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Bingchen Lang,1 Lingli Zhang,1–3 Fengshan Li,1 Yunzhu Lin,1 Wensheng Zhang,4 Chunsong Yang11Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, People’s Republic of China; 4Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaObjective: Myoclonus was considered as one conundrum in etomidate induction, which led to multiple risks during clinical anesthesia. The present study was conducted to compare the efficacy of pretreatment with remifentanil to different pharmacological approaches on reducing etomidate-induced myoclonus.Methods: We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure from the inception to October 2018. Randomized controlled trials comparing remifentanil versus other pharmacological approaches in reducing etomidate-induced myoclonus were eligible to be analyzed.Results: Overall, 13 trials with 1,392 patients met with the inclusion criteria. 1) Pretreatment with remifentanil could reduce the incidence of etomidate-induced myoclonus compared to placebo and fentanyl; few differences were found between the use of remifentanil and the use of midazolam: (incidence of myoclonus: 5.56% with remifentanil vs 71.65% with saline, RR=0.08, with 95% CI [0.05, 0.12], P

Liu Ouyang, Yang Dan, Zengwu Shao, Shuhua Yang, Cao Yang, Guohui Liu, Wu Zhou, Deyu Duan Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China Purpose: Umbelliferone (Umb), a member of coumarin family, is found in many plants and is a promising molecule with potential anti-inflammatory, anti-oxidative, and anti-tumor activities. However, the effect of Umb on arthritis remains unclear.Methods: A rat model with Freund’s complete adjuvant (FCA)-induced arthritis was developed and used to test the efficacy of Umb on arthritis rats. Rats were given an intragastric injection of Umb (20 and 40 mg/kg) once daily from days 21 to 28 after the administration of FCA. Hind paw volume was assessed using a volume meter. The pro-inflammatory cytokine levels and prostaglandin E2 (PEG2) level in serum and synovial fluid were detected by ELISA. HE staining was used to determine representative histological changes in joint tissues, and Western blot analysis was employed to study the effects of Umb on MAPK/NF-κB signaling pathway.Results: Our results showed that Umb suppressed the release of IL-6, IL-1β, tumor necrosis factor-alpha, and PEG2. In addition, Umb could also dramatically ameliorate the pathological changes observed in rat joints. Based on the results of Western blot, we also observed that Umb could strikingly suppress the expression of MAPK/NF-κB pathway molecules.Conclusion: These results proved that treatment with Umb is very effective for arthritis and inhibiting the MAPK/NF-κB signaling pathway may be a potential therapeutic target for treatment of arthritis. Keywords: umbelliferone, arthritis, inflammation, MAPK/NF-κB pathway

Fei Ji,1,* Wei-Kai Xiao,2,* Ci-Qiu Yang,1,* Mei Yang,1 Liu-Lu Zhang,1 Hong-Fei Gao,1 Yu-Feng Lin,1 Teng Zhu,1 Min-Yi Cheng,1 Wei-Ping Li,1 Wei-Jun Pan,1 Xiao-Sheng Zhuang,1 Kun Wang1 1Department of Breast Cancer, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P. R. China; 2Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R. China *These authors contributed equally to this work Background: Tumor location in the breast varies, with the highest frequency in the upper outer quadrant and lowest frequency in the lower inner quadrant. Nevertheless, tumors in the central and nipple portion (TCNP) are poorly studied types of breast cancer; therefore, we aimed to clarify the clinicopathological characteristics and prognostic features of TCNP. Methods: Using the Surveillance, Epidemiology, and End Results database, we identifed 105,037 patients diagnosed with tumor in the breast peripheral quadrant (TBPQ) (n=97,046) or TCNP (n=7,991). The chi-squared test was used to compare categorical variables across TCNP and TBPQ. Cox proportional hazard models with hazard ratios were applied to estimate the factors associated with prognosis.Results:The median follow-up was over 43 months. Compared with TBPQ, TCNP patients were signifcantly older (age ≥66 years: 40.4% vs 34.1%, P20 mm size: 46.9% vs 37.3%, P

Bao Hai,1 Yunlong Ma,2 Xiaoyu Pan,1 Lei Yong,1 Chen Liang,1 Guanping He,1 Chenlong Yang,1 Bin Zhu,2 Xiaoguang Liu1 1Department of Orthopedics, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 2The Center for Pain Medicine, Peking University Third Hospital, Beijing 100191, People’s Republic of China Background: Disc degeneration (DD) is one of the common diseases worldwide, which deeply influences normal life and leads to excruciating pain. However, an effective treatment for DD is still not identified.Method: The present study systemically examined the effect of melatonin on annulus fibrosus (AF) cells of patients with DD.Results: Melatonin had the effect of promoting proliferation, inducing autophagy, and suppressing apoptosis on AF cells of patients with DD. Moreover, melatonin contributed to the translation and transcription of autophagy-related protein ATG7 and inhibited the function of miR-106a-5p in AF cells. In addition, the results suggested that miR-106a-5p mediated the expression of ATG7 by directly binding to its 3'UTR in AF cells.Conclusion: This research not only gained a deep insight of melatonin mode of action, but also indicated its potential target signaling pathway in AF cells. Keywords: disc degeneration, melatonin, ATG7, miR-106a-5p

Hua Xiong,1,2 Ping Yin,3 Xiaojiao Li,1,2 Chao Yang,1,2 Dan Zhang,1,2 Xianlong Huang,1,2 Zhuoyue Tang1,2 1Department of Radiology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400014, China; 2Molecular and Functional Imaging Laboratory, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400014, China; 3Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China Objective: To investigate the features of cerebral permeability and perfusion detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with Patlak model in relapsing–remitting multiple sclerosis (RRMS) and their correlations with Expanded Disability Status Scale (EDSS) scores and disease duration. Patients and methods: Twenty-seven RRMS patients underwent conventional MRI and DCE-MRI with 3.0 T magnetic resonance scanner were enrolled in the study. A Patlak model was used to quantitatively measure MRI biomarkers, including volume transfer constant (Ktrans), fractional plasma volume (Vp), cerebral blood flow (CBF), and cerebral blood volume (CBV). The correlations of MRI biomarkers with EDSS scores and disease duration were analyzed. Results: The MRI biomarkers Ktrans, Vp, CBF, and CBV of contrast-enhancing (CE) lesions were significantly higher (P0.05). Conclusion: Our study demonstrated the abnormalities of permeability and perfusion characteristics in multiple sclerosis (MS) lesions and NAWM regions by DCE-MRI with Patlak model. The Ktrans, Vp, CBF, and CBV of CE lesions were significantly higher than that of NE lesions, but these MRI biomarkers did not associate with the severity and duration of the disease. The skewness and kurtosis of Ktrans value in CE lesions were significantly higher than that in NE lesions, indicating that these parameters of Ktrans histogram can be used to distinguish the pathology of MS lesions. Keywords: dynamic contrast-enhanced magnetic resonance imaging, Patlak model, multiple sclerosis, permeability, perfusion, histogram

Yu-jin Tang,1,* Kai Li,2,* Cheng-liang Yang,1 Ke Huang,1 Jing Zhou,3 Yu Shi,1 Ke-gong Xie,1 Jia Liu1 1Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China; 2Academy of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China; 3Department of Anatomy, Youjiang Medical University for Nationalities, Baise, Guangxi, China *These authors contributed equally to this work Background: Spinal cord injury (SCI) is a disease of the central nervous system with few restorative treatments. Autophagy has been regarded as a promising therapeutic target for SCI. The inhibitor of phosphatase and tensin homolog deleted on chromosome ten (PTEN) bisperoxovanadium (bpV[pic]) had been claimed to provide a neuroprotective effect on SCI; but the underlying mechanism is still not fully understood.Materials and methods: Acute SCI model were generated with SD Rats and were treated with control, acellular spinal cord scaffolds (ASC) obtained from normal rats, bpV(pic), and combined material of ASC and bpV(pic). We used BBB score to assess the motor function of the rats and the motor neurons were stained with Nissl staining. The expressions of the main autophagy markers LC3B, Beclin1 and P62, expressions of apoptosis makers Bax, Bcl2, PARP and Caspase 3 were detected with IF or Western Blot analysis.Results: The bpV(pic) showed significant improvement in functional recovery by activating autophagy and accompanied by decreased neuronal apoptosis; combined ASC with bpV(pic) enhanced these effects. In addition, after treatment with ERK1/2 inhibitor SCH772984, we revealed that bpV(pic) promotes autophagy and inhibits apoptosis through activating ERK1/2 signaling after SCI.Conclusion: These results illustrated that the bpV(pic) protects against SCI by regulating autophagy via activation of ERK1/2 signaling. Keywords: bisperoxovanadium, spinal cord injury, autophagy, apoptosis, ERK1/2 signaling

Jun Pan,1,2 Chenghui Yang,1,2 Zhou Jiang,1,2 Jian Huang1,2 1Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P.R. China; 2Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P.R. China Abstract: Trametes robiniophila Murr also known as Huaier, one of the traditional Chinese medicines, has been shown an effective adjuvant of cancer therapy. Accumulating evidence suggests that the anti-cancer effects of Huaier can be briefly divided into two aspects: the direct effects on tumor cells and the indirect effects on immune cells. In vitro and in vivo experiment showed Huaier directly inhibited tumor cell proliferation, induced tumor cell death, prevented metastasis and interfered with angiogenesis via various signaling pathways. The immunomodulatory effect of Huaier is associated with enhancement of the number and function of CD4+ T cells and NK cells, regulation of the polarization and function of macrophages, and elevated secretion of immune stimulatory cytokines. In this review, the anti-cancer effects and combined treatments of Huaier with other anti-cancer therapies, and the underlying mechanisms are summarized and discussed. Keywords: Huaier, cancer, anti-tumor therapy, traditional Chinese medicine, adjuvant

Patients with intracranial artery stenosis show high incidence of stroke. Angiography reports contain rich but underutilized information that can enable the detection of cerebrovascular diseases. This study evaluated various natural language processing (NLP) techniques to accurately identify eleven intracranial artery stenosis from angiography reports. Three NLP models, including a rule-based model, a recurrent neural network (RNN), and a contextualized language model, XLNet, were developed and evaluated by internal–external cross-validation. In this study, angiography reports from two independent medical centers (9614 for training and internal validation testing and 315 as external validation) were assessed. The internal testing results showed that XLNet had the best performance, with a receiver operating characteristic curve (AUROC) ranging from 0.97 to 0.99 using eleven targeted arteries. The rule-based model attained an AUROC from 0.92 to 0.96, and the RNN long short-term memory model attained an AUROC from 0.95 to 0.97. The study showed the potential application of NLP techniques such as the XLNet model for the routine and automatic screening of patients with high risk of intracranial artery stenosis using angiography reports. However, the NLP models were investigated based on relatively small sample sizes with very different report writing styles and a prevalence of stenosis case distributions, revealing challenges for model generalization.

Hongliang Li,1,* Xiaopeng Guo,1,* Qiutian Li,2,* Pengzhan Ran,1 Xudong Xiang,3 Yuncang Yuan,1 Tianqi Dong,1 Bei Zhu,1 Lei Wang,1 Fangfang Li,1 Chunyan Yang,1 Dengcai Mu,1 Dan Wang,4 Chunjie Xiao,1 Shangyong Zheng1 1School of Medicine, Yunnan University, Kunming, China; 2Department of Oncology, Kunming General Hospital of Chengdu Military Command, Teaching Hospital of Kunming Medical University, Kunming, China; 3Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China; 4Department of Pharmacy, Kunming General Hospital of Chengdu Military Command, Teaching Hospital of Kunming Medical University, Kunming, China *These authors contributed equally to this work Purpose: Emerging evidence suggests that many differentially expressed long non-coding RNAs (lncRNAs) are involved in tumorigenesis. However, the functional roles of these transcripts and the mechanisms responsible for their deregulation in non-small-cell lung cancer (NSCLC) remain elusive. Here, we identified a novel lncRNA (lncRNA 1308), which was significantly upregulated in NSCLC tissues and investigated its biological function and potential molecular mechanism.Methods: Differences in the lncRNA expression profiles between NSCLC and tumor-adjacent normal tissues were assessed by lncRNA expression microarray analysis. The microRNA in vivo precipitation (miRIP) method was used to identify the targeting microRNAs (miRNAs) on lncRNA 1308, and luciferase reporter assays were performed. Loss-of-function studies were used to explore the effect of lncRNA 1308 on lung carcinogenesis in NSCLC cells.Results: The novel lncRNA 1308 was upregulated in NSCLC tissues and cell lines. By using biotin-labeled lncRNA 1308 for miRIP in NSCLC cells and dual-luciferase reporter assays, the results suggested that miRNA-124 was associated with lncRNA 1308. Furthermore, the expression of a disintegrin and a metalloproteinase 15 (ADAM 15) was downregulated in NSCLC cells when silencing of lncRNA 1308, the target of oncogenic miR-124, inhibits NSCLC cell proliferation and invasion. Conversely, the expression of ADAM 15 was significantly increased, when inhibiting the expression of miR-124, and alleviated cell invasion inhibition.Conclusion: The results suggested that lncRNA 1308 may function as a competing endogenous RNA (ceRNA) for miR-124 to regulate cell invasion through the miR-124/ADAM 15 signaling pathway, indicating that lncRNA 1308 plays an important role in the disease progression of NSCLC. Keywords: lung cancer, lncRNA 1308, miR-124, ADAM 15, competing endogenous RNA

Zhang Y, Zhou J, Yang C, et al. Int J Nanomedicine. 2016;11:1119–1130. The authors have advised due to an error at the time of figure assembly, Figure 4 on page 1124 is incorrect. The correct Figure 4 is shown in Download Article. Page 1126, Table 1, the authors have advised a mistake was made in calculating the Drug loading content (DLC) in the manuscript. The correct Table 1 is shown in Download Article. The authors apologize for these errors and advise it does not affect the results of the paper. Read the original article

The ground or naive pluripotent state of human pluripotent stem cells (hPSCs), which was initially established in mouse embryonic stem cells (mESCs), is an emerging and tentative concept. To verify this vital concept in hPSCs, we performed a multivariate meta-analysis of major hPSC datasets via the combined analytic powers of percentile normalization, principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and SC3 consensus clustering. This robust bioinformatics approach has significantly improved the predictive values of our meta-analysis. Accordingly, we revealed various similarities or dissimilarities between some naive-like hPSCs (NLPs) generated from different laboratories. Our analysis confirms some previous studies and provides new evidence concerning the existence of three distinct naive-like pluripotent states. Moreover, our study offers global transcriptomic markers that define diverse pluripotent states under various hPSC growth protocols.

Chungmo Yang,1,* Hae Hyun Hwang,2,* Soohyun Jeong,1 Deokwon Seo,1 Yoon Jeong,1 Dong Yun Lee,2,3 Kangwon Lee1,4 1Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; 2Department of Bioengineering, College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 04763, Republic of Korea; 3Institute of Nano Science & Technology (INST), Hanyang University, Seoul 04763, Republic of Korea; 4Advanced Institutes of Convergence Technology, Gyeonggi-do 16229, Republic of Korea *These authors contributed equally to this work Purpose: Nitric oxide (NO) can be clinically applied at low concentrations to regulate angiogenesis. However, studies using small molecule NO donors (N-diazeniumdiolate, S-nitrosothiol, etc) have yet to meet clinical requirements due to the short half-life and initial burst-release profile of NO donors. In this study, we report the feasibility of methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) as NO-releasing polymers (NO-NPs) for inducing angiogenesis.Materials and methods: The mPEG–PLGA copolymers were synthesized by typical ring-opening polymerization of lactide, glycolide and mPEG as macroinitiators. Double emulsion methods were used to prepare mPEG–PLGA NPs incorporating hydrophilic NONOate (diethylenetriamine NONOate).Results: This liposomal NP encapsulates hydrophilic diethylenetriamine NONOate (70%±4%) more effectively than other previously reported materials. The application of NO-NPs at different ratios resulted in varying NO-release profiles with no significant cytotoxicity in various cell types: normal cells (fibroblasts, human umbilical vein endothelial cells and epithelial cells) and cancer cells (C6, A549 and MCF-7). The angiogenic potential of NO-NPs was confirmed in vitro by tube formation and ex vivo through an aorta ring assay. Tubular formation increased 189.8% in NO-NP–treated groups compared with that in the control group. Rat aorta exhibited robust sprouting angiogenesis in response to NO-NPs, indicating that NO was produced by polymeric NPs in a sustained manner.Conclusion: These findings provide initial results for an angiogenesis-related drug development platform by a straightforward method with biocompatible polymers. Keywords: mPEG-PLGA nanoparticles, sprouting angiogenesis, low concentration of nitric oxide, liposomal nanoparticles, amphiphilic polymers

Menghao Shi,1 Xiufeng Zhao,2 Jiulong Zhang,1 Shuang Pan,1 Chunrong Yang,3 Ying Wei,1 Haiyang Hu,1 Mingxi Qiao,1 Dawei Chen,1 Xiuli Zhao1 1Department of pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China; 2Oncology Department, Affiliated Hongqi Hospital of Mudanjiang Medical College, Mudanjiang 157000, PR China; 3Department of pharmaceutics, School of Pharmacy, Jiamusi University, Jiamusi, Heilongjiang 154007, PR China Introduction: Specific polo-like kinase (PLK1) silencing with small interface RNA (siRNA) may be an effective approach for PLK1-overexpressed lung cancer. However, low siRNA concentration into cytoplasm of tumor tissue severely limits its application.Materials and methods: In this study, a novel triblock copolymer methoxy poly(ethylene glycol)-poly(histidine)-poly(sulfadimethoxine) (mPEG-PHis-PSD, shorten as PHD) was synthesized and used to construct novel nonviral gene vector with cationic liposomes.Results: The resulting hybrid nanoparticles (PHD/LR) loaded with siPLK1 possessed excellent physiochemical properties. In vitro study indicated that PHD/LR could be efficiently internalized into human lung adenocarcinoma A549 cells and downregulated PLK1 protein expression to induce cell apoptosis, which was attributed to pH-induced instantaneous dissociation, efficient endo/lysosomal escape arose from PHD copolymer. Furthermore, in vivo antitumor activity demonstrated that PHD/LR could efficiently accumulated into tumor tissue and silenced PLK1 expression to possess antitumor activity.Conclusion: Taken all these together, PHD/LR was expected to be a suitable carrier for specific delivering siRNA for lung cancer therapy. Keywords: pH-responsive, siRNA delivery, hybrid nanoparticles, systematic evaluation

Chaogang Yang,1–3,* Dongdong Shi,1–3,* Shuyi Wang,1–3 Chen Wei,1–3 Chunxiao Zhang,1–3 Bin Xiong1–3 1Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Hubei Key Laboratory of Tumor Biological Behaviors, Hubei, People’s Republic of China; 3Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Background: Circulating tumor cells (CTCs) have been regarded as a promising biomarker for colorectal cancer (CRC); however, the prognostic value of post-operative (op) CTCs is still unclear. This study aimed to compare the recurrence prediction value of pre- and post-op CTCs in CRC patients treated with curative resection.Patients and methods: Consecutive CRC patients treated with curative resection from January 2014 to March 2015 were identified. CTCs from 2.5 mL peripheral blood were enumerated with an ISETdevice-CTCBIOPSY® before and after surgery. Based on the status of pre- and post-op CTCs, the included patients were grouped into four cohorts: pre- and post-op CTCs−, pre-op CTCs− but post-op CTCs+, pre-op CTCs+ but post-op CTCs−, and pre- and post-op CTCs+. The 3-year recurrence-free survival (RFS) rate of patients was analyzed.Results: A total of 138 patients (79 [57.2%] male; median age=62 [43–75] years) were enrolled. Patients with pre-op CTCs− had a 19.2% higher 3-year RFS rate (86.2%) than the combined cohorts with pre-op CTCs+ (67.0%) (P=0.038). Patients with post-op CTCs+ had aa 25.6% lower 3-year RFS rate (57.1%) than the combined cohorts with post-op CTCs− (82.7%) (P=0.001). Moreover, patients with pre- and post-op CTCs+ had a 25.1% lower 3-year RFS rate (53.8%) than patients with pre-op CTCs+ but post-op CTCs− (78.9%) (P=0.004). Multivariate analyses confirmed that post-op CTCs+ (HR=2.82, 95% CI=1.39–5.75, P=0.004), but not but pre-op CTCs+ (HR=2.17, 95% CI=0.75–6.31, P=0.153), was independently associated with shorter 3-year RFS rate.Conclusion: Post-op CTCs+, but not pre-op CTCs+, is an independent indicator of poor prognosis for CRC patients treated with curative resection. Patients with post-op CTCs+ have a higher risk of recurrence those with pre-op CTCs+. Evaluation of post-op, rather than pre-op, CTCs is warranted. Keywords: circulating tumor cells, colorectal cancer, preoperative, postoperative, recurrence

Bingchen Lang,1 Lingli Zhang,1–3 Chunsong Yang,1 Yunzhu Lin,1 Wensheng Zhang,4 Fengshan Li1 1Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, People’s Republic of China; 3Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Objective: One conundrum that frequently occurs during clinical anesthesia is etomidate-induced myoclonus, which results in multiple risks. The aim of the study was to evaluate systematically the effect of pretreatment with lidocaine on preventing etomidate-induced myoclonus. Materials and methods: The literature search was performed from the inception to April 2018 in PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure. All randomized controlled trials that used lidocaine to prevent etomidate-induced myoclonus were enrolled. The primary outcome included the incidence and severity of etomidate-induced myoclonus. The data were combined to calculate the risk ratio and relevant 95% CI. A meta-analysis was performed following the guidelines of the Cochrane Reviewer’s Handbook and the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. Results: A total of eight studies were enrolled, and the existing evidence indicated that 1) pretreatment with lidocaine can reduce the incidence of etomidate-induced myoclonus (the incidence of myoclonus: 37.6% in lidocaine vs 73.6% in saline, risk ratio =0.46, with 95% CI [0.34, 0.63], P

Dan Zhang,1,2 Xiaojiao Li,2,3 Hua Xiong,2,3 Chao Yang,2,3 Fajin Lv,1 Xianlong Huang,2,3 Qi Li,1 Zhuoyue Tang,2,3 Tianyou Luo1 1Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; 2Department of Radiology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400014, China; 3Molecular and Functional Imaging Laboratory, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400014, China Objectives: To characterize clinical, computed tomography (CT) and magnetic resonance imaging (MRI) features of tuberculosis (TB) of the parotid nodes. Materials and methods: CT (n=21) and MR (n=7) images, and clinical data from 25 patients with TB of the parotid nodes were retrospectively analyzed by two experienced radiologists who reached consensus. Results: Younger patients (aged

Xiwen Liao,1 Chuangye Han,1 Xiangkun Wang,1 Ketuan Huang,1 Tingdong Yu,1 Chengkun Yang,1 Rui Huang,2 Zhengqian Liu,1 Quanfa Han,1 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China Background: The aim of the current study was to investigate the potential prognostic value of minichromosome maintenance (MCM) genes in patients with early-stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy by using the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA).Methods: An RNA-sequencing dataset of 112 early-stage PDAC patients who received a pancreaticoduodenectomy was obtained from TCGA. Survival analysis was used to identify potential prognostic values of MCM genes in PDAC overall survival (OS).Results: Through mining public databases, we observed that MCM genes (MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7) were upregulated in pancreatic cancer tumor tissue and have a strong positive coexpression with each other. Multivariate survival analysis indicated that a high expression of MCM4 significantly increased the risk of death in patients with PDAC, and time-dependent receiver operating characteristic analysis showed an area under the curve of 0.655, 0.587, and 0.509 for a 1-, 2-, and 3-year PDAC OS prediction, respectively. Comprehensive survival analysis of MCM4 using stratified and joint effects survival analysis suggests that MCM4 may be an independent prognostic indicator for PDAC OS. Gene set enrichment analysis indicated that MCM4 may participate in multiple biologic processes and pathways, including DNA replication, cell cycle, tumor protein p53, and Notch signaling pathways, thereby affecting prognosis of PDAC patients.Conclusions: Our study indicates that MCM2–7 were upregulated in pancreatic cancer tumor tissues, and mRNA expression of MCM4 may serve as an independent prognostic indicator for PDAC OS prediction after pancreaticoduodenectomy. Keywords: minichromosome maintenance, mRNA, pancreatic ductal adenocarcinoma, prognosis, pancreaticoduodenectomy

Xiwen Liao,1 Xiangkun Wang,1 Ketuan Huang,1 Chengkun Yang,1 Tingdong Yu,1 Chuangye Han,1 Guangzhi Zhu,1 Hao Su,1 Rui Huang,2 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China Background: The aim of the study was to investigate potential prognostic microRNA (miRNA) biomarkers for patients with early stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using a miRNA-sequencing (miRNA-seq) data set from The Cancer Genome Atlas (TCGA). A miRNA expression-based prognostic signature was generated, and the potential role of target genes in overall survival (OS) in patients with PDAC was examined.Methods: A miRNA-seq data set of 112 PDAC patients who underwent pancreaticoduodenectomy was obtained from TCGA. Survival analysis was performed to identify potential prognostic biomarkers. Results: Eleven miRNAs (hsa-mir-501, hsa-mir-4521, hsa-mir-5091, hsa-mir-24-1, hsa-mir-126, hsa-mir-30e, hsa-mir-3157, hsa-let-7a-3, hsa-mir-133a-1, hsa-mir-4709, and hsa-mir-421) were used to construct a prognostic signature using the step function. The 11-miRNA prognostic signature showed good performance for prognosis prediction (adjusted P

Menghao Shi,1 Jiulong Zhang,1 Xiaowei Li,1 Shuang Pan,1 Jie Li,2 Chunrong Yang,3 Haiyang Hu,1 Mingxi Qiao,1 Dawei Chen,1 Xiuli Zhao1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People’s Republic of China; 2Department of Pharmacy, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, People’s Republic of China; 3College Pharmacy of Jiamusi University, Jiamusi, Heilongjiang 154007, People’s Republic of China Introduction: Multidrug resistance (MDR) of breast cancer is the major challenge to successful chemotherapy while mitochondria-targeting therapy was a promising strategy to overcome MDR. Materials and methods: In this study, HER-2 peptide-PEG2000-Schiff base-cholesterol (HPSC) derivate was synthesized successfully and incorporated it on the surface of the doxorubicin (DOX)-loaded dequalinium (DQA) chloride vesicle (HPS-DQAsomes) to treat drug-resistant breast cancer. Evaluations were performed using human breast cancer cell and DOX-resistant breast cancer cell lines (MCF-7 and MCF-7/ADR). Results: The particle size of HPS-DQAsomes was ~110 nm with spherical shape. In vitro cytotoxicity assay indicated that HPS-DQAsomes could increase the cytotoxicity against MCF-7/ADR cell line. Cellular uptake and mitochondria-targeting assay demonstrated that HPS-DQAsomes could target delivering therapeutical agent to mitochondria and inducing mitochondria-driven apoptosis process. In vivo antitumor assay suggested that HPS-DQAsomes could reach favorable antitumor activity due to both tumor targetability and sub-organelles’ targetability. Histological assay also indicated that HPS-DQAsomes showed a strong apoptosis-inducing effect. No obvious systematic toxicity of HPS-DQAsomes could be observed. Conclusion: In summary, multifunctional HPS-DQAsomes provide a novel and versatile approach for overcoming MDR via mitochondrial pathway in cancer treatment. Keywords: mitochondrial target, DQAsomes, pH responsive, HER-2 peptide

Tingdong Yu, Xiangkun Wang, Guangzhi Zhu, Chuangye Han, Hao Su, Xiwen Liao, Chengkun Yang, Wei Qin, Ketuan Huang, Tao Peng Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China Objective: The activities of four cytochrome P3A (CYP3A) subfamily members (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) are well documented in drug metabolism. However, the association between CYP3A subfamily members and hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic value of CYP3A subfamily mRNA expression levels with HCC prognosis. Materials and methods: Data from a total of 360 HCC patients were retrieved from The Cancer Genome Atlas database, and data from 231 HCC patients were retrieved from the Gene Expression Omnibus database. Kaplan–Meier analysis and Cox regression models were utilized to determine median survival, overall survival, and recurrence-free survival. Hazard ratios and 95% CI were calculated. Results: Low expression of CYP3A4, CYP3A5, and CYP3A43 in the tumor tissue was associated with short median survival (crude p=0.004, 0.001, and 0.001; adjusted p=0.022, 0.005, and 0.013, respectively). Joint-effects combination analysis of CYP3A4, CYP3A5/CYP3A4, CYP3A43/CYP3A5, and CYP3A43 revealed that high expression groups of two genes (group C, group c, group 3) were associated with a reduced risk of death, as compared to low expression of two genes (group A, group a, group 1), and the adjusted p values were 0.001, 0.004, and 0.001, respectively. Joint-effects analysis of CYP3A4, CYP3A5, and CYP3A43 showed that groups III and IV had a reduced risk of death, as compared to group I (adjusted p=0.024 and 0.002, respectively). Conclusion: CYP3A4, CYP3A5, and CYP3A43 mRNA expression levels are potential prognostic markers of HCC. Keywords: mRNA expression, CYP3A subfamily, hepatocellular carcinoma, prognosis, biomarker

Xiwen Liao,1,* Long Yu,1,* Xiaoguang Liu,1,2 Chuangye Han,1 Tingdong Yu,1 Wei Qin,1 Chengkun Yang,1 Guangzhi Zhu,1 Hao Su,1 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China *These authors contributed equally to this work Background: The aim of this investigation was to identify candidate single nucleotide polymorphisms (SNPs) and molecular pathways associated with tumor protein p53 (TP53) expression status in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), clarify their potential mechanisms, and generate SNP-to-gene to pathway hypothesis. Materials and methods: Identify candidate Causal SNPs and Pathways (ICSNPathway) was used to perform pathway analysis based on the results of our previous genome-wide association study of TP53 expression status in 387 HBV-related HCC patients. Results: Through the ICSNPathway analysis, we identified 18 candidate SNPs and 10 candidate pathways that are associated with TP53 expression status in HBV-related HCC. The strongest mechanism involved the modulation of major histocompatibility complex, class II, DP beta 1 (human leukocyte antigen [HLA]-DPB1-rs1042153), major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1-rs1130399, HLA-DQB1-rs1049056, HLA-DQB1-rs1049059, and HLA-DQB1-rs1049060), and major histocompatibility complex, class II, DR beta 1 (HLA-DRB1-rs35445101). SNPs consequently affected regulatory roles in all the candidate pathways except hematopoietic cell lineage pathways. Association analysis using the GSE14520 data set, Gene Multiple Association Network Integration Algorithm, and Search Tool for the Retrieval of Interacting Genes/Proteins suggests that all genes of the candidate SNPs were associated with TP53. Survival analysis showed that the collagen type VI alpha 3 chain (COL6A3) rs111231885 and COL6A3-rs113155945 and COL6A3 block 4 CC haplotypes with TP53 negative status may have protective effects in HBV-related HCC patients after hepatectomy. Conclusion: Our pathway analysis identified 18 candidate SNPs and 10 candidate pathways that were associated with TP53 expression status in HBV-related HCC. Among these candidate SNPs, the genetic variation of COL6A3 may be a potential prognostic biomarker of HBV-related HCC. Keywords: TP53, hepatocellular carcinoma, hepatitis B virus, genome-wide association study, pathway analysis

Xiwen Liao,1 Guangzhi Zhu,1 Rui Huang,2 Chengkun Yang,1 Xiangkun Wang,1 Ketuan Huang,1 Tingdong Yu,1 Chuangye Han,1 Hao Su,1 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China Background: The aim of the present study was to identify potential prognostic microRNA (miRNA) biomarkers for hepatocellular carcinoma (HCC) prognosis prediction based on a dataset from The Cancer Genome Atlas (TCGA). Materials and methods: A miRNA sequencing dataset and corresponding clinical parameters of HCC were obtained from TCGA. Genome-wide univariate Cox regression analysis was used to screen prognostic differentially expressed miRNAs (DEMs), and multivariable Cox regression analysis was used for prognostic signature construction. Comprehensive survival analysis was performed to evaluate the prognostic value of the prognostic signature. Results: Five miRNAs were regarded as prognostic DEMs and used for prognostic signature construction. The five-DEM prognostic signature performed well in prognosis prediction (adjusted P < 0.0001, adjusted hazard ratio = 2.249, 95% confidence interval =1.491–3.394), and time-dependent receiver–operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.765, 0.745, 0.725, and 0.687 for 1-, 2-, 3-, and 5-year HCC overall survival (OS) prediction, respectively. Comprehensive survival analysis of the prognostic signature suggests that the risk score model could serve as an independent factor of HCC and perform better in prognosis prediction than other traditional clinical indicators. Functional assessment of the target genes of hsa-mir-139 and hsa-mir-5003 indicates that they were significantly enriched in multiple biological processes and pathways, including cell proliferation and cell migration regulation, pathways in cancer, and the cyclic adenosine monophosphate (cAMP) signaling pathway. Conclusion: Our study indicates that the novel miRNA expression signature may be a potential prognostic biomarker for HCC patients. Keywords: miRNA, TCGA, hepatocellular carcinoma, prognosis, biomarker

Chengkun Yang,1,* Hao Su,1,* Xiwen Liao,1 Chuangye Han,1 Tingdong Yu,1 Guangzhi Zhu,1 Xiangkun Wang,1 Cheryl Ann Winkler,2 Stephen J O’Brien,3–5 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China; 2Basic Research Laboratory, CCR, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD, USA; 3Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, MD, USA; 4Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St Petersburg, Russia; 5Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL, USA *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver. Transforming growth factor beta 1 (TGFB1) and marker of proliferation Ki-67 (MKI67) regulate cell proliferation, differentiation, and growth. The association between MKI67 and TGFB1 expression and its clinical implications in HCC remain unknown.Methods: Public databases were used to analyze TGFB1 and MKI67 expression in different pathologic grades/stages and tissue types of HCC. The association between MKI67 and TGFB1 expression was explored using pathway analysis and in a HepG2 cell line treated with TGFB1. Survival analysis was performed to evaluate the prognostic value of TGFB1 and MKI67 expression in patients with hepatitis B virus (HBV)-related HCC. Results: We identified that MKI67 expression was upregulated in liver cancer tissues. MKI67 and TGFB1 expression levels were different in various stages and tissue types of liver cancer. Furthermore, MKI67 expression was associated with TGFB1 expression in liver cancer tissues and HepG2 cells. Patients with HBV-related HCC and a higher level of MKI67 expression had a worse prognosis. Moreover, a nomogram was conducted to predict the clinical outcomes of patients with HBV-related HCC. Conclusion: MKI67 expression level was associated with TGFB1 expression in liver cancer tissues and a HepG2 cell line. MKI67 expression level can predict the clinical outcomes of patients with HBV-related HCC. Keywords: MKI67, TGFB1, HBV-related HCC, nomogram

Zhi Gang Lan,1 Seidu A Richard,1–3 Jin Li,1 Chaohua Yang1 1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Immunology, Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 3Department of Surgery, Volta Regional Hospital, Ho, Ghana, West Africa Introduction: Nonprojectile penetrating skull base injuries as a result of falls have rarely been confronted in normal neurosurgery although a few nonmissile injuries have been reported. These kinds of injuries represent a life-threatening emergency. Case presentation: We present an unusual case of a 25-year-old male construction worker who suffered an accidental penetrating skull base injury when he fell on a metal rod while he was walking on a 2-meter-high platform. He was clinically stable at presentation. Skull radiograph showed a solid metallic bar, 30 cm long, that penetrated through the right anguli oris eminence and was lodged low in the right occipital bone. Conclusion: Penetrating injury to the head is considered a form of severe traumatic brain injury. Although case of penetrating head injuries as a result of fall from heights are very rare, we anticipate the construction works on high-rise buildings are at maximum risk. We advise that removal of this kind of foreign bodies be done in the theater and not outside because of risk of involvement of larger vessels leading to fatal hemorrhage. We further suggest that patients with nonprojectile injuries should undergo a preoperative computed tomography-angiography to rule out any vascular injury. Keywords: nonprojectile, fall, hemorrhage, skull, penetrating injury, construction

Methylprednisolone (MP) is an anti-inflammatory drug approved for the treatment of acute spinal cord injuries (SCIs). However, MP administration for SCIs has become a controversial issue while the molecular effects of MP remain unexplored to date. Therefore, delineating the benefits and side effects of MP and determining what MP cannot cure in SCIs at the molecular level are urgent issues. Here, genomic profiles of the spinal cord in rats with and without injury insults, and those with and without MP treatment, were generated at 0, 2, 4, 6, 8, 12, 24, and 48 h post-injury. A comprehensive analysis was applied to obtain three distinct classes: side effect of MP (SEMP), competence of MP (CPMP), and incapability of MP (ICMP). Functional analysis using these genes suggested that MP exerts its greatest effect at 8~12 h, and the CPMP was reflected in the immune response, while SEMP suggested aspects of metabolism, such as glycolysis, and ICMP was on neurological system processes in acute SCIs. For the first time, we are able to precisely reveal responsive functions of MP in SCIs at the molecular level and provide useful solutions to avoid complications of MP in SCIs before better therapeutic drugs are available.

Long Chen,1,* Conghui Yang,1,* Jun Feng,2,* Xin Liu,3,* Yadong Tian,1 Lei Zhao,1 Ran Xie,1 Chao Liu,4 Sheng Zhao,1 Hua Sun1 1Department of PET/CT Center, 2Department of Radiology, 3Department of Pathology, 4Department of Nuclear Medicine, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China *These authors contributed equally to this work Purpose: To evaluate the possible roles of miR-34a expression in thyroid lesions, to unravel the correlation between fluorodeoxyglucose (FDG) uptake and miR-34a expression and moreover, to discover the underlying mechanisms by which miR-34a regulates FDG avidity. Methods: We retrospectively reviewed 75 patients with pathology-confirmed thyroid diseases who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) within 3 months before undergoing thyroid surgery and miR-34a analysis from June 2012 to July 2017. 18F-FDG uptake of thyroid lesions was also analyzed semiquantitatively using maximum standardized uptake value (SUVmax). The association between miR-34a expression and clinicopathological variables (age, sex, TNM stage, histopathology, lesion numbers, location and 18F-FDG avidity) was investigated. When there were multiple lesions in thyroid bed, only the one with the highest 18F-FDG uptake was analyzed. Next, we inhibited the miR-34a expression in TPC-1 cells and detected the expression of glucose transporter 1 (GLUT1) mRNA and protein. Results: In the patients cohort, miR-34a was upregulated in those with malignant thyroid diseases compared with benign lesions. The expression of miR-34a was associated with tumor stages, histopathological types and SUVmax. There was an inverse relationship between miR-34a expression and SUVmax in patients with thyroid diseases (Spearman correlation coefficient = –0.553, P < 0.0001). With an SUVmax of 4.3 as the threshold, sensitivity and specificity of the prediction of miR-34a expression (low or high) were 70% and 94.3%, respectively. The area under the receiver operating characteristic curve was 0.843 (95% confidence interval: 0.749, 0.936; P = 0.001). Inhibiting miR-34a in TPC-1 cells significantly increased GLUT1 mRNA and protein expression. Conclusion: miR-34a expression was upregulated in thyroid lesions, negatively correlated with SUVmax and can be predicted by FDG SUVmax. In addition, miR-34a may regulate FDG avidity via targeting GLUT1. Keywords: miR-34a, thyroid cancer, PET/CT