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Xianchuang Liu,1 Xinyang Zhu,1 Xun Qi,1 Xianwei Meng,2 Ke Xu1 1Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Laboratory of Controllable Preparation and Application of Nanomaterials, Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCorrespondence: Ke XuDepartment of Interventional Radiology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110000, Liaoning, People’s Republic of ChinaTel +86 24 8328 2999Fax +86 24 8328 2997Email kxu@cmu.edu.cnPurpose: Hepatocellular carcinoma (HCC) is one of the most common fatal cancers, with no curative therapy available. The concept of ferroptosis is attracting increasing attention in cancer research. Herein, we describe the use of a nanodevice as an effective strategy for inducing ferroptosis to manage HCC.Methods: To improve ferroptosis-induced treatment of HCC, we constructed sorafenib (sor)-loaded MIL-101(Fe) nanoparticles (NPs) [MIL-101(Fe)@sor] and evaluated the efficacy of ferroptosis-based HCC therapy after co-administration with the iRGD peptide both in vitro and in vivo.Results: The prepared MIL-101(Fe) NPs have several promising characteristics including drug-loading, controllable release, peroxidase activity, biocompatibility, and T2 magnetic resonance imaging ability. MIL-101(Fe)@sor NPs significantly induced ferroptosis in HepG2 cells, increased the levels of lipid peroxidation and malondialdehyde, and reduced those of glutathione and glutathione peroxidase 4 (GPX-4). The in vivo results showed that the MIL-101(Fe)@sor NPs significantly inhibited tumor progression and decreased GPX-4 expression levels, with negligible long-term toxicity. Meanwhile, co-administration of MIL-101(Fe)@sor NPs with iRGD significantly accelerated ferroptosis.Conclusion: Our findings suggest that MIL-101(Fe)@sor NPs co-administered with iRGD are a promising strategy for inducing HCC ferroptosis.Keywords: iron-based metal-organic framework, iRGD, sorafenib, ferroptosis, HCC, nanoparticles

Kaikai Zhao,1 Zhaoqin Huang,2 Youjiao Si,3 Liangchao Sun,4 Jinming Yu,4 Xiangjiao Meng4 1Department of Radiation Oncology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, People’s Republic of China; 2Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, People’s Republic of China; 4Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaCorrespondence: Xiangjiao MengDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, People’s Republic of ChinaTel +86 13793150996Email mengxiangjiao@126.comPurpose: Currently, there are no standard treatments for primary small cell carcinoma of the esophagus (PSCCE), particularly in cases of limited-stage disease. This retrospective study aimed to assess the treatment strategies and the relevant prognostic factors of limited-stage PSCCE (LS-PSCCE).Patients and Methods: We retrospectively evaluated 129 patients with LS-PSCCE between June 2009 and December 2018. The χ 2 test was performed to examine the frequencies between different groups. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS).Results: Through a median follow-up of 23 months, the median OS of all patients was 25.0 months and the median recurrence-free survival (RFS) was 15.0 months. Univariate and multivariate analyses showed that alcohol abuse (p=0.046) and TNM stage (p< 0.001) were independent prognostic factors. There was no significant difference in OS and RFS rates between the patients treated with chemoradiotherapy (CRT) and those treated with surgery and chemotherapy with or without radiotherapy (S+CT±RT) (p> 0.05). Patients who received concurrent CRT had better OS and RFS than those who received sequential CRT (p< 0.05). Postoperative adjuvant RT for high-risk patients can further improve the local control rate but has no significant effect on OS.Conclusion: LS-PSCCE patients treated with CRT had similar OS and RFS compared to those treated with S+CT±RT. This study shows that concurrent CRT confers a survival advantage for patients with LS-PSCCE compared to those with sequential CRT.Keywords: primary small cell carcinoma of the esophagus, limited-stage, chemoradiotherapy, surgery

Shuai Li,1,* Shuping Yang,2,* Chong Liu,1 Jintong He,1 Tian Li,1 Changhui Fu,3 Xianwei Meng,3 Haibo Shao1 1Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, People’s Republic of China; 2Department of Pain Medicine, The First Hospital of China Medical University, Shenyang 110001, Liaoning, People’s Republic of China; 3Laboratory of Controllable Preparation and Application of Nanomaterials, Chinese Academy of Sciences Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haibo Shao Department of Interventional RadiologyThe First Hospital of China Medical University, Shenyang 110001, Liaoning, People’s Republic of ChinaEmail haiboshao@aliyun.comXianwei MengLaboratory of Controllable Preparation and Application of Nanomaterials, Chinese Academy of Sciences Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of ChinaEmail mengxw@mail.ipc.ac.cnPurpose: P-glycoprotein (P-gp), which is highly expressed in liver cancer cells, is one of the obstacles for the treatment of cancer. In this study, we have prepared and characterized a kind of novel ICG&Cur@MoS2 (ICG and Cur represent indocyanine green and curcumin, respectively) nanoplatform, which can achieve photothermal-photodynamic therapy and inhibit the P-gp effectively and safely.Methods: In this work, plenty of studies including drug release, acute toxicity, Western blot, real-time PCR, cell viability, therapeutic experiment in vivo, immunofluorescence and so on were conducted to test the antitumor potential of ICG&Cur@MoS2 and the inhibitory effect of curcumin on P-gp.Results: The ICG&Cur@MoS2 NPs exhibit an excellent photothermal effect and relatively low toxicity. Cell viability in the ICG&Cur@MoS2 + NIR group was significantly lower than that in ICG@MoS2 + NIR group (75.3% vs 81.2%, 59.0% vs 64.4%, 20.3% vs 27.5%, and 15.4% vs 22.3%) at the concentration of ICG at 0.5, 5, 25, 50 μg/mL (P< 0.05 at each concentration). Western blot, Q-PCR, and immunofluorescence assay indicate ICG&Cur@MoS2 NPs can inhibit the P-gp effectively and safely. In vivo, the tumors in the ICG@MoS2 + NIR group are significantly smaller than those in the MoS2 + NIR group (95.0 vs 420.9 mm3, p< 0.05).Conclusion: In conclusion, we have successfully synthesized ICG&Cur@MoS2 nanoparticles which can not only achieve PTT-PDT but also inhibit P-gp effectively. Our findings indicate that the PTT-PDT exhibits great potential in the treatment of hepatocellular carcinoma. Meanwhile, ICG&Cur@MoS2 can effectively inhibit the expression of P-gp, which will enhance the PDT effect.Keywords: P-glycoprotein, hepatocellular carcinoma, indocyanine green, curcumin, MoS2, photothermal-photodynamic therapy

Jun Zhang,1 Hai-yan Piao,2 Yue Wang,1 Xiang-yu Meng,1 Dong Yang,1 Yan Zhao,1 Zhi-chao Zheng1 1Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People’s Republic of China; 2Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People’s Republic of ChinaCorrespondence: Zhi-chao Zheng Professor of Gastric Cancer DepartmentLiaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042, People’s Republic of ChinaTel +86-24-31916823Fax +86-24-24315679Email zhengzhichao@cancerhosp-ln-cmu.comBackground: Gastric cancer (GC) accounts for high mortality. RNA methylation has recently gained interest as markers in specific tumors. This study aimed to uncover the function of the roles of 25 RNA methylation regulators in GC.Methods: RNA sequence and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. “STRING” and R were performed to analyze the correlation among the methylase. COX and LASSO were performed to screen for prognostic associated RNA methylation regulators. A prognostic model was established based on the expression of methylase. RT-PCR and immunohistochemistry detected the expression of methylase in GC cells and tissue. Kaplan–Meier curve and Cox analysis were applied to evaluate the effectiveness of the model.Results: The prediction model was established based on the expression of m6A RNA methylation regulators FTO (fat mass and obesity-associated) and RBM15 (RNA binding motif protein 15). Based on the model, GC patients were divided into “high risk” and “low risk” groups to compare the differences in survival. The model was re-evaluated with the clinical data of our center.Conclusion: The two-methylase combination model was an independent prognostic factor of GC.Keywords: gastric cancer, prognosis, least absolute shrinkage and selection operator, survival analysis, RNA methylation

Leilei Wu,1,2 Zhenshan Zhang,1 Shuo Li,2 Linping Ke,2 Jinming Yu,2 Xue Meng2 1Department of Radiation Oncology, School of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaCorrespondence: Jinming Yu; Xue MengDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440 Jiyan Road, Jinan, Shandong, People’s Republic of ChinaTel/ Fax +86 531-67627082Email sdyujinming@163.com; mengxuesdzl@163.comIntroduction: Postoperative adjuvant radiation therapy (RT) and chemotherapy (aCRT) have been supposed to improve prognosis and outcomes in patients with node-positive thoracic esophageal squamous cell carcinoma (TESCC). Our aim was to analyze the impacts of interval between surgery and aCRT on prognosis, determining the optimal time interval.Methods: We retrospectively reviewed 520 patients with TESCC between 2007 and 2015 treated with aCRT following radical esophagectomy without neoadjuvant chemotherapy and RT. These patients underwent RT (50– 60 Gy) combined with 2– 6 cycles chemotherapy after surgery. The time intervals were from 17 days to 145 days and divided into three groups: short interval group (≤ 28 days, S-Int group), medial interval group (≥ 29 and ≤ 56 days, M-Int group) and long interval group (≥ 57 days, L-Int group).Results: Median follow-up was 35.6 months and the 3-, 5-year survival rates and median survival were 49.5%, 36.6% and 35.9 months. The duration of postoperative interval was a predictor of survival outcomes. The median survival and 5-year survival rates in S-Int, M-Int and L-Int groups were 23.6 (32.1%), 44.2 (43.3%) and 32.0 (31.5%) months (P=0.007). The difference was statistically significant between the M-Int and S-Int or L-Int group but was not between the S-Int and L-Int group. Besides, toxic reactions including early, late and adverse events (grade ≥ 3) in M-Int group were significantly less than S-Int and show no significant differences with L-Int group.Conclusion: The optimal time interval was from 29 days to 56 days (5– 8 weeks) both in terms of survival outcomes and toxic reactions.Keywords: thoracic esophageal squamous cell carcinoma, TESCC, adjuvant chemotherapy and radiation therapy, aCRT, time interval, survival, toxic reactions

Meizhu Yan1 ,* Manru Shen1 ,* Linfang Xu1 ,* Jiying Huang,1 Guijun He,1 Min An,1 Xiaocui Li,1 Zhenjun Gao,1 Xin Meng2 1Department of Gastroenterology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai 201700, People’s Republic of China; 2Department of Hospital Infection Management, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai 201700, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenjun GaoDepartment of Gastroenterology, Zhongshan Hospital Qingpu Branch, Fudan University, 1158 East Gongyuan Road, Shanghai 201700, People’s Republic of ChinaEmail prom_doc@163.comXin MengDepartment of Hospital Infection Management, Zhongshan Hospital Qingpu Branch, Fudan University, 1158 East Gongyuan Road, Shanghai 201700, People’s Republic of ChinaTel +86-21-69719190-5515Email qphospital_mx@126.comBackground: Pancreatic stellate cells (PSCs) are precursor cells of cancer-associated fibroblasts that promote tumor proliferation, invasion, and metastasis. The glucagon-like peptide-1 receptor agonist exendin-4 has been reported to exhibit anticancer effects against several tumor cells; however, the function and mechanism underlying the effects of exendin-4 on pancreatic cancer cells remain unclear.Methods: Gene expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay. Cell viability, migration and invasion were assessed using the cell counting kit-8 (CCK-8), wound healing, and transwell assays, respectively. A xenografted tumor model was established in mouse to evaluate the effects of exendin-4 in vivo.Results: Exendin-4 treatment led to the inactivation of PSCs and suppressed their proliferation and migration. Moreover, we also found that exendin-4 attenuated NF-κB-dependent SDF-1 secretion. Furthermore, pancreatic cancer cells incubated with conditioned medium obtained from exendin-4-treated PSCs showed a decreased ability to proliferate, migrate, and invade as compared to the control cells, which is similar to the effects induced by the CXCR4 inhibitor, AMD3100. Consistent with in vitro results, we also confirmed that exendin-4 indirectly targeted pancreatic cancer cells in vivo by attenuating the function of PSCs and suppressing the deposition of extracellular matrix.Conclusion: These results revealed that exendin-4-treated PSCs could suppress pancreatic cancer cell proliferation and invasion, offering a potential strategy for the treatment of pancreatic cancer.Keywords: pancreatic cancer, pancreatic stellate cells, exendin-4, SDF-1

Guoxin Cai,1,2 Jinming Yu,2 Xue Meng2 1Department of Radiation Oncology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Jinming Yu; Xue Meng Tel +86-531-67627082Fax +86-531-67627083Email sdyujinming@163.com; mengxue5409@126.comPurpose: Our purpose was to evaluate the association between hematologic markers and mortality and adverse events in patients with esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT).Patients and Methods: A total of 311 patients with ESCC treated with nCRT from 2012 to 2014 were enrolled retrospectively. The Kaplan–Meier method with a Log rank test was used to calculate five-year overall survival (OS). Receiver operating characteristic (ROC) curves were plotted to determine the cut-off values for hematologic markers. Multivariate analysis was performed using Cox regression analysis model. Model performance was evaluated by predicted nomogram, concordance index (C-index) and calibration curve.Results: Median follow-up was 22 months. High pretreatment platelet to lymphocyte ratio (PLR, p = 0.047) and systemic immune-inflammation index (SII, p = 0.027) were significantly associated with pathologic complete response (pCR). In multivariate analysis, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, invasion depth, lymph node metastasis, PLR, and SII were independent factors to predict five-year OS. Multivariate analysis showed a lower neutrophil to lymphocyte ratio (NLR) at baseline (p = 0.007) was significantly associated with development of grade ≥ 3 hematologic toxicity, and none of inflammatory biomarkers could predict grade ≥ 3 non-hematologic toxicity or radiation pneumonitis (RP).Conclusion: SII and PLR were independent indicators to predict prognosis in patients with ESCC treated with nCRT, and a lower NLR at baseline was an independent indicator to predict grade ≥ 3 hematologic toxicity.Keywords: esophageal squamous cell carcinoma, neoadjuvant chemoradiotherapy, inflammatory biomarkers, overall survival, adverse events

Weiqing Wang,1,2 Zhenhua Gao,2 Lu Wang,2 Jianing Li,2 Jinming Yu,1,2 Shumei Han,2 Xue Meng2 1School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, People’s Republic of ChinaCorrespondence: Xue MengDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, People’s Republic of ChinaTel/Fax +86 0531-67627081Email mengxue123999@163.comAbstract: Recently, immunotherapies that target the interactions of programmed cell death 1 (PD-1) with its major ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), have achieved significant success. To date, several immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have been developed to treat melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma, and urothelial carcinoma. Despite promising outcomes with immunotherapy, there are many limitations to several current immune biomarkers for predicting immune benefits and to traditional imaging for evaluating the efficacy and prognosis of immunotherapy and monitoring adverse reactions. In this review, we recommend a novel imaging method, molecular imaging. This paper reviews the application and prospects of molecular imaging in the context of current immunotherapies in regard to the following aspects: 1) detecting the expression of PD-1/PD-L1; 2) evaluating the efficacy of immunotherapy; 3) assessing patient prognosis with immunotherapy; 4) monitoring the toxicity of immunotherapy; and 5) other targets imaging.Keywords: tumor, immunotherapy, PD-1, PD-L1, PET, SPECT

Zhe Dong,1,* Shuai Guo,1,* Yue Wang,2 Jun Zhang,2 Haojie Luo,1 Guoliang Zheng,2 Dong Yang,2 Tao Zhang,2 Liucun Yan,3 Li Song,3 Kejia Liu,3 Zhe Sun,3 Xiangyu Meng,2 Zhichao Zheng,2 Jianjun Zhang,2 Yan Zhao2 1Postgraduate School of China Medical University, Shenyang 110001, Liaoning Province, People’s Republic of China; 2Department of Stomach Surgery, Cancer Hospital of China Medical University (Liaoning Cancer Hospital and Institute), Shenyang 110042, Liaoning Province, People’s Republic of China; 3Yidu Cloud (Beijing) Technology Co., Ltd., Beijing 100083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan ZhaoSurgeon, Department of Stomach Surgery, Cancer Hospital of China Medical University (Liaoning Cancer Hospital and Institute), No. 44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, People’s Republic of ChinaTel +86-24-31916622Fax +86-24-24315679Email dr.zhaoyan@126.comBackground: To investigate the clinical significance of ubiquitin-specific peptidase 19 (USP19) expression in gastric cancer (GC) compared with that in normal tissues and gastric cell lines.Methods: USP19 protein expression was analyzed in 212 paired GC samples using immunohistochemical staining. Quantitative real-time PCR (qRT-PCR) and Western blotting were used to detect the level of USP19 in gastric cell lines. The biological functions of USP19 were investigated by MTT assay, colony-forming assay, wound healing assay and gelatin zymography, and apoptotic cells were detected by immunohistochemistry assays in SGC7901 xenograft models.Results: USP19 expression was significantly increased in GC cells and tissues, and the high level of USP19 expression was positively correlated with the Lauren’s classification and poor prognosis. Moreover, USP19 was identified as a novel independent prognostic biomarker in GC patients. Enhanced USP19 expression promoted GC cell proliferation and metastasis through reduced cleaved caspase-3 and increased MMP2/MMP9 expression and promoted enzyme activity in the study, and verified the results through The Cancer Genome Atlas (TCGA) and bioinformatic websites from the Kaplan–Meier plotter (http://kmplot.com) and GEPIA (http://gepia2.cancer-pku.cn.).Conclusion: Our study suggests that USP19 promoted tumor progression by inducing MMP2/MMP9 expression and related enzyme activity. Hence, USP19 may be a valuable prognostic predictor for GC, and the USP19-MMP2/MMP9 axis could serve as a therapeutic target.Keywords: USP19, MMP2/MMP9, gastric cancer, prognosis, invasion, metastasis, TCGA

Shuheng Liu,1 Xianghai Meng2 1Department of Spine Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan City, Shandong Province, People’s Republic of China; 2Trauma Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan City, Shandong Province, People’s Republic of ChinaCorrespondence: Xianghai Meng, Jinan City, Shandong Province, People’s Republic of ChinaTel + 86- 0531- 55865483Email mxh0531999@163.comPurpose: Osteosarcoma (OS) is a frequently occurring malignancy in children and adolescents. In this study, we aimed to investigate the effects of the long non-coding RNA (lncRNA) LINC00662 (LINC00662) in OS and the underlying molecular mechanism.Methods: The expression of LINC00662, microRNA-15a-5p (miR-15a-5p), and Notch2 in OS was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, and invasion of OS cells were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing, and transwell assay. The interactions among LINC00662, miR-15a-5p, and Notch2 were determined by dual-luciferase reporter assays. A tumor xenograft model was established in mice for evaluating tumor growth in vivo.Results: The expression of LINC00662 and Notch2 was found to be upregulated in OS, but the expression of miR-15a-5p was downregulated. The results demonstrated that LINC00662 knockdown attenuated the proliferation, migration, and invasion of OS cells and suppressed tumor growth in mice. The study further demonstrated that LINC00662 directly interacted with miR-15a-5p, and that Notch2 was a target of miR-15a-5p. The inhibition of miR-15a-5p or Notch2 overexpression markedly reversed the suppressive effect of sh-LINC00662 on the proliferation, migration, and invasion of OS cells.Conclusion: The study demonstrated that LINC00662 could be a potential biomarker for OS therapy, and LINC00662 knockdown suppressed the proliferation, migration, and invasion of OS cells by regulating the miR-15a-5p/Notch2 axis.Keywords: osteosarcoma, long non-coding RNA LINC00662, microRNA-15a-5p, Notch2, proliferation

Kelie Chen,1,2,* Yuequn Niu,3,* Shengchao Wang,1,* Zhiqin Fu,4 Hui Lin,1,2 Jiaoying Lu,2 Xinyi Meng,2 Bowen Yang,2 Honghe Zhang,1 Yihua Wu,1,2 Dajing Xia,1,2 Weiguo Lu1 1Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, People’s Republic of China; 2Department of Toxicology, School of Public Health, School of Medicine, Zhejiang University, Hangzhou 310058, People’s Republic of China; 3Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China; 4Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dajing XiaDepartment of Toxicology, School of Public Health, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, People’s Republic of ChinaTel/ Fax +86-0571-88208140Email dxia@zju.edu.cnWeiguo LuDepartment of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang 310006, People’s Republic of ChinaTel +86-571-8706-1501Fax +86-571-87061878Email lbwg@zju.edu.cnBackground: Heterogeneity plays an essential role in ovarian cancer. Patients with different clinical features may manifest diverse patterns in diagnosis, treatment, and prognosis. The aim of the present study was to identify a novel ovarian cancer–classification model through cluster analysis and assess its significance in prognosis.Methods: Among patients diagnosed with ovarian cancer in the Women’s Hospital School of Medicine, Zhejiang University between January 2014 and May 2019, 328 patients were included in a K-mean cluster analysis and 176 patients followed up. Major clinical indicators, overall survival, and recurrence-free survival in different subgroups were compared.Results: Two clusters for ovarian cancer were identified and grouped as noninflammatory (n=247) and inflammatory subtypes (n=81). Compared with the noninflammatory subgroup, the inflammatory subgroup presented a statistically significantly higher level of median CRP (median (IQR) 20.4 [7.8– 47.3] vs 1.2 [0.4– 3.5], p< 0.001), neutrophil percentage (median (IQR) 76.9 [72.6– 81.3] vs 66.2 [61.0– 72.0], p< 0.001), leukocyte count (median (IQR) 8.9 [7.0– 10.0] vs 6.0 [5.1– 7.2], p< 0.001), fibrinogen (median (IQR) 5.0 [4.4– 6.0] vs 3.4 [2.9– 3.9], p< 0.001), and platelet count (median (IQR) 324 [270– 405] vs 229 [181.5– 269], p< 0.001). During a median follow-up of 52 months, 21 participants (16.3%) died in the noninflammatory group, while 14 (29.8%) died in the inflammatory group (HR 2.15, 95% CI 1.09– 4.23; p=0.024). Death/recurrence was observed in 38 (29.5%) patients from the noninflammatory group and 25 (53.2%) from the inflammatory group (HR 2.32, 95% CI 1.40– 3.85; p< 0.001).Conclusion: Our study revealed a novel classification model of ovarian cancer that features inflammation. Inflammation predicts shorter survival and poorer prognosis, suggesting the significance of inflammation in the management of ovarian cancer.Keywords: ovarian cancer, classification, heterogeneity, cluster analysis, inflammation, prognosis

Jun Chen,1,* Xiangchao Meng,2,* Qinyi Zhou,1 Jialin Feng,1 Wenjie Zheng,1 Zhuoying Wang,1 Jiadong Wang,1 You Wang2 1Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Bone and Joint Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiadong WangHead and Neck Surgery,Ren Ji Hospital,School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaEmail wangjiadong097@163.comYou WangBone and Joint Surgery,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaEmail Drwangyou@126.comPurpose: CXCR5-positive (CXCR5+) tumor cell infiltration has different prognostic values in different types of cancer. The objective was to evaluate the effect of CXCR5+ cell infiltration in head and neck squamous cell carcinoma (HNSCC).Patients and Methods: The study included two patient cohorts: The Cancer Genome Atlas cohort (TCGA, n = 472) and the Renji Hospital cohort (RJHC, n = 201). The TCGA and RJHC cohorts were analyzed for CXCR5-related mRNAs and CXCR5+ cell infiltration, respectively. We then evaluated the correlation between CXCR5 mRNA and CXCR5+ cell infiltration in terms of overall survival and the immune contexture.Results: The 5-year overall survival rate was significantly correlated with high CXCR5 mRNA expression and CXCR5+ cell infiltration in the TCGA and RJHC cohorts, respectively (p < 0.01), even after adjusting for confounders. Moreover, high CXCR5 mRNA expression was associated with more CD4+ T cells, CD8+ T cells, plasma cells, and less dendritic cells. A high CXCR5 mRNA expression was also correlated with increased expression of cytotoxic IFNG, TNFSF11 (RANKL), GZMA, GZMB, GZMK, GZMM, and PRF1 and increased expression of the immunosuppressive gene PDCD1 (PD-1), CD274 (PD-L1), CTLA4, LAG3, HAVCR2 (TIM-3), BTLA, and TIGIT.Conclusion: HNSCC patients with a high intratumoral CXCR5 expression had a better prognosis than those with low intratumoral CXCR5 expression. Moreover, CXCR5+ cell infiltration could be used as an independent prognostic biomarker or as a potential therapeutic target. The presence of CXCR5+ cells affects the infiltration of immunocytes in head and neck cancer, differently from what was reported in other cancer types. Further randomized controlled trials or studies with more patients are needed to validate our results.Keywords: CXCR5-producing cells, immune contexture, prognosis, head and neck squamous cell carcinoma

Benli Jia,1 Xiaoqiang Yin,2 Yong Wang,2 Jin Qian,2 Yan He,2 Chuang Yang,2 Gang Yu,2 Bing Guo,3 Xiangling Meng1 1Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of China; 3Department of Oncology, Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, People’s Republic of ChinaCorrespondence: Xiangling MengDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, Anhui 230022, People’s Republic of ChinaEmail ahmengxiangling@163.comBing GuoDepartment of Oncology, Cancer Hospital, Chinese Academy of Sciences, Hefei, 350 Shushan Lake Road, Hefei, Anhui 230031, People’s Republic of ChinaEmail bingguo_anhui@163.comBackground: Mounting evidences reveal that circular RNAs (circRNAs) are critical to regulate biological behavior and process of tumor. Our objective is to explore the role of circRNA-PTN (circPTN) and explain the exact mechanism in hepatocellular carcinoma (HCC).Methods: Real-time polymerase chain reaction assay was used to detect the level of circPTN and miR-326. The proliferation of cell was measured by CCK-8 assay and EdU assay. Western blot assay was performed to assess ErbB/PI3K expression. Luciferase and RNA pull-down assays were carried out to confirm the interaction between circPTN and miR-326.Results: Our results indicated that circPTN was upregulated in human hepatocellular carcinoma tumor tissues and cell lines, compared with paratumor tissues and immortalized normal liver cell line. circPTN could significantly promote HCC tumor growth according to gain-and loss-of-function assays. Additionally, we determined that circPTN acted as a sponge through interacting with miR-326. Overexpression of miR-326 could rescue the cell proliferation inhibition and ErbB/PI3K downregulation in HCC cells by circPTN. Besides, the effects of miR-326 on HCC were missing when circPTN binding sites were mutated.Conclusion: Our study indicates that circPTN acts as an oncogenic factor via sponging miR-326 in HCC.Keywords: circRNA-PTN, HCC, miR-326, proliferation

Xiao-ling Liao,1 Li-jun Zuo,1 Ning Zhang,2 Yang Yang,2 Yue-song Pan,3 Xiang-long Xiang,3 Ling-yun Chen,4 Xia Meng,3 Hao Li,3 Xing-quan Zhao,1 Yi-long Wang,1 Chun-xue Wang,2 Jiong Shi,3 Yong-jun Wang1 On behalf of the Impairment of CognitiON and Sleep quality for patients after acute ischemic stroke or transient ischemic attack (ICONS) Investigators1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neuropsychology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Medicine, Eisai China INC, Shanghai, People’s Republic of ChinaCorrespondence: Yong-jun WangDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel +86-10-59978350Fax +86-10-59973383Email yongjunwang@ncrcnd.org.cnBackground and Purpose: More and more evidence suggests that cognitive impairment (CI) after stroke is closely related to the quality of life of stroke patients. The primary aim of this study is to investigate the occurrence and longitudinal changes of CI at different stages after acute ischemic stroke (AIS) in Chinese patients.Methods: The data of this study come from the impairment of cognition and Sleep after acute ischemic stroke or transient ischemic attack in Chinese patients study (ICONS), a nationwide multicenter prospective registry that recruited consecutive AIS or transient ischemic attack in-hospital patients within 7 days after onset. Patients were followed for Montreal Cognitive Assessment (MoCA) scale at 2-week (2w), 3 months (3m) and 12 months (12m). CI was defined as MoCA score≦22. No cognitive impairment (NCI) was defined as MoCA score> 22.Results: A total of 2432 AIS patients were enrolled in this study. Overall, 72.94% of patients were male and the average age was 60.95 years. Median National Institutes of Health Stroke Scale score was 3. The occurrence rate of CI was 52.38%, 35.55% and 34.16% at 2w, 3m and 12m. Among patients with CI at 2w and 3m, 39.9% and 27.9% of patients returned to NCI at next follow-up point. At 3m and 12m follow-up, there were also 9.6% and 12.7% new CI patients. The two cognitive items with the highest abnormal rate were “Delayed recall” (89.35%, 83.33% and 82.80%) and “Visuospatial/executive” (78.91%, 73.42% and 70.08%). The cognitive item with the highest percentage of improved patients was “Orientation” (60.91– 76.68%), and the cognitive item with the lowest percentage of improved patients was “Language” (35.85– 44.50%).Conclusion: CI had a relatively high occurrence at 2w to 12m after AIS. CI at 3m and 12m was significantly lower than that at 2w after stroke. The occurrence of abnormalities and recovery probability for different cognitive items also differed greatly.Keywords: cognitive impairment, ischemic stroke, longitudinal cohort study, occurrence

Zhengyu Hu,1,* Yan Li,2,* Weipu Mao,3 Bo Chen,1 Lin Yang,2 Xiangling Meng1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province 230032, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province 230032, People’s Republic of China; 3Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangling Meng Tel +86-551-62922035Fax +86-551-62922049Email ayfy105080@163.comLin Yang Tel/ Fax +86-551-62923545Email Yanglin_ah@163.comBackground: The effect of preoperative nutritional status on the survival of patients with colorectal cancer is still unknown. The purpose of our study was to examine the impact of the prognostic nutritional index (PNI), prealbumin (PAB) and the albumin to globulin ratio (AGR) on survival outcomes in patients with colon and rectal cancer.Methods: Between January 2012 and December 2013, 361 patients with colorectal cancer who underwent curative surgery in the survey and various clinical and haematological parameters were recorded. The optimal cut-off values of the PNI, PAB and AGR were determined by MedCalc software, and Cox regression analysis was performed to investigate the effect of the PNI, PAB and AGR on the overall survival (OS) of patients with colon and rectal cancer.Results: In patients with colon and rectal cancer, a high PNI, PAB, and AGR correlate with higher survival times. Receiver operating characteristic (ROC) curve analysis showed that at most time points, the PNI has a higher area under the curve (AUC) in predicting colon and rectal cancer OS. Multivariate Cox regression analysis showed that of the PNI, PAB and AGR, only the PNI was an independent risk factor for OS in patients with colon and rectal cancer. Patients with a high PNI were predicted to have higher OS (hazard ratio [HR]: 0.479; 95% confidence interval [CI]: 0.233– 0.985; P = 0.045) in colon cancer and higher OS (HR: 0.225; 95% CI: 0.111– 0.454; P < 0.001) in rectal cancer compared with patients with a low PNI.Conclusion: Preoperative PNI, PAB and AGR may be predictors of OS in patients with colon and rectal cancer after radical surgery, especially the PNI, which has a good ability to predict OS in both tumours.Keywords: PNI, PAB, AGR, colon cancer, rectal cancer, overall survival

Xiangrui Meng,1,* Yanyao Deng,2,* Zhicheng Lv,3 Chao Liu,2 Ziqing Guo,2 Yuan Li,2 Hua Liu,2 Bing Xie,2 Ziqi Jin,2 Fangbo Lin,2 Hongwei Zhu1 1Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Neurology, The First Hospital of Changsha, Changsha, Hunan, People’s Republic of China; 3Department of Neurosurgery, Chenzhou First People’s Hospital, Chenzhou, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongwei ZhuDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha, Hunan Province, People’s Republic of ChinaTel +86-13657351235Fax +86-15526491006Email zhw_xysyy@163.comBackground: Glioma is a common primary brain tumor with extremely poor prognosis outcomes. Increasing evidences have proved the relation between lncRNAs and glioma onset and progression. LncRNA SNHG5 involves in the biological activities of tumor cells, such as proliferation, migration and metastasis. Nevertheless, it is still necessary to explain the molecular mechanism and biofunction of SNHG5 in glioma.Materials and methods: Quantitative real-time PCR (qRT-PCR) was performed to analyze expressions of SNHG5, miR-205-5p and ZEB2 in tumor tissues and cell lines. The cell counting kit-8 (CCK-8) assay, plate and soft agar colony formation assays were performed to evaluate cell proliferation ability. RNA immunoprecipitation assay and dual-luciferase reporter assay were used to confirm the interaction among SNHG5, miR-205-5p and ZEB2. The protein level of ZEB2 was measured by Western blot.Results: Based on our findings, compared with normal tissues, the elevated expression of SNHG5 and decreased expression of miR-205-5p were observed in glioma tissues. The downregulation of SNHG5 exerted an obvious inhibitory effect on glioma cells in terms of their proliferation. With regard to the underlying mechanism, SNHG5 presented a direct inhibitory influence on miR-205-5p which targeted to the 3′-UTR region of zinc finger E-box binding homeobox 2 (ZEB2) mRNA. As a competing endogenous RNA (ceRNA), SNHG5 sponged miR-205-5p, regulating the expression of ZEB2 thereby.Conclusion: These discoveries indicate that SNHG5 promotes proliferation of glioma by regulating miR-205-5p/ZEB2 axis.Keywords: long non-coding RNA, SNHG5, miR-205-5p, ZEB2, glioma

Yong Wang, Xiangji Meng, Shizhen Zhou, Yufang Zhu, Jun Xu, Rongjie Tao Department of Neurosurgery, Shandong Cancer Hospital Affiliated to Shandong University; Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaCorrespondence: Rongjie Tao; Jun XuDepartment of Neurosurgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan 250117, People’s Republic of ChinaEmail rongjietao@163.com; sdszlyy03@163.comObjective: This study aimed to determine the efficacy and tolerability of apatinib plus dose-dense temozolomide (TMZ) as first-line treatment for recurrent glioblastoma (rGBM).Methods: Patients with rGBM were enrolled in this study. Patients were subjected to concurrent treatment of apatinib (500 mg qd) and dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until disease progression or intolerable toxicity. Efficacy was evaluated using Response Assessment in Neuro-Oncology criteria for high-grade glioma. Safety was assessed using NCI-CTCAE 4.0. Survival was estimated with Kaplan–Meier curve and log rank test.Results: From March 2016 to January 2018, 20 eligible patients who had relapsed from the standard chemoradiotherapy regimen (TMZ and radiotherapy) were enrolled in this study. The median follow-up time was 12 months. All patients were eligible for efficacy analysis. The objective response rate (ORR) was 45%. The disease control rate (DCR) was 90%. The median progress-free survival time was 6 months (95% CI, 5.3 to 7.8 months). The 6-month progression-free survival rate was 50%. The median overall survival was 9 months (95% CI, 8.2 to 12.2 months). The most common treatment-related adverse events were hypertension (21%), hand–foot syndrome (16%), leukopenia (14%), and thrombocytopenia (12%).Conclusion: Apatinib combined with dose-dense TMZ was effective in terms of PFS, ORR, and DCR and was well tolerated after appropriate dose reduction in the Chinese population tested. Further randomized controlled clinical studies are needed to confirm the efficacy of apatinib combined with TMZ for treatment of rGBM.Keywords: central nervous system, recurrence, glioblastoma, apatinib, temozolomide, vascular endothelial growth factor receptor

Yue Yang,1,2 Huihui Bao,1 Qianqian Chai,3 Zhiwen Wang,2 Zhenning Sun,2 Changhui Fu,3 Zhaoping Liu,1 Zhongjie Liu,2 Xianwei Meng,3 Tianlong Liu21China National Center for Food Safety Risk Assessment, Beijing 100022, People’s Republic of China; 2Key Laboratory of Animal Epidemiology of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, People’s Republic of China; 3Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of ChinaBackground: As a promising nanomaterial for biomedical applications, zirconia nanoparticles (ZrO2) have aroused concern recently, but the toxicity of ZrO2 in vivo has received little attention.Purpose: The aim of this study is to demonstrate the systematic single dose toxicity, biodistribution and oxidative damage of ZrO2 in vivo after intravenous injection in mice.Materials and methods: Ten ICR mice were used at the high dose of ZrO2 including 600, 500, 400 and 300mg/kg. Maximum tolerated dose (MTD) of 150 nm ZrO2 was determined as 500mg/kg. Hematology analysis and blood biochemical assay were determined for the evaluation of oxidative damage caused by ZrO2. Biodistribution of ZrO2 was investigated by ICP-OES and TEM.Results: Mice treated with higher dose (500mg/kg) showed significant spread in white blood cell counts (p

Wen Sun,1 Liwen Zhang,2 Ranran Yan,2 Ying Yang,2 Xiangli Meng31Teaching Administration Office, Affiliated Hospital of Jining Medical University, Jining, People’s Republic of China; 2Intensive Care Unit, Affiliated Hospital of Jining Medical University, Jining, People’s Republic of China; 3Nursing Department, Affiliated Hospital of Jining Medical University, Jining, People’s Republic of ChinaBackground: Non-small cell lung cancer (NSCLC) has a significant impact on human health. The aim of this study was to explore the role of long non-coding RNA DLX6-AS1 in the proliferation, migration, and invasion of NSCLC cells.Methods: The expression of DLX6-AS1 in NSCLC tumor tissues and cell lines was examined by qRT-PCR. The effects of DLX6-AS1 knockdown on cell proliferation, migration, and invasion were assessed by Cell Counting Kit-8, wound healing, and transwell assays, respectively. Bioinformatics analyses, luciferase reporter assays, and RNA pull-down assays were employed to examine the mechanism by which DLX6-AS1 exerted its oncogenesis effects in NSCLC. The anti-tumor effect of silencing DLX6-AS1 in vivo was also evaluated.Results: DLX6-AS1 was over-expressed in NSCLC tumor tissues and cell lines and its level of expression was found to be associated with tumor size and advanced clinical stage in patients with NSCLC. Downregulation of DLX6-AS1 inhibited cell proliferation, cell clone formation, migration, and invasion of NSCLC cells. DLX6-AS1 was found to interact with miR-27b-3p/GSPT1. DLX6-AS1 expression was negatively correlated with miR-27b-3p expression, but positively correlated with GSPT1 expression in NSCLC samples. DLX6-AS1 knockdown also effectively suppressed tumor growth in an in vivo xenograft model.Conclusion: DLX6-AS1 regulated NSCLC progression by targeting the miR-27b-3p/GSPT1 axis, which may provide novel insights for NSCLC prognosis and therapy.Keywords: DLX6-AS1, NSCLC, miR-27b-3p, GSPT1, invasion

Yan-Mei Zhu,1 Qiang Li,1 Xiao-Zhuo Gao,1 Xiao Meng,1 Li-Li Sun,1 Yu Shi,2 En-Tian Lu,3 Yong Zhang1 1Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China; 2Department of Pathology, People’s Hospital of Dawa District, Panjin, Liaoning 124200, P.R. China; 3Department of Pathology, Central Hospital of Pulandian District, Dalian, Liaoning 116200, P.R. China Background: C14orf159, a new protein, has been identified recently. But its expression in tissues and clinicopathologic correlation is still unknown. Patients and methods: We carried out immunohistochemistry staining in 144 gastric cancer cases in this study. Then Western blot was used to detect the expression of protein. MTT and matrigel invasion assay were used to assess the biological effects.Results: The immunohistochemical results indicated that the expression of C14orf159 in normal gastric mucosa close to cancer tissue was remarkably higher than that in stomach carcinoma samples (63.9% and 34.7%, respectively, P

Xingchu Meng, Wei Gao, Kai Wang, Chao Han, Wei Zhang, Chao Sun Department of Organ Transplantation, Tianjin First Center Hospital, Tianjin, China Purpose: Adherence to the medical regimen after pediatric liver transplantation is crucial for good clinical outcomes. However, the existing literature provides inconsistent evidence regarding the prevalence of and risk factors for nonadherence to the medical regimen after pediatric liver transplantation. This study aimed to investigate such nonadherence after pediatric liver transplantation and risk factors associated with this nonadherence using findings of reported studies. Methods: The electronic databases of Excerpta Medica, Ovid Technologies, PubMed and WanFang Data were searched using the keywords “adherence”, “liver transplant” and ­“paediatric”. Additionally, relevant references cited in related studies were used to obtain original articles. Using 22 original articles, data regarding nonadherence to the medical regimen after pediatric liver transplantation were quantitatively combined, and risk factors associated with nonadherence were qualitatively identified. Average rates of nonadherence in four areas of medical regimens were calculated. The heterogeneity of the included original articles was also analyzed. When I2>50 and P0.05 were considered to have no publication bias. Results: The clinical attendance nonadherence rate was 45% (95% confidence interval [CI]: 39–51), global nonadherence rate was 17% (95% CI: 13–21) and immunosuppression nonadherence rates were 39% (95% CI: 26–52) and 34% (95% CI: 30–39) for cyclosporine and tacrolimus, respectively. Risk factors included older age of the pediatric patient, low family cohesion, poor social functioning, poor mental health and single-parent family. Conclusions: The nonadherence rate in pediatric liver transplantation is high. Therefore, intervention on the basis of risk factors, such as mental health and family function, may be necessary. Moreover, a standard technique for assessing nonadherence to the medical regimen after pediatric liver transplantation, comprising as many dimensions as possible, is required in order to be more objective and comprehensive when assessing nonadherence. Keywords: compliance, transplant, pediatrics, hepar, hepatic

Na Zuo,1,* Hongzhen Hu,1,2,* Niresh Thapa,1,3 Zhen Li,1 Daqiong Jiang,1 Xiangyu Meng,4 Jing Yang,1 Xiaoxing Chen,5 Hongbing Cai1 1Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, Hubei, People’s Republic of China; 2Department of Obstetrics and Gynecology, Shenzhen Futian Maternity and Child Care Hospital, Shenzhen 518030, Guangdong, People’s Republic of China; 3Karnali Academy of Health Sciences, Jumla, Nepal; 4Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Department of Evidence-Based Medicine and Clinical Epidemiology, Second Clinical College of Wuhan University, Wuhan 430071, Hubei, People’s Republic of China; 5Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan 430071, Hubei, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study was to investigate the impact of vaginal cuff length (VCL) resected during radical hysterectomy (RH) on the long-term survival outcomes of patients with cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IB–IIA) and to explore whether VCL is a prognostic factor for cervical cancer. Methods: A total of 435 eligible patients with stage IB and IIA cervical cancer who underwent RH in Zhongnan Hospital of Wuhan University (Wuhan, People’s Republic of China) from January 2007 to February 2017 were retrospectively analyzed. These patients were divided into two groups (VCL ≤2.0 cm and >2.0 cm) for further analysis according to the VCL during RH. The Kaplan–Meier method was adopted to calculate the survival rates. Univariate and multivariate Cox regression models were used to analyze independent prognosis factors for survival. Results: Of the 435 identified patients, 196 had VCL ≤2.0 cm and 239 had VCL >2.0 cm after RH. The 5-year disease-free survival (DFS) for the group who had VCL ≤2.0 cm vs the group who had VCL >2.0 cm was 68.1% vs 87.5% (P2.0 cm in RH has a more favorable long-term outcome than VCL ≤2.0 cm among patients with cervical cancer (FIGO stage IB–IIA); shorter VCL resection was significantly associated with local recurrence, DFS, and OS; thus, it can be considered as a prognostic factor for cervical cancer. Keywords: cervical cancer, vaginal cuff length, lymph node involvement, prognosis, local recurrence, distant metastasis

Xiangbin Meng,1,* Wenyao Wang,2,* Kuo Zhang,2,* Yu Qi,2 Shimin An,2 Siyuan Wang,2 Jilin Zheng,2 Joyce Kong,3 Henghui Liu,4 Jing Wu,4 Yong Zhou,5 Chuanyu Gao,1 Yi-Da Tang2 1Department of Cardiology, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China; 2Department of Cardiology Medicine, Coronary Heart Disease Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3New York Institute of Technology-College of Osteopathic Medicine, Old Westbury, NY, USA; 4Beijing Recdata Technology Co., Ltd., Beijing, China; 5Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vascular Diseases, Beijing, China *These authors contributed equally to this work Background: Epicardial adipose tissue (EAT) is considered an important source of bioactive molecules that can influence coronary arteries directly and is related to the concurrent presence of both obstructive coronary stenosis and myocardial ischemia independently. Non-alcoholic fatty liver disease (NAFLD) has become an emergent health problem worldwide. Aim: This cross-sectional study aimed to address the relationship between the volume of EAT and NAFLD and other cardiovascular risk factors in the general population. Materials and methods: In this study, we selected a total of 2,238 participants aged at least 40 years from the Jidong community in Tangshan, China. The 64-slice CT was used to survey the volume of EAT and liver ultrasonography was used for the diagnosis of NAFLD. The study cohorts were compared according to EAT volume. Results: Cardiovascular risk factors, such as coronary artery calcium score, carotid intima-media thickness, NAFLD, and ideal cardiovascular health metrics were also found to be related to EAT. In multivariate logistic regression analysis, NAFLD groups showed significant association with higher EAT volume, after correcting for main cardiovascular disease risk factors (OR [95% CI], 1.407 [1.117, 1.773]). Conclusion: Our findings in a general community population provide evidence that EAT is strongly associated with NAFLD and other cardiovascular risk factors. Keywords: epicardial adipose tissue, EAT, coronary artery calcium, CAC, carotid intima-media thickness, CIMT, ideal cardiovascular health metrics, CVH

Chao Liu,1,2 Bing Sun,2 Bin Xu,1 Xiangying Meng,2 Lan Li,1 Yang Cong,2 Jiannan Liu,2 Qian Wang,2 Liang Xuan,2 Qibin Song,1 Shikai Wu2 1Cancer Center, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China Introduction: Programmed cell death protein 1 (PD-1), an immune checkpoint molecule, has recently been recognized as a predictive and prognostic biomarker in several malignant tumors, but its diagnostic value remains largely unknown. We aimed to investigate the differential diagnostic efficiency of PD-1 and other immune molecules and propose a panel of immune molecules combined with cancer antigen 15-3 (CA15-3) to distinguish breast cancer (BC) from benign breast disease (BBD).Patients and methods: Ninety-one eligible BC patients and 31 BBD patients were enrolled. Pretreatment peripheral blood was collected and tested for mRNA expression of PD-1, cytotoxic T lymphocyte antigen 4, forkhead box P3, transforming growth factor beta, interleukin-10 (IL-10), IL-2 receptor alpha (IL-2Rα), and cluster of differentiation 28 by quantitative reverse transcription PCR.Results: The diagnostic areas under curve (AUCs) of PD-1, IL-2Rα, and IL-10 for BC–BBD discrimination were 0.764, 0.758, and 0.743, respectively. The diagnostic efficiencies of these three parameters in distinguishing early-stage or advanced BC from BBD were consistent with a role in BC–BBD discrimination. A panel of PD-1 + IL-10 + IL-2Rα + CA15-3 showed the highest AUC (0.862), with a sensitivity of 0.933 and a specificity of 0.724, for BC–BBD discrimination. In addition, for early-stage BC discrimination, this panel also had the highest AUC (0.811), with a sensitivity of 0.933 and a specificity of 0.614, while for advanced BC discrimination, a panel of PD-1 + IL-10 + CA15-3 exhibited the highest AUC (0.896), with a sensitivity of 0.933 and a specificity of 0.783.Conclusion: These data indicate that the panel containing PD-1, IL-2Rα, IL-10, and CA15-3 can effectively discriminate BC from BBD with a high efficiency. After further confirmation, it could be used to complement conventional imaging modalities, especially in discriminating early-stage BC from BBD. Keywords: breast cancer, immune checkpoint, PD-1, CTLA-4, IL-2Rα, diagnosis, biomarker

Ting Li, Ruochuan Sun, Mingdian Lu, Jiacong Chang, Xiangling Meng,* Huo Wu* Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, He Fei, 230222, China *These authors contributed equally to this work Background: NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. Methods: Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. Results: Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. Conclusion: Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene. Keywords: NDRG3, colorectal cancer, metastasis, Src

Xiaomin Meng, Rao Fu Department of Applied Chemistry, Northeast Electric Power University, Jilin, People’s Republic of China Introduction: Previous studies have found that miRNAs play a key role in drug resistance. Multiple reports show that miRNAs act as regulators in colorectal cancer (CRC) cells, but the role of miR-206 in CRC is still not well understood. The current study aimed to explore the potential function of miR-206 in 5-FU resistance. Methods: To indentify the role of miR-206 in 5-FU resistance, the expression of miR-206 was examined by real-time polymerase chain reaction (RT-PCR) in 5-FU-resistant (FR) CRC (HCT116/FR and RKO/FR) and their parental cell lines. miR-206 mimic was transfected to 5-FU-FR CRC, and the 5-FU sensitivity was detected by MTS and flow cytometry. Using miRNA target prediction software, we found that miR-206 could target the 3' untranslated region (3'UTR) sequence of Bcl-2. Results: miR-206 was found to be downregulated in 5-FU-FR CRC in comparison with their parental cell lines, suggesting its crucial relevance for colon cancer biology. Downregulation of miR-206 promoted drug resistance and decreased apoptosis of parental cells, while overexpression of miR-206 promoted drug cytotoxicity and apoptosis of HCT116/FR cells. We also identified miR-206 targeting Bcl-2 directly in CRC, which is required for miR-206 mediated-5-FU resistance. Conclusion: Our results show that miR-206 targets Bcl-2 to mediate chemoresistance, proliferation, and apoptosis in CRC. This study provides a novel promising candidate for colon cancer therapy. Keywords: miR-206, 5-FU, resistance, Bcl-2, colorectal cancer

Yong Zhu,1,* Guoying Deng,2,* Anqi Ji,2 Jiayi Yao,1 Xiaoxiao Meng,1 Jinfeng Wang,1 Qian Wang,2 Qiugen Wang,2 Ruilan Wang1 1Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, 2Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Acute paraquat (PQ) poisoning is one of the most common forms of pesticide poisoning. Oxidative stress and inflammation are thought to be important mechanisms in PQ-induced acute lung injury (ALI). Selenium (Se) can scavenge intracellular free radicals directly or indirectly. In this study, we investigated whether porous Se@SiO2 nanospheres could alleviate oxidative stress and inflammation in PQ-induced ALI. Male Sprague Dawley rats and RLE-6TN cells were used in this study. Rats were categorized into 3 groups: control (n=6), PQ (n=18), and PQ + Se@SiO2 (n=18). The PQ and PQ + Se@SiO2 groups were randomly and evenly divided into 3 sub-groups according to different time points (24, 48 and 72 h) after PQ treatment. Porous Se@SiO2 nanospheres 1 mg/kg (in the PQ + Se@SiO2 group) were administered via intraperitoneal injection every 24 h. Expression levels of reduced glutathione, malondialdehyde, superoxide dismutase, reactive oxygen species (ROS), nuclear factor-κB (NF-κB), phosphorylated NF-κB (p-NF-κB), tumor necrosis factor-α and interleukin-1β were detected, and a histological analysis of rat lung tissues was performed. The results showed that the levels of ROS, malondialdehyde, NF-κB, p-NF-κB, tumor necrosis factor-α and interleukin-1β were markedly increased after PQ treatment. Glutathione and superoxide dismutase levels were reduced. However, treatment with porous Se@SiO2 nanospheres markedly alleviated PQ-induced oxidative stress and inflammation. Additionally, the results from histological examinations and wet-to-dry weight ratios of rat lung tissues showed that lung damage was reduced after porous Se@SiO2 nanosphere treatment. These data indicate that porous Se@SiO2 nanospheres may reduce NF-κB, p-NF-κB and inflammatory cytokine levels by inhibiting ROS in PQ-induced ALI. This study demonstrates that porous Se@SiO2 nanospheres may be a therapeutic method for use in the future for PQ poisoning. Keywords: porous Se@SiO2 nanospheres, acute lung injury, paraquat poisoning, oxidative stress, inflammatory cytokines, ROS, NF-kappa B

Xiaoping Liu,1,* Jiarui Chen,2,* Yuncen A He,3 Xiangyu Meng,1 Kaili Li,4 Colin K He,5 Shangqin Liu4 1Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, 2School of Basic Medical Science, Wuhan University, Wuhan, Hubei, People’s Republic of China; 3School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 4Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 5Orient Healthcare, New York, NY, USA *These authors contributed equally to this work Objective: The aim of this study was to evaluate the efficacy and clinical outcome of initial therapies for elderly patients with multiple myeloma (MM).Methods: Randomized controlled trials (RCTs) were obtained through a comprehensive search. Response rate, progression-free survival (PFS) and overall survival (OS) were the interested outcome measures. Network meta-analysis (NMA) using graph theory methodology to construct an NMA model, and sensitivity analysis were performed.Results: Nineteen RCTs containing 7,235 participants and 17 treatments were included in the NMA. As compared to the classic melphalan plus prednisone (MP) regimen, the majority of other initial regimens showed higher rates of complete response/near complete response, overall response rate (ORR) and better PFS as well as OS. These four outcomes favored the two lenalidomide plus dexamethasone regimens (continuous lenalidomide and 18 cycles of lenalidomide plus dexamethasone), especially continuous lenalidomide plus dexamethasone regimen, over the majority of other regimens including the two established standard treatments (MP plus thalidomide or bortezomib) for elderly patients with newly diagnosed MM.Conclusion: Continuous lenalidomide plus dexamethasone ranked as the best regimen in terms of ORR and OS for the treatment of elderly patients with newly diagnosed MM. Keywords: multiple myeloma, previously untreated, elderly patients, initial therapies, network meta-analysis

Bo Yang,1,2 Chen Dai,1,2 Rumeng Tan,1,2 Bo Zhang,1,2 Xiao Meng,3 Jing Ye,3 Xinqiang Wang,1,2 Lai Wei,1,2 Fan He,4 Zhishui Chen1,2 1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Key Laboratory of Ministry of Health and Key Laboratory of Ministry of Education, Wuhan, Hubei, People’s Republic of China; 3Department of Pathology, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 4Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China Background: The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide. As a consequence, there is an urgent need for identifying molecular markers of HCC development and progression. Recently, several studies have suggested that the Lrig1 may have prognostic implications in various cancer types, but its clinical value in HCC is not well evaluated. Materials and methods: In this study, the expression level of Lrig1 was examined in 133 HCC tissues and adjacent normal tissues by immunohistochemistry. Furthermore, potential associations between Lrig1 expression and the carcinoma clinical parameters were investigated, including recurrence and survival rate. We silenced the Lrig1 in the normal liver cell line (LO2) and liver cancer cell line (Hep-G2) in vitro by the small interference RNA and detected its influence on proliferation, migration, and invasion. Results: The expression of Lrig1 was significantly downregulated in liver cancer tissues and cell lines, and its expression levels were related to tumor size, tumor–node–metastasis staging and tumor recurrence. Furthermore, analysis of 6-year survival of 133 HCC patients showed that those with stronger Lrig1 expression had significantly longer overall survival time than those with weaker Lrig1 expression. In addition, decreased expression of Lrig1 in vitro promoted the growth, migration, or invasion of normal liver cells and cancer cells. Conclusion: Our findings demonstrate that Lrig1 could serve as a potential marker in the prognosis of patients with HCC. We also revealed that Lrig1 might be involved in the metastatic progression of liver cancer. However, its clinical value should be further investigated in the future. Keywords: Lrig1, hepatocellular carcinoma, prognosis, immunohistochemistry, siRNA, invasion, migration

Liangchao Sun,1,2,* Yali Qi,1,3,* Xindong Sun,2 Jinming Yu,2 Xue Meng2 1Medical College of Shandong University, 2Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Science, Jinan, 3Department of Oncology, The Second Hospital of Lanzhou University, Lanzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Orbital metastasis as the initial presentation of lung adenocarcinoma is very rare, and so the lack of knowledge about this phenomenon can easily result in misdiagnosis, either as a orbital primary tumor or benign lesion. Here, we report a rare case in which the orbital symptom appeared first without any pulmonary manifestations. Our patient developed decreasing vision in his right eye over a 3-month duration. He then presented with proptosis and multiple aches from head to back. After systemic evaluation, our patient was diagnosed with Stage IV non-small-cell lung cancer and was managed with palliative chemoradiotherapy. The final result of treatment suggests that the therapeutic efficacy of chemotherapy on orbital metastasis is uncertain, and only some orbital metastatic masses may have a favorable response to radiation. Furthermore, we review the recent data and provide an in-depth discussion on the clinical features and course of ocular pulmonary metastases, and explain a new type of non-small-cell lung cancer metastatic pattern for ophthalmologists and oncologists to help them distinguish the orbital metastasis as the first manifestation. Keywords: orbital metastasis, skeletal metastasis, rare metastasis, initial presentation, lung adenocarcinoma

Xuquan Jing,1,2,* Xue Meng,2,* Xindong Sun,2 Jinming Yu2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, People’s Republic of China *These authors contributed equally to this work Abstract: With the high locoregional relapse rate and the improvement of radiation technology, postoperative radiotherapy (PORT) has been widely used in the treatment of completely resected stage IIIA-pN2 non-small-cell lung cancer (NSCLC). However, there is still no definitive consensus on clinical target volume for the pN2 subgroup. This review will discuss how to delineate the clinical target volume (CTV) for pN2 subgroups of IIIA-N2 NSCLC based on the published literature and to investigate the optimal PORT CTV in this cohort of patients. Besides overall survival (OS), locoregional recurrence (LR), and radiotherapy-related toxicity of this subset of the population in the modern PORT era, selection of proper patients will also be considered in this review. In summary, it is appropriate to include involved lymph node stations and uninvolved stations at high risk in PORT CTV for patients with pN2 disease when PORT is administered. PORT can reduce LR and has the potential to improve OS. In the current era of modern radiation technology, PORT can be administered safely with well-tolerated toxicity. Clinicopathological characteristics may be helpful in selecting proper candidates for PORT. Keywords: stage IIIA, non-small-cell lung carcinoma, postoperative radiotherapy, target volume

Jing Liu,* Ligang Xing,* Xue Meng, Jinbo Yue, Xiangjiao Meng, Peng Xie, Xiaolin Li, Li Kong, Jinming YuDepartment of Radiation Oncology, Shandong Province Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workPurpose: Brain metastasis (BM) is associated with impaired quality of life and increased mortality. The study aimed to compare BM risk after erlotinib administration and chemotherapy in stage IIIB/IV pulmonary adenocarcinoma patients harboring epidermal growth factor receptor (EGFR) mutation.Patients and methods: Eligible patients underwent match pair process with matching factors, including age, sex, performance status score, first-line or second-line treatment, first-line chemotherapy regimen (for the second-line treatment subgroup), stage IIIB or IV, and genotypes of EGFR mutation. BM and mortality risk of both groups were recorded and compared.Results: In total 129 matched pairs were included for analysis. During a median follow-up of 21.5 months, time to BM risk was longer and incidences of BM within 2 years were lower in patients who received erlotinib than chemotherapy in total population, as well as subgroups of first-line treatment, second-line treatment, stage IIIB, stage IV, exon 19 deletion mutation, and exon 21 L858R mutation. Similar overall survival time and 2-year survival rates were seen in two groups totally or in any subgroup. Multivariate analysis showed that BM was retarded in patients who received erlotinib administration (hazard ratio, 1.695; P=0.001) and in patients who were in stage IIIB (hazard ratio, 1.751; P=0.001).Conclusion: Erlotinib administration decreases BM risk in advanced pulmonary adenocarcinoma patients harboring sensitive EGFR mutations.Keywords: pulmonary adenocarcinoma, brain metastasis, epidermal growth factor receptor, erlotinib, match pair analysis

Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS−LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS−LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS−LABAs to their own rates of exacerbation when off controller medications. We found ICS−LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93), p = 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53), p = 0.037). In conclusion, ICS−LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.

We have upgraded the new Tibet ASgamma experiment in China since 2014 to measure the chemical composition of cosmic rays around the knee. This hybrid experiment consist of an air-shower-core detector array (YAC-II) to detect high energy electromagnetic component, the Tibet air-shower array (Tibet-III) and a large underground water-Cherenkov muon-detector array (MD). We have carried out a detailed air-shower Monte Carlo (MC) simulation to study the performance of the hybrid detectors by using CORSIKA (version 7.5000), which includes EPOS-LHC, QGSJETII-04, SIBYLL2.1 and SIBYLL2.3 hadronic interaction models. The preliminary results of the interaction model checking above 50 TeV energy region are reported in this paper, and the primary proton and helium spectra in the energy range 50 TeV to 1015 eV was derived from YAC-I data and is smoothly connected with direct observation data at lower energies and also with our previously reported works at higher energies within statistical errors. The knee of the (P+He) spectra is located around 400 TeV. The interaction model dependence in deriving the primary (P+He) spectra is found to be small (less than 25% in absolute intensity, 10% in position of the knee), and the composition model dependence is less than 10% in absolute intensity.

We analyze the temporal variation of the solar diurnal anisotropy of the multi-TeV cosmic-ray intensity observed with the Tibet air shower array from 2000 to 2009, covering the maximum and minimum of the 23rd solar cycle. We comfirm that a remarkable additional anisotropy component is superposed on the Compton-Getting anisotropy at 4.0 TeV, while its amplitude decreases at higher energy regions. In constrast to the additional anisotropy reported by the Matsushiro experiment at 0.6 TeV, we find the residual component measured by Tibet at multi-TeV energies is consistent with being stable, with a fairly constant amplitude of 0.041% ± 0.003% and a phase at around 07.17 ± 00.16 local solar time at 4.0 TeV. This suggests the additional anisotropy observed by the Tibet experiment could result from mechanisms unrelated to solar activities.

A hybrid experiment has been started by the ASγ experiment at Yangbajing (4300m a.s.l.) in Tibet since May 2009, that consists of a high-energy air-shower-core array (YAC-I) and a high-density air-shower array (Tibet-III). In this paper, we report our results to check the hadronic interaction models SIBYLL2.3, SIBYLL2.1, EPOS-LHC and QGSJETII-04 in the multi-tens TeV energy region using YAC-I+Tibet-III experimental data from May 2009 through January 2010. The effective live time is calculated as 106.05 days. The results show that the description of transverse momentum, inelastic cross-section and inelasticity for the 4 hadronic interaction models is consistent with YAC-I experimental data within 15% systematic errors range in the forward region below 100 TeV. Among them, the EPOS-LHC model is the best hadronic interaction model. Furthermore, we find that the H4a composition model is the best one below the 100 TeV energy region.

Fei-Fei Teng, Xue Meng, Xin-Dong Sun, Jin-Ming YuDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, People's Republic of ChinaAbstract: Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future.Keywords: molecular imaging, targeted therapy, PET, MRI, US, CT

We review comprehensive observations of electromagnetic ion cyclotron (EMIC) wave-driven energetic electron precipitation using data collected by the energetic electron detector on the Electron Losses and Fields InvestigatioN (ELFIN) mission, two polar-orbiting low-altitude spinning CubeSats, measuring 50-5000 keV electrons with good pitch-angle and energy resolution. EMIC wave-driven precipitation exhibits a distinct signature in energy-spectrograms of the precipitating-to-trapped flux ratio: peaks at >0.5 MeV which are abrupt (bursty) (lasting ∼17 s, or ΔL∼0.56) with significant substructure (occasionally down to sub-second timescale). We attribute the bursty nature of the precipitation to the spatial extent and structuredness of the wave field at the equator. Multiple ELFIN passes over the same MLT sector allow us to study the spatial and temporal evolution of the EMIC wave - electron interaction region. Case studies employing conjugate ground-based or equatorial observations of the EMIC waves reveal that the energy of moderate and strong precipitation at ELFIN approximately agrees with theoretical expectations for cyclotron resonant interactions in a cold plasma. Using multiple years of ELFIN data uniformly distributed in local time, we assemble a statistical database of ∼50 events of strong EMIC wave-driven precipitation. Most reside at L∼5-7 at dusk, while a smaller subset exists at L∼8-12 at post-midnight. The energies of the peak-precipitation ratio and of the half-peak precipitation ratio (our proxy for the minimum resonance energy) exhibit an L-shell dependence in good agreement with theoretical estimates based on prior statistical observations of EMIC wave power spectra. The precipitation ratio's spectral shape for the most intense events has an exponential falloff away from the peak (i.e., on either side of ∼1.45 MeV). It too agrees well with quasi-linear diffusion theory based on prior statistics of wave spectra. It should be noted though that this diffusive treatment likely includes effects from nonlinear resonant interactions (especially at high energies) and nonresonant effects from sharp wave packet edges (at low energies). Sub-MeV electron precipitation observed concurrently with strong EMIC wave-driven >1 MeV precipitation has a spectral shape that is consistent with efficient pitch-angle scattering down to ∼ 200-300 keV by much less intense higher frequency EMIC waves at dusk (where such waves are most frequent). At ∼100 keV, whistler-mode chorus may be implicated in concurrent precipitation. These results confirm the critical role of EMIC waves in driving relativistic electron losses. Nonlinear effects may abound and require further investigation.