associated with exercise intolerance according to logistic regression models that controlled for potential confounders.Conclusion: Among the three variables examined, CC and walking distance may have the strongest association in COPD patients. CC may have value in serving as an adjunct to 6MWD in evaluating exercise intolerance of patients with COPD.Keywords: 6-minute walk distance, BMI, calf circumference, COPD, mid-arm circumference

Hong Gao,1,* Jianqing Q Ruan,2,* Jie Chen,1 Na Li,2 Changqiang Q Ke,3 Yang Ye,3–5 Ge Lin,2,4,5 Jiyao Y Wang1,61Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong; 3Shanghai Institute of Materia Medica, Shanghai, People’s Republic of China; 4Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines, Shanghai Institute of Materia Medica, 5Chinese University of Hong Kong, Hong Kong; 6Center of Evidence-Based Medicine Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this work and share first authorship Background: The diagnosis of hepatic sinusoidal obstruction syndrome (HSOS) induced by pyrrolizidine alkaloids is mainly based on clinical investigation. There is currently no prognostic index. This study evaluated the quantitative measurement of blood pyrrole-protein adducts (PPAs) as a diagnostic and prognostic index for pyrrolizidine alkaloid-induced HSOS.Methods: Suspected drug-induced liver injury patients were prospectively recruited. Blood PPAs were quantitatively measured using ultra-performance liquid chromatography-tandem mass spectrometry. Patients’ age, sex, biochemistry test results, and a detailed drug history were recorded. The patients were divided into two groups, ie, those with HSOS induced by pyrrolizidine alkaloid-containing drugs and those with liver injury induced by drugs without pyrrolizidine alkaloids. The relationship between herb administration, clinical outcomes, blood sampling time, and blood PPA concentration in pyrrolizidine alkaloid-associated HSOS patients was analyzed using multiple linear regression analysis.Results: Forty patients met the entry criteria, among whom 23 had pyrrolizidine alkaloid-associated HSOS and 17 had liver injury caused by drugs without pyrrolizidine alkaloids. Among the 23 patients with pyrrolizidine alkaloid-associated HSOS, ten recovered, four developed chronic disease, eight died, and one underwent liver transplantation within 6 months after onset. Blood PPAs were detectable in 24 of 40 patients with concentrations from 0.05 to 74.4 nM. Sensitivity and specificity of the test for diagnosis of pyrrolizidine alkaloid-associated HSOS were 100% (23/23) and 94.1% (23/24), respectively. The positive predictive value was 95.8% and the negative predictive value was 100%, whereas the positive likelihood ratio was 23.81. The level of blood PPAs in the severe group (died or received liver transplantation) was significantly higher than that in the recovery/chronicity group (P=0.004). Conclusion: Blood PPAs measured by ultra-performance liquid chromatography-tandem mass spectrometry are highly sensitive and specific for pyrrolizidine alkaloid-associated HSOS. The blood PPA concentration is related to the severity and clinical outcome of pyrrolizidine alkaloid-associated HSOS. Keywords: drug-induced liver injury, herb, blood protein adducts, prognostic marker

Li-Yong Zhang,1,* Tao Xing,1,* Li-Xin Du,1,* Qing-Min Li,2 Wei-Dong Liu,1 Ji-Yue Wang,1 Jing Cai31Department of neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 2Department of Neurosurgery, Tai’an Central Hospital, Tai’an, Shandong, People’s Republic of China; 3Department of Neurosurgery, LinYi People Hospital, LinYi, Shandong, People’s Republic of China*These authors contributed equally to this workBackground: Glial cell line-derived neurotrophic factor (GDNF) is a small protein that potently promotes the survival of many types of neurons. Detection of GDNF is vital to monitoring the survival of sympathetic and sensory neurons. However, the specific method for GDNF detection is also un-discovered. The purpose of this study is to explore the method for protein detection of GDNF.Methods: A novel visual detection method based on a molecular translator and isothermal strand-displacement polymerization reaction (ISDPR) has been proposed for the detection of GDNF. In this study, a molecular translator was employed to convert the input protein to output deoxyribonucleic acid signal, which was further amplified by ISDPR. The product of ISDPR was detected by a lateral flow biosensor within 30 minutes.Results: This novel visual detection method based on a molecular translator and ISDPR has very high sensitivity and selectivity, with a dynamic response ranging from 1 pg/mL to 10 ng/mL, and the detection limit was 1 pg/mL of GDNF.Conclusion: This novel visual detection method exhibits high sensitivity and selectivity, which is very simple and universal for GDNF detection to help disease therapy in clinical practice.Keywords: lateral flow biosensor, molecular translator, isothermal strand-displacement polymerization reaction

Nianhong Lu, Caihong Liu, Jiangyuan Wang, Ying Ding, Qing Ai Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, People’s Republic of China Abstract: Toxoplasmosis complicating lung cancer has been described only rarely. Here, we report a case of acute Toxoplasma gondii infection in a patient with squamous lung cancer. A 64-year-old woman was admitted to our hospital with a history of cough of 6 months' duration and chest pain of 1 week’s duration. Further examination revealed multiple swollen lymph nodes, palpable on the top of the right collarbone and without tenderness. The chest X-ray, bronchoscopy, and computed tomography scan confirmed squamous carcinoma of the right lung. The Wright-stained bronchoalveolar-lavage fluid cytology diagnosis was positive for T. gondii and tachyzoites were detected. All of them were of free type (ectocytic), without intracellular parasites. Serological examination revealed that the anti-T. gondii immunoglobulin (Ig) M and IgG antibodies were positive. Unfortunately the patient did not continue treatment and was lost to follow-up. Toxoplasmosis is a life-threatening opportunistic infection in patients with lung cancer. Prompt recognition of T. gondii infection among cancer patients with subsequent targeted treatment of toxoplasmosis could help alleviate symptoms and improve survival. Keywords: lung cancer, Toxoplasma gondii, bronchoalveolar-lavage fluid, tachyzoite

Jiyao WangZhongshan Hospital, Fudan University, Shanghai, Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai, People’s Republic of ChinaAbstract: The People’s Republic of China has one of the highest rates of hepatitis B virus (HBV) infection. This review summarizes recent data from studies of entecavir, one of the recommended first-line oral therapies for treating chronic hepatitis B, in Chinese HBV-infected patients. Long-term treatment with entecavir is efficacious and well tolerated, and studies comparing entecavir with other nucleos(t)ide therapies, such as lamivudine, adefovir, and telbivudine, demonstrate superior antiviral effects for entecavir therapy and comparable safety profiles. Entecavir monotherapy and combination treatment with other nucleos(t)ide analogs has been shown to be efficacious in the treatment of lamivudine-resistant and adefovir-resistant patients with HBV infection, as well as in patients with multidrug-resistant disease. Entecavir has also been shown to be effective in patients with HBV-associated clinical morbidity, including cirrhosis and liver failure, as well as in preventing recurrence of HBV following liver transplantation and in preventing reactivation of HBV after immunosuppressive therapy. Although the cost of anti-HBV therapy is a particular concern in the People’s Republic of China, a number of studies have recently demonstrated that entecavir (particularly long-term therapy) represents a more cost-effective treatment strategy compared with other nucleos(t)ide therapies. Further research is required to assess the effects of entecavir combination therapy on hepatitis B surface antigen clearance, and in drug-resistant patients in the People’s Republic of China.Keywords: hepatitis B, entecavir, People’s Republic of China, nucleos(t)ides

CRISPR-Cas immunity requires integration of short, foreign DNA fragments into the host genome at the CRISPR locus, a site consisting of alternating repeat sequences and foreign-derived spacers. In most CRISPR systems, the proteins Cas1 and Cas2 form the integration complex and are both essential for DNA acquisition. Most type V-C and V-D systems lack the cas2 gene and have unusually short CRISPR repeats and spacers. Here, we show that a mini-integrase comprising the type V-C Cas1 protein alone catalyzes DNA integration with a preference for short (17- to 19-base-pair) DNA fragments. The mini-integrase has weak specificity for the CRISPR array. We present evidence that the Cas1 proteins form a tetramer for integration. Our findings support a model of a minimal integrase with an internal ruler mechanism that favors shorter repeats and spacers. This minimal integrase may represent the function of the ancestral Cas1 prior to Cas2 adoption.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

Loss of DNA mismatch repair has been observed in a variety of human cancers. Recent studies have shown that loss of DNA mismatch repair results in resistance to cisplatin but not oxaliplatin, suggesting that the mismatch repair proteins serve as a detector for cisplatin but not oxaliplatin adducts. To identify the signal transduction pathways with which the detector communicates, we investigated the effect of loss of DNA mismatch repair on activation of known damage-responsive pathways, and recently reported that cisplatin differentially activates c-Jun NH2-terminal kinase (JNK) and c-Abl in repair-proficient vs.-deficient cells. In the current study, we directly compared differential activation of these pathways by cisplatin vs. oxaliplatin. The results confirm that cisplatin activates JNK kinase 5.7 +/- 1.5 (s.d.)-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that the c-Abl response to cisplatin is completely absent in DNA mismatch repair-deficient cells. In contrast, there was no detectable activation of the JNK or c-Abl kinases in DNA mismatch repair-proficient or -deficient cells exposed to oxaliplatin. The present study demonstrates that, despite the similarity of the adducts produced by cisplatin and oxaliplatin, they appear to be recognized by different detectors. The DNA mismatch repair system plays an important part in the recognition of cisplatin adducts, and activation of both the JNK and c-Abl kinases in response to cisplatin damage is dependent on the detector function of the DNA mismatch repair proteins. In contrast, this detector does not respond to oxaliplatin adducts.